Burixafor HBr   中文名称: 氢溴酸布利沙福

CXCR4

TG-0054 是一种水溶性良好的抗血管生成药物，在治疗脉络膜新生血管方面具有潜在价值。在确定工艺参数对粒度和药物含量的影响后，制备了可通过 27 G 针头注射的球形微粒，平均直径为 7.6 μm，负载量为 10% w/w TG-0054，体外药物缓释至少 6 个月，残留有机溶剂含量低（~ 1 ppb/mg）。

在新西兰白兔玻璃体内注射微粒和药物溶液 3 个月后，对其体内药物输送情况进行了评估。3 个月时，微粒给药眼中的药物水平分别为 43.7 ± 16.2、243 ± 42.6、62.8 ± 22.6 μg/g 玻璃体、视网膜和脉络膜 RPE，与 1 个月时的水平相似。玻璃体内注射纯药物溶液导致给药眼中的药物量明显降低，1 个月时玻璃体、视网膜和脉络膜 RPE 中的药物水平分别为 0.8 ± 0.5、2.7 ± 2.8 和 4.9± 4.2 μg/g，3 个月时未检测到药物。尽管表面降解明显，但微粒在 6 个月的体外研究和 3 个月的体内研究期间仍保持其球形结构，1 个月和 3 个月的玻璃体颗粒保留率分别为 60% 和 27%。

将称量好的（5 至 10 毫克）载有 TG-0054 的微粒分散在 1 毫升含有 0.05% 叠氮化钠的磷酸盐缓冲盐水 (PBS，pH 7.4) 中。叠氮化钠可作为防腐剂，防止微粒制剂的微生物降解。将这些分散的微粒添加到透析袋 (7Spectra/por®，MWCO 25 kDa) 中，透析袋的一端用夹子预先密封。加入微粒分散液后，关闭透析袋的另一端。将装有微粒分散液的透析袋放入试管中的药物释放介质 (10 毫升 PBS，pH 7.4，含有 0.05% 叠氮化钠)。将试管在 37 °C 下孵育，同时以 200 rpm 的速度搅拌内容物。在 0.5 小时、1 小时、2 小时、4 小时、8 小时、16 小时、1 天、2 天以及此后每周等离散时间间隔内，将整个释放介质替换为保持在 37°C 的新鲜介质。使用紫外分光光度计分析在每个时间间隔移除的溶解介质，并测定释放介质中的 TG-0054 量。所有体外研究均重复进行三次。[1]

The in vivo intravitreal delivery of TG-0054 from microparticle formulation was tested in male New Zealand white rabbits and compared with TG-0054 solution. Male New Zealand white rabbits weighing 2-3 kg were assigned to two groups. Group 1 (n = 6) received TG-0054-PLA microparticles intravitreally in one eye. Group 2 (n = 6) received TG-0054 solution intravitreally in both eyes. The rabbits were anaesthetized by intramuscular injection of ketamine : xyalazine mixture (50:10 v/v) in the hind limb of rabbits (400 μl/rabbit). Once the rabbits were in deep anesthesia, betadine solution was applied on eye surface and intravitreal injections were made using a 27G needle. Group 1 animals received 50 microliters of 300 mg microparticles/ml PBS (pH 7.4) [TG-0054-PLA microparticles with 10% drug loading; 15mg microparticles containing 1.5mg TG-0054/ 50μl] in the vitreal cavity of the right eye while the left eye was not dosed. Group 2 animals received 50 microliters of 20 mg TG-0054/ml PBS (pH 7.4) [1 mg/50 μl] in both eyes. After intravitreal injection, gentamicin ointment was applied at the injection site to prevent infections. The animals were regularly monitored for any abnormal signs. Three rabbits from each group were sacrificed at the end of 1 or 3 months post-dosing, in order to compare drug delivery between the formulations at the end of 1 and 3 months. Animals were euthanized by intravenous injection of sodium pentobarbital (150 mg/kg), and both eyes were enucleated and blood was collected. The eyes were immediately frozen in isopentane : dry ice bath and stored at −80 °C until further analysis.[1]

[1]. Intravitreal Poly(L-lactide) Microparticles Sustain Retinal and Choroidal Delivery of TG-0054, a Hydrophilic Drug Intended for Neovascular Diseases. Drug Deliv Transl Res. 2011 Feb;1(1):76-90.

[2]. CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction. Cell Transplant. 2015;24(7):1313-28.

Burixafor Hydrobromide is the hydrobromide salt form of burixafor, an orally bioavailable inhibitor of CXC chemokine receptor 4 (CXCR4) with hematopoietic stem cell (HSC)-mobilization and chemosensitizing activities. Upon administration, burixafor binds to the chemokine receptor CXCR4, thereby preventing the binding of stromal cell-derived factor-1 (SDF-1 or CXCL12) to the CXCR4 receptor and subsequent receptor activation. This may induce the mobilization of hematopoietic stem and progenitor cells from the bone marrow into the peripheral circulation. Additionally, burixafor-mediated mobilization of disseminated tumor cells (DTCs) from the bone marrow into the blood may make these metastatic tumor cells more susceptible to the actions of chemotherapeutic agents. CXCR4, a chemokine receptor belonging to the G protein-coupled receptor (GPCR) gene family, plays an important role in chemotaxis and angiogenesis and is upregulated in several tumor cell types. CXCL12/CXCR4 interaction induces retention of hematopoietic cells in the bone marrow.

C27H52BRN8O3P

647.631345748901

646.31

C, 37.56; H, 7.00; Br, 27.76; N, 12.98; O, 11.12; P, 3.59

1191450-19-7

1191450-19-7 (HBr); 1191448-17-5 (free acid)

154575080

White to off-white solid powder

152

7

11

14

40

724

0

ZXUVXYNBMUFEMK-UHFFFAOYSA-N

InChI=1S/C27H51N8O3P.BrH/c28-25-19-26(35-15-13-34(14-16-35)17-18-39(36,37)38)33-27(32-25)31-21-23-9-7-22(8-10-23)20-29-11-4-12-30-24-5-2-1-3-6-24;/h19,22-24,29-30H,1-18,20-21H2,(H2,36,37,38)(H3,28,31,32,33);1H

2-[4-[6-amino-2-[[4-[[3-(cyclohexylamino)propylamino]methyl]cyclohexyl]methylamino]pyrimidin-4-yl]piperazin-1-yl]ethylphosphonic acid;hydrobromide

TG-0054; Burixafor; TG0054; Burixafor HBr; TG 0054; Burixafor HBr hydrate; Burixafor trihydrobromide trihydrate

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: ~50 mg/mL (~65.0 mM)

配方 1 中的溶解度: 20 mg/mL (26.01 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。