CN102368999A - 抗坏血酸磷酸酯缓释体系 - Google Patents
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Abstract
本发明公开了一种制备控释组合物的新型方法。具体地讲，本发明涉及制备抗坏血酸磷酸酯和可吸收聚合物的控释组合物的方法。本发明还公开了由本发明的方法制备的抗坏血酸磷酸酯的新型控释组合物。
Description
技术领域
本发明一般地涉及抗坏血酸磷酸酯的控释组合物以及它们在组织修复和再生中的应用的领域，特别地，涉及抗坏血酸磷酸酯和可生物降解聚合物的控释组合物。
背景技术
胶原是包括皮肤、腱、骨骼、软骨、血管和韧带的所有结缔组织的细胞外基质的主要蛋白组分。已经证实，胶原对于建立和维持人体组织的结构发挥着至关重要的作用。最近的研究显示，胶原与结缔组织中的细胞相互作用，并转导用于调节细胞贴壁、迁移、增殖、分化和存活的重要信号。
众所周知，抗坏血酸是胶原羟基化所必需的。抗坏血酸是脯氨酰羟化酶和赖氨酰羟化酶的辅因子。脯氨酸的羟基化对于胶原三螺旋的稳定性是必要的，而赖氨酸的羟基化对于胶原交联是必需的。据信，与抗坏血酸缺乏相关的失能性胶原产生将导致伤口愈合不良，并可能产生其他不利影响。
Shukla和Mason等人(Shukla，S.P，.Plasma and Urinary Ascorbic Acid Levels in the Postoperative Period，.Experientia 25：704，1969(Shukla，S.P，“术后血浆和尿液中的抗坏血酸含量”，《实验》，1969年第25卷第704页))表明，手术应激导致抗坏血酸需求量增大。然而，Levenson等人(Levenson et al.，Vitamins in Acute Illness，Annals of Surgery 24(5)p840-856 1946(Levenson等人，“急性病症中的维生素”，《外科学年鉴》，1946年，第24卷第5期第840至856页))报道，重伤患者中血浆抗坏血酸含量低于正常值。在一些患者中，血浆抗坏血酸含量在严重损伤后几小时内不可测量。Levenson等人还报道说，即使每日肌内注射1000mg抗坏血酸直至第八天，抗坏血酸的血液含量仍保持低于正常值。将抗坏血酸结合到可植入装置和组织工程支架中，用于在需要生物合成胶原的位点中局部控释抗坏血酸制剂，对于促进组织修复和再生将是可取的。
已通过溶剂浇铸制备了抗坏血酸磷酸酯的控释制剂。例如，Hyongbum Kim等人(Kim H.et al(2003)：Sustained Release of Ascorbic-2-phosphate and Deamethasone from Porous PLGA Scaffolds for Bone Tissue Engineering Using Mesenchymal Stem Cells， Biomaterials 24：4671-4679(Kim H.等人(2003年)：“抗坏血酸-2-磷酸酯和地塞米松从用于使用间充质干细胞的骨组织工程的PLGA多孔支架的缓释”，《生物材料》，第24卷第4671至4679页))描述了用于控释为抗坏血酸的稳定形式的抗坏血酸磷酸酯的PLGA多孔支架。通过溶剂浇铸/粒子沥滤法制备包含抗坏血酸磷酸酯和地塞米松的PLGA多孔基质。使用已知的溶剂浇铸法制备抗坏血酸磷酸酯控释制剂存在缺点。所述缺点包括需要移除残余溶剂、通过溶剂浇铸很难或无法制备三维(3-D)医疗器件部件，并且体内和体外均有大量抗坏血酸磷酸酯从溶剂浇铸结构中突释。因此，本领域需要用于制备抗坏血酸控释组合物的新型和改进的方法，以及由此类组合物制备的医疗器件和元件。
发明内容
本发明涉及制备控释组合物的方法。具体地讲，本发明涉及制备抗坏血酸磷酸酯的控释组合物的方法。
本发明的用于制备新型抗坏血酸磷酸酯控释组合物的新型方法具有以下步骤。在不大于约160℃的温度下干燥抗坏血酸磷酸酯约30分钟。在不大于约160℃的温度下熔融共混干燥的抗坏血酸磷酸酯和可吸收的脂族聚酯聚合物，以形成抗坏血酸磷酸酯和聚合物的组合物。任选地，该方法还包括在不大于约160℃的温度下将所述抗坏血酸和聚合物的组合物加工为期望形式的步骤。
本发明的另一个方面为通过上述方法制备的新型抗坏血酸磷酸酯组合物。通过在不大于160℃的温度下熔融加工，该新型组合物可进一步加工为医疗器件或元件。
本发明的又一个方面为由本发明的控释组合物制造的医疗器件。
本发明的这些方面和其他方面以及优点将通过下列具体实施方式和附图变得更为显而易见。
附图说明
图1示出采用现有技术溶剂浇铸法制备的载有抗坏血酸磷酸酯的40/60PCL/PLA薄膜的释放曲线。
图2示出如实例3中所述制备的载有抗坏血酸磷酸酯的40/60PCL/PLA薄膜的横截面SEM图。
图3示出如实例5中所述制备的载有抗坏血酸磷酸酯的40/60PCL/PLA薄膜的释放曲线。
图4示出如实例4中所述制备的载有抗坏血酸磷酸酯的35/65PCL/PGA薄膜的释放曲线。
具体实施方式
抗坏血酸磷酸酯(AZP)是抗坏血酸的稳定形式，其具有约260℃的熔融温度。抗坏血酸磷酸酯是极易吸湿的白色粉末。按来样计算，AZP可含有最多约7.5重量％的水分。生物相容的可吸收脂族聚酯聚合物对水分敏感，水分可导致该聚合物降解，尤其是在高温下。采用常规的熔融加工条件将AZP熔融共混到可吸收的脂族聚酯聚合物中的尝试通常都失败了，并产生了失败的结果。本发明提供通过熔融加工制备抗坏血酸磷酸酯控释组合物的新型方法。抗坏血酸磷酸酯控释组合物可用于组织修复和再生，并且可能对某些医学病症和某些患者的治愈过程至关重要。
通过干燥AZP粉末并将该AZP粉末与预先干燥的生物相容性可吸收脂族聚酯聚合物熔融共混，来制备本发明的新型抗坏血酸磷酸酯(AZP)控释组合物。然后可将熔融共混的AZP/聚合物组合物进一步熔融加工为期望的医疗器件或元件形式，所述医疗器件或元件包括但不限于纤维、杆、螺钉、缝钉(staples)、缝合锚(suture anchors)、薄膜等。根据本发明的工艺要求，可用于由本发明的新型组合物形成此类医疗器械的熔融加工包括常规方法，例如注模法、压缩模塑法、挤出法等。尤其优选的是，由本发明的控释组合物制备的医疗器件可植入身体组织和/或体腔内，但是它们可用于外部应用，例如安装至皮肤的网或板。
如本文所用，术语“控释”定义为通过对治疗剂在人类和动物健康方面的生物效应进行时间和空间控制来缓释治疗剂。
如本文所用，术语“突释”的定义为在控释过程开始时观察到的药物初始高速释放。“突释”可由多种机制引起，包括表面解吸附、孔隙扩散或扩散前阻挡层的缺乏，用于调节扩散过程。该初始非稳态时期也可称为“突然释放”。
如本文所用，术语“可吸收聚合物”的定义为合成的生物相容性聚合物(包括共聚物)，所述聚合物可降解，并且在植入人体和动物体内后可被身体吸收。可吸收聚合物在接触潮湿的身体组织时容易分解成小片段。这些片段随后会被身体吸收或排泄。更具体地讲，由于可生物降解的片段被身体吸收或排泄，使得体内不会永久性保留痕量或残余片段，因此不会引起永久性的慢性异物反应。
在本发明的方法中，将AZP干燥，以使结合水含量最小化。通过在不大于约160℃的温度下加热约30分钟来去除AZP中的结合水。将AZP充分干燥到一定量，以便在加工过程中有效地防止聚合物降解。例如，将残余水分减少到不超过约1％。可以常规方式，使用常规干燥装置，在真空下或在惰性气氛，如氮气或氩气下干燥AZP。虽然AZP制造商提供的材料安全性数据表指出AZP的降解温度为约260℃，但是人们发现在较高温度下较长时间地干燥AZP会导致AZP逐渐降解。
可用于本发明的方法中的可吸收脂族聚酯聚合物也必须在加工前进行干燥，以使水分含量最小化。可以常规方式来干燥可吸收脂族聚酯聚合物，例如通过贮存在室温和真空下，直到对其进行加工。可以常规方式来保持聚合物干燥，例如通过贮存在干燥惰性气体条件下。
可用于制备本文所述的AZP控释组合物的合适的可吸收脂族聚酯聚合物是熔融温度不大于160℃并且可在不大于160℃的温度下熔融加工的那些聚合物。合适的可吸收脂族聚酯聚合物是由单体制备的均聚物或共聚物，所述单体包括但不限于丙交酯(包括乳酸)、乙交酯(包括乙醇酸)、ε-己内酯、二氧杂环己酮和三亚甲基碳酸酯。在一个实施例中，可吸收脂族聚酯聚合物由单体制成，所述单体包括但不限于ε-己内酯、乙交酯(包括乙醇酸)和丙交酯(包括乳酸)。在另一个实施例中，可吸收脂族聚酯聚合物是ε-己内酯和丙交酯摩尔比为约40/60的共聚物。在另一个实施例中，可吸收脂族聚酯聚合物是ε-己内酯和乙交酯摩尔比为约35/65的共聚物。
称取预先干燥的AZP粉末和可吸收脂族聚酯聚合物，并在干燥惰性气体下使用常规熔融共混机器将它们熔融共混以形成组合物，所述常规熔融共混机器为例如以商品名BRABENDER(Hackensack，NJ)出售的那些。AZP可以以足够有效量，例如，占组合物总重量约0.5重量％至约20重量％的量添加到聚合物中。在一个实施例中，AZP可以以占组合物总重量约2重量％至约10重量％的量添加到聚合物中。然后将干燥的AZP粉末和可吸收脂族聚酯聚合物送入预热到不大于160℃的温度的混合机中，并在干燥惰性气体下熔融共混约5分钟至约30分钟，以形成AZP/聚合物组合物。在一个实施例中，将混合物熔融共混约5分钟至约15分钟。在另一个实施例中，将混合物熔融共混约10分钟。
然后可将AZP/聚合物组合物进一步加工为合适形式的控释组合物，或者可将其制成粒状或制成丸状，并贮存在干燥条件下，直至准备将其进一步加工为合适形式的控释组合物。控释组合物的合适形式是包括但不限于纤维、杆、螺钉、缝钉、缝合锚、薄膜等的医疗器件。尤其优选的是将本发明的组合物加工为植入式医疗器件和元件，但是不限于此，所述组合物也可用于非植入式器件和元件。这些形式或实施例可通过常规熔融加工方法，包括挤出法、注模法或压缩模塑法来制备，只要加工温度不大于约160℃即可。
在一个实施例中，可任选地将一种或多种生物活性剂与AZP控释组合物结合使用。生物活性剂可在如本文所述制备的AZP控释组合物内或包被在其上。
合适的生物活性剂包括但不限于防止感染的活性剂(例如抗微生物剂和抗生素)、减少感染的活性剂(例如抗炎剂)、如氧化的再生纤维素(例如以商品名INTERCEED和SURGICEL得自Ethicon，Inc.的那些)和透明质酸等防止或尽可能减少粘连形成的活性剂、抑制免疫系统的活性剂(例如免疫抑制剂)、异源或自体同源生长因子、蛋白质(包括基质蛋白质)、肽、抗体、酶、血小板、富血小板血浆、糖蛋白、激素、细胞因子、糖胺聚糖、核酸、止痛剂、病毒、病毒粒子和细胞类型、趋化剂、抗生素以及甾体和非甾体止痛剂。
还可将活组织与本发明的AZP控释组合物结合，以促进组织再生。活组织源可以变化，并且组织可具有多种构型，然而在一个实施例中，所述组织任选地以切碎的组织片段形式存在，这样可以提高组织再生长效率并促进愈合反应。在另一个实施例中，活组织可以任选地是从健康组织获得的组织切片或组织条的形式，其包含能够组织再生和/或重塑的活细胞。
AZP控释组合物还可与细胞结合使用，以促进胶原沉积。合适的细胞类型包括但不限于骨细胞、成骨细胞、破骨细胞、成纤维细胞、干细胞、多能细胞、软骨细胞祖细胞、软骨细胞、内皮细胞、脐带细胞、基质细胞、间充质干细胞、上皮细胞、成肌细胞、腱细胞、韧带成纤维细胞、神经元、骨髓细胞、滑膜细胞、胚胎干细胞、衍自脂肪组织的前体细胞、外周血祖细胞、从成人组织分离的干细胞、遗传转化的细胞、软骨细胞和其他细胞的组合、骨细胞和其他细胞的组合、滑膜细胞和其他细胞的组合、骨髓细胞和其他细胞的组合、间充质细胞和其他细胞的组合、基质细胞和其他细胞的组合、干细胞和其他细胞的组合、胚胎干细胞和其他细胞的组合、从成人组织分离的前体细胞和其他细胞的组合、外周血祖细胞和其他细胞的组合、从成人组织分离的干细胞和其他细胞的组合以及遗传转化的细胞和其他细胞的组合。
本领域技术人员应当知道，外科医生、保健专业人员或其他生命科学专业人员可根据医学科学原理和适当的治疗目的确定生物活性剂的种类。
本发明的AZP控释组合物可用于以下需要促进胶原合成的常规外科手术中，包括但不限于腹部外科手术，例如疝修复和骨盆底修复；表皮伤口愈合、软骨修复、骨骼修复、韧带修复等和类似手术，以及任何可能开发的其中需要促进胶原合成以改善医疗结果的新型手术。
以下实例为本发明的原理和操作的示例性的说明，而非限制本发明。一旦具有本公开的有益效果，本发明的范围和精神内的许多其他实施例对本领域技术人员来说将显而易见。
实例1：AZP干燥条件评价
测试了下列用于L-抗坏血酸-2-磷酸三钠盐(AZP)(＞98％(HPLC)，Fluka，批号：1322473 52607420)的干燥条件：90℃/24小时，真空下；160℃/30分钟，干燥氮封下；以及200℃/30分钟，干燥氮封下。测试时间包括估计的配制时间和样品采集与冷却的时间。
将6个玻璃小瓶置于真空烘箱内，在160℃下预干燥30分钟，然后转移至用干燥氮气吹扫的手套箱。在手套箱中在每个小瓶(参见表1)中称取AZP粉末。然后让AZP粉末小瓶经受如下表所示的加热条件。
表
用石蜡膜密封干燥的AZP粉末小瓶，并将这些小瓶贮存在干燥氮封下直到进行评估。重量损失％是在两次加热条件下累积得到。将室温/N2条件下的样品贮存在氮箱中。评估样品在加热条件过程中的颜色改变。颜色改变是AZP发生降解的标示。加热不超过30分钟的样品保持AZP粉末的原始白色。在90℃/24小时条件下加热处理的样品显示出非常浅的黄色，因此即使在低温下加热长时间也会导致AZP部分降解。经过两次加热处理的样品变为浅黄色。加热到200℃的样品号6具有最深的黄色。显示在90℃/真空/24小时条件下干燥完全，因为在更高的温度下进一步干燥不会导致重量减小。更高的温度和更短的时间在重量损失方面可具有相同的干燥效果。对照物样品的重量改变最小，表明该处理方法是合理的。因此，选择160℃和30分钟作为干燥和加工条件的上限。
最终确定的干燥方法如下：将烘箱在干燥氮封下预热到160℃；将8盎司小瓶及其瓶盖在160℃下加热30分钟，使其干燥，然后将其转移到用干燥氮气吹扫的手套箱中并称重；在手套箱中在小瓶内称取AZP；将AZP小瓶放入烘箱保持30分钟；在约15分钟的时间点振动小瓶一次；在烘箱中用AZP小瓶的预干燥瓶盖将小瓶封盖并密封；将封盖的AZP小瓶取出烘箱并称重。计算AZP重量和重量损失百分比。将AZP小瓶贮存在干燥氮气氛中，直至准备用于加工。
实例2：溶剂浇铸薄膜配方的对比及评估
在干燥氮封下的手套箱中，在20ml的瓶中称取32毫克如实例1所述在160℃/30分钟条件下预干燥的AZP。立即使用注射器向瓶中加入9.0ml的CH2Cl2，并将瓶封盖。从手套箱中取出AZP溶液，然后经超声波处理10分钟。将该溶液放回手套箱中，然后在手套箱向AZP溶液加入0.6克40/60PCL/PLA聚合物(批号D99069，BirminghamPolymer，Inc.)，并再次封盖。从手套箱中取出混合物，并在室温下摇晃，直至聚合物完全溶解。通过下述步骤制备溶剂浇铸薄膜：将VirTic冷冻干燥机(型号：AdVantage，MFR：VirTic)的搁板预冷至6℃。将AZP/聚合物溶液倒入5cm×5cm涂覆特氟隆的金属模具中，然后立即转移到预冷的搁板上。在氮封下进行缓慢蒸发，以防止水冷凝。溶剂移除后，收集厚度为约150微米至200微米的薄膜，并贮存在真空下，用于后续工序或/和鉴定。
采用表皮活检钻孔从溶剂浇铸薄膜上钻取8mm圆片。然后将圆片转移至HPLC小瓶中。向每个小瓶加入2mL磷酸盐缓冲盐水(PBS)(pH＝7.4)。将小瓶置于加热、振动的水浴中，于37℃和100rpm下进行温育。在每个时间点，移除释放介质，并更换为2ml的新鲜PBS。采用HPLC测定释放介质中的AZP。使用Gemini色谱柱(Phenomenex(Torrance，CA，USA))和2695型HPLC系统(Waters(Milford，MA，USA))以及PDA检测器进行HPLC分析。测量在238nm处的紫外吸收。使用含有5mM KH2PO4、6mM H3PO4、12mM四丁基硫酸氢铵和10％甲醇，pH值为2.5的等度流动相。流速为1ml/min。在10ml容量瓶中，将5mg AZP溶解于水中并充分混匀，制备AZP标准储备液。在使用前按1∶10和1∶100的比例稀释储备溶液。释放曲线示出在图1中。
使用溶剂浇铸的抗坏血酸磷酸酯控释体系的现有技术配方仅取得了有限成功。如图1中所示，现有技术的通过溶剂浇铸制备的40/60(摩尔/摩尔)PCL/PLA薄膜中的抗坏血酸磷酸酯显示出占组合物中AZP总量的高达40重量％的高突释。不期望的高突释是由于AZP的亲水性以及溶剂蒸发在薄膜中形成的多孔性造成的。
实例3：在200℃的加工温度下制备AZP/(25/75PCL/PGA)薄
膜及其评估
按如下所述制备AZP/聚合物组合物：在用干燥氮气吹扫的手套箱中，在容器中称取30.4克25/75PCL/PGA聚合物(批号UAZC020，Ethicon)和0.63克如实例1所述在160℃/30分钟条件下预干燥的AZP，并干混在一起，从而制备2重量％的AZP/聚合物组合物。同时，将30ml Brabender混合机(型号：R.E.E.6/2，C.W.Brabender Instruments(Hackensack，NJ))预热到200℃。维持干燥氮封条件。将混合机速度设置为30rpm。将AZP/聚合物混合物从手套箱快速转移到混合机中并关闭。使材料混合约10分钟。停止混合并收集AZP聚合物组合物。将组合物贮存在真空下，直至准备将其进一步加工为控释组合物。
按如下所述制备薄膜：将压缩模塑器械(Carver Laboratory Press，型号：2696)的压板预热到205℃。将约3.5克组合物置于压板上并加热5分钟。施加压力(约20,000lbs)约2分钟。停止加热，并且在水冷却和持续压力下使压板和薄膜冷却至室温。薄膜未受损，其厚度为约150微米至200微米，但薄膜为棕色，指示已发生降解。
采用HPLC检测分析法测定AZP回收率。将121mg薄膜转移到50ml容量瓶中。向容量瓶中加入10ml HFIP并搅拌。待样品完全溶解后，逐滴加入去离子水，充满到容量瓶标线。在进行HPLC分析之前，用0.2微米针筒式滤器过滤该溶液。使用Gemini色谱柱(Phenomenex(Torrance，CA，USA))和2695型HPLC系统(Waters(Milford，MA，USA))以及PDA检测器进行HPLC分析。测定在238nm处的紫外吸收。使用含有5mM KH2PO4、6mM H3PO4、12mM四丁基硫酸氢铵和10％甲醇，pH值为2.5的等度流动相。流速为1ml/min。在10ml容量瓶中，将5mg AZP溶解于水中并充分混匀，制备AZP标准储备液。在使用前按1∶10和1∶100的比例稀释储备溶液。AZP的回收率小于1％。
抗坏血酸磷酸酯的熔融温度为260℃。可以假定，任何可以在低于260℃的温度下热加工的聚合物均可用于采用熔融共混法制备的控释组合物的组分。人们意外地发现，在200℃下热加工干燥AZP和可吸收聚合物的组合物导致AZP几乎完全降解。相比之下，如下面的实例4和5中所示，在不大于约160℃的加工温度下制备的薄膜显示出薄膜中AZP的回收率显著增大。
实例4：在160℃的加工温度下制备AZP/(40/60PCL/PLA)薄
膜及其评估
按如下所述制备AZP/聚合物组合物：在用干燥氮气吹扫的手套箱中，在容器中称取30.4克40/60PCL/PLA聚合物(批号UAZC020，Ethicon，Inc(Somerville，NJ))和0.63克如实例1所述在160℃/30分钟条件下预干燥的AZP，并干混在一起，从而制备2重量％的AZP/聚合物组合物。在干燥氮封下混合AZP/聚合物。将30ml Brabender混合机(型号：R.E.E.6/2，C.W.Brabender Instruments(Hackensack，NJ))预热到160℃。维持干燥氮封条件。将混合机速度设置为30rpm。将AZP/聚合物混合物快速加入混合机中并关闭。使材料混合约10分钟。停止混合并收集AZP聚合物组合物。将组合物贮存在真空下，直至准备将其进一步加工为期望的控释组合物。重复该方法，制备5重量％和10重量％的AZP/聚合物组合物。
使用2重量％、5重量％和10重量％的AZP聚合物组合物按如下所述制备薄膜：将压缩模塑仪器(Carver Laboratory Press，型号：2696，Wabash，IN)的压板预热到160℃。将约3.5克组合物置于压板上并加热5分钟。施加压力(约20,000lbs)约2分钟。停止加热，并且采用水冷却在压力下使压板和薄膜冷却至室温。收集薄膜，其厚度为150微米至200微米，并将其贮存在干燥氮气中，直至准备用于测试。
沿截面剪切一片薄膜，安装到显微镜立柱上，并使用EMS 550溅射镀膜机(Electron Microscopy Sciences(Hatfield，PA))涂覆薄薄的一层金。.使用JEOL JSM-5900LV SEM(JEOL(Tokyo，Japan))进行SEM分析。检查各样品的表面和横截面区域。SEM图象显示，AZP颗粒嵌入并均匀分布于薄膜中。参见图2中的示例性SEM显微照片。
采用HPLC检测分析法测定AZP回收率。采用HPLC检测分析法测定AZP回收率。将27mg样品转移至50ml容量瓶中。向容量瓶中加入10ml二氧杂环己烷，并在30至50℃的微热下搅拌。待样品完全溶解后，逐滴加入去离子水至50mL，以充满到容量瓶标线。在进行HPLC分析之前，用0.2微米针筒式滤器过滤该溶液。使用Gemini色谱柱(Phenomenex(Torrance，CA，USA))和2695型HPLC系统(Waters(Milford，MA，USA))以及PDA检测器进行HPLC分析。测定在238nm处的紫外吸收。使用含有5mM KH2PO4、6mM H3PO4、12mM四丁基硫酸氢铵和10％甲醇，pH值为2.5的等度流动相。流速为1ml/min。在10ml容量瓶中，将5mg AZP溶解于水中并充分混匀，制备AZP标准储备液。在使用前按1∶10和1∶100的比例稀释储备溶液。干燥AZP用作对照物，所述干燥AZP以与薄膜相同的方式处理。填充有10重量％AZP的薄膜中AZP的回收率为约84重量％。采用相同方法测定填充有5重量％AZP的薄膜中AZP的回收率。回收率为78％。
通过以下方法测定AZP/聚合物薄膜中AZP的释放：采用表皮活检钻孔从薄膜上钻取10mm圆片。然后将圆片转移至HPLC小瓶中。向每个小瓶中加入1.5mL磷酸盐缓冲盐水(PBS)(pH＝7.4)。将小瓶置于加热、振动的水浴中，于37℃和100rpm下进行温育。在每个时间点，移除释放介质，并更换为2ml的新鲜PBS。采用HPLC测定释放介质中的AZP。使用Gemini色谱柱(Phenomenex(Torrance，CA，USA))和2695型HPLC系统(Waters(Milford，MA，USA))以及PDA检测器进行HPLC分析。测定在238nm处的紫外吸收。使用含有5mM KH2PO4、6mM H3PO4、12mM四丁基硫酸氢铵和10％甲醇，pH值为2.5的等度流动相。流速为1ml/min。在10ml容量瓶中，将5mg AZP溶解于水中并充分混匀，制备AZP标准储备液。在使用前按1∶10和1∶100的比例稀释储备溶液。释放曲线示出在图3中。
实例5：在130℃的加工温度下制备AZP/(35/65PCL/PGA)薄
膜
按如下所述制备AZP/聚合物组合物：在用干燥氮气吹扫的手套箱中，在容器中称取30.4克35/65PCL/PGA聚合物(批号UAZC020，Ethicon)和0.63克如实例1所述在160℃/30分钟条件下预干燥的AZP，并干混在一起，从而制备2重量％的AZP/聚合物组合物。同时，将30ml Brabender混合机(型号：R.E.E.6/2，C.W.Brabender Instruments)预热到130℃。维持干燥氮封条件。将混合机速度设置为30rpm。将AZP/聚合物混合物从手套箱快速转移到混合机中并关闭。使材料混合约10分钟。停止混合并收集AZP聚合物组合物。将组合物贮存在真空下，直至准备将其进一步加工为控释组合物。重复该方法，制备5重量％和10重量％的AZP/聚合物组合物。
使用2重量％、5重量％和10重量％的AZP/聚合物组合物按如下所述制备薄膜：将压缩模塑器械(Carver Laboratory Press，型号：2696，Wabash，IN)的压板预热到130℃。将约3.5克组合物置于压板上并加热5分钟。施加压力(约20,000lbs)约2分钟。停止加热，然后采用水冷却在压力下使压板和薄膜冷却至室温。收集薄膜，其厚度为150至200微米，并将其贮存在干燥氮气条件下，直至准备用于测试。
采用HPLC检测分析法测定AZP回收率。将50mg薄膜转移到50ml容量瓶中。向容量瓶中加入10ml二氧杂环己烷，并在30至50℃的微热下搅拌。待样品完全溶解后，逐滴加入去离子水，充满到容量瓶标线。在进行HPLC分析之前，用0.2微米针筒式滤器过滤该溶液。使用Gemini色谱柱(Phenomenex(Torrance，CA，USA))和2695型HPLC系统(Waters(Milford，MA，USA))以及PDA检测器进行HPLC分析。测定在238nm处的紫外吸收。使用含有5mM KH2PO4、6mMH3PO4、12mM四丁基硫酸氢铵和10％甲醇，pH值为2.5的等度流动相。流速为1ml/min。在10ml容量瓶中，将5mg AZP溶解于水中并充分混匀，制备AZP标准储备液。在使用前按1∶10和1∶100的比例稀释储备溶液。将干燥AZP用作对照物，所述干燥AZP以与薄膜相同的方式处理。填充有5重量％AZP的薄膜中AZP的回收率为约92％。使用以下方法测定AZP/聚合物薄膜中AZP的释放：采用表皮活检钻孔从薄膜上钻取10mm圆片。然后将圆片转移至HPLC小瓶中。向每个小瓶中加入1.5mL磷酸盐缓冲盐水(PBS)(pH＝7.4)。将小瓶置于加热、振动的水浴中，于37℃和100rpm下进行温育。在每个时间点，移除释放介质并更换为2ml的新鲜PBS。采用HPLC测定释放介质中的AZP。使用Gemini色谱柱(Phenomenex(Torrance，CA，USA))和2695型HPLC系统(Waters(Milford，MA，USA))以及PDA检测器进行HPLC分析。测定在238nm处的紫外吸收。使用含有5mMKH2PO4、6mM H3PO4、12mM四丁基硫酸氢铵和10％甲醇，pH值为2.5的等度流动相。流速为1ml/min。在10ml容量瓶中，将5mg AZP溶解于水中并充分混匀，制备AZP标准储备液。在使用前按1∶10和1∶100的比例稀释储备溶液。释放曲线示出在图4中。
制造本发明的AZP组合物的方法和通过本方法制造的新型组合物具有很多优点。这些优点包括更可取的AZP释放曲线，该释放曲线具有小于20重量％的低突释，随后是缓释。缓释时间为1周或更长。在一个实施例中，缓释时间为约3周或更长。另一个优点是适于制备各种几何形状的装置，和比溶剂浇铸法更佳的机械性能，以及广泛选择材料的有效性，包括可安全地用于加工的溶剂中的可溶性材料和不可溶性材料。
虽然本发明已通过其详细实施例得到了显示和描述，但本领域的技术人员将会理解，在不脱离受权利要求书保护的本发明的精神和范围的前提下，可以对本发明进行形式上和细节上的各种更改。
Claims (24)
1.一种制备抗坏血酸磷酸酯控释组合物的方法，所述方法包括以下步骤：
在不大于约160℃的温度下干燥抗坏血酸磷酸酯约30分钟；以及
在不大于约160℃的温度下熔融共混所述干燥的抗坏血酸磷酸酯和可吸收脂族聚酯聚合物，以形成抗坏血酸磷酸酯和聚合物的组合物。
2.根据权利要求1所述的方法，其还包括在不大于约160℃的温度下，将所述抗坏血酸和聚合物的组合物加工为期望形式的另外的步骤。
3.根据权利要求1所述的方法，其中所述组合物包含占所述组合物约0.5重量％至约20重量％的量的抗坏血酸。
4.根据权利要求1所述的方法，其中所述组合物包含占所述组合物约2重量％至约10重量％的量的抗坏血酸。
5.根据权利要求1所述的方法，其中所述可吸收脂族聚酯聚合物是由选自丙交酯、乙交酯、ε-己内酯、二氧杂环己酮和三亚甲基碳酸酯的单体制备的均聚物或共聚物。
6.根据权利要求1所述的方法，其中所述可吸收脂族聚酯聚合物是由ε-己内酯和乙交酯制备的共聚物。
7.根据权利要求2所述的方法，其中所述组合物形成选自纤维、杆、螺钉、缝钉、缝合锚、薄膜以及它们的组合的医疗器件。
8.根据权利要求1所述的方法，其中所述可吸收聚合物和所述抗坏血酸磷酸酯被熔融共混约5分钟至约30分钟。
9.根据权利要求1所述的方法，其还包括将所述组合物和至少一种生物活性剂结合的步骤。
10.根据权利要求1所述的方法，其还包括将所述组合物和活组织结合的步骤。
11.根据权利要求1所述的方法，其还包括将所述组合物和细胞结合的步骤。
12.一种控释组合物，其包括：
通过包括以下步骤的方法制备的抗坏血酸磷酸酯的控释组合物：
在不大于160℃的温度下干燥抗坏血酸磷酸酯约30分钟；以及
在不大于约160℃的温度下熔融共混所述干燥的抗坏血酸磷酸酯和可吸收脂族聚酯聚合物，从而形成所述抗坏血酸磷酸酯和聚合物的组合物。
13.根据权利要求1所述的组合物，其中所述方法还包括在不大于约160℃的温度下，将所述抗坏血酸和聚合物的组合物加工为期望形式的另外的步骤。
14.根据权利要求12所述的组合物，其中所述组合物包含约0.5重量％至约20重量％的量的抗坏血酸磷酸酯。
15.根据权利要求12所述的组合物，其中所述组合物包含约2重量％至约10重量％的量的抗坏血酸磷酸酯。
16.根据权利要求12所述的组合物，其中所述可吸收脂族聚酯聚合物是由选自丙交酯、乙交酯、ε-己内酯、二氧杂环己酮和三亚甲基碳酸酯的单体制备的均聚物或共聚物。
17.根据权利要求12所述的组合物，其中所述可吸收脂族聚酯聚合物是由ε-己内酯和乙交酯制备的共聚物。
18.根据权利要求13所述的组合物，其中所述组合物形成选自纤维、杆、螺钉、缝钉、缝合锚、薄膜以及它们的组合的医疗器件。
19.根据权利要求12所述的组合物，其中所述可吸收聚合物和所述抗坏血酸磷酸酯被熔融共混约5分钟至约30分钟。
20.根据权利要求12所述的组合物，其中所述组合物还包含至少一种生物活性剂。
21.根据权利要求12所述的组合物，其中所述组合物还包含活组织。
22.根据权利要求12所述的方法，其中所述组合物还包含细胞。
23.一种控释组合物，所述组合物包含抗坏血酸磷酸酯和可吸收脂族聚酯聚合物，具有不大于20重量％的突释，随后是控释。
24.一种医疗器件，其包含：
通过包括以下步骤的方法制备的抗坏血酸磷酸酯的控释组合物：
在不大于160℃的温度下干燥抗坏血酸磷酸酯约30分钟；和
在不大于约160℃的温度下熔融共混所述干燥的抗坏血酸磷酸酯和可吸收脂族聚酯聚合物，从而形成所述抗坏血酸磷酸酯和聚合物的组合物。
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| PCT/US2009/067289 WO2010068654A1 (en) | 2008-12-11 | 2009-12-09 | Sustained release systems of ascorbic acid phosphate |
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| CN103073703A (zh) * | 2013-01-29 | 2013-05-01 | 武汉大学 | L-抗坏血酸-6-聚（ε-己内酯）及其合成方法和控制释放方法 |
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| JP2012512159A (ja) | 2012-05-31 |
| WO2010068654A1 (en) | 2010-06-17 |
| CN102368999B (zh) | 2014-07-16 |
| CA2745934A1 (en) | 2010-06-17 |
| EP2358356B1 (en) | 2012-09-19 |
| BRPI0923362B8 (pt) | 2021-07-27 |
| EP2358356A1 (en) | 2011-08-24 |
| US20100150981A1 (en) | 2010-06-17 |
| JP5684140B2 (ja) | 2015-03-11 |
| US8197838B2 (en) | 2012-06-12 |
| CA2745934C (en) | 2018-01-02 |
| BRPI0923362A2 (pt) | 2015-07-21 |
| US8034363B2 (en) | 2011-10-11 |
| US20110104232A1 (en) | 2011-05-05 |
| BRPI0923362B1 (pt) | 2020-10-13 |
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