CN115624658B - 一种可降解宫腔给药器及其制备方法 - Google Patents
一种可降解宫腔给药器及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种可降解宫腔给药器及其制备方法,所述宫腔给药器由载药的可降解微纳纤维膜制成的外层包膜和可吸水膨胀的生物降解高分子材料制备的内芯膜片组成,该给药器在吸收水分的过程中内芯膜片逐步膨胀,撑开微纳纤维外层包膜贴敷在子宫内壁上,随着可降解微纳纤维膜的降解,药物逐步释放,可以满足缓控释制剂产品的质量标准的要求。
Description
技术领域
本发明属于医疗技术领域,具体涉及一种可降解宫腔给药器及其制备方法,该给药器外层微纳纤维膜片中载有活性药物,在降解的过程中,药物缓慢释放,起到宫腔局部给药的作用。
背景技术
子宫内靶向用药对治疗子宫内膜炎、子宫内膜异位症、子宫肥大、子宫息肉、子宫肌瘤、子宫囊肿、子宫脱垂、子宫内膜癌等子宫疾病可以达到小剂量,高效率和低副作用的效果,尤其在增长子宫内膜方面的局部用药,口服药物作用甚微,而且对患者有很大副作用。宫腔上药主要是采用宫腔灌注的方法,主要就是用无菌导管将药物通过阴道注射到宫腔内,宫腔给药可以用来多种妇科炎症或生殖系统疾病,比如治疗盆腔炎、子宫内膜炎、子宫内膜过薄引起的不孕不育等达到治疗的目的,但都无法实现药物长期缓释的临床效果。
本领域的专家们对宫腔局部给药做了大量的研究,很多文献公开了植入宫腔局部缓释药物的方案,但均存在药物释放后,部分药物随宫腔分泌物排出体外而造成临床无法定量给药的缺陷,基于缓控释药物质量的技术要求,该类产品无法制成局部给药缓释药物制剂进行产业转化。
子宫肌瘤是女性妇科常见的疾病,发病率大概在20%左右。一般子宫肌瘤是良性病变,如果对患者的身体、生活没有什么影响,可以不用治疗。如果肌瘤生长过快造成压迫或者肌瘤体积较大,直径超过5厘米,而且导致患者月经过多,甚至造成贫血,在这种情况下需要对子宫肌瘤进行治疗。目前治疗子宫肌瘤的方法比较多,有保守治疗,如药物治疗,也可以手术治疗。在保守的药物治疗里,主要用降低雌激素水平的药物,可以抑制子宫肌瘤生长。但是目前没有任何一种药物通过药物治疗可以使子宫肌瘤消失,不再复发,中药也是一样。因此,子宫肌瘤主要还是以物理治疗,比如手术或者消融等进行治疗,药物治疗效果非常差,不可能导致肌瘤脱落。
手术切除+宫腔内能防粘连+局部给药的临床方案是医生和患者都希望的,但目前还没有满足临床需求的给药器械上市,为此,研制这种符合临床预期的可降解局部给药器械是临床非常需要的。
发明内容
为解决现有技术的不足,满足临床的需要,本发明研制一种新型的缓释药物的可降解宫腔给药器及其制备方法,载药的可降解微纳纤维膜在膨胀内芯膜片的支撑下,贴敷在宫腔内壁,微纳纤维膜在降解的过程中实现药物的定量缓释,解决了宫腔给药物无法持续维持一定给药浓度而达到治疗效果的临床难题,本发明具体实施方案如下:
本发明提供一种可降解宫腔给药器,由负载药物的可降解微纳纤维膜制成的外层包膜和可吸水膨胀的高分子材料制备的内芯膜片组成,内芯膜片封闭在外层包膜内,可降解宫腔给药器为子宫形状,长30mm-70mm、宽30mm-65mm、厚度为0.1mm-2mm。
内芯膜片尺寸小于外层包膜,封闭在外层包膜内;可降解宫腔给药器为子宫形状,长30-70mm、宽30-65mm、厚度为0.1mm-2mm;纳纤维膜纤维直径为0.01um-10um,厚度为0.01mm-1mm,内芯膜片形状为子宫性状、梯形、椭圆形或者其它异形,长10-60mm、宽10-55mm,厚度为0.1-2mm,吸收液体的倍数大于自身重量的10倍,微纳纤维膜和负载药物的重量比为1:0.01-1。
负载治疗宫腔疾病药物的可降解微纳纤维膜采用静电纺丝技术制成,可降解微纳纤维膜在吸水膨胀的内芯膜片作用下贴敷在宫腔内壁,在降解的过程中缓慢释放药物,制备方法举例如下:
1、可降解宫腔给药器负载雌激素类药物,其制备方法为:
(1-1)将可降解聚合物材料和一定剂量的雌激素溶解在有机溶剂中,配成10-15%浓度的溶液;
(1-2)采用静电纺丝工艺,纺丝速度10-50mm/h,电压15-30V,接收距离15-20cm,制成纤维直径0.1-10um、厚度为0.02-0.2mm的载药可降解微纳纤维膜;
(1-3)吸水高分子材料干燥膜片切割成需要的尺寸;
(1-4)将(1-3)制备的膜片包裹在(1-2)制备的可降解微纳纤维膜内,模具加热切割封边得到类子宫形状的产品。
2、可降解宫腔给药器负载治疗子宫肌瘤或恶性肿瘤的药物,其制备方法为:
(2-1)将可降解生物材料和药物溶解在有机溶剂的溶液中,配成10-15%浓度的溶液,搅拌均匀;
(2-2)采用静电纺丝工艺,纺丝速度10-50mm/h,电压15-30V,接收距离15-20cm,制成纤维直径0.01-10um、厚度为0.1-1mm的载药可降解微纳纤维膜;
(2-3)吸水高分子材料干燥膜片切割成需要的尺寸;
(2-4)将(2-3)制备的吸水高分子材料干燥膜片包裹在(2-2)制备的膜内,模具加热切割封边得到类子宫形状的产品。
3、可降解宫腔给药器负载多肽类或治疗药物,其制备方法为:
(3-1)将多肽溶于注射用水中,形成水溶液,浓度为治疗剂量;
(3-2)将可降解生物材料溶解在有机溶剂中,配成5-15%浓度的溶液,搅拌均匀;
(3-3)采用静电纺丝工艺,选用同轴喷头,核芯为(3-1)为多肽水溶液,壳层为(3-2)为可降解高分子材料有机溶剂,壳层纺丝速度20-50mm/h,核芯纺丝速度1-5mm/h,电压20-35V,接收距离15-20cm,制成纤维直径0.1um-10um、厚度为0.1-1mm的载药可降解微纳纤维膜;
(3-4)吸水高分子材料干燥膜片切割成需要的尺寸;
(3-5)将(3-4)制备的膜片包裹在(3-3)制备的载药可降解微纳纤维膜内,模具加热切割封边得到类子宫形状的产品。
其中,负载的活性药物举例如下:
(1)促进伤口愈合的多肽或蛋白类活性成分,包括表皮生长因子(EGF)转化生长因子β超家族(TGF)、成纤维细胞生长因子(FGF)、胰岛素样生长因子(IGF)等任意一种或两种的组合;
(2)雌激素类,具体选自17β-雌二醇、雌酮、雌三醇、雌二醇衍生物、苯甲酸雌二醇、戊酸雌二醇、炔雌醇、炔雌醚、妊马雌酮、乙烯雌酚、尼尔雌醇或普罗雌烯中的任意一种或两种的组合;
(3)治疗肿瘤的药物,具体选自醋酸甲羟孕酮、甲地孕酮、己酸孕酮、顺铂、长春花碱、长春新碱、博来霉素、异环磷酰胺、5-氟尿嘧啶、阿霉素、表阿霉素、丝裂霉素、紫杉醇、多西紫杉醇、吉西他滨等药物中的任意一种或两种的组合;
(4)多肽类药物,比如人绒毛膜促性腺激素、促性腺激素释放激素激动剂,选自曲普瑞林、亮丙瑞林、戈舍瑞林、普罗瑞林、戈那瑞林和丙氨瑞林中的任意一种或两种的组合;
(5)多药联合方案,比如卡铂+紫杉醇(首选,对于癌肉瘤为 1 类证据)、卡铂/紫杉醇/曲妥珠单抗(HER-2 阳性浆液性腺癌)、多西他赛+卡铂(对于紫杉醇禁忌者)、卡铂/紫杉醇/贝伐珠单抗、顺铂+多柔比星±紫杉醇异环磷酰胺+紫杉醇(用于癌肉瘤 1 类证据),顺铂/异环磷酰胺(用于癌肉瘤)、顺铂,卡铂,多柔比星(或多柔比星脂质体),紫杉醇(或白蛋白结合紫杉醇),托泊替康,贝伐珠单抗,多西他赛,异环磷酰胺(应用于癌肉瘤),坦罗莫司激素治疗(主要用于 G1~2 子宫内膜样癌)、醋酸甲羟孕酮/他莫昔芬(交替使用)、甲地孕酮/他莫昔芬(交替使用)、醋酸甲羟孕酮、甲地孕酮、他莫昔芬、托瑞米芬、来曲唑、阿那曲唑、氟维司群、左炔诺孕酮缓释系统。
可降解微纳纤维膜材料选自可降解聚氨酯(PU)、可吸收聚酯、可吸收聚醚、可吸收聚氨基酸、用赖氨酸二异氰酸酯交联多聚赖氨酸的PU材料、天然高分子羧甲基纤维素、葡聚糖、透明质酸为软段并以赖氨酸二异氰酸酯为硬段的PU材料,其中可吸收聚酯,具体包括PLGA(LA:GA=1:0.5-1)和由聚乙二醇开环的PLGA,其中聚乙二醇(PEG200、400、600、1000)开环的聚乳酸(PLGA)聚合物,PEG:LA:GA质量百分比为:1:10-5000:10-5000 。
其中可降解聚氨酯进一步优选聚酯型聚氨酯,具体包括聚赖氨酸PU、以CL、PDO、LA、GA为主要原料合成的聚合物二醇为软段并以赖氨酸二异氰酸酯(LDI)为硬段的PU材料以及聚乙二醇(PEG200、400、600、1000)开环的己内酯(CL)聚合物二醇与LDI为硬端的可降解聚氨酯。
进一步,可降解聚氨酯优选小分子二醇(1、3-丙二醇、1、4-丁二醇)、聚乙二醇(PEG200、400、600、1000)开环的己内酯(CL)聚合物二醇与LDI和扩链剂反应后得到的可降解聚氨酯。
进一步,可降解聚氨酯优选小分子二醇(1、3-丙二醇、1、4-丁二醇)、聚乙二醇(PEG200、400、600、1000)开环的己内酯(CL)聚合物二醇与LDI和扩链剂反应后由氨基酸或其衍生物或多肽封端的可降解聚氨酯。
其中扩链剂,选自乙二醇、丙二醇、丁二醇、戊二醇、丁二胺、戊二胺、羟浦氨酸(甲酯/乙酯)、精氨酸(甲酯/乙酯)、半胱氨酸(甲酯/乙酯)、胱氨酸(甲酯/乙酯)、丝氨酸(甲酯/乙酯)、谷氨酸(甲酯/乙酯)、苏氨酸(甲酯/乙酯)、天冬氨酸(甲酯/乙酯)、络氨酸(甲酯/乙酯)、赖氨酸(甲酯/乙酯)、精氨酸(甲酯/乙酯)、类二元胺中的一种或两种组合以上,其中类二元胺选自两分子氨基酸(常用20种氨基酸中的一种)和一分子乙二醇或1、3丙二醇通过酯化反应后酯键合成的化合物,比如:两分子苯丙氨酸和一分子1、3丙二醇通过酯化反应后得到的通过两个酯键相连的拥有两个活波氨基的化合物,具体如下:
。
其中,封端的氨基酸或其衍生物选自羟浦氨酸(甲酯/乙酯)、精氨酸(甲酯/乙酯)、半胱氨酸(甲酯/乙酯)、胱氨酸(甲酯/乙酯)、丝氨酸(甲酯/乙酯)、谷氨酸(甲酯/乙酯)、苏氨酸(甲酯/乙酯)、天冬氨酸(甲酯/乙酯)、络氨酸(甲酯/乙酯)、赖氨酸(甲酯/乙酯)中的一种或两种组合;
其中封端的多肽选自氨基酸或其衍生物选自赖氨酸或赖氨酸乙酯/甲酯、精氨酸或精氨酸乙酯/甲酯、组氨酸或组氨酸乙酯/甲酯、胶原三肽或胶原三肽乙酯/甲酯、纤连蛋白RGD、层粘连蛋白或其乙酯/甲酯、亲和TGF-β1多肽、骨髓归巢多肽、成骨生长多肽、层粘连蛋白序列、可结合神经干细胞表面分子、成骨细胞粘附分子以及VEGF中的一种或两种以上。
所述的可降解聚氨酯,在材料合成过程中,加入了少量的催化剂(总量的0.01wt%-0.03wt%),比如有机锡类和有机铋类,优选毒性较小的催化剂,比如:辛酸亚锡、二醋酸二丁基锡、二月桂酸二丁基锡、MB20、DY-20中的一种或两种组合。
所述溶解可降解聚氨酯制备微纳纤维膜的有机溶剂,选自DMF、DMSO、四氢呋喃、乙醇、异丙醇、正丁醇、丙酮、丁酮、环己酮、乙酸异戊酯、乙酸乙酯、二氯甲烷、三氯甲烷、1、4-二氧六环或六氟异丙醇中的一种或两种以上组合。
所述内芯膜片选自高吸水性可降解材料,优选吸水性聚合物材料,具体包括海藻酸盐、改性海藻酸盐及其降解成氨基己糖和 N- 乙酰氨基葡萄糖的海藻酸盐、高分子抗菌吸水材料、聚氨基酸、壳聚糖及其衍生物、聚赖氨酸及其衍生物、聚乙烯醇、卡波姆、聚乙烯比咯烷酮、透明质酸、交联透明质酸钠、透明质酸锌、交联透明质酸锌、胶原、有机硅、多肽类、氨基酸以及各种抗炎药物中的一种或两种组合。
进一步,内芯膜片材料优选壳聚糖及其衍生物、透明质酸、交联透明质酸钠中的一种或两种组合;其中交联透明质酸钠可以是采用BDDE或DVS或文献中公开的交联方式获得的交联透明质酸钠凝胶,也可以粘均分子量大于100万的高分子透明质酸钠;
更优选交联透明质酸钠与非交联高分子透明质酸钠的重量比为1: 0.1-10;
更优选交联透明质酸钠与非交联高分子透明质酸钠的重量比为1: 0.1-1。
在本发明中,所述药物和可降解微纳纤维膜材料的质量比为(0.01%-20%):(80%-99.99%),例如0.1%:99.9%、5%:95%、10%:90%、20%:80%、50%:50%等。
本发明的目的之一是提供了一种新型的缓释药物的可降解宫腔给药器,该给药器由载药的微纳纤维膜和可吸水膨胀的内芯膜片组成,内芯膜片吸水膨胀后将微纳纤维膜贴敷在宫腔内壁表面,微纳纤维膜在降解过程中缓慢释放药物,解决了治疗剂量的药物被宫腔内膜充分吸收而不会随渗液排出的问题。
本发明的目的之二是公开了一种新型的缓释药物的可降解宫腔给药器的制备方法,筛选了由不同降解时间的可降解聚氨酯配比制成稳定释放药物的微纳纤维膜材料,采用静电纺丝技术负载酯溶性药物,采用静电纺丝技术通过同轴喷头负载水溶性药物,从而实现了给药器宫腔植入后药物的释放过程中维持一定的治疗剂量,从而有效的治疗宫腔疾病。
本发明的有益效果总结如下:
1、设计了一种新型的缓释药物的可降解宫腔给药器,由负载治疗药物可降解微纳纤维膜膜和可吸水膨胀的内芯膜片组成,内芯膜片吸水膨胀后将微纳纤维膜贴敷在宫腔内壁表面,微纳纤维膜在降解的过程中缓慢释放药物,在宫腔内持续维持一定的给药浓度,可以满足局部治疗的确切效果;
2、本发明设计的新型缓释药物的可降解宫腔给药器,可吸水膨胀的内芯膜片封闭在外层包膜内,外层包膜为子宫形状(图1所示),内芯膜片可以吸收比自身重量大于10倍以上的液体,吸收渗液后给药器膨胀为子宫大小,将外层包膜完整贴敷在子宫内壁上,形成子宫内壁保护膜,形成湿性敷料的愈合环境,可以防止术后粘连,同时促进创面修复;另一方面由于用可降解聚氨酯制备的微纳纤维膜具有诱导组织增生的功能,可以增加子宫内膜的厚度,添加雌激素类缓释药物,为子宫内膜过薄引起的不孕不育患者提供了一种有效的局部给药解决方案;
3、为实现可降解宫腔给药器的可降解聚氨酯微纳纤维膜具有在不同治疗周期内拥有稳定缓释药物的功能,本发明筛选了不同结构的可降解聚氨酯材料,软端选用PEG(200-600)引发PDO和PEG(200-600)引发己内酯(CL)、硬端选用LDI的可降解聚氨酯(PU)按一定比例配比,制成微纳纤维膜,可以满足1-6个月不同药物的释放要求,比如:以PEG(200-600)引发PDO为软端的PU与以PEG(200-600)引发CL为软端的PU的重量比为:1:0.1-1制成的微纳纤维膜,可以维持1-2个月内的较稳定的释药浓度;以PEG(200-600)引发PDO为软端的PU与以PEG(200-600)引发CL为软端的PU的重量比为:1:1-10制成的微纳纤维膜,可以维持3-6个月内较稳定的释药浓度。
附图说明
图1 为宫腔给药器的产品结构示意图;
图2为宫腔给药器的示意图;
图3为宫腔给药器吸水膨胀后的示意图;
图4为实施例二不同样品的释药曲线;
图5为实施例三不同样品的释药曲线。
附图标记说明:
1、外层包膜;2、内芯膜片。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚,下面将结合附图及具体实施例进行详细描述。
如图1-图3所示,本发明提供的可降解宫腔给药器由负载药物的可降解微纳纤维膜制成的外层包膜1和可吸水膨胀的高分子材料制备的内芯膜片2组成,内芯膜片封闭在外层包膜内,可降解宫腔给药器为子宫形状,长30mm-70mm、宽30mm-65mm、厚度为0.1mm-2mm。
可降解微纳纤维膜与其负载的药物的重量比为1:0.01-1。
所述内芯膜片的厚度为0.1mm-2mm、长10mm-60mm、宽10mm-55mm,吸收液体的倍数大于自身重量的10倍,形状为子宫性状、梯形、椭圆形或者其它异形,尺寸小于外层包膜。
可降解微纳纤维膜负载治疗宫腔疾病的药物,可降解微纳纤维膜采用静电纺丝技术制成,厚度为0.01mm-1mm,纤维直径为0.01um-10um,可降解微纳纤维膜含有的可降解高分子材料在降解过程中缓释药物。
实施例一、不同生物降解材料制备微纳纤维膜降解行为
可降解生物材料由珠海睿展生物材料有限公司提供,数均分子量(Mn)在8-10万之间,用三氯甲烷配和DMSO的混和溶液配成10%的溶液,采用静电纺丝工艺,在电压20V,纺丝速度10mm/h,接收距离为15cm的条件下,得到厚0.05mm的微纳纤维膜,微纳纤维膜材料的主要结构和在37℃生理盐水溶液中浸泡(7天、15天、30天、60天),观察形态变化,试验结果如下:
编号 | 材料 | 软段 | 软端分子量 | 扩链剂 | Mn | 浸泡7天 | 浸泡15天 | 浸泡30天 | 浸泡60天 |
1 | 羟基封端的聚氨酯 | PEG600引发CL | 2000 | 1、4-丁二醇 | 8.2 | 完整 | 完整柔软、无明显变化 | 完整柔软、浸泡液变浑浊 | 完整柔软,变薄、有絮状物 |
2 | 精氨酸乙酯封端的聚氨酯 | PEG600引发CL | 2000 | 1、4-丁二醇 | 8.25 | 完整 | 完整柔软、无明显变化 | 完整柔软、浸泡液变浑浊 | 完整柔软、变薄、有絮状物 |
3 | 胶原三肽物封端的聚氨酯 | PEG600引发CL | 2000 | 1、4-丁二醇 | 8.27 | 完整、 | 完整柔软、无明显变化 | 完整柔软、浸泡液变浑浊 | 完整柔软、变薄、有絮状物 |
4 | 羟基封端的聚氨酯 | PEG600引发PDO | 2000 | 1、4-丁二醇 | 8.5 | 完整、变浑浊 | 有絮状物、膜柔软 | 碎裂成渣 | 成浑浊液 |
5 | 羟基封端的聚氨酯 | PEG600引发GA | 2000 | 1、4-丁二醇 | 8.8 | 完整 | 有絮状物、膜变硬 | 碎裂成渣 | 成浑浊液 |
6 | PLGA(LA:GA=7:3) | - | - | - | 8.3 | 完整 | 有絮状物、膜变硬 | 碎裂成渣 | 成浑浊液 |
7 | PPDO | - | - | - | 完整 | 有絮状物,膜裂成几片 | 碎裂成渣 | 成浑浊液 |
试验结果显示,编号1、2、3的可降解聚氨酯微纳纤维膜在30天左右出现明显的降解,而编号4的微纳纤维膜在7天之内就出现了降解,PLGA和PPDO呈现出碎裂式崩解,为得到可以均匀缓释给药的可降解聚氨酯微纳纤维膜,满足植入宫腔内不同时间的药物维持治疗剂量,选择编号1、2、3和编号4的混合材料比较理想。
实施例二:释药时间28天的醋酸亮丙瑞林缓释给药器的制备
根据实施例一中的试验结果,选用编号2和4(数均分子量Mn=8-10万)不同重量比的混合材料进行释药性能研究,制备方法如下:
(1)将醋酸亮丙瑞林溶于注射用水中,配成浓度为10mg/ml的醋酸亮丙瑞林溶液;
(2)将实施例一中编号2和4不同重量比(见本实施例表中所述)的混合材料的可降解聚氨酯分别溶于三氯甲烷和DMSO的混合溶剂中,配成10%溶液;
(3)选用壳核结构的喷头,步骤(1)中的醋酸亮丙瑞林溶液为核材,步骤(2)中的有机溶液为壁材,采用静电纺丝工艺,在电压20V,步骤(1)中的醋酸亮丙瑞林溶液纺丝速度2mm/h,步骤(2)中的有机溶液纺丝速度为10mm/h,接收距离为15cm的条件下,得到载药浓度为 0.1875mg /cm2 的微纳纤维膜;
(4)将交联透明质酸钠膜片(吸水倍数约20倍)裁剪成子宫形状3.5×4.5cm大小;
(5)将步骤(3)制备的微纳纤维膜包裹(5×6cm)大小(约20cm2)步骤(4)的交联透明质酸钠膜,模具切割热封如图(1)的形状;
(6)步骤(5)中得到的产品,采用超声雾化技术精密喷涂醋酸亮丙瑞林水溶液,使产品表面增加0.75mg游离的醋酸亮丙瑞林;
(7)将步骤(6)制备的载药器,置于25 mL塑料离心管中,加入释放介质为生理盐水20 mL,放入温度为37 ℃、转速为50 r/min的恒温水浴振荡器中,在预定的时间间隔(1天、3天、7天、15天、21天、28天)精密量取每份溶液4 mL,同时补加等体积的释放介质,取出溶液以10000 r/min转速离心10 min,离心结束后,取上清液作为供试品溶液,用HPLC进行测定,计算释药量,绘制释放曲线如图4所示(图4中,横坐标为取样时间,纵坐标单位为mg,为药物释放量;系列1为样品A,系列2为样品B,系列3为样品C,系列4为样品D),样品配比及释药量如下表所示:
样品编号 | 聚氨酯种类 | PU重量比 | 1天 | 3天 | 7天 | 15天 | 21天 | 28天 |
A | 1号 | --- | 0.7mg | 0.15mg | 0.48mg | 0.57mg | 0.50mg | 0.49mg |
B | 1号:4号 | 1:1 | 0.75mg | 0.37mg | 0.73mg | 0.81mg | 0.75mg | 0.45mg |
C | 1号:4号 | 1:3 | 0.72mg | 0.49mg | 0.83mg | 0.89mg | 0.70mg | 0.62mg |
D | 1号:4号 | 1:5 | 0.8mg | 0.5mg | 1.1mg | 1.3mg | 0.3mg | 0.1mg |
试验结果表明,不同编号的载药器浸泡后,游离的醋酸亮丙瑞林很快释放,样品A在28天内释放了约66%,平均释药浓度低于治疗剂量;样品B和C,在第3天出现了较低的释药,7-28天出现了较为平稳的释药,30天释放药物均超过90%;样品D植入后25天释药就达到了90%,释放速度过快,分析原因可能是编号4的聚氨酯微纳纤维膜降解速度太快所致,为此,编号1:编号4的重量比为1:1-3,可以得到一个月内满足临床需要的缓释给药器。
实施例三:释药时间为90天的β-雌二醇缓释给药器的制备
选择实施例一中编号2和编号4结构可降解聚氨酯,数均分子量范围为:20万-22万,编号2和编号4不同重量比的混合材料进行释药性能研究。
(1)取β-雌二醇0.1g,不同比例的混合材料的可降解聚氨酯50g,用丙酮和DMSO的混合溶液中,配成10%溶液;
(2)将步骤(1)中配好的溶液,采用静电纺丝工艺,在电压30V,纺丝速度20mm/h,接收距离为20cm的条件下,得到载药浓度为 0.04mg /cm2 的微纳纤维膜;
(3)将交联透明质酸钠膜片(吸水倍数约20倍)裁剪成子宫形状7*6.5cm大小(约25cm2);
(4)将步骤(3)制备的微纳纤维膜包裹步骤(4)的交联透明质酸钠膜(约20cm2),模具切割热封如图(1)的形状;
(5)在(4)得到的产品,在表面超声雾化精密喷涂β-雌二醇丙酮溶液,使产品表面增加0.2mg游离的β-雌二醇;
(6)将制备的载药器,置于25 mL塑料离心管中,加入释放介质 5%(v/v)乙醇水溶液20 mL,放入温度37℃、转速为50 r/min的恒温水浴振荡器中,在预定的时间间隔(1天、15天、30天、45天、60天、90天)精密量取每份溶液4 mL,同时补加等体积的释放介质,取出溶液以10000 r/min转速离心10 min,离心结束后,取上清液作为供试品溶液,用HPLC进行测定,计算释药量(单位mg),绘制释放曲线如图5所示(图5中,横坐标为取样时间,纵坐标单位为mg,为药物释放量;系列1为样品A,系列2为样品B,系列3为样品C,系列4为样品D),样品编号配比及释药情况如下表所示:
样品编号 | 聚氨酯种类 | 重量比 | 1天 | 15天 | 30天 | 45天 | 60天 | 90天 |
A | 2号 | --- | 0.10 | 0.01 | 0.05 | 0.15 | 0.30 | 0.49 |
B | 2号:4号 | 10:1 | 0.15 | 0.10 | 0.13 | 0.16 | 0.25 | 0.30 |
C | 2号:4号 | 5:1 | 0.17 | 0.11 | 0.16 | 0.20 | 0.30 | 0.15 |
D | 2号:4号 | 1:1 | 0.19 | 0.15 | 0.20 | 0.23 | 0.31 | 0.05 |
试验结果显示,样品A释药速度较慢,样品D释药速度较快,样品B和C呈现了较为平稳的释放,分析原因可能是编号4结构的聚氨酯降解速度过快,当编号2结构的聚氨酯的重量比大于编号4时,可以得到释放时间90天的缓释给药器。
Claims (7)
1.一种可降解宫腔给药器,其特征在于,由负载药物的可降解微纳纤维膜制成的外层包膜(1)和可吸水膨胀的高分子材料制备的内芯膜片(2)组成,内芯膜片封闭在外层包膜内,可降解宫腔给药器为子宫形状,长30mm-70mm、宽30mm-65mm、厚度为0.1mm-2mm;其中所述内芯膜片的厚度为0.1mm-2mm、长10mm-60mm、宽10mm-55mm,吸收液体的倍数大于自身重量的10倍,形状为子宫性状、梯形、椭圆形或者其它异形,尺寸小于外层包膜;可降解微纳纤维膜与其负载的药物的重量比为1:0.01-1,其中可降解微纳纤维膜由不同结构的可降解聚氨酯材料组成;
所述可降解聚氨酯材料,其特征在于以PEG200-PEG600引发PDO为软端的聚氨酯与以PEG200-PEG600引发CL为软端的聚氨酯的重量比为:1:0.1-1配比制成,可以维持1-2个月内的释药;或者,以PEG200-PEG600引发PDO为软端的聚氨酯与以PEG200-PEG600引发CL为软端的聚氨酯的重量比为:1:1-10配比制成,可以维持3-6个月内的释药。
2.根据权利要求1所述的可降解宫腔给药器,其特征在于,可降解微纳纤维膜采用静电纺丝技术制成,厚度为0.01mm-1mm,纤维直径为0.01um-10um,可降解微纳纤维膜含有的可降解高分子材料在降解过程中缓释药物。
3.根据权利要求1-2中任一项所述的可降解宫腔给药器,其特征在于,所述可降解微纳纤维膜负载活性药物,用于宫腔疾病的局部给药;其中活性药物包括:促进伤口愈合的多肽或蛋白类活性成分,包括表皮生长因子EGF转化生长因子β超家族TGF、成纤维细胞生长因子FGF、胰岛素样生长因子IGF中一种或两种的组合;雌激素类,具体选自17β-雌二醇、雌酮、雌三醇、雌二醇衍生物、苯甲酸雌二醇、戊酸雌二醇、炔雌醇、炔雌醚、妊马雌酮、乙烯雌酚、尼尔雌醇或普罗雌烯中的任意一种或两种的组合;治疗肿瘤的药物,具体选自醋酸甲羟孕酮、甲地孕酮、己酸孕酮、顺铂、长春花碱、长春新碱、博来霉素、异环磷酰胺、5-氟尿嘧啶、阿霉素、表阿霉素、丝裂霉素、紫杉醇、多西紫杉醇、吉西他滨药物中的任意一种或两种的组合;多肽类药物,选自曲普瑞林、亮丙瑞林、戈舍瑞林、普罗瑞林、戈那瑞林和丙氨瑞林中的任意一种或两种的组合。
4.根据权利要求1-2中任一项所述的可降解宫腔给药器,其特征在于,所述内芯膜片的制备材料为吸水性可降解聚合物材料,包括:海藻酸盐、改性海藻酸盐及其降解成氨基己糖和 N- 乙酰氨基葡萄糖的海藻酸盐、高分子抗菌吸水材料、聚氨基酸、壳聚糖及其衍生物、聚赖氨酸及其衍生物、聚乙烯醇、卡波姆、聚乙烯比咯烷酮、透明质酸、交联透明质酸钠、透明质酸锌、交联透明质酸锌、胶原、有机硅、多肽类、氨基酸以及各种抗炎药物中的一种或两种组合。
5.一种如权利要求1-4任一项所述的可降解宫腔给药器的制备方法,其特征在于,可降解微纳纤维膜负载雌激素类药物,可降解宫腔给药器的制备方法为:
(1-1)将可降解聚合物材料和一定剂量的雌激素溶解在有机溶剂中,配成8-15%浓度的溶液;
(1-2)采用静电纺丝工艺,纺丝速度10-50mm/h,电压15-30V,接收距离15-20cm,制成纤维直径0.1um-10um、厚度为0.02mm-0.2mm的负载药物的可降解微纳纤维膜;
(1-3)可吸水膨胀的高分子材料干燥膜片切割成需要的尺寸,制成内芯膜片;
(1-4)将(1-3)制备的内芯膜片包裹在(1-2)制备的可降解微纳纤维膜内,模具加热切割封边得到类子宫形状的可降解宫腔给药器。
6.一种如权利要求1-4任一项所述的可降解宫腔给药器的制备方法,其特征在于,可降解宫腔给药器负载治疗子宫肌瘤或恶性肿瘤的药物,可降解宫腔给药器的制备方法为:
(2-1)将可降解生物材料和药物溶解在有机溶剂的溶液中,配成8-15%浓度的溶液,搅拌均匀;
(2-2)采用静电纺丝工艺,纺丝速度10-50mm/h,电压15-30V,接收距离15-20cm,制成纤维直径0.01-10um、厚度为0.05-1mm的负载药物的可降解微纳纤维膜;
(2-3)可吸水膨胀的高分子材料干燥膜片切割成需要的尺寸,制成内芯膜片;
(2-4)将(2-3)制备的内芯膜片包裹在(2-2)制备的可降解微纳纤维膜内,模具加热切割封边得到类子宫形状的可降解宫腔给药器。
7.一种如权利要求1-4任一项所述的可降解宫腔给药器的制备方法,其特征在于,可降解宫腔给药器负载多肽类治疗药物,可降解宫腔给药器的制备方法为:
(3-1)将多肽溶于注射用水中,形成水溶液,浓度为治疗剂量;
(3-2)将可降解生物材料溶解在有机溶剂中,配成5-15%浓度的溶液,搅拌均匀;
(3-3)采用静电纺丝工艺,选用同轴喷头,核芯为(3-1)水溶液,壳层为(3-2)可降解生物材料的有机溶液,壳层纺丝速度20-50mm/h,核芯纺丝速度1-5mm/h,电压20-35V,接收距离15-20cm,制成纤维直径0.1um-10um、厚度为0.1-1mm的负载药物的可降解微纳纤维膜;
(3-4)可吸水膨胀的高分子材料干燥膜片切割成需要的尺寸,制成内芯膜片;
(3-5)将(3-4)制备的内芯膜片包裹在(3-3)制备的可降解微纳纤维膜内,模具加热切割封边得到类子宫形状的可降解宫腔给药器。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103041455A (zh) * | 2013-01-10 | 2013-04-17 | 扬州大学临床医学院 | 生物可降解纳米载药缓释宫内节育器及其制备方法 |
CN104998343A (zh) * | 2015-07-24 | 2015-10-28 | 严聪颖 | 用于子宫的带药缓释装置和植入方法 |
CN108888798A (zh) * | 2018-09-12 | 2018-11-27 | 圆容生物医药无锡有限公司 | 一种柔性可折叠生物膜及其制备方法 |
CN109925537A (zh) * | 2018-04-19 | 2019-06-25 | 易浦润(上海)生物技术有限公司 | 一种弹性膜、其制备方法和应用 |
CA3136905A1 (en) * | 2019-04-18 | 2020-10-22 | Cannassure Ltd | Cannabinoid polymeric compositions |
CN114947996A (zh) * | 2021-02-23 | 2022-08-30 | 诺一迈尔(苏州)医学科技有限公司 | 子宫内膜修复膜 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT201700036930A1 (it) * | 2017-04-04 | 2018-10-04 | Silk Biomaterials S R L | Sistema che comprende idrogel e nanofibre |
-
2022
- 2022-10-20 CN CN202211289211.2A patent/CN115624658B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103041455A (zh) * | 2013-01-10 | 2013-04-17 | 扬州大学临床医学院 | 生物可降解纳米载药缓释宫内节育器及其制备方法 |
CN104998343A (zh) * | 2015-07-24 | 2015-10-28 | 严聪颖 | 用于子宫的带药缓释装置和植入方法 |
CN109925537A (zh) * | 2018-04-19 | 2019-06-25 | 易浦润(上海)生物技术有限公司 | 一种弹性膜、其制备方法和应用 |
CN108888798A (zh) * | 2018-09-12 | 2018-11-27 | 圆容生物医药无锡有限公司 | 一种柔性可折叠生物膜及其制备方法 |
CA3136905A1 (en) * | 2019-04-18 | 2020-10-22 | Cannassure Ltd | Cannabinoid polymeric compositions |
CN114947996A (zh) * | 2021-02-23 | 2022-08-30 | 诺一迈尔(苏州)医学科技有限公司 | 子宫内膜修复膜 |
Non-Patent Citations (2)
Title |
---|
张济忠等主编.《现代薄膜技术》.第16-17页,2009,第16-17页. * |
覃小红主编.《纳尺度纺织纤维科学工程》.东华大学出版社,2019,第195页. * |
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