CN113797160B - 一种盐酸米诺环素纳米缓释凝胶及其制备方法和应用 - Google Patents
一种盐酸米诺环素纳米缓释凝胶及其制备方法和应用 Download PDFInfo
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Abstract
一种盐酸米诺环素纳米缓释凝胶及其制备方法和应用，属于药物技术领域，通过引入一种由盐酸米诺环素、金属离子以及具有多个硫酸盐、磺酸盐或磷酸盐官能团的化合物以螯合形成新型络合物的形式来解决小分子亲水性药物包封率低的问题。制备的盐酸米诺环素复乳纳米粒光滑圆整，包封率高，载药能力强。将其分散在温敏性凝胶基质中构建具有一定的生物粘附性，牙周滞留性好，便于给药的双层递送系统。本发明在发挥凝胶定位优势的同时，还能够显著减少药物的突释，有利于延长给药周期，为进一步牙周炎的牙周袋局部给药治疗创造了可能，纳米粒可以穿透牙槽骨小梁、底层结缔组织，增强药物在病灶部位的分布，显著提高药物的抗菌效果。
Description
技术领域
本发明属于药物技术领域，具体涉及一种盐酸米诺环素纳米缓释凝胶及其制备方法和应用。
背景技术
牙周炎是一种常见的慢性口腔疾病，临床表现为牙龈的炎症出血、牙周袋形成、附着丧失和牙槽骨吸收破坏，最终导致牙齿松动脱落，这是成人失牙的主要原因。在众多致病因素中，细菌感染是诱导和维持炎症的主要因素，同时由于牙周袋结构复杂，机械刮治很难有效去除深部的微生物而导致病变复发，因此，基本的机械刮治辅以局部的抗生素治疗已经成为牙周炎治疗的一种趋势。迄今为止，已上市的牙周局部缓释制剂主要为以下几种：一、纤维型，商品名为但由于其不可生物降解的特性已经停用；二、薄膜型，是一种可吸收的膜剂产品，但其大小和形状的可变性差，给药后容易脱落，且患者依从性很差。三、微球型，2001年FDA批准米诺环素微球/>用于治疗慢性牙周炎，由于粉末状的微球很难长期停留在牙周患病处，因此限制了它的应用；四、凝胶/软膏型，多西环素凝胶/>和盐酸米诺环素软膏/>均通过了FDA批准用于牙周炎治疗，其不足之处在于缓释效果较差，往往还存在初始的突释效应。因此研究一种理想的局部牙周缓释递药系统具有重要的临床价值，同时，这也是该领域当前的难题和热点所在。
盐酸米诺环素为半合成四环素类抗生素，对牙周各种可疑致病菌均高度敏感。小剂量的盐酸米诺环素就能有效缓解牙周炎症反应，而且该药物不易引起细菌的耐药性，也不会影响正常牙周组织的新陈代谢。研究表明，盐酸米诺环素除了具有抗菌、改善牙周袋菌群结构等作用外，还有抑制胶原酶活性，预防组织破坏等作用，是目前公认的治疗牙周病的首选药物。
聚合物纳米粒是大小介于1-1000nm之间的一种固态胶体颗粒，在口腔疾病治疗领域，与其他新型制剂相比，纳米制剂有其独特的优点。例如，由于纳米粒尺寸较小，它们能够穿透牙槽骨小梁、底层结缔组织，甚至牙龈下的牙周袋区域，从而显著提高抗菌效果。水凝胶是一种具有三维网络结构的亲水性材料，因其具有良好的生物相容性，而在药物递送方面发挥着重要的作用。刺激响应性水凝胶可以通过改变凝胶结构来实现可控的药物释放和靶向给药，以精确匹配生理需求的方式进行药物递送。目前，温度敏感性水凝胶作为一种典型的刺激响应性水凝胶，在生理温度附近具有良好的相变可控性。温敏性水凝胶在室温下呈现透明液体状态，便于实现注射给药和药物包载，而将其注射到体内后温度升高并超过其临界胶凝温度时，它能以物理交联的方式快速凝胶化，从而实现原位控释给药。将纳米粒分散在温敏性水凝胶基质中构建复合体系是近年来出现的一种新的载药形式，它能够整合纳米制剂和温敏性水凝胶两者的优点，得到一个便于给药、稳定长效、生物粘附性强和牙周滞留性好的双层递送系统。另外由于纳米制剂和水凝胶共同控制体系内的药物释放，能够有效降低药物突释，呈现零级释放，并且延长药物释放时间。但相比于亲脂性药物来讲，亲水小分子药物的包封率通常较低，难以在病灶部位达到有效浓度，这是因为在制剂固化之前，水溶性药物分子可能被分配到外部水相继而被除去。通过引入一种由药物、金属离子以及具有多个硫酸盐、磷酸盐或者磺酸盐官能团的化合物以螯合形成新型络合物的形式可以改变药物的水溶性，从而解决小分子亲水性药物包封率低的问题。
发明内容
本发明的首要目的是提供一种综合牙周炎局部给药要求的牙周炎新型治疗制剂，即盐酸米诺环素纳米缓释凝胶。
本发明的另一目的是提供一种制备这种纳米缓释凝胶的方法。
本发明的再一目的是提供一种解决聚合物纳米制剂对小分子亲水性药物包封低的技术。
为实现上述目的，采用以下技术方案：
一种盐酸米诺环素纳米缓释凝胶，该纳米缓释凝胶是由温敏性凝胶包裹载药纳米粒构建而成，纳米粒在体内的穿透性好，能增强药物在病灶部位的分布，温敏性凝胶具有定位和缓释的功能，纳米缓释凝胶将这两种递送系统相结合，形成一种双层递送系统。在1000mL的盐酸米诺环素纳米缓释凝胶中包括以下组分：0.3～30g盐酸米诺环素、0.1～20g金属离子、0.2～100g含多个硫酸盐、磺酸盐或磷酸盐官能团的化合物、2～300g生物可降解聚合物材料、0.5～50g乳化剂和10～300g生物可降解水凝胶材料。其中，盐酸米诺环素和金属离子的质量比例为(1.5～4.5):1，含多个硫酸盐、磺酸盐或磷酸盐官能团的化合物和金属离子的质量比例为(2～5):1。
所述的金属离子为铁离子、铜离子、钙离子和镁离子中的一种或多种的混合物。
所述的含多个硫酸盐、磺酸盐或磷酸盐官能团的化合物为蔗糖八硫酸酯、硫酸壳聚糖、硫酸葡聚糖、多磺酸粘多糖、磺酸化环糊精和磷酸化壳聚糖中的一种或多种的混合物。
所述的生物可降解聚合物材料为聚乳酸(PLA)、聚乙二醇-聚乳酸(PEG-PLA)、聚乙醇酸(PGA)、聚乳酸-羟基乙酸(PLGA)、聚乙二醇-聚乳酸-羟基乙酸(PEG-PLGA)、聚己内酯(PCL)、聚己内酯-丙交酯(PCLA)和聚甲基丙烯酸甲酯(PMMA)中的一种或多种的混合物。
所述的乳化剂为聚维酮、聚乙烯醇、聚山梨酯80、胆酸钠、脱氧胆酸钠和维生素E聚乙二醇琥珀酸酯中的一种或多种的混合物。
所述的生物可降解水凝胶材料为PEO-PPO-PEO、PLGA-PEG-PLGA、PCLA-PEG-PCLA、PCL-PEG-PCL、PEO-PPO-PCL和壳聚糖中的一种或多种的混合物。
本发明还提供了所述盐酸米诺环素纳米缓释凝胶的制备方法，首先利用乳化-溶剂挥发法制备盐酸米诺环素复乳纳米粒，如果需要浓缩，则按需求通过透析、切向流超滤或冻干的方法对纳米粒进行进一步浓缩，然后将其分散在生物可降解水凝胶中制备得到。如图1所示，具体步骤如下：
1)制备盐酸米诺环素复乳纳米粒：将盐酸米诺环素溶于蒸馏水I中，将金属离子和含多个硫酸盐、磺酸盐或磷酸盐官能团的化合物溶于蒸馏水II中，得到两个内水相I和II。将生物可降解聚合物材料溶解于有机溶剂中，制成高分子溶液，再将其均分作为两个油相，油相I和油相II。将两份内水相I和II分别滴入到油相I和油相II中，探头超声或剪切制备得到两个W/O初乳，初乳I和初乳II，再将两个初乳混匀后探头超声或剪切，得到W/O乳剂，之后将其滴入到外水相中探头超声或剪切，外水相中包含乳化剂，得到W/O/W复乳，将得到的W/O/W复乳中的有机溶剂除去，如果需要浓缩，则按需求通过透析、切向流超滤或冻干的方法对纳米粒进行进一步浓缩即得盐酸米诺环素复乳纳米粒，也称之为盐酸米诺环素复乳纳米制剂；
2)制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将生物可降解水凝胶材料溶解于制得的盐酸米诺环素复乳纳米粒中构建盐酸米诺环素纳米缓释凝胶。本发明提供的盐酸米诺环素纳米缓释凝胶组成示意图如图2所示。
上述制备方法，其中：
所述步骤1)中，所述有机溶剂包括乙酸乙酯、二氯甲烷、甲醇、乙醇、乙腈及环己烷，优选二氯甲烷。
所述步骤1)中，将两份内水相I和II分别滴入到油相I和油相II中时，内水相与油相的体积之比均为1:1～1:5。
所述步骤1)中，将得到的W/O乳剂滴入到外水相中探头超声或剪切，油相与外水相的体积之比为1:2～1:10。
本发明还提供了所述盐酸米诺环素纳米缓释凝胶的应用，其应用于制备治疗牙周炎疾病的药物中。
本发明方法解决了聚合物纳米制剂对小分子亲水性药物包封低的技术难题。
所述盐酸米诺环素纳米缓释凝胶的这种双层递送系统，同样适用于提高其他类似的亲水性小分子药物的包封率。比如四环素、多西环素。
本发明的有益效果：
(1)本发明通过引入一种由盐酸米诺环素、金属离子以及具有多个硫酸盐、磺酸盐或磷酸盐官能团的化合物以螯合形成新型络合物的形式来解决小分子亲水性药物包封率低的问题。
(2)本发明采用乳化-溶剂挥发法制备的盐酸米诺环素复乳纳米粒粒径在20-1000nm之间，光滑圆整，包封率高，载药能力强。纳米制剂穿透力强，药物以纳米粒的形式到达病灶部位，能显著提高抗菌效果。然后将该纳米制剂分散在温敏性凝胶基质中构建具有一定的生物粘附性，牙周滞留性好，便于给药的双层递送系统。由于本发明所使用的凝胶材料具有温敏性，因此，将该递药系统注入到牙周袋后，可立即胶凝并保留在原位，药物以纳米粒的形式从凝胶中释放出来，穿透牙槽骨小梁、底层结缔组织，这增强了药物在病灶部位的分布，能够最大程度地发挥抗炎活性以及逆转牙槽骨吸收破坏的功能。
(3)由于盐酸米诺环素的释放受纳米粒和水凝胶的双重控制，使得本发明所构建的双层递药系统在发挥水凝胶定位优势的同时，还能够显著减少药物的突释，延长给药周期。
(4)本发明的纳米制剂材料及水凝胶材料均采用具有生物相容性的可降解吸收的材料，用药后无需取出，且不会对组织造成任何刺激。
(5)本发明的盐酸米诺环素纳米缓释凝胶中，盐酸米诺环素纳米粒的PDI小于0.2，载药量为2％～10％，包封率大于90％，盐酸米诺环素纳米缓释凝胶24h的累积释放量低于20％，最终的累积释放量大于85％，接近完全释放，且呈现零级释放。
附图说明
图1为本发明提供的盐酸米诺环素复乳纳米粒制备流程图。
图2为本发明提供的盐酸米诺环素纳米缓释凝胶组成示意图。
图3为本发明提供的盐酸米诺环素复乳纳米粒的透射电镜图、粒径及其分布图。
图4为本发明提供的盐酸米诺环素复乳纳米粒以及盐酸米诺环素纳米缓释凝胶的释放曲线图。
图5为本发明提供的一系列温敏性凝胶的胶凝温度测定结果图，A、B、C和D分别对应PLGA-PEG-PLGA、PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 80:20)、PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 50:50)、PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 40:60)四种温敏性凝胶的胶凝温度测定结果图。
图6为本发明提供的PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 80:20)、PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 50:50)两种温敏性凝胶的凝胶窗测定结果图。
图7为本发明提供的空白纳米缓释凝胶和盐酸米诺环素纳米缓释凝胶在胶凝前后的外观照片。
图8为本发明的体内实验结果：盐酸米诺环素纳米缓释凝胶治疗牙周炎的药效结果，即给药一段时间后各组牙周部位的TNF-α和IL-10的表达情况。
具体实施方式
下面实施例是对本发明的进一步说明，但并不意味着本发明局限于此。
实施例1
一种盐酸米诺环素纳米缓释凝胶的制备方法，按以下步骤操作：
1)制备盐酸米诺环素复乳纳米粒：取20mg盐酸米诺环素溶于1mL蒸馏水中，8mg氯化镁和15mg蔗糖八硫酸酯钠溶于另外1mL的蒸馏水中，得到两个内水相。取150mg的PLGA溶解于6mL二氯甲烷中，再将其均分作为两个油相。将两份内水相分别滴入到两份油相中，通过探头超声制备得到两个W/O初乳，再将两个初乳混匀并探头超声，将得到的乳剂滴入到12mL的外水相中探头超声，外水相为2％的聚维酮溶液，通过减压蒸馏将得到的W/O/W复乳中的二氯甲烷除去，并通过透析法对乳剂进行适当浓缩，即得到盐酸米诺环素复乳纳米粒。该纳米粒对盐酸米诺环素的包封率为92％。
2)制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将1g的PEO-PPO-PEO溶解于5mL浓缩后的盐酸米诺环素复乳纳米粒中构建。
实施例2
一种盐酸米诺环素纳米缓释凝胶的制备方法，按以下步骤操作：
1)制备盐酸米诺环素复乳纳米粒：取40mg盐酸米诺环素溶于2mL蒸馏水中，18mg氯化钙和38mg硫酸葡聚糖溶于另外2mL的蒸馏水中得到两个内水相。取300mg的PCL溶解于5mL二氯甲烷中，再将其均分作为两个油相。将两份内水相分别滴入到两份油相中，通过探头超声制备得到两个W/O初乳，再将两个初乳混匀并探头超声，将得到的乳剂滴入到25mL的外水相中，探头超声，外水相为0.5％的胆酸钠溶液，通过减压蒸馏将得到的W/O/W复乳中的二氯甲烷除去，即得到盐酸米诺环素复乳纳米粒。该复乳纳米粒对盐酸米诺环素的包封率为94％。
2)制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将2g的PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 50:50)溶解于上述的盐酸米诺环素复乳纳米粒中构建。
实施例3
一种盐酸米诺环素纳米缓释凝胶的制备方法，按以下步骤操作：
1)制备盐酸米诺环素复乳纳米粒：取80mg盐酸米诺环素溶于4mL蒸馏水中，35mg氯化钙和100mg硫酸葡聚糖溶于另外4mL的蒸馏水中，得到两个内水相。取720mgPLGA溶解于8mL二氯甲烷中，再将其均分作为两个油相。将两份内水相分别滴入到两份油相中，通过探头超声制备得到两个W/O初乳，再将初乳混匀，探头超声，将得到的乳剂滴入到40mL的外水相中，探头超声，外水相为1％的胆酸钠溶液，通过减压蒸馏将得到的W/O/W复乳中的二氯甲烷除去，并用冻干复溶法对其进行浓缩，即得盐酸米诺环素复乳纳米粒。该复乳纳米粒对盐酸米诺环素的包封率为95.58％。
2)制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将2g的PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 50:50)溶解于10mL浓缩后的盐酸米诺环素复乳纳米粒中构建。
实施例4
一种盐酸米诺环素纳米缓释凝胶制备方法，按以下步骤操作：
1)制备盐酸米诺环素复乳纳米粒：取300mg盐酸米诺环素溶于5mL蒸馏水中，70mg氯化亚铁和370mg硫酸壳聚糖溶于另外5mL的蒸馏水中，得到两个内水相。取1.5gPEG-PLA溶解于10mL二氯甲烷中，再将其均分作为两个油相。将两份内水相分别滴入到两份油相中，通过剪切制备得到两个W/O初乳，再将初乳混匀，剪切，将得到的乳剂滴入到30mL的外水相中，探头超声，外水相为1％的维生素E聚乙二醇琥珀酸酯溶液，通过减压蒸馏将得到的W/O/W复乳中的二氯甲烷除去，通过切向流超滤法对其进行浓缩，即得盐酸米诺环素复乳纳米粒。该复乳纳米粒对盐酸米诺环素的包封率为91％。
2)制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将3g的PLGA-PEG-PLGA溶解于10mL浓缩后的盐酸米诺环素复乳纳米粒中构建。
实施例5
一种盐酸米诺环素纳米缓释凝胶的制备方法，按以下步骤操作：
1)制备盐酸米诺环素复乳纳米粒：取100mg盐酸米诺环素溶于4mL蒸馏水中，50mg氯化镁和200mg多磺酸粘多糖官能团溶于另外4mL的蒸馏水中，得到两个内水相。取1.5gPCLA溶解于20mL二氯甲烷中，再将其均分作为两个油相。将两份内水相分别滴入到两份油相中，通过探头超声制备得到两个W/O初乳，再将初乳混匀，探头超声，将得到的乳剂滴入到70mL的外水相中，探头超声，外水相中为0.5％的聚乙烯醇溶液，通过减压蒸馏将得到的W/O/W复乳中的二氯甲烷除去，即得盐酸米诺环素复乳纳米粒。该复乳纳米粒对盐酸米诺环素的包封率为93％。
2)制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将2.5g的PCLA-PEG-PCLA溶解于10mL浓缩后的盐酸米诺环素复乳纳米粒中构建。
测试例：
一.盐酸米诺环素PLGA纳米粒的质量评价
1.纳米粒的外观及形态
肉眼观察实施例1-5制备的盐酸米诺环素纳米粒外观为淡黄色乳光的半透明均匀液体。取实施例3的样品适量，用蒸馏水稀释至适宜的浓度，取适量置于铜网上，用滤纸吸掉周围多余液体，待完全干燥后，用1％磷钨酸负染1min，至完全干燥后，在透射电镜下观察纳米粒的形态，结果显示，纳米粒粒径大小在100nm左右，呈圆整的球状结构，分布均匀(见附图3A)。
2.纳米粒的粒径及粒径分布考察
粒径和粒度分布是纳米制剂的一个关键性指标，粒度分布通常用多分散系数(polydispersity index,PDI)来表示。利用动态光散射原理测定纳米粒的粒径和PDI，具体操作如下：将实施例3所制备的样品用蒸馏水稀释，吸取适量稀释液放入清洗干净的样品池内，设置操作参数：温度为25℃，调节Count rate数值在200-400之间，进行测定。结果显示纳米粒的粒径为109.2nm，PDI值为0.136(见附图3B)。
3.Zeta电位测定
用胶头滴管取适量实施例3制备的样品溶液滴入比色杯，另加入适量蒸馏水进行稀释，将电极插入，不得产生气泡，将比色杯放入样品池中，调节光强度为2000左右，室温测定2min，测得Zeta电位值为-44.0±7.98mV。
4.载药量及包封率测定
(1)药物总量的测定：精密吸取实施例3制备的样品1mL，置25mL量瓶中，加入约4mL乙腈超声振荡溶解，加入蒸馏水定容至刻度，混匀，经高速离心机15000rpm离心10min后取上清液待测，采用紫外-可见分光光度计在350nm的波长下测定吸光度。
(2)游离药物含量的测定：取实施例3制备的纳米粒溶液约1mL，置超滤离心管中(100000Da)，3000rpm离心10min，取离心管中的滤过液体，经高速离心机15000rpm离心10min后取上清液待测，采用紫外-可见分光光度计在350nm的波长下测定吸光度。
包封率的计算公式如下：
EE％＝(Wtotal–Wfree)/Wtotal×100％
载药量的计算公式如下：
DL％＝(Wtotal–Wfree)/Wnanoparticles×100％
其中：
Wtotal为盐酸米诺环素总量；
Wfree为未包进去的游离盐酸米诺环素的量；
Wnanoparticles为盐酸米诺环素纳米制剂的量。
经计算得实施例3中盐酸米诺环素的载药量为9.59％，包封率为95.58％。
5.药物释放行为考察
采用透析法考察盐酸米诺环素的体外释放情况。具体操作如下：称取适量实施例3制备的样品溶液，将其置于已活化的透析袋内(MWCO＝14000Da)，透析袋两端封紧后放入释放小瓶中，加入适量定量的释放介质(PBS；0.01M,pH 7.4)将透析袋完全浸泡，将释放小瓶放置于设定转速为100rpm/min，温度为37±0.5℃的水浴摇床中恒温振荡。在每个预设时间点，取出所有释放介质，并加入等温等体积的新鲜介质。取出的释放介质经15000rpm离心10min后取上清液待测，采用紫外-可见分光光度法在350nm的吸收波长下测定各个时间点下的药物累积释放量，以释放时间为横坐标，药物累积释放百分数为纵坐标，绘制体外释放曲线。释放结果表明，盐酸米诺环素纳米粒在最初的24h内释放达到52.25％，存在突释现象。实施例3的盐酸米诺环素PLGA纳米粒的药物累积释放曲线图见附图4。
二.凝胶的流变学性质考察
1.凝胶胶凝温度测定
温敏性凝胶材料为两亲性聚合物，在适当浓度和温度条件下，能够发生胶凝。储能模量也称为弹性模量，是指材料在发生形变时，由于弹性(可逆)形变而储存能量的大小，反映材料弹性大小；耗能模量又称粘性模量，是指材料在发生形变时，由于粘性形变(不可逆)而损耗的能量大小，反映材料的粘性大小；当储能模量和损耗模量相当时，材料为半固态，这一时刻的温度即为胶凝温度(Tgel)。Tgel是温敏性水凝胶的一个重要参数，当Tgel低于室温时，不利于制剂的制备和应用；当Tgel高于口腔温度时，注入牙周袋不能发生胶凝，不利于发挥定位缓释作用。可接受的口腔热凝胶溶液的Tgel必须在30-35℃范围内，以便在室温下呈液态，并在牙周袋中立即形成凝胶相。PLGA-PEG-PLGA，PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 80:20)，PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m50:50)，以及PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 40:60)，这四种温敏性水凝胶材料的胶凝温度测定结果分别对应附图5的A、B、C和D，胶凝温度依次为36.4℃、33.7℃、31.5℃和29.5℃。结果表明PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 80:20)，PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m50:50)具有适合牙周袋给药的胶凝温度，这两种水凝胶材料所制备得到的水凝胶在室温下呈液体状态，通针性良好，而注入牙周袋后可立即形成凝胶相，固定在病灶部位，从而使药物在病灶部位持续而缓慢地释放。
2.凝胶的凝胶窗考察
根据试管倒置法得到PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 80:20)，PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m50:50)两种水凝胶材料所制备凝胶的相图如附图6所示。结果表明PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m50:50)具有比PLGA-PEG-PLGA和PCLA-PEG-PCLA(m/m 80:20)更宽的凝胶窗，更适合用作温敏性凝胶材料用于牙周袋局部给药。
三.盐酸米诺环素纳米缓释凝胶的质量评价
1.外观
该温敏型凝胶在低温时是溶液状态，可以自由流动；当温度高于临界胶凝温度时，发生胶凝现象，变为不能流动的、具有高粘度的凝胶状态。见附图7。
2.含量测定
精密吸取1mL的盐酸米诺环素纳米缓释凝胶，置100mL量瓶中，加入19mL乙腈超声振荡溶解，用蒸馏水定容至刻度，混匀，经高速离心机15000rpm离心10min后取上清液待测。采用紫外-可见分光光度计在350nm的波长下测定吸光度。经计算盐酸米诺环素纳米缓释凝胶中的盐酸米诺环素含量为1.286mg/mL。
3.药物释放行为考察
取实施例3制备得到的盐酸米诺环素纳米缓释凝胶预先在37℃摇床中放置10min，待其发生相变胶凝后，再加入事先预热的释放介质(37℃)。采用透析法考察药物的累积释放情况，释放条件和测定方法同盐酸米诺环素纳米粒。以释放时间为横坐标，药物累积释放百分数为纵坐标，绘制体外释放曲线。实施例3的盐酸米诺环素纳米缓释凝胶的药物累积释放曲线图见附图4。释放结果表明，盐酸米诺环素纳米缓释凝胶24h的累积释放量低于20％，最终的累积释放量大于85％，接近完全释放，且呈现零级释放。
4.盐酸米诺环素纳米缓释凝胶的药效学考察
牙周炎模型构建：将SD大鼠麻醉后，用牙科探针分离左侧上颌第一和第二磨牙的牙间间隙，采用0.2mm直径的正畸不锈钢丝在大鼠左侧上颌第一磨牙与第二磨牙的间隙结扎，用镊子夹持结扎丝从大鼠上颌内侧第一磨牙与第二磨牙的间隙进入，环绕间隙上牙体一周后，在腭侧偏近中处打结固定，术后观察大鼠的状态，直至大鼠全部苏醒，术后12h后方可进食，并辅助喂食高糖饮食(高糖牙周炎食谱组成：脱脂奶粉28g、面粉6g、蔗糖56g、酵母粉4g、肝粉1g、少量食盐和新鲜蔬菜)。牙周结扎4周后，观察结扎牙的牙周组织，肉眼见牙龈红肿，探诊出血，龈沟液溢出增多，牙周袋形成，表明牙周炎模型建立完成。
分组如下：
Healthy组：8只正常大鼠，不做任何处理；
Control组：8只牙周炎模型大鼠，不做任何治疗；
MIN-NPs-in-gel组：8只牙周炎模型大鼠，给予盐酸米诺环素纳米缓释凝胶治疗；
Solution组：8只牙周炎模型大鼠，给予盐酸米诺环素溶液治疗；
体内药效结果表明盐酸米诺环素纳米缓释凝胶显著降低了TNF-α和IL-10在模型大鼠牙周组织的表达，盐酸米诺环素溶液组虽也有降低，但降低程度明显不如纳米缓释凝胶组，如附图8所示。这是由于该纳米缓释凝胶所使用的凝胶材料具有温敏性，因此，将该纳米缓释凝胶注入到牙周袋后，可立即胶凝并保留在原位，药物以纳米粒的形式从凝胶中持续缓慢地释放出来，穿透牙槽骨小梁、底层结缔组织，这增强了药物在病灶部位的分布，能够最大程度地发挥抗炎活性。
对比例：
取20mg盐酸米诺环素溶于2％(W/V)的PVA溶液中，作为水相，称取150mg的PLGA溶于10mL二氯甲烷，制成有机相。将有机相逐滴加入到水相中，用高速剪切机在冰浴下剪切适当时间制备成初乳，将初乳置于两倍体积的2％氯化钠水溶液中稀释，冰浴搅拌除去有机溶剂。18000rpm离心15min收集盐酸米诺环素纳米粒，并用2％的氯化钠水溶液洗涤三遍，冷冻干燥即得。使用动态光散射法测定该纳米粒的粒径为261.5nm，PDI为0.317。纳米粒的包封率为40％左右。而本发明所制备的盐酸米诺环素PLGA纳米粒的载药量为2％-10％，包封率大于90％，这表明本发明提供的技术，即通过引入一种由盐酸米诺环素、金属离子以及具有多个硫酸盐、磺酸盐或磷酸盐官能团的化合物以螯合形成新型络合物的形式有效地解决了盐酸米诺环素包封率低的问题。
Claims (6)
1.一种盐酸米诺环素纳米缓释凝胶，其特征在于，在1000mL的盐酸米诺环素纳米缓释凝胶中包括以下组分：0.3~30g盐酸米诺环素、0.1~20g金属离子、0.2~100g 硫酸葡聚糖、2~300g PLGA、0.5~50g乳化剂和10~300g生物可降解水凝胶材料；该纳米缓释凝胶是由温敏性凝胶包裹载药纳米粒构建而成，纳米粒在体内的穿透性好，能增强药物在病灶部位的分布，温敏性凝胶具有定位和缓释的功能，纳米缓释凝胶将这两种递送系统相结合，形成一种双层递送系统；
所述生物可降解水凝胶材料为PLGA-PEG-PLGA和PCLA-PEG-PCLA质量比80:20，或者是PLGA-PEG-PLGA和PCLA-PEG-PCLA质量比50:50；
所述盐酸米诺环素和金属离子的质量比例为（1.5 ~ 4.5）: 1，硫酸葡聚糖和金属离子的质量比例为（2 ~ 5）: 1；
所述的盐酸米诺环素纳米缓释凝胶的制备方法，包括如下步骤：
1）制备盐酸米诺环素复乳纳米粒：将盐酸米诺环素溶于蒸馏水I中，将金属离子和硫酸葡聚糖溶于蒸馏水II中，得到两个内水相I和II；将PLGA溶解于有机溶剂中，制成高分子溶液，再将其分作为两个油相，油相I和油相II；将两份内水相I和II分别滴入到油相I和油相II中，内水相与油相的体积之比均为1:1~1:5，探头超声或剪切制备得到两个W/O初乳，初乳I和初乳II，再将两个初乳混匀后探头超声或剪切，得到W/O乳剂，之后将其滴入到外水相中探头超声或剪切，油相与外水相的体积之比为1:2~1:10，外水相中包含乳化剂，得到W/O/W复乳，将得到的W/O/W复乳中的有机溶剂除去，通过透析、切向流超滤或冻干的方法对纳米粒进行进一步浓缩得盐酸米诺环素复乳纳米粒；
2）制备盐酸米诺环素纳米缓释凝胶：在持续搅拌的条件下，将生物可降解水凝胶材料溶解于制得的盐酸米诺环素复乳纳米粒中构建。
2.根据权利要求1所述的一种盐酸米诺环素纳米缓释凝胶，其特征在于，所述的金属离子为铁离子、铜离子、钙离子和镁离子中的一种或多种的混合物；所述的乳化剂为聚维酮、聚乙烯醇、聚山梨酯80、胆酸钠、脱氧胆酸钠和维生素E聚乙二醇琥珀酸酯中的一种或多种的混合物。
3.根据权利要求1所述的一种盐酸米诺环素纳米缓释凝胶，其特征在于，所述盐酸米诺环素纳米缓释凝胶24h的累积释放量低于20%，最终的累积释放量大于85%，接近完全释放，且呈现零级释放。
4.根据权利要求1所述的一种盐酸米诺环素纳米缓释凝胶，其特征在于，制备的盐酸米诺环素复乳纳米粒粒径在20-1000nm之间；PDI小于0.2，载药量为2%~10%，包封率大于90%。
5.一种权利要求1~4任一项所述的盐酸米诺环素纳米缓释凝胶的应用，其特征在于，应用于制备治疗牙周炎疾病的药物中。
6.一种权利要求1~4任一项所述的盐酸米诺环素纳米缓释凝胶的应用，其特征在于，用于提高亲水性小分子药物的包封率，所述亲水性小分子药物包括四环素、多西环素。
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