CN109925537A - 一种弹性膜、其制备方法和应用 - Google Patents
一种弹性膜、其制备方法和应用 Download PDFInfo
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- CN109925537A CN109925537A CN201910270119.3A CN201910270119A CN109925537A CN 109925537 A CN109925537 A CN 109925537A CN 201910270119 A CN201910270119 A CN 201910270119A CN 109925537 A CN109925537 A CN 109925537A
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- elastic membrane
- drug
- silicon rubber
- estrogen
- estradiol
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Abstract
本发明提供了一种弹性膜、其制备方法和应用,所述弹性膜包括硅橡胶和药物,所述药物以涂层的方式负载在硅橡胶表面,所述药物包括雌激素;弹性膜具有低药量高效率的治疗效果,且具有较久的释药周期和较好的缓释能力,用于子宫宫腔损伤的治疗;弹性膜的制备方法简单,原料易得,价格低廉,便于工业大规模的生产应用。
Description
技术领域
本发明属于医疗器械领域,涉及一种弹性膜、制备方法和应用。
背景技术
子宫是产生月经和孕育胎儿的器官,位于骨盆腔中央,是女性独有的脏器。子宫大小与年龄及生育有关,未产者约长7.5cm、宽5cm、厚3cm,子宫可分为底、体与颈三个部分。宫腔呈倒置三角形,深约6cm,上方两角为“子宫角”,通向输卵管。下端狭窄为“峡部”,长约1cm。
流产、放取环、手术等宫腔操作、以及感染等原因,会引起子宫区域发生各种病变,子宫疾病是女性最常见的疾患之一,严重影响到患者的正常生活和健康,进而影响孕育新生命的能力。这些病变包括,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。
药物治疗对上述病变治疗的效果有限,随着微创技术在手术领域的迅速发展,宫腔镜检查和手术在妇科诊疗领域得到了广泛的推广,创伤小、术中出血少等一系列的优势,使宫腔镜称为微创外科手术重要的组成部分。
然而,大部分手术都要对宫腔造成损伤,息肉、肌瘤、囊肿、粘连切除,刮宫等一系列操作都可能会导致子宫内膜基底层受损,导致内膜纤维化和宫腔粘连。
子宫主要组成部分是肌肉,宫体的前壁和后壁几乎相互接触,中间的子宫腔仅为一裂缝。宫体壁由三层组织所组成,即浆膜层、肌肉层和黏膜层;黏膜层即子宫内膜层,又可分为三层,致密层、海绵层和基底层。致密层和海绵层是由基底层再生的增殖带,合称为功能层,对性激素敏感,在卵巢激素的影响下发生周期性变化,若未受孕则功能层在每一周期最后脱落伴子宫出血,临床上表现为月经来潮。基底层紧贴肌肉层,对卵巢激素不敏感,无周期性变化。正常子宫内膜腺体可分泌稀薄的碱性液体,以保持宫腔潮湿,因此,正常子宫前壁和后壁虽然离得很近,但不会粘连和生长在一起。
宫内手术后,子宫内膜基底层受损,特别是相同位置的前壁和后壁同时受损,宫腔即发生粘连。目前一致认为,对妊娠子宫的创伤是宫腔粘连的主要原因。创伤经常发生在产后或流产后1-4周因过量出血需刮宫者。在易感期,任何创伤都可引起子宫内膜基底层脱落,导致子宫壁相互粘着,形成永久粘连,致使子宫变形和对称性消失。其次,对非孕子宫内膜的创伤也可以引起宫腔粘连。文献报道,宫腔粘连可以发生在诊断性刮宫、开腹肌瘤剔除、宫颈活检、子宫内膜息肉取出术、宫内置避孕器或者应用放射线治疗后。此外宫腔粘连还可以发生在各种宫腔镜手术后,例如宫腔镜下子宫肌瘤切除术、子宫纵膈切除术后等。
由此可见,在微创手术后,由于宫腔受损,相对创面贴合后粘连在一起的几率很大,宫腔粘连后经血无法畅通排出,育龄女性没有办法正常受孕,通常的方法是再次采用宫腔镜粘连切开术将粘连部位分割开来。但是,尽管宫腔镜手术得到了广泛应用,宫腔粘连的治疗仍然十分困难,宫腔粘连治疗的预后仍不理想,宫角等部位粘连或严重宫腔粘连,即便经过了宫腔分离术,仍然很容易出现复发现象,很难根治。而宫腔粘连术后妊娠为具有高度流产危险和胎盘异常的高危妊娠,需密切监护,防治并发症出现。因此,宫腔粘连的治疗不仅包括宫腔镜手术恢复宫腔正常形态,还应采取措施促进子宫内膜修复,预防宫腔粘连复发,最终恢复患者正常生活和生育功能。
目前对宫腔粘连分离术后预防再次粘连有众多的方法和手段,主要有,药物治疗、宫内屏障介质、球囊扩张法、生物胶治疗、羊膜移植、纤维宫腔镜探查及钝性分离术。但至今仍缺乏能绝对有效完全避免再次粘连的方法,也缺乏一个统一的治疗标准。
口服雌二醇药物对预防粘连有效果,但由于口服药物的肝脏首过效应,再加上盆腔血液循环系统的相对独立性,导致口服性激素药物大部分被肝脏截留,全身血药浓度不高,而尤其到达子宫内部的浓度甚低,生物利用度很低。
临床有很多透皮给药的案例,有文献显示口服4mg(2mg bid)戊酸雌二醇,血清雌二醇(简称E2)测值上升211.89±57.40pg/ml。阴道外用0.5mg芬吗通雌二醇,血清雌二醇测值上升201.01±51.196pg/ml,阴道外用1mg芬吗通雌二醇,血清中雌二醇测值约589.65pg/ml,观察已知芬吗通雌二醇阴道用药吸收效果可达口服的约10~20倍。
戊酸雌二醇或雌二醇经阴道给药时,雌激素能快速有效地被阴道粘膜吸入血。戊酸雌二醇在阴道用药时,通过血液中的酯酶解链,这个过程十分迅速,但由于阴道粘膜的吸收效率,对吸收利用稍有影响。一般认为戊酸雌二醇的阴道用药约为口服效应的4~8倍左右。口服时,雌激素有95%被肝脏代谢失活,而阴道内雌激素吸收后,通过阴道静脉直接进入下腔静脉,不经过肝门静脉,从而避免了肝脏的首过效应。经阴道给药可以避免雌二醇在肠、肝脏大量被转变为雌酮(简称E1),使E2/E1更近生理比值。阴道用药时,E2直接作用于内膜相关受体,对内膜局部产生影响。
这些事例表明,子宫内靶向用药可以达到小剂量,高效率的效果。
上述众多治疗方法大部分只是暂时性的将粘连几率降低,等到器械或药物作用消失后,再次粘连的概率很大,特别是对于中重度粘连患者。而增长子宫内膜,特别是增长已破坏到基底层的内膜是个难题,大剂量的口服药物对破坏了基底层的内膜作用甚微,而且对患者有很大副作用。子宫内膜厚度不足,是不孕症的主要因素之一。因此,如何激活基底层细胞,使其再次活化分化出功能层,使内膜厚度达到合理受孕的厚度,是防止粘连和恢复生育能力的关键。
因此,开发一种低剂量高效率的能够抗子宫损伤的弹性模非常有必要。
发明内容
本发明的目的在于提供一种弹性膜、其制备方法和应用,本发明所述的弹性膜具有较久的释药周期,能实现药物的稳态释放,且能通过小剂量的用药量从而达到高效的治疗效果,此外还能通过对硅橡胶表面进行改性,从而使改性硅橡胶和改性硅橡胶表面的涂层保持较好的附着力;弹性膜的制备方法简单,原料易得,易于实现,在治疗子宫损伤具有较好的效果,便于工业大规膜生产应用;弹性膜制备的子宫内植入物通过将弹性膜植入子宫内部,达到较好的治疗效果,且能有效避免基质型弹性膜自身的粘连,从而达到和子宫较好的贴合,从而达到更好的治疗效果。
为达到此发明目的,本发明采用以下技术方案:
本发明的目的之一在于提供一种弹性膜,所述弹性膜包括硅橡胶和药物,所述药物以涂层的方式负载在硅橡胶表面,所述药物包括雌激素。
本发明中弹性膜具有低药量高效率的治疗效果,且具有较久的释药周期和较好的缓释能力,用于子宫宫腔损伤的治疗。
在本发明中,所述药物经过雾化成微粒后喷涂在硅橡胶膜表面。
在本发明中,所述硅橡胶为对预制品硅橡胶表面进行处理得到的。
在本发明中,所述处理的方式包括等离子处理、溶胀处理、喷砂处理、磨砂处理、皮纹处理、静电处理或润湿处理中的任意一种或至少两种的组合。
在本发明中,将所述药物雾化成粒径为50nm-500μm的微粒并喷涂在硅橡胶表面。优选地,药物雾化微粒的粒径为10-500μm为最佳。在其他实施方式中,所述微粒可为不均匀粒径的微粒,但总体在所述粒径范围内,优选地,在所述微粒的粒径在所述粒径范围内呈正态分布。
本发明中,弹性膜包括硅橡胶以及位于硅橡胶表面的涂层,其中硅橡胶具有较高的稳定性和生物相容性,硅橡胶具有良好的记忆弹性,可以保证在体内有良好的形状保持,且可以通过对预制品硅橡胶表面进行溶胀或其他改性,例如可将预制品硅橡胶浸泡在易挥发的有机溶剂中,置换出预制品硅橡胶内部的水分,可使喷涂后的硅橡胶和涂层微粒间具有较好的附着力,在弹性膜发生形变时,使涂层相对应的保持同等的形变,仍使涂层和硅橡胶保持较好的附着力;通过将涂层喷涂至硅橡胶表面,能够使硅橡胶表面的药物分布均匀,便于药物的均匀稳定释放,从而达到较好的治疗效果,此外也可针对局部治疗,在子宫宫腔出现局部损伤,可以通过局部喷涂涂层,达到局部治疗的目的。
在本发明中,所述涂层包括药物和控释因子。
在本发明中,所述药物和控释因子的质量比为(10%-90%):(90%-10%),例如10%:90%、20%:80%、30%:70%、40%:60%、50%:50%、60%:40%、70%:30%、80%:20%、90%:10%等。
在本发明中,所述涂层的厚度为0.02-0.2mm,例如0.02mm、0.05mm、0.07mm、0.1mm、0.12mm、0.15mm、0.17mm、0.2mm等。
本发明中涂层的厚度为0.02-0.2mm,在该厚度范围内,即可保持弹性膜有足够支撑弹性且不增加整体厚度;又可保证足够带药量,保证较久的释放周期以及治疗效果,当涂层的厚度低于0.02mm时,则会降低药物含量以及药物释放周期,从而影响治疗效果;当涂层的厚度过高时,可能会影响整体弹性膜的厚度,同时也会出现治疗周期结束后,药物未释放完全,造成原料浪费。
在本发明中,所述控释因子为可降解聚合物。
本发明中,控释因子为可降解聚合物,此类弹性膜大部分药物会随可降解聚合物的降解而释放,在膜片使用过程中,可降解聚合物的降解过程比较均匀稳定,因此药物的释放相对更均匀稳定。从而达到较好的治疗效果,因此药物粒径对于释放影响没那么显著,可以不需要做微粉处理。
在本发明中,所述控释因子包括壳聚糖、明胶、褐藻胶、淀粉、透明质酸、纤维素及其衍生物、聚丙交酯、聚丙交酯-乙交酯、聚乙交酯、聚乳酸、L-聚乳酸、D-聚乳酸、聚乙烯醇、聚乙烯吡咯烷酮、聚羟基乙酸/聚乳酸共聚物、聚乙二醇、聚己内酯、聚正酯或聚乙醇酸中的任意一种或至少两种的组合。
在本发明中,所述药物和所述可降解聚合物的质量比为(30%-50%):(70%-50%),例如30%:70%、35%:65%、40%:60%、45%:55%、50%:50%等。
在本发明中,所述弹性膜中的雌激素的用量为10mg至200mg,例如10mg、30mg、50mg、70mg、100mg、120mg、150mg、170mg、200mg等。
在本发明中,所述雌激素每天的释放10μg至4mg的药量,例如10μg、100μg、500μg、800μg、1mg、2mg、3mg、4mg等。
通常,当子宫的基底层发生损伤后,被损伤部位不会随激素变化发生改变,因此,采用已知的方式分离粘连后,因为粘连部位仍然不能生出功能层,因此,容易再次发生粘连。令人惊奇的是,发明人通过将雌激素负载在硅橡胶上,通过药物刺激持续激活子宫内膜基底层,可以让基底层再次增殖功能层,从而还原正常子宫内膜结构,达到彻底防止粘连的目的。特别地,对于瘢痕性子宫或子宫纤维化的患者,只需要将纤维化内膜基底层或瘢痕用手术方式剥开以创造创面,然后再通过雌激素持续刺激即可重新激活内膜功能层再生能力。优选地,雌激素每天释放10μg至4mg的药量,达到作用的阀值,持续至少一周,从而得到一个可以控制释放度和释放周期的缓释系统。优选地,雌激素的每天释放量为20μg至1mg,每个弹性膜的雌激素的用量为10mg至200mg。
在本发明中,所述雌激素包括17β雌二醇、雌酮、雌三醇或雌二醇衍生物中的任意一种或至少两种的组合。
在本发明中,所述雌激素包括苯甲酸雌二醇、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至少两种的组合。
本发明中相对于口服或其他方式服用的雌激素,本发明选用的雌激素能够实现局部靶向释放,起到刺激内膜增生的作用,不会带来大剂量导致的激素紊乱等副作用。
在本发明中,所述药物还包括改善子宫内膜血流药物和/或集落刺激因子。
本发明中集落刺激因子能够用于对宫腔局部的免疫进行调节,促进子宫内膜基底细胞增殖。
本发明中通过雌激素、改善子宫内膜血流药物和集落刺激因子的共同使用,能够增加毛细管供血,促进药物的局部靶向释放,能够刺激内膜增生,达到低剂量高效率的治疗效果,避免大量药剂使用带来的激素紊乱等副作用。
在本发明中,所述改善子宫内膜血流药物包括阿司匹林、枸橼酸西地那非、己酮可可碱、维生素E、L-精氨酸或低分子肝素中的任意一种或至少两种的组合。
在本发明中,所述集落刺激因子包括粒细胞集落刺激因子和/或粒细胞-巨噬细胞集落刺激因子。
在本发明中,所述雌激素和改善子宫内膜血流药物的质量比为1:(0.1-1),例如1:0.1、1:0.2、1:0.3、1:0.4、1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1等,优选1:(0.3-0.6)。
在本发明中,所述集落刺激因子和雌激素的质量比为(0.05-0.5):1,例如0.05:1、0.1:1、0.15:1、0.2:1、0.25:1、0.3:1、0.35:1、0.4:1、0.45:1、0.5:1等。
在本发明中,所述预制品硅橡胶包括热硫化硅橡胶、室温硫化硅橡胶、低温硫化硅橡胶、美国道康宁Silastic-382医用级硅橡胶、美国道康宁Q7医用级硅橡胶系列或植入级MDX系列或相应系列的医用硅橡胶中的任意一种或至少两种的组合。
在本发明中,所述弹性膜的弹性模量为0.5-3MPa,例如0.9MPa、1.0MPa、1.1MPa、1.2MPa、1.3MPa、1.4MPa、1.5MPa、1.8MPa、2.0MPa、2.5MPa等,优选1.0-2MPa。
在本发明中,所述弹性膜的厚度为0.1-4mm,例如0.1mm、0.5mm、1mm、1.5mm、2mm、2.5mm、3mm、3.5mm、4mm等,优选0.2-0.8mm。
在本发明中,所述药物涂层膜的层数为2层以上,例如2层、3层、4层、5层、6层等。
在本发明中,所述弹性膜的缓释周期为3-90天,例如3天、10天、20天、30天、40天、50天、60天、70天、80天、90天等。
在本发明中,所述弹性膜的形状为倒梯形。
在本发明中,所述倒梯形的高度为25-35mm,(例如25mm、26mm、27mm、28mm、29mm、30mm、31mm、32mm、33mm、34mm、35mm等),上底长度为20-40mm,(例如20mm、22mm、25mm、28mm、30mm、32mm、35mm、37mm、40mm等),下底长度为5-15mm,(例如5mm、6mm、7mm、8mm、9mm、10mm、11mm、12mm、13mm、14mm、15mm等)。
应该理解,弹性膜呈倒梯形薄片状,植入后梯形长边底部位于宫底,梯形短边顶部位于宫口位置,在植入宫腔后展开状态下,该弹性膜的形状被选择为适应于子宫的生理形状和尺寸而将子宫前壁和后壁尽可能全面积隔离,从而将子宫前壁和后壁的接触机会降至最低。弹性膜在植入时,医生仅需要持常规或定制器械辅助,将薄片放入子宫内即可。应该理解,医生还可以根据需要,将薄片状器械蜷缩成圆柱状,束缚在管内,借助管道将其通过宫颈管送入子宫内,植入后器械再次铺展开来。当所述硅橡胶的弹性模量到达1.2-1.5MPa,可以使得弹性膜在收卷的状态下进入宫腔后,由于其弹性特征,能在宫腔内最大程度的自动舒展,并且在不会随着宫腔运动过程而再次卷曲收缩,最大面积地隔离宫前后壁。
本发明的目的之二在于提供一种如目的之一所述弹性膜的制备方法,所述制备方法包括:将药物和控释因子的混合液涂覆至硅橡胶表面,得到弹性膜。
本发明采用将药物因子、控释因子共同溶解或均匀分散在溶剂中,混合成均匀的溶液,采用设备将溶液雾化成均匀的混合液微粒,雾化后的混合液微粒粒径均匀,大小一致的混合液微粒在湿润或半干燥状态喷涂在预制硅橡胶弹性膜表面,控释因子之间或控释因子与硅橡胶表面通过交联作用形成涂层膜。
本发明所述的雾化微粒粒径范围在50nm-500μm之间,优选10μm-500μm。雾化后的混合液微粒大小均一,有利于控制或调整释放速率。
本发明所述的湿润或半干燥状态指雾化后的混合液微粒状态,雾化后的混合液微粒可以通过自然挥发、吹气干燥、加热干燥一种或两种以上组合方式使其呈现半干燥状态。
本发明所述的交联包括化学交联和物理交联,化学交联包括但不仅限于缩聚交联、加聚交联等,物理交联包括但不仅限于光交联、热交联、辐射交联、自然交联等。
本发明中,药物涂层为1层时,制备方法为上述制备方法,本发明制备的弹性膜可用于子宫宫腔创伤的整体治疗,也可进行局部治疗,在进行局部治疗时,根据子宫宫腔创伤情况,进行局部涂覆从而进行局部针对性治疗,或将两面涂覆不同药物,分别对应不同适应症;也可以整体涂覆进行治疗;
当弹性膜涂层为2层时,可以选择不同药物,通过覆盖式喷涂实现,即先喷涂一层药物,半干燥或干燥后进行第2种药物的喷涂。此种可以实现不同药物不同量或不同时间段释放治疗。本领域技术人员可根据实际需求进行调整。
在本发明中,所述药物和控释因子的混合液是将药物和控释因子溶解至溶剂中得到的。
在本发明中,所述溶剂为有机溶剂。
在本发明中,所述有机溶剂包括二氯甲烷、三氯甲烷、丙酮、异丙醇、乙醇、四氢呋喃、六氟异丙醇、六氟丙酮、二甲基亚砜、乙腈、乙醚、醋酸乙酯、正己烷、吡啶、甲苯、苯、二甲基甲酰胺、正庚烷、甲醇、乙胺、乳酸、石油醚、甘油、辛酸、正己醇或环己烷中的任意一种或至少两种的组合。
在本发明中,所述药物在混合液中的浓度为0.1%-50%,例如0.1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%等,优选5%-30%。
在本发明中,所述控释因子在混合液中的浓度为0.1%-50%,例如0.1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%等,优选5%-30%。
在本发明中,使用雾化设备将所述混合液雾化成粒径为50nm-500μm的微粒并喷涂在硅橡胶表面。
药物因子和控释因子在溶剂溶解或分散的过程中被初步混合均匀,而且在雾化过程中被进一步均匀化,药物因子最终可被均匀从弹性膜释放出来,达到对病变部位进行均匀给药并实现减少并发症等目的。
本发明的目的之三在于提供一种如目的之一所述弹性膜在药物缓释系统中的应用。
本发明中,药物释放系统是指药物与载体或介质制成的,能使药物按设计剂量和可控方式释放的装置,已达到治疗某种疾病或者提高机体免疫能力等目的。
相对于现有技术,本发明具有以下有益效果:
本发明中弹性膜包括硅橡胶以及位于硅橡胶表面的涂层,具有低药量高效率的治疗效果,且具有较久的释药周期和较好的缓释能力,用于子宫宫腔损伤的治疗;其中硅橡胶具有较高的稳定性和生物相容性,且具有良好的记忆弹性,可以保证在体内有良好的形状保持,且可以通过对预制品硅橡胶表面进行溶胀或其他改性,可使喷涂后的硅橡胶和涂层微粒间具有较好的附着力,在弹性膜发生形变时,使涂层相对应的保持同等的形变,仍使涂层和硅橡胶保持较好的附着力;通过将涂层喷涂至硅橡胶表面,能够使硅橡胶表面的药物分布均匀,便于药物的均匀稳定释放,从而达到较好的治疗效果;此外弹性模可针对整体治疗,也可针对局部治疗;弹性膜的制备方法简单,原料易得,价格低廉,便于工业大规膜的生产应用。
附图说明
图1是本发明实施例1和对比例1中弹性膜30天体外释放曲线对比图;
图2是本发明实施例1和实施例2中弹性膜30天体外释放曲线对比图;
图3是本发明实施例3和对比例2中弹性膜60天体外释放曲线对比图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施例1
本实施例提供一种弹性膜,所述弹性膜包括硅橡胶以及位于硅橡胶表面的涂层,所述硅橡胶是对预制品硅橡胶表面进行等离子处理得到的,将药物雾化成粒径为10-300μm;其中涂层包括药物和控释因子,其中药物为雌二醇,控释因子为D-聚乳酸,二者的质量比为10%:90%,涂层的厚度为0.1mm;其中一个弹性膜中雌二醇的含量为10mg;弹性膜的厚度为0.5mm,形状为倒梯形,倒梯形的高度为30mm,上底长度为30mm,下底长度为10mm,所述弹性膜的弹性模量为1.2MPa。
本实施例还提供一种弹性膜的制备方法,所述制备方法如下:
(1)称取一定量的HTV医用硅橡胶热压成厚度为0.1mm的预制硅橡胶弹性膜,备用。
(2)称取100mg雌二醇、900mg PLGA(mol比例10:90)一起混合搅拌溶解在50ml丙酮中,将获得药液均匀喷洒在第一步获取的预制硅橡胶弹性膜两面,然后挥干溶剂(即挥发干燥去除溶剂),得到弹性膜。
根据膜片的增重计算出一个弹性膜中雌二醇的含量为10mg,计算方法:一个弹性膜中药物的含量=涂层增重×(药液中药物重量/(药液中药物重量+控释因子重量)),使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在30天内,前7天药物溶出最大量为309μg/d,后面逐渐平稳趋缓,30天内平均释放度为267μg/d。
取新西兰试验兔试验,在植入子宫前,通过手术方式将子宫刮宫获得创伤模型6只,分为两组A和B,A组喂食体重等剂量的雌二醇,B组植入相应大小的膜片,不进行额外药物喂食。30日后探查子宫,A组试验动物发生不同程度的粘连。B组内膜未见粘连发生。
对比例1
本对比例提供一种基质型弹性膜,所述基质型弹性膜包括硅橡胶以及均匀分散在硅橡胶内部的药物,所述药物为雌二醇,粒径为3000目,其中一个基质型弹性膜中雌二醇的含量为25mg;弹性膜的厚度为0.5mm,形状为倒梯形,倒梯形的高度为30mm,上底长度为30mm,下底长度为10mm。
本对比例还提供一种基质型弹性膜的制备方法,所述制备方法如下:
将1gβ雌二醇、30g HTV医用硅橡胶(分子量20-100万)、10g二氧化硅、5g羟基硅油、6g医用级硫酸钡,0.5g氧化铁红,2g过氧化苯甲酰在炼胶机上混炼至均匀,在平板硫化机上热压制成厚度0.5mm薄片,然后进行剪裁成需要的形状即得到基质型弹性膜。
根据膜片的体积计算出一个基质型弹性膜中雌二醇的含量为25mg,通过药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在30天内,前3天药物溶出最大量为427μg/d,后面逐渐平稳趋缓,30天内平均释放度为218μg/d。
取新西兰试验兔试验,在植入子宫前,通过手术方式将子宫刮宫获得创伤模型6只,分为两组A和B,A组喂食体重等剂量的雌二醇,B组植入相应大小的弹性膜,不进行额外药物喂食。30日后探查子宫,A组试验动物发生不同程度的粘连。B组虽仍能看到手术痕迹,但内膜增长良好,未见粘连发生。
图1为实施例1和对比例1制备的弹性膜在30天体外释放曲线对比图,从图1可知,实施例1中弹性模药物释放比对比例1中弹性模药物释放更稳定均匀,且避免了基质型前期的突释现象,涂层型用药量少,且对药物粒径无显著要求。
实施例2
与实施例1的区别仅在于将实施例1中的雌二醇进行微粉处理,其粒径为2000目,其余组成与制备方法均与实施例1相同。
使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在30天内,前7天药物溶出最大量为317μg/d,后面逐渐平稳趋缓,30天内平均释放度为276μg/d。
图2为实施例1和实施例2制备的弹性膜在30天体外释放曲线对比图。
实施例3
本实施例提供一种弹性膜,所述弹性膜包括硅橡胶以及位于硅橡胶表面的涂层,所述硅橡胶是对预制品硅橡胶表面进行异丙醇擦拭溶胀处理得到的,将药物雾化成粒径为10-300μm;其中涂层包括药物和控释因子,其中药物为雌二醇,控释因子为D-聚乳酸,二者的质量比为28%:72%,涂层的厚度为0.2mm;其中一个弹性膜中雌二醇的含量为20mg;弹性膜的厚度为0.1mm,形状为倒梯形,倒梯形的高度为25mm,上底长度为20mm,下底长度为5mm,所述弹性膜的弹性模量为1.2MPa。
本实施例还提供一种弹性膜的制备方法,所述制备方法如下:
(1)称取一定量的HTV医用硅橡胶热压成厚度为0.1mm的预制硅橡胶弹性膜,备用。
(2)称取200mg雌二醇、500mg PLGA一起混合搅拌溶解在50ml丙酮中,将获得药液均匀喷洒在第一步获取的预制硅橡胶弹性膜两面,然后挥干溶剂,得到弹性膜。
根据膜片的增重计算出一个弹性膜膜中雌二醇的含量为20mg,使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在60天内,前7天药物溶出最大量为472μg/d,后面逐渐平稳趋缓,60天内平均释放度为391μg/d。
取新西兰试验兔试验,在植入子宫前,通过手术方式将子宫刮宫获得创伤模型6只,分为两组A和B,A组喂食体重等剂量的雌二醇,B组植入相应大小的膜片,不进行额外药物喂食。60日后探查子宫,A组试验动物发生不同程度的粘连。B组内膜未见粘连发生。
对比例2
本实施例提供一种弹性膜,所述弹性膜包括硅橡胶以及分散于硅橡胶内部的药物,所述药物为雌二醇,粒径为5000目,其中一个弹性膜中雌二醇的含量为100mg。
本实施例还提供一种弹性膜的制备方法,所述制备方法包括如下步骤:
将5g雌二醇、30g HTV医用硅橡胶、10g二氧化硅、5g羟基硅油、6g医用级硫酸钡、0.5g氧化铁红和2g过氧化苯甲酰在炼胶机上混炼至均匀,在平板硫化机上热压制成厚度0.2mm薄片,然后进行剪裁成需要的形状即得到弹性膜。
根据膜片的体积计算出一个弹性膜中雌二醇的含量为100mg,使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在60天内,前3天药物溶出最大量为903μg/d,后面逐渐平稳趋缓,60天内平均释放度为333μg/d。
取新西兰试验兔试验,在植入子宫前,通过手术方式将子宫刮宫获得创伤膜型6只,分为两组A和B,A组喂食体重等剂量的雌二醇,B组植入相应大小的膜片,不进行额外药物喂食。60日后探查子宫,A组试验动物发生不同程度的粘连。B组内膜增长良好,未见粘连发生。
图3为实施例3和对比例2制备的弹性膜60天体外释放曲线对比图,从图2可知,实施例3中弹性模药物释放比对比例2中弹性模药物释放更稳定均匀,且避免了基质型前期的突释现象,涂层型用药量少,且对药物粒径无显著要求。
实施例4
本实施例提供一种弹性膜,所述弹性膜包括硅橡胶以及位于硅橡胶表面的涂层,所述硅橡胶是对预制品硅橡胶表面进行异丙醇擦拭溶胀处理得到的,将药物雾化成粒径为10-300μm;其中涂层包括药物和控释因子,其中药物为雌二醇和维生素E,控释因子为D-聚乳酸,药物和控释因子的质量比为12%:88%,涂层的厚度为0.08mm;其中一个弹性膜中雌二醇的含量为10mg,维生素E的含量为2mg,弹性膜的厚度为0.2mm,形状为倒梯形,倒梯形的高度为35mm,上底长度为40mm,下底长度为15mm,所述弹性膜的弹性模量为0.9MPa。
本实施例还提供一种弹性膜的制备方法,所述制备方法如下:
(1)称取一定量的HTV医用硅橡胶热压成厚度为0.1mm的预制硅橡胶弹性膜,备用。
(2)称取100mg雌二醇、20mg维生素E、900mg D-聚乳酸一起混合搅拌溶解在50ml丙酮中,将获得药液均匀喷洒在第一步获取的预制硅橡胶弹性膜两面,然后挥干溶剂,得到弹性膜。
根据膜片的增重计算出一个弹性膜中雌二醇的含量为10mg,使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在30天内,前3天药物溶出最大量雌二醇为379μg/d,维生素E为146μg/d,后面逐渐平稳趋缓,30天内平均释放度为雌二醇294μg/d,维生素E为116μg/d。
取新西兰试验兔试验,在植入子宫前,通过手术方式将子宫刮宫获得创伤膜型6只,分为两组A和B,A组喂食体重等剂量的雌二醇,B组植入相应大小的膜片,不进行额外药物喂食。30日后探查子宫,A组试验动物发生不同程度的粘连。B组内膜未见粘连发生。
实施例5
本实施例提供一种弹性膜,所述弹性膜包括改性硅橡胶以及位于改性硅橡胶表面的涂层,所述改性硅橡胶是对硅橡胶表面进行等离子处理得到的,将药物雾化成粒径为10-300μm,其中涂层包括药物和控释因子,其中药物为雌二醇和阿司匹林,控释因子为聚乳酸,药物和控释因子的质量比为15%:85%,涂层厚度为0.2mm,其中弹性膜膜涂层的层数为2层,一层膜是雌二醇,含量为10mg;另一层膜是阿司匹林,含量为5mg;弹性膜的厚度为0.6mm,形状为倒梯形,倒梯形的高度为30mm,上底长度为30mm,下底长度为10mm。所述弹性膜的弹性模量为1.5MPa。
本实施例还提供一种弹性膜的制备方法,所述制备方法如下:
(1)称取一定量的HTV医用硅橡胶热压成厚度为0.2mm的预制硅橡胶弹性膜,备用。
(2)称取50mg阿司匹林、900mg聚乳酸一起混合搅拌溶解在50ml丙酮中,将获得药液均匀喷洒在第一步获取的预制硅橡胶弹性膜的两面,然后挥干溶剂,得到第一层涂层膜;
(3)称取100mg雌二醇、900mg聚乳酸一起混合搅拌溶解在50ml丙酮中,将获得药液均匀喷洒在第二步获取的带涂层弹性膜上,然后挥干溶剂,得到第二层弹性膜。
根据膜片的增重计算出一个基质型弹性膜中雌二醇的含量为10mg,阿司匹林的含量为5mg,使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在30天内,雌二醇平均释放量为372μg/d,阿司匹林为0μg/d,后30天内雌二醇平均释放量为31μg/d,阿司匹林平均释放量为172μg/d。
取新西兰试验兔试验,在植入子宫前,通过手术方式将子宫刮宫获得创伤膜型6只,分为两组A和B,A组喂食体重等剂量的雌二醇,B组植入相应大小的膜片,不进行额外药物喂食。30日后探查子宫,A组试验动物发生不同程度的粘连。B组内膜增长良好,未见粘连发生。
对比例3
与实施例1的区别仅在于不对预制品硅橡胶表面进行等离子处理,其余组成以及制备方法均与实施例1相同。
膜片喷涂制作完成后,卷曲弹性膜会有10%左右的涂层脱落,造成药物涂层不牢固,影响带药量以及药物释放量。
根据对比例3和实施例1的对比可知,不对预制硅橡胶弹性膜表面处理会引起涂层脱落。
对比例4
与实施例1的区别仅在于涂层雾化微粒粒径在500μm以上,其余组成以及制备方法均与实施例1相同。
使用药物溶出试验仪对样品在37℃的PBS溶液中进行药物溶出,用HPLC测试溶出药物量,可见在30天内,前20天雌二醇平均释放量为593μg/d,后10天内雌二醇平均释放量为26μg/d。
根据对比例4和实施例1的对比可知,涂层雾化微粒越大,药物释放量大且速度加快。
由于设备最小雾化微粒在50nm左右,且较小微粒对设备会造成较大损害,设备故障率较高,为实际考虑不建议做低于此粒径的喷雾。
申请人声明,以上所述仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,所属技术领域的技术人员应该明了,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种弹性膜,其特征在于,所述弹性膜包括硅橡胶和药物,所述药物以涂层的方式负载在硅橡胶表面,所述药物包括雌激素。
2.根据权利要求1所述的弹性膜,其特征在于,所述药物经过雾化成微粒后喷涂在硅橡胶膜表面;
优选地,所述硅橡胶为对预制品硅橡胶表面进行处理得到的;
优选地,所述处理的方式包括等离子处理、溶胀处理、喷砂处理、磨砂处理、皮纹处理、静电处理或润湿处理中的任意一种或至少两种的组合;
优选地,将所述药物雾化成粒径为50nm-500μm的微粒后喷涂在硅橡胶表面。
3.根据权利要求1或2所述的弹性膜,其特征在于,所述涂层包括药物和控释因子;
优选地,所述药物和控释因子的质量比为(10%-90%):(90%-10%);
优选地,所述涂层的厚度为0.02-0.2mm;
优选地,所述控释因子为可降解聚合物;
优选地,所述药物和所述可降解聚合物的质量比为(30%-50%):(70%-50%)。
4.根据权利要求1-3任一项所述的弹性膜,其特征在于,所述弹性膜中的雌激素的用量为10mg至200mg;
优选地,所述雌激素每天的释放10μg至4mg的药量。
5.根据权利要求1-4任一项所述的弹性膜,其特征在于,所述雌激素包括17β雌二醇、雌酮、雌三醇或雌二醇衍生物中的任意一种或至少两种的组合;
优选地,所述雌激素包括苯甲酸雌二醇、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至少两种的组合。
6.根据权利要求1-5任一项所述的弹性膜,其特征在于,所述药物还包括改善子宫内膜血流药物和/或集落刺激因子;
优选地,所述改善子宫内膜血流药物包括阿司匹林、枸橼酸西地那非、己酮可可碱、维生素E、L-精氨酸或低分子肝素中的任意一种或至少两种的组合;
优选地,所述集落刺激因子包括粒细胞集落刺激因子和/或粒细胞-巨噬细胞集落刺激因子;
优选地,所述改善子宫内膜血流药物和雌激素的质量比为(0.1-1):1,优选(0.3-0.6):1;
优选地,所述集落刺激因子和雌激素的质量比为(0.05-0.5):1。
7.根据权利要求1-6任一项所述的弹性膜,其特征在于,所述预制品硅橡胶包括热硫化硅橡胶、室温硫化硅橡胶、低温硫化硅橡胶、美国道康宁Silastic-382医用级硅橡胶、美国道康宁Q7医用级硅橡胶系列或植入级MDX系列或相应系列的医用硅橡胶中的任意一种或至少两种的组合;
优选地,所述弹性膜的弹性模量为0.5-3MPa,优选1.0-2MPa。
8.根据权利要求1-7任一项所述的弹性膜,其特征在于,所述弹性膜的厚度为0.1-4mm,优选0.2-0.8mm;
优选地,所述药物涂层的层数为≥2层;
优选地,所述弹性膜的缓释周期为3-90天;
优选地,所述弹性膜的形状为倒梯形;
优选地,所述倒梯形的高度为25-35mm,上底长度为20-40mm,下底长度为5-15mm。
9.根据权利要求1-8任一项所述的弹性膜的制备方法,其特征在于,所述制备方法包括:将药物和控释因子的混合液涂覆至硅橡胶表面,得到弹性膜;
优选地,所述药物和控释因子的混合液是将药物和控释因子溶解至溶剂中得到的;
优选地,所述溶剂包括有机溶剂;
优选地,所述有机溶剂包括二氯甲烷、三氯甲烷、丙酮、异丙醇、乙醇、四氢呋喃、六氟异丙醇、六氟丙酮、二甲基亚砜、乙腈、乙醚、醋酸乙酯、正己烷、吡啶、甲苯、苯、二甲基甲酰胺、正庚烷、甲醇、乙胺、乳酸、石油醚、甘油、辛酸、正己醇或环己烷中的任意一种或至少两种的组合;
优选地,所述药物在混合液中的浓度为0.1%-50%,优选5%-30%;
优选地,所述控释因子在混合液中的浓度为0.1%-50%,优选5%-30%;
优选地,使用雾化设备将所述混合液雾化成粒径为50nm-500μm的微粒后喷涂在硅橡胶表面。
10.根据权利要求1-8任一项所述的弹性膜在药物缓释系统中的应用。
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- 2019-03-29 CN CN201910252398.0A patent/CN109758622B/zh active Active
- 2019-04-04 CN CN202011416292.9A patent/CN112494464A/zh active Pending
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EP3639864A1 (en) | 2020-04-22 |
CN109925538B (zh) | 2022-03-01 |
CN113318279B (zh) | 2022-09-20 |
CN112535795B (zh) | 2022-03-15 |
CN113262332A (zh) | 2021-08-17 |
JP2022002751A (ja) | 2022-01-11 |
CN109758622B (zh) | 2021-08-06 |
EP3639864B1 (en) | 2022-11-02 |
JP7033342B2 (ja) | 2022-03-10 |
CN109925537B (zh) | 2022-03-01 |
CN113318279A (zh) | 2021-08-31 |
ES2930330T3 (es) | 2022-12-12 |
JP7245552B2 (ja) | 2023-03-24 |
KR20240063996A (ko) | 2024-05-10 |
CN112535795A (zh) | 2021-03-23 |
WO2019200694A1 (zh) | 2019-10-24 |
CN109758622A (zh) | 2019-05-17 |
US20190328659A1 (en) | 2019-10-31 |
JP2020534039A (ja) | 2020-11-26 |
KR20200144138A (ko) | 2020-12-28 |
CN112494464A (zh) | 2021-03-16 |
CN109925539A (zh) | 2019-06-25 |
EP3639864A4 (en) | 2021-03-10 |
CN109925539B (zh) | 2021-12-07 |
CN113262332B (zh) | 2022-06-24 |
CN109925538A (zh) | 2019-06-25 |
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