公开(公告)号：WO2002068383A2

公开(公告)日：2002-09-06

申请号：PCT/US2002/005081

申请日：2002-02-21

Applicant: ANIKA THERAPEUTICS, INC.

Inventor： BULPITT, Paul, C., A. ,  SHERWOOD, Charles, H. ,  SADOZAI, Khalid, K.

IPC: C07C323/25

CPC classification number: C07C323/25 ,  C07C323/32 ,  C07C323/37 ,  C07C323/44 ,  C07C335/08 ,  C07C335/16 ,  C08B37/0072

Abstract: The present invention relates to biscarbodiimides, thiourea derivatives, urea derivatives, and cross-linked hyaluronan derivatives having at least one intramolecular disulfide bond, and methods of preparation thereof. The invention also includes thiolated hyaluronan derivatives and salts thereof having at least one pendant thiol group or a modified pendant thiol group, and methods of preparation thereof. An example of a modified pendant thiol group is a sulfhydryl group linked to a small molecule such as a bioactive agent, for example a drug or pharmaceutically active moiety. A hyaluronan derivative having a sulfhydryl group linked to a pharmaceutically active moiety is useful as a sustained or controlled release drug delivery vehicle. Compositions containing the hyaluronan derivatives of the invention can reversibly viscosify in vivo or in vitro , in response to mild changes in condition, and are thus useful in ophthalmic surgery and in tissue engineering.

Abstract translation: 本发明涉及双碳二亚胺，硫脲衍生物，脲衍生物和具有至少一个分子内二硫键的交联透明质酸衍生物及其制备方法。 本发明还包括硫醇化透明质酸衍生物及其盐，其具有至少一个硫醇基侧基或修饰侧链巯基，及其制备方法。 修饰的侧链硫醇基团的实例是与小分子连接的巯基，例如生物活性剂，例如药物或药学活性部分。 具有与药学活性部分连接的巯基的透明质酸衍生物可用作持续或控释药物递送载体。 包含本发明的透明质酸衍生物的组合物可以在体内或体外可逆地粘稠，以响应于条件的轻微变化，因此可用于眼科手术和组织工程。

公开(公告)号：WO2005067994A1

公开(公告)日：2005-07-28

申请号：PCT/US2003/041354

申请日：2003-12-23

Applicant: ANIKA THERAPEUTICS, INC. ,  SADOZAI, Khalid, K. ,  GOODING, Tamara, B. ,  BUI, Kyle ,  SHERWOOD, Charles, H.

Inventor： SADOZAI, Khalid, K. ,  GOODING, Tamara, B. ,  BUI, Kyle ,  SHERWOOD, Charles, H.

IPC: A61L27/52

CPC classification number: A61K31/24 ,  A61K9/0019 ,  A61K9/0021 ,  A61K9/0024 ,  A61K9/1652 ,  A61K47/36

Abstract: A hyaluronic acid (HA) composition includes crosslinked, water-insoluble, hydrated HA gel particles. The HA includes crosslinks represented by the following structural formula: HA′-U-R 2 -U- HA′. The variables are defined herein. A method of augmenting tissue in a subject includes inserting a needle into a subject at a location in the subject that is in need of tissue augmentation, wherein the needle is coupled to a syringe loaded with the HA composition, and applying force to the syringe, to deliver the HA composition into the subject. A method of preparing the HA composition, includes forming water-insoluble, dehydrated crosslinked HA particles, separating the water-insoluble, dehydrated particles by average diameter, selecting a subset of particles by average diameter, and hydrating the subset of dehydrated particles with a physiologically compatible aqueous solution. Another method of preparing the crosslinked HA composition includes crosslinking a precursor of the crosslinked HA with a biscarbodiimide in the presence of a pH buffer and dehydrating the crosslinked HA.Also included is a method of augmenting tissue in a subject that is in need of tissue augmentation. A method of stabilizing crosslinked HA includes hydrating water-insoluble, dehydrated crosslinked HA with a physiologically compatible aqueous solution that includes a local anesthetic, wherein the value of storage modulus G' for the stabilized composition is at least about 110% of the value of G' for a non-stabilized composition. Also included is the stabilized HA composition.

Abstract translation: 透明质酸（HA）组合物包括交联的水不溶性水合HA凝胶颗粒。 HA包括由以下结构式表示的交联：HA'-U-R2-U-HA'。 变量在此定义。 增加受试者中的组织的方法包括在需要组织增大的受试者的位置处将针插入受试者，其中针联接到装有HA组合物的注射器，并向注射器施加力， 将HA组合物输送到受试者。 制备HA组合物的方法包括形成不溶于水的，脱水的交联HA颗粒，将水不溶性脱水颗粒分离成平均直径，通过平均直径选择颗粒子集，并将生理学上的脱水颗粒子集合 相容的水溶液。 制备交联HA组合物的另一种方法包括在pH缓冲剂存在下使双碳二亚胺交联HA的前体，并使交联的HA脱水。还包括增加需要组织增加的受试者中的组织的方法 。 稳定交联HA的方法包括用包含局部麻醉剂的生理相容性水溶液水合非水溶性脱水交联HA，其中稳定化组合物的储能模量G'的值至少为G值的约110％ “为非稳定组合物。 还包括稳定的HA组合物。

公开(公告)号：WO2007070617A1

公开(公告)日：2007-06-21

申请号：PCT/US2006/047658

申请日：2006-12-13

Applicant: ANIKA THERAPEUTICS, INC. ,  SADOZAI, Khalid, K. ,  TOTH, Carol, A. ,  SHERWOOD, Charles, H.

Inventor： SADOZAI, Khalid, K. ,  TOTH, Carol, A. ,  SHERWOOD, Charles, H.

IPC: A61F2/38 ,  A61L27/20 ,  A61K31/728 ,  A61P19/02

CPC classification number: A61K31/728 ,  A61K9/0019 ,  A61K9/0024 ,  A61K9/06 ,  A61K31/573 ,  A61K31/729 ,  A61K35/28 ,  A61K35/32 ,  A61K38/1841 ,  A61K45/06 ,  A61K47/36 ,  A61L27/20 ,  A61L27/227 ,  A61L27/3817 ,  A61L27/3834 ,  A61L27/3843 ,  A61L27/48 ,  A61L27/52 ,  A61L27/56 ,  A61L2430/06 ,  A61M5/178 ,  C08L5/08 ,  A61K2300/00

Abstract: A method for treating an osteochondral defect or a chondral defect in a subject includes implanting a composite in a site of the osteochondral or chondral defect. The composite includes a hyaluronic acid derivative; and at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor, which is impregnated in, or coupled to, the hyaluronic acid derivative. In one embodiment, carboxyl functionalities of the hyaluronic acid derivative are. each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. In another embodiment, the hyaluronic acid derivative is prepared by reacting an uncrosslinked hyaluronic acid with a biscarbodimide in the presence of a pH buffer in a range of between about (4) and about (8). The composite can be used for regenerating or stimulating regeneration of meniscal tissues in a subject in need thereof.

Abstract translation: 用于治疗受试者的骨软骨缺损或软骨缺损的方法包括在骨软骨或软骨缺损的部位植入复合物。 该复合材料包括透明质酸衍生物; 和由透明质酸衍生物浸渍或偶联的由细胞，细胞生长因子和细胞分化因子组成的组中的至少一个成员。 在一个实施方案中，透明质酸衍生物的羧基官能度为。 各自独立地衍生为包括N-酰基脲或O-酰基异脲，或N-酰基脲和O-酰基异脲二者。 在另一个实施方案中，透明质酸衍生物通过在约（4） - （8）之间的pH缓冲剂存在下使未交联的透明质酸与双碳酰亚胺反应来制备。 复合材料可用于再生或刺激有需要的受试者的半月板组织的再生。

公开(公告)号：WO2007070547A2

公开(公告)日：2007-06-21

申请号：PCT/US2006/047474

申请日：2006-12-13

Applicant: ANIKA THERAPEUTICS, INC. ,  SADOZAI, Khalid, K. ,  SHERWOOD, Charles, H. ,  BUI, Kyle, X. ,  GOODING, Tamera, B. ,  BASSETT, Michael, J. ,  KENNEDY, Stephen, J.

Inventor： SADOZAI, Khalid, K. ,  SHERWOOD, Charles, H. ,  BUI, Kyle, X. ,  GOODING, Tamera, B. ,  BASSETT, Michael, J. ,  KENNEDY, Stephen, J.

IPC: A61K31/728 ,  A61P19/02

CPC classification number: A61L27/3843 ,  A61K9/0024 ,  A61K9/06 ,  A61K31/573 ,  A61K31/728 ,  A61K31/729 ,  A61K35/28 ,  A61K35/32 ,  A61K38/1841 ,  A61K47/36 ,  A61L27/20 ,  A61L27/227 ,  A61L27/3817 ,  A61L27/3834 ,  A61L27/48 ,  A61L27/52 ,  A61L27/56 ,  A61L2430/06 ,  C08L5/08 ,  A61K2300/00

Abstract: A method of treating a subject having a musculoskeletal'disorder includes administering to a subject's articular site in need thereof an effective amount of a hyaluronic acid (HA) composition. In one embodiment, the HA composition includes an HA derivative, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. In another embodiment, the HA composition includes a crosslinked HA gel that is prepared by reacting an uncrosslinked HA with a biscarbodiimide in the presence of pH buffer in a range of between about 4 and about 8. The composite can optionally include at least one second bioactive agent other than the HA derivative, such as a steroid.

Abstract translation: 治疗具有肌肉骨骼病症的受试者的方法包括向有此需要的受试者的关节部位施用有效量的透明质酸（HA）组合物。 在一个实施方案中，HA组合物包含HA衍生物，其中透明质酸衍生物的羧基官能团各自独立地衍生为包括N-酰基脲或O-酰基异脲或N-酰基脲和O-酰基异脲二者。 在另一个实施方案中，HA组合物包含交联的HA凝胶，其通过未交联的HA与双碳二亚胺在约4至约8范围内的pH缓冲剂存在下反应而制备。复合材料可任选地包含至少一种第二生物活性 除了HA衍生物之外的药物，例如类固醇。