CN110290783A - 用于制备具有高含量生物粘附物质的电纺纤维的方法 - Google Patents
用于制备具有高含量生物粘附物质的电纺纤维的方法 Download PDFInfo
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- CN110290783A CN110290783A CN201880007823.3A CN201880007823A CN110290783A CN 110290783 A CN110290783 A CN 110290783A CN 201880007823 A CN201880007823 A CN 201880007823A CN 110290783 A CN110290783 A CN 110290783A
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Abstract
本发明涉及一种制备电纺纤维的方法,该方法包含:v)将形成纤维的亲水聚合物溶解在选自C1‑C3醇的醇中,vi)将生物粘附物质溶解在水中,其中生物粘附物质在25℃下在水中的溶解度为3g/100ml或以上或在25℃下为10g/100ml或以上,并且其中生物粘附物质具有在选自C1‑C3醇的醇中、在25℃下的溶解度为0.5g/100ml或更低,或在25℃下为0.1g/100ml或更低,vii)在搅拌下将得到的来自ii)的溶液加入到来自i)的所得溶液中,由此生物粘附物质沉淀并形成均匀的悬浮液,其中生物粘附物质作为颗粒悬浮,和viii)电纺均匀悬浮液以获得亲水性纤维。
Description
发明领域
本发明涉及具有高含量生物粘附物质的生物粘附电纺纤维,即基于干重,纤维中生物粘附物质的浓度为30%w/w或以上。该纤维用于药物或化妆品组合物中,其应用于粘膜或皮肤,特别是口腔粘膜,以便通过口腔粘膜或皮肤将药物物质递送至体循环。
发明背景
许多物质具有生物粘附特性。在具有生物粘附物质含量的电纺纤维的制备中,挑战在于平衡各个成分,以使生物粘附物质的掺入量足以在粘膜或皮肤上获得粘附期望的时间期限和还要确保纤维(例如药物或化妆品组合形式)不会从应用部位释放或脱离。
本发明是申请人的在先专利申请的进一步发展,该专利申请公开为WO2015189212,涉及生物粘附电纺纤维。从该公开中可以清楚地看出,例如聚环氧乙烷(PEO)可以用作生物粘附物质,并且由于其粘合性和溶解性,优选高分子量聚环氧乙烷,例如具有分子量2,000,000道尔顿的聚环氧乙烷。WO 2015189212中描述的电纺方法涉及使用一种溶剂,其中亲水性成纤维聚合物是可溶的,而生物粘附性物质是不可溶的并且以固体形式加入到溶剂中。
Xin等人:Flurorescent poly(p-phenylene vinylen)/poly(ethylene oxide)nanofibers obtained by electrospinning,Journal or Polymer Research,第18卷,第4期,2010年4月27日涉及通过电纺得到的荧光PPV/PEO纳米纤维。PPV是疏水聚合物。本发明涉及亲水性纤维形成聚合物。
发明描述
本发明通过提供一种制备电纺纤维的方法解决了这些问题,该方法包含将生物粘附物质的溶液加入到亲水性成纤维聚合物的溶液中,该加入导致生物粘附物质的沉淀。
因此,本发明提供了制备电纺纤维的方法,该方法包含:
i)将形成纤维的亲水性聚合物溶解在选自C1-C3醇的醇中,
ii)将生物粘附物质溶解在水中,其中生物粘附物质在25℃下在水中具有3g/100ml或以上或在25℃下为10g/100ml或以上的溶解度,并且其中生物粘附物质在25℃下具有在选自C1-C3醇的醇中的溶解度为0.5g/100ml或更低,或在25℃下为0.1g/100ml或更低,
iii)在搅拌下将得到的来自ii)的溶液加入到来自i)的所得溶液中,由此生物粘附物质沉淀并形成均匀的悬浮液,其中生物粘附物质作为颗粒悬浮,和
iv)电纺均匀悬浮液以获得亲水性纤维。
因此,本发明基于生物粘附物质在水中-其中它可溶-和在醇中-在其中它沉淀的溶解度差异。从上面可以看出,步骤i)中醇的含水量必须相对较低;这是因为亲水性聚合物可溶于醇的事实,并且应注意准备好电纺的悬浮液中水的最终含量不得超过20-50%w/w,因为亲水性成纤维聚合物通常在水或含水介质中溶胀,并且重要的是控制溶胀以避免具有粘度过厚的悬浮液,使得悬浮液不因凝结无法形成纤维而不能通过针头递送。如果水的量相当于例如50%w/w,则预期在混合乙醇和水溶液之后不久(在30分钟至1小时内)开始纺丝过程以避免溶胀。
因此,亲水性成纤维聚合物在醇中以及在所得的醇-水混合物中的溶解度是重要的。亲水性聚合物在醇和所得的醇-水混合物中的溶解度在25℃下为3g/100ml或以上或在25℃下为10g/100ml或以上。
此外,生物粘附物质在所得的醇-水混合物中的溶解度在25℃下为0.5g/100ml或更低,或者在25℃下为0.1g/100ml或更低。
药物物质可以包括在该方法的步骤i)或ii)中,这取决于其溶解性。
尽管例如具有分子量为2,000,000道尔顿的聚环氧乙烷具有优异的生物粘附性质,但本发明人发现当使用PEO 2,000,000时,电纺方法不是最佳的。由于PEO的高分子量,其涉及相对长的PEO链,PEO 2,000,000倾向于与纤维中的形成纤维的亲水聚合物混合,但是由于链长,PEO中2,000,000的PEO分布可能过于随机,例如由于PEO 2,000,000的小表面积。为了减轻这种情况并且为了获得更均匀的分布,已经进行了微粉化PEO 2,000,000的实验。然而,不可能获得足够小的PEO 2,000,000粒径。因此,在纺丝过程中使用的针-当使用微粉化PEO 2,000,000时-显然易于阻塞,并且所得纤维显然不如期望的那样坚固。
此外,从本文的实施例可以看出,即使PEO的分子量显著降低,但PEO在醇溶剂中与亲水性聚合物一起悬浮也会导致PEO在电纺材料中的不均匀分布。然而,应用本发明的方法,其中PEO首先在水中溶解,然后,将该水溶液与含有亲水性聚合物的醇溶液混合以沉淀PEO,得到期望的结果,其中PEO均匀分布在通过电纺获得的纤维材料上。预期PEO不是纤维材料的整体部分,而是作为极细颗粒定位在纤维上。
当与WO 2015/189212中的公开内容相比降低生物粘附物质的分子量时,预期纤维中生物粘附物质的浓度增加是必要的,以便获得期望的生物粘附。
为了实现强生物粘附,必须在电纺纤维中以相对高的浓度使用生物粘附物质,例如浓度为30%w/w。这进一步使制造纤维的方法复杂化。
特别感兴趣的是根据本发明制备的组合物,并且其包含抗炎药物物质,例如皮质类固醇。皮质类固醇可选自:安西奈德、倍他米松、布地奈德、氯倍他索、氯倍他松、可的松、地奈德、脱氧可的松、desoximethasone、地塞米松、二氟可龙、二氟拉松、flucortisone、氟米松、氟尼缩松、醋酸氟轻松、肤轻松、氟米龙、氟泼尼龙、氟氢缩松、氟替卡松、氯氟舒松、halobetasol、氢化可的松、甲泼尼松、甲基强的松、莫米松、帕拉米松、泼尼卡酯、泼尼松、泼尼松龙和曲安奈德或其药学上可接受的酯或丙酮化合物。皮质类固醇可优选选自倍他米松、布地奈德、氯倍他索、氯倍他松、去氧噻吩酮、二氟拉索、二氟噻嗪、氟喹诺酮、氟喹诺酮、哈西奈德、卤代甜醇、氢化可的松、莫米松和曲安西龙或其药学上可接受的酯。皮质类固醇酯优选地可以选自例如醋酸倍他米松、二丙酸倍他米松、倍他米松戊酸酯、丙酸氯倍他索、醋酸地塞米松、特戊酸氟地塞米松、丙酸氟替卡松、醋酸氢化可的松、丁酸氢可的松或糠酸莫米松。丙酮化合物可选自氟轻松(fluocinolone acetonide)或曲安奈德(triamcinoloneacetonide)。皮质类固醇优选为二丙酸倍他米松、戊酸倍他米松或丙酸氯倍他索。在本文上下文中优选的是氯倍他索或其衍生物,例如丙酸氯倍他索。
皮质类固醇是一类在脊椎动物的肾上腺皮质中产生的类固醇激素。
皮质类固醇可用于治疗各种病症/疾病,包括
i)过敏和呼吸系统疾病,如哮喘(严重恶化)、慢性阻塞性肺病(CPOD)、过敏性鼻炎、特应性皮炎、荨麻疹、血管性水肿、过敏反应、食物过敏、药物过敏、鼻息肉、过敏性肺炎、结节病、嗜酸细胞性肺炎和间质性肺病;
ii)皮肤病,如寻常型天疱疮和接触性皮炎;
iii)内分泌科,包括肾上腺功能减退和先天性肾上腺皮质增生;
iv)消化内科,包括溃疡性结肠炎、克罗恩病和自身免疫性肝炎;
v)血液科,例如淋巴瘤、白血病、溶血性贫血和特发性血小板减少性紫癜;
vi)风湿病科/免疫科,包括类风湿性关节炎、系统性红斑狼疮、风湿性多肌痛、多发性肌炎、皮肌炎、多发性动脉炎和血管炎;
vii)眼科,包括葡萄膜炎和角膜结膜炎;
viii)其他病症,包括多发性硬化、器官移植、肾病综合征、慢性肝炎(突然发作)和脑水肿。
皮质类固醇通常分为糖皮质激素和盐皮质激素。在本文的上下文中,特别是糖皮质激素是令人感兴趣的。在本文上下文中,感兴趣的糖皮质激素是通常用于治疗疾病的那些,其中可以以相对容易的方式应用包含电纺纤维的组合物。关于皮质类固醇,预期将许多组合物应用于皮肤或粘膜,并且应用这类组合物:
i)直接应用于粘膜,例如口腔、鼻腔、直肠或阴道粘膜;
ii)直接应用于皮肤;
iii)在移植到移植组织期间-以无菌形式提供提组合物;
iv)手术期间应用于身体受感染或患病区域;
v)直接应用于伤口上-体外或体内伤口。
在本文上下文中感兴趣的其他药物是:止痛药或antiesthetics(例如利多卡因、辣椒辣素),免疫应答调节剂(例如咪喹莫特),炎性疾病例如扁平苔藓例如生殖器扁平苔藓包括外阴阴道-ginival综合征。
然而,预期可包括任何药物物质。
亲水性电纺层
亲水性聚合物是亲水性材料中的基本成分,其为具有形成纤维材料能力的成分。为了避免与电纺纤维或其组合物中存在的其它成分混淆,使用术语“形成纤维的亲水性聚合物”。形成纤维的亲水聚合物适合地是在C1-C3链烷醇中可溶或形成凝胶的聚合物,例如甲醇、乙醇、丙醇或异丙醇,特别是乙醇、丙醇或异丙醇,或其水混合物,其中水含量至多为20%w/w,优选低得多,例如至多5-10%w/w或3-5%w/w。纺丝过程要求作为纤维主要成分的聚合物呈溶解形式,以使得溶解的聚合物的稳定流在纺丝过程中以喷射样方式从针头流到接地的收集板。
适合的形成纤维的亲水聚合物是聚乙烯吡咯烷酮(PVP)、丙烯酸酯和丙烯酸共聚物(例如),及其混合物。也可以使用其他聚合物,例如乙基纤维素(EC)、羟丙基纤维素(HPC)或其混合物。乙基纤维素(EC)、羟丙基纤维素(HPC)或其混合物可以特别地与聚乙烯吡咯烷酮(PVP)和/或丙烯酸酯组合使用,丙烯酸酯包括丙烯酸共聚物(例如)。在实施例中,特别地已经使用PVP和丙烯酸共聚物。其他亲水聚合物可以是聚乙烯醇和羧甲基纤维素(包括其碱金属盐),及其混合物。
聚乙烯吡咯烷酮可以以具有约2,500Da至3,000,000Da的分子量的级别使用(例如,具有K-值为12至120的聚维酮)。PVP可以以购得:
在低MW范围内,预期适合的等级具有约25,000至约120,000Da的MW,特别是约70,000至约100,000Da。在本文的实施例中,主要使用90F,因此,优选的PVP具有约900,000-约3,000,000、特别是约1,000-约1,500,000的Mw。
乙基纤维素以商标ETHOCELTM(Dow Chemical Company)销售,并且有许多不同等级。Dow Chemical Company生产两种乙氧基类型的乙基纤维素(标记为标准和中等)。根据其乙氧基含量的不同,乙基纤维素可具有不同的软化点和熔点温度。乙基纤维素也以许多不同的粘度生产。在下表中给出了可获得的乙基纤维素的列表。
ETHOCEL聚合物
在塑化形式中,它具有优异的热塑性,并且可用于通过模塑、挤出或层压制备的组合物。乙基纤维素也是优异的成膜剂,并且用于例如片剂的包衣。上述乙基纤维素品质具有至少45.0%的乙氧基含量,因此它们可溶于乙醇,但几乎不溶于水。
丙烯酸酯和丙烯酸衍生物包括聚甲基丙烯酸酯、甲基丙烯酸酯共聚物、丙烯酸共聚物和甲基丙烯酸酯聚合物。优选的丙烯酸酯是以商标销售的那些,它们可溶于乙醇或丙烯酸酯/八丙烯酰胺共聚物(以商品名DERMACRYL 79销售)。它们包括E12,5(甲基丙烯酸氨基酯共聚物)、E100(甲基丙烯酸氨基酯共聚物;碱性丁基化甲基丙烯酸酯共聚物)、EPO(甲基丙烯酸氨基酯共聚物)、L100-55、L 100(甲基丙烯酸-甲基丙烯酸甲酯共聚物1:1)、S100(甲基丙烯酸-甲基丙烯酸甲酯共聚物1:2)、RL100、RL100(甲基丙烯酸铵基酯共聚物A型)、RL PO、RS100(甲基丙烯酸铵基酯共聚物B型)、RSPO。E是一种基于甲基丙烯酸二甲基氨基乙酯和其他中性甲基丙烯酸酯的阳离子聚合物:L和S是甲基丙烯酸共聚物,并且是甲基丙烯酸和甲基丙烯酸甲酯的阳离子共聚产物。RL或RS是由丙烯酸和甲基丙烯酸合成的甲基丙烯酸铵基酯共聚物。
E 100在高至pH 5.5可溶,且E 12.5在pH 5以上可溶。
L30 D-55、L-100-55(甲基丙烯酸-丙烯酸乙酯共聚物1:1),L100、L 12,5通常用于肠溶制剂,但可用于延迟释放来自本发明纤维的药物物质。L30D-55和L-100-55在pH约5.5时溶解,并且等级L 100和L 12,5在pH 6或以上时溶解。
由于唾液中的pH通常约为5-6,因此这些聚合物对于口服使用的纤维是有意义的。如果需要持续或延长释放,则在较高pH的较低时可溶的聚合物可能更适合使用。
产品也可用于持续释放制剂,并且这些等级可能有意义地单独或与另一种亲水性聚合物一起掺入本发明的纤维中。相关等级属于RL,RS,NE和NM系列,例如RL 100、RL PO、RL 30D和RL 12,5、RS 100、RS PO、RS 30D和RS 12,5、NE 30D和NE 40D以及NM 30D。
羟丙基纤维素是非离子型水溶性纤维素醚。它合并了有机溶剂的溶解性、热塑性和表面活性以及增稠和稳定特性。纤维在高湿度下具有柔韧性和不粘性。羟丙基纤维素以KLUCELTM的名称销售。
羧甲基纤维素具有广泛等级可供选择。粘度范围为10至100,000mPa*s。它也可以作为钠盐利用,具有广泛的取代水平。Dow Chemical Company以WALOCELTM的名称销售羧甲基纤维素钠。
聚乙烯醇可以以具有约20,000Da至200,000Da的分子量的等级使用。
优选的形成纤维的亲水聚合物选自PVP、羟丙基纤维素(HPC)、丙烯酸酯和丙烯酸衍生物,及其混合物。
电纺纤维层的形式的亲水性材料也可含有一种或多种药物物质,一种或多种生物粘附物质,一种或多种药学上或化妆品可接受的赋形剂。这类赋形剂包括pH调节剂、防腐剂、掩味剂、抗氧化剂、稳定剂、渗透促进剂等。此外,根据预期用途的不同,可以存在其它赋形剂,例如增塑剂、表面活性剂等。
本发明的亲水性材料中形成纤维的亲水性聚合物的浓度通常至多为100%w/w。当包括其他成分时,形成纤维的亲水性聚合物的最低浓度通常约为25%w/w,以确保形成含有所有成分的纤维。值得注意的是,浓度约40%-约92%w/w、特别是约50-约85%w/w或约60%-75%w/w。
在组合物被设计用于粘膜表面的那些情况下,可能感兴趣的是包括生物粘附物质以促进与粘膜的粘附。
如果需要强生物粘附,则电纺纤维中生物粘附物质的浓度必须是相对高的浓度,例如20%w/w或以上,特别是40%w/w或以上。为了获得具有如此高含量的生物粘附物质的纤维,有必要选择在电纺过程中使用的溶剂中具有低溶解度的生物粘附物质-如果它们是可溶的,它们会溶胀并使电纺不可能或至少非常困难。
如果需要温和的生物粘附,则电纺纤维中生物粘附物质的浓度必须至多为20%w/w或更低,特别是10%w/w或更低。
本发明的纤维还含有生物粘附物质。为了确保纤维的容易制造并且在应用于粘膜后就地获得期望的生物粘附性质,重要的是生物粘合剂本身对含有成纤维的亲水聚合物的溶液的粘度没有显著贡献。
在本文的上下文中,术语“生物粘附,,或“生物粘着”表示附着于特定的生物位置,例如附着于皮肤表面、唇部或粘膜表面。生物粘附性物质赋予本发明的含药物的纤维生物粘附性,或者在某些情况下,它可以包括含在本发明的组合物中,例如作为单独的层,其在应用后是面向皮肤或粘膜的内层,即与皮肤或粘膜接触的层。
用于本发明的生物粘附物质可选自葡聚糖、聚环氧乙烷、藻酸盐、黄蓍胶、角叉菜胶、果胶、明胶、瓜尔胶、黄原胶、胶凝糖、甲基纤维素、羟丙基甲基纤维素(HPMC)、羧甲基纤维素及其碱金属盐、丙烯酸聚合物(PAA衍生物)、脱乙酰壳多糖、外源凝集素、硫醇化聚合物、polyox WSRA、PAA-共-PEG(PEG是聚乙二醇),及其混合物。
通常,预期聚合物的粘合效果随着分子量的增加而增加。因此,通常优选具有相对高分子量的粘附聚合物。
聚环氧乙烷可以以分子量约为100,000至4,000,000的等级使用。聚环氧乙烷以POLYOXTM(Dow Chemical Company)的名称销售,其分子量为100,000至700,000Da,如前所述。具有分子量低于500,000道尔顿的PEO是优选的,特别是具有分子量约为100,000至约400,000道尔顿的PEO,例如具有分子量约为200,000道尔顿的聚环氧乙烷。这可以归因于本文讨论的溶解度问题。
类似的考虑适用于本文举出的其他生物粘附物质。用例如具有高分子量的葡聚糖的实验已经表明,葡聚糖的微粉化也是困难的,即当分子量大于1,000,000道尔顿时难以获得微粉化形式的葡聚糖。
葡聚糖可以以分子量为400,000Da至约1,000,000Da的等级使用。葡聚糖具有约为400,000至约700,000道尔顿的分子量。
纤维素衍生物包括羟丙基甲基纤维素、甲基纤维素和羧甲基纤维素。
甲基纤维素以METHOCELTM(Dow Chemical Company)的名称销售,并且可以以广泛粘度等级(从小于3至超过100,000mpa*s)获得。
HPMC以各种品质销售,这取决于粘度。HPMC以和的名称销售。适合的HPMC具有约为80,000至约140,000的平均分子量。
优选的生物粘附物质是聚环氧乙烷、葡聚糖或其组合。
用于制造本发明的双层产品的亲水性材料可含有药物物质。通常上,药物物质可以是适于应用于粘膜或皮肤以治疗疾病或病症的任何药物物质。特别感兴趣的是选自药物物质的药物物质,指示其用于治疗皮肤、唇或粘膜疾病,或者在纤维包括在应用于如本文所述的内表面上的组合物中的情况下,药物物质可以是指定用于特定治疗的任何药物物质。在本文的上下文中,药物物质可以选自药物物质,其用于治疗口腔疾病,例如指示用于局部治疗口腔疾病的药物物质。药物物质可以溶解、未溶解或部分溶解的形式存在,这取决于所用亲水聚合物和生物混合物质中的药物溶解度。
疏水性电纺层及其应用于亲水性电纺层的方法
疏水材料是疏水电纺层。值得注意的是,它是不透水的,例如能够产生闭塞效应和/或对诸如体液的流体的保护作用。后者与双层产品用于特别潮湿环境的情况相关,其中期望保护亲水材料内的药物物质不溶于流体中。用于提供不透水涂层的适合材料包括聚乙烯-共-醋酸乙烯酯、乙基纤维素,聚(己内酯),carbothane或polysoftane。
如关于亲水性材料所述,该材料可含有一种或多种可接受的赋形剂。在亲水性材料下举出的赋形剂也可用于疏水性材料中,且反之亦然。
将亲水性纤维制备成薄层。例如疏水性成纤聚合物的另一电纺层可以附着到亲水层上。这可以通过涉及包含压力和热的方法来完成,该方法适用于制造双层产品,该产品包含由电纺纤维制成的亲水性第一材料,该第一材料连接到由电纺纤维制成的疏水性第二材料,并且其中所述第一材料可以含有药物,并且所述方法的特征在于:
-所述方法包含使用包含第一表面和第二表面的压力机,并且其中所述第二表面具有高于所述第一表面的温度,
-所述第一和第二材料在所述压力机的第一与第二表面之间以分层组合排布,其中从所述压力机的所述第一和第二表面朝向所述层状组合提供压力,并且由此所述第一材料与所述压力机的第一表面接触,
-其中第一与第二表面之间的压力与所述第二材料的温度的组合将所述第一和第二材料连接成所述双层产品。
所谓分层组合是指第一材料和第二材料布置成使得它们的主平面是平行的,即所述材料彼此叠置,类似于叠层或夹层。
第一材料与第二材料之间的连接是指任何种类的物理和/或化学连接,确保所述材料不会意外分离。物理连接可以是电纺纤维之间的缠结,而化学连接可以表现为化学键。通过物理连接或分子水平的弱相互作用(离子-离子相互作用,范德瓦尔斯力)建立连接。
通过第二表面加热疏水性第二材料增加了亲水性第一与疏水性第二材料之间的结合强度。更具体地,通过将疏水性第二材料的聚合物加热到低于该聚合物熔点的温度,或者加热到熔点或以上的温度,但是持续时间相对短,以避免聚合物的完全熔化和聚合物与第二表面的粘附。通过随后经终止加热冷却双层产品,亲水和疏水电纺层被锁定在它们的新位置。
亲水性第一材料可含有本发明的药物物质,并且所述亲水性第一材料的升高的温度可改变所述药物的性质。因此,期望避免加热所述第一亲水材料。然而,这可能取决于所用的药物。
加热装置可以是能够将压力机的表面加热到预定温度的任何装置。加热可以源自电阻,将热量传递到表面的热流体,或者如所公开的能够被并入压力机的任何其他加热装置。
与待粘合材料接触的压力机表面材料可以是不损害电纺纤维化学组成的任何材料。此外,需要一种具有优异的热传递容量的材料和一种能够承受高压的材料。因此,金属是优选的材料,但也预见到陶瓷也在本发明的范围内。
在一个实施方案中,压力机是具有两个相对旋转的辊子的辊压机,也是表示压光机。辊子可以由这种压力机领域中常用的任何机械驱动。两个辊相互平行并对齐以具有尺寸的间隙,该间隙有助于将第一和第二材料粘合到双层产品中所需的压力。一个辊的表面被加热到高于另一个辊表面温度的温度。由于辊子在彼此相反的方向上旋转,产生输入,其中两个辊子的表面会聚到间隙中,而产生输出,其中两个辊子的表面偏离间隙。为了获得双层产品,疏水性材料和亲水性材料以分层组合的方式排列并进料到输入路径中,使得疏水性材料与具有加热表面的辊接触。由于辊子的旋转、确保承受足够压力的间隙的尺寸以及辊子表面的温度,这两种材料被粘合到双层产品中并通过辊子的输出路径导出。
在一个实施方案中,压力机是压板机,其包含基本上平坦且相互平行的第一和第二表面。所述两个相互平行的表面能够相对于彼此缩回和移动得更近。将所述表面之一加热到高于另一表面温度的温度。在粘合之前,待粘合的第一亲水材料和第二疏水材料以与疏水材料分层组合的方式布置在两个表面之间,以与加热表面接触。通过使第一和第二表面相互靠近移动,将压力施加到层状组合上,并且结合表面的温度,发生粘合。随后,平行表面缩回,并且从压力机中取出由粘合形成的双层产品。压力机可以由液压驱动,但是在本发明的范围内可以预见其他机器压力机。
压力机可以是平坦表面和设置成滚过所述表面的辊子的组合。辊子表面或平坦表面被加热到高于相对表面温度的温度。亲水性第一材料和疏水性第二材料在平坦表面上以层状组合布置,第二疏水性材料与加热的表面接触。将辊子设置成滚过所述层状组合,施加足以将第一和第二材料粘合到双层产品中的压力。压力机可以通过设置在平坦表面上方的预定距离处施加,或者可以通过使用外部机械(例如液压)进一步向下压到层状组合上。
在一个实施方案中,疏水材料和亲水材料在粘合过程之前成形为片或层,其中所述片的厚度显著小于片的任何其他尺寸。
亲水和疏水材料的厚度不必相同。疏水层越厚,其柔韧性越差。因此,为了获得柔性层,疏水层的涂覆厚度等于或小于亲水层。在那些情况下,疏水层的功能是保持水或体液通过疏水层进入亲水层,该层必须足够厚且坚固以承受水或体液的冲击。通常,疏水层的存在量为10-50g/m2。通常获得小于100μm的厚度。
还可能存在疏水材料具有比亲水材料更大的延伸的情况,使得疏水材料也覆盖亲水材料的边缘。
在一个实施方案中,压力机的第一和第二表面都被加热到预定温度,或者两个表面都可以具有被加热的能力。表面温度具有温差。
除了本文前面提到的赋形剂之外,疏水和/或亲水纤维可以含有增塑剂。增塑剂赋予纤维一定的可塑性,它可以促进制造过程和/或改善聚合物的柔韧性和可加工性。适合的增塑剂的实例是柠檬酸酯如乙酰基三乙基柠檬酸酯、柠檬酸三丁酯或柠檬酸三乙酯、蓖麻油、二乙酰化单甘油酯、癸二酸二丁酯、邻苯二甲酸二乙酯、山梨醇、甘油或甘油衍生物如三醋精或三丁精、纤维素衍生物如硝酸纤维素、二醇类如聚乙二醇,特别是分子量约为100至约1500的聚乙二醇、聚乙二醇单甲醚、丙二醇或其混合物。
附图说明
图1.来自以下的电纺膜:A)原始配方溶液,和B)本发明涉及PEO的沉淀的配方。
实施例
溶液制备和电纺方法
a)制备纤维的对比方法:
称重无水乙醇。在搅拌期间缓慢加入6.52wt。%Kollidon 90F和8.15wt%EudragitRS100(醇量)。持续搅拌24h。在搅拌的同时缓慢地加入13.05wt.%Polyox WSR N-80(PEO 200,000Mw)。继续搅拌直至产生均匀悬浮液。最终混合物具有27.72%的总固体(原配方的66%)。
使用单针注射器(15G)以2mL/h的速度进行处理,针尖与收集器之间的距离为10cm,并且3小时内的差异为13kV。最终的膜(纤维层)为147.4g/m2。
b)本发明的处方:
称重无水乙醇。在搅拌的同时缓慢地加入8wt.%Kollidon 90F和10wt.%的EudragitRS100(醇量)。持续搅拌24h。
称重蒸馏水。在搅拌的同时缓慢地加入16wt.%Polyox WSR N-80(PEO 200,000Mw)。在24h期间保持搅拌。
在搅拌下将酒精溶液缓慢地加入水溶液中。继续搅拌直至形成均匀混合物。最终混合物含有17%的总固体。
使用多针注射器(56针20G)以110mL/h进行处理,针尖与收集器之间的距离为19cm,并且在几个小时内差异为60kV。最终的膜(纤维层)具有160/m2。切下12x5cm的一小片用于进一步分析。
膜形态表征
通过扫描电子显微镜检查两个膜(纤维层)。在180秒期间用金-钯的混合物溅射样品,并在加速电压为5kV和工作距离为8mm的Hitachi S4800中观察。
图1显示了两个膜在1500放大倍数下拍摄的图像。根据本发明制备的样品具有较小的纤维直径,这主要是由于较低的总固体含量和较高的施加电压差导致的。如上述所观察到的,对比样品在纤维之间显示出大的PEO颗粒。
Claims (15)
1.用于制备电纺纤维的方法,该方法包含:
i)将形成纤维的亲水性聚合物溶解在选自C1-C3醇的醇中,
ii)将生物粘附物质溶解在水中,其中生物粘附物质在25℃下在水中具有3g/100ml或以上或在25℃下为10g/100ml或以上的溶解度,并且其中生物粘附物质在25℃下具有在选自C1-C3醇的醇中的溶解度为0.5g/100ml或更低,或在25℃下为0.1g/100ml或更低,
iii)在搅拌下将得到的来自ii)的溶液加入到来自i)的所得溶液中,由此生物粘附物质沉淀并形成均匀的悬浮液,其中生物粘附物质作为颗粒悬浮,和
iv)电纺均匀悬浮液以获得亲水性纤维。
2.根据权利要求1的方法,其还包含在步骤i)或步骤ii)中溶解或悬浮药物物质。
3.根据权利要求1或2的方法,其中亲水性聚合物选自聚乙烯吡咯烷酮、乙基纤维素、羟丙基纤维素、丙烯酸酯和丙烯酸共聚物及其混合物。
4.根据上述权利要求任一项的方法,其中生物粘附物质选自葡聚糖、聚环氧乙烷(PEO)、藻酸盐、黄蓍胶、角叉菜胶、果胶、明胶、瓜尔胶、黄原胶、胶凝糖、甲基纤维素、羟丙基甲基纤维素(HPMC)、聚乙烯醇(PVA)、丙烯酸聚合物(PAA衍生物)、脱乙酰壳多糖、外源凝集素、硫醇化聚合物、polyoxo WSRA、PAA-共-PEG(PEG是聚乙二醇)及其混合物。
5.根据上述权利要求任一项的方法,其中生物粘附物质为PEO。
6.根据上述权利要求任一项的方法,其中生物粘附物质是具有约100,000-约500,000道尔顿的分子量的PEO。
7.根据上述权利要求任一项的方法,其中生物粘附物质是具有约200,000道尔顿的分子量的聚环氧乙烷。
8.根据权利要求1或2的方法,其中纤维包含亲水性聚合物,其选自聚乙烯吡咯烷酮、丙烯酸酯和丙烯酸共聚物及其混合物。
9.根据上述权利要求任一项的方法,其中形成纤维的亲水性聚合物在纤维中的浓度约为40%-约70%w/w,特别是约45-约70%w/w或约50%-约70%w/w,以总干重之和为基准。
10.根据上述权利要求任一项的方法,其中生物粘附物质在纤维中的浓度约为30%-约60%w/w,特别是约35-约60%或约40%-约55%w/w,以总干重之和为基准。
11.根据上述权利要求任一项的方法,其中C1-C3溶剂为乙醇。
12.根据上述权利要求任一项的方法,其中将药物物质加入到步骤i)中。
13.根据上述权利要求任一项的方法,其中所述药物物质为抗炎药物物质。
14.根据上述权利要求任一项的方法,其中所述药物物质为皮质类固醇。
15.根据上述权利要求任一项的方法,还包含使电纺亲水纤维与电纺疏水层接触的步骤。
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KR20190126306A (ko) | 2019-11-11 |
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JP2020506307A (ja) | 2020-02-27 |
RU2019126497A3 (zh) | 2021-05-26 |
DK3570822T3 (da) | 2021-07-26 |
RU2019126497A (ru) | 2021-02-24 |
CA3050026A1 (en) | 2018-07-26 |
JP7353980B2 (ja) | 2023-10-02 |
US20190254986A1 (en) | 2019-08-22 |
WO2018133910A1 (en) | 2018-07-26 |
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US11045430B2 (en) | 2021-06-29 |
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