CN101274099B - 具传递作用的高分子基质的制备方法 - Google Patents
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Abstract
本发明涉及一种具传递作用的高分子基质的制备方法。本发明利用氨基酸螯合矿物质(amino acid chelated minerals)为离子性架桥剂,与含被传递分子的脱乙酰几丁质酸溶液充分混合后,形成含被传递分子的胶体溶液,本发明以氨基酸螯合矿物质与脱乙酰几丁质进行离子性架桥制成高分子基质(polymer matrix)来传递分子,为一创新的工艺的产品。
Description
技术领域
本发明涉及一种具传递作用的高分子基质的制备方法,尤指一种经离子性架桥的脱乙酰几丁质制备成有控释放的生物医药材料的工艺及产品。
背景技术
生物技术与医药为21世纪最具潜力科技,而控制药物传递技术一直是医药研究科学中相当活跃的领域之一,这其中包含以许多种的科学技术来精进人类的健康。而这些物质传递系统通常使用微脂粒或高分子作为载体,近年来利用生物可降解高分子所制成的载体受到极大关注,被认为是相当有潜力的物质传递系统。
其中微脂粒传递系统(Liposomal Drug Delivery System)是一种物质传递技术。微脂粒是由磷脂质水合后所形成的双层脂肪球,由于其特殊的双层膜结构类似细胞膜,因此可用来包覆亲水性或疏水性药物,并作为标的给药的药物载体。而微脂粒作为药物传递系统可归纳为以下几个特点:具有包覆亲水性、疏水性药物的特质、具有生物兼容性及生物降解性的特性、可保护药物使其输入身体后不受到新陈代谢系统的分解、能达到缓释控制的效果等。
而用于药物释放系统的高分子范围很广泛,分成生物可分解性(biodegradable)以及生物不可分解性(non-biodegradable)两种,包括天然高分子如胶原蛋白(collagen)、多醣类生物高分子,例如:脱乙酰几丁质(chitosan)、透明质酸(hyaluronicacid,HA),化学合成的聚氨基甲酸酯(polyurethane)、压克力系高分子(acrylic-basedpolymers),以及生物吸收性的乙交酯丙交酯共聚物【poly(glycolide co-lactide),PLGA】等。一般而言,生物高分子可以被身体吸收或是代谢,是较佳的考虑。目前先进技术主要着重于生物可分解性的药物释放系统上的开发,其分解的机制主要有两种,一种为裂解(degradation),另一种为溶蚀(erosion),裂解为化学反应,由高分子化学键断裂所造成,而溶蚀为一种物理现象,主要依赖溶解以及扩散的速率来决定,对大部份的生物医学高分子而言,两者都会发生,主要取决于化学结构的不同。且为了配合各式药物应用的限制,对药物释放系统有许多考虑,如药物需在病患的胃部持续释放一段时间的话,需考虑pH值的变化以及环境的改变,因此高分子载体的设计,就变得十分重要了。
本发明技术是利用天然材料进行产品制造,采用的甲壳素天然高分子,广泛存在于低等藻类、菇类和真菌的细胞壁,以及动物的上皮角质层、海洋无脊椎动物和昆虫外壳,其中以虾蟹壳为甲壳素最常见的来源,为自然界中分布最广的多醣类之一,仅次于纤维素。一般制备方式以废弃虾蟹壳为原料,经过酸、碱处理后便可分离纯化,初制成的甲壳素高分子学术上称为几丁质(chitin),为N-乙酰-D-葡醣胺(N-acetyl-D-glucosamine)以β-1,4键所构成的高分子多醣体,其分子大小取决于来源及后续处理过程。几丁质经由热碱处理后,可以去除N-乙酰基(N-acetylgroup)而形成脱乙酰几丁质(chitosan),其去乙酰基程度一般以70%~90%最常见,几丁质与脱乙酰几丁质两者之间的差异仅在于第二个碳上所接的官能基不同,几丁质为乙酰氨基(-NHCOOH3)而脱乙酰几丁质为氨基(-NH2)。
几丁质与脱乙酰几丁质是由天然的生物中所制备的生物高分子,与生物有良好的生物兼容性、生物黏着性、生物活性、生物可分解性、无毒性及抗菌性,并广泛的被应用在食品、医药、化工、环保、农业、生物技术等领域。近几年来脱乙酰几丁质被大量应用在生医材料上,其原因为脱乙酰几丁质是天然高分子,且与生物体细胞有良好的生物兼容性,不会造成排斥现象,并带正电和具有活性官能基的特色,使得脱乙酰几丁质被应用于载体时,可增加物质的生物体可利用率,且可稳定物质成分、促进物质的吸收、控制物质的溶解速度、帮助物质送达目的器官。
本发明最主要的是将脱乙酰几丁质经离子性架桥过后,来增加其利用价值,由于脱乙酰几丁质分子在第二个碳上的氨基易与氢离子结合而离子化,其官能基与盐类结合后,能保留几丁质优异的性质且改善其低水溶性的缺点,使得脱乙酰几丁质盐类的加工性质优于几丁质,而利于生物医学材料上的应用。
发明内容
本发明的目的是提供一种具有控释放传递作用的高分子基质的制备方法。
本发明是一种具有控释放传递作用的高分子基质的制备方法,先将脱乙酰几丁质与被传递分子混合均匀,再利用快速均质混合氨基酸螯合矿物质水溶液,制备成具传递作用的高分子基质。本发明采用天然高分子与氨基酸盐利用螯合及物理性力量制备成胶体颗粒状,有别于一般物质传递基质的制备方法,其配方、制备工艺及产品特色如下:
1.本发明使用甲壳素高分子-脱乙酰几丁质,其为由天然生物所制备的生物高分子,与生物有良好的生物兼容性、生物黏着性、生物活性、生物可分解性、无毒性及抗菌性,并广泛的被应用在食品、医药、化工、环保、农业、生物技术等领域。
2.本发明利用两种氨基酸螯合矿物质与脱乙酰几丁质进行离子性架桥,可依顾客需求调整比例,使被传递物质有不同的释放速率,来达到客户最高满意效果。本发明所用氨基酸螯合矿物质为氨基酸盐的水溶液,优选天冬氨酸盐和谷氨酸盐的水溶液。
3.本发明利用快速均质混合的方式,所制备出的具传递作用的高分子基质粒径为纳米尺度,其粒径大小可控制在20纳米(nm)至500纳米(nm)间,并由此形成分散于水中的胶体溶液。
4.本发明采用脱乙酰几丁质及氨基酸螯合矿物质构成高分子基质,用来包覆及携带短链肽分子,载体与被载物间有良好的兼容性质,可大大提高包覆率及提高控制释放效果。
5.本发明的工艺简单快速,采用的脱乙酰几丁质可以从废弃虾蟹壳中提炼,不但节省成本,而且重视环保,而采用氨基酸螯合矿物质为离子性架桥剂,并无化学反应而进行高分子架桥及短链肽包覆,可为一创新发明的工艺。
为能明了此发明的特征及实施功效,兹配合附图详述如下:
附图说明
图1是具传递作用的高分子基质的制备流程;
图2是天冬氨酸螯合矿物质(pH=7水溶液);
图3是谷氨酸螯合矿物质(pH=7水溶液);
图4是氨基酸架桥脱乙酰几丁质示意图;
图5是具传递作用的高分子基质示意图;
图6是高分子基质的穿透式电子显微镜(TEM)实图。
具体实施方式
本发明以氨基酸螯合矿物质与脱乙酰几丁质进行离子性架桥制成具传递作用的高分子基质,参考附图(一)流程所示,逐项将本发明的制造流程加以说明如下:
A:脱乙酰几丁质酸溶液
脱乙酰几丁质为无色、无毒、无味的生物可分解性高分子,其难溶于水中,但可溶于弱酸溶液中,所以本发明以酸(例如乙酸、甲酸、氢氯酸、丙酸、磷酸、乳酸、苹果酸、琥珀酸、硝酸、草酸、己二酸等)液溶解脱乙酰几丁质,其脱乙酰度为50%至99.9%,数均分子量为1000至1500000,将其配制成水溶液状态。其中脱乙酰几丁质在水溶液中浓度为0.01~5%(w/v),酸浓度依种类之不同其浓度为0.1~10%(w/v)。
B:被传递分子水溶液
本发明的被传递分子为短链肽分子,其氨基酸重复单位数为2至30个分子,将其溶于水中,配制成水溶液状态。其中被传递分子在水溶液中之浓度为0.01~20%(w/v)
C:混合
本发明将上述的被传递分子水溶液以1:1至1:10比例加入脱乙酰几丁质酸溶液中,并用磁石搅拌器将其混合均匀。
D:氨基酸螯合矿物质水溶液
本发明所用的氨基酸螯合矿物质在pH=7缓冲液下为具负电荷性的天冬氨酸(aspartate)及谷氨酸(glutamate)盐。其中阴离子为天冬氨酸根及谷氨酸根,阳离子为镁、钙、锶、锌、铜、铁、银、铝、硼及钛离子等阳离子。将氨基酸螯合矿物质溶于水中搅拌,配制成氨基酸螯合矿物质水溶液备用。其中氨基酸盐在水溶液中之浓度为0.1~5%(w/v)。
E:快速均质混合
将上述的氨基酸螯合矿物质水溶液以1:1至1:10比例快速加入正在均质的脱乙酰几丁质酸溶液与被传递分子混合液中,利用均质效果使其分散均匀,并产生离子性架桥。
F:缓冲液
配制pH=7缓冲溶液,用其来调整上述的快速均质混合液至中性为止。
G:具传递作用的高分子基质
本发明将上述快速均质混合液的pH调整为中性后,就可形成已包覆及具传递作用的高分子基质胶体溶液,该胶体溶液系粒径为纳米尺度的微粒分散于水中形成的。
为能进一步了解本发明的创新效果,兹举出数个实施例如下,所举实施例是对本发明做概括性例示,并无限制本发明范围之意,就此先作声明。
实施例一:
依配方表中编号1和2的配方分别进行配制,制备出二个样品(见表一)。将去乙酰度90%的脱乙酰几丁质10g溶于800mL浓度3%(w/v)乙酸水溶液中以定温70℃,及搅拌速度50rpm进行固体溶解30分钟,待固成份全部溶解冷确后,形成脱乙酰几丁质浓度为1.25%的酸溶液备用。另外取胸腺五肽10g溶于100mL纯水中形成浓度10%(w/v)被传递分子水溶液。将上述被传递分子水溶液与脱乙酰几丁质浓度的酸溶液以1:10比例混合,另以转速15000rpm进行高速均质。此时分别在编号1和2的溶液中快速加入浓度为2%(w/v)体积200mL天冬氨酸钙和谷氨酸钙水溶液,经高速均质5分钟使带负电的氨基酸与带正电的脱乙酰几丁质形成离子性架桥,由于快速均质造成温度上升,均质后待溶液温度降至常温,此时溶液呈弱酸性,再利用pH=7的磷酸缓冲溶液调整成中性,即形成已包覆及具传递作用的高分子基质胶体溶液,以上所得两样品分别编号为1和2。
实施例二:
如实施例一中的方法,将氨基酸钙的浓度由2%改为5%,其余过程与实施例一相同,产品样本编号为3和4。
实施例三:
将实施例一中溶解脱乙酰几丁质的溶剂由乙酸改为甲酸,其余过程与实施例一相同,分别得到二个编号为5~6的产品样本。
实施例四:
将实施例一中的方法,将氨基酸钙改为氨基酸镁,其余过程与实施例一相同,分别得到二个编号为7~8的产品样本。
实施例五:
将实施例一至四中的方法,胸腺五肽改为胆囊收缩素八肽(CCK-8),其余过程与实施例一至四中的相同,分别得到八个编号为9~16的产品样本。
实施例六:
如实施例一中配方1的方法,但是不添加氨基酸螯合矿物质水溶液,其余过程与实施例一相同,产品样本编号17。
实施例七:
将各样本进行穿透式电子显微镜(TEM)照射,以观察其形态与粒径大小,样品编号3结果如图6所示,且各个样品的平均粒径大小经取样计算过后如表二所示。
实施例八:
将各样本进行包覆率实验,以观察具传递作用的高分子基质包覆情形。首先将各样本调整至pH值大于9,使脱乙酰几丁质载体析出,再经由0.22μm滤膜过滤,取得澄清溶液后利用高效能液相层析仪(HPLC),以UV侦测器来测其溶液中游离未被包覆的胸腺五肽浓度,经换算后可得其游离量,并计算其包覆率,各样本测得数据如表二所示。其中包覆率公式计算如下:
实施例九:
将各样本进行肽释放率实验,以观察具传递作用的高分子基质释放情形。首先将各样本取10mL加入90mL的PBS缓冲溶液当中,以50rpm的速度搅拌,每隔6小时取样一次,将取出的样品调整pH值大于9,使脱乙酰几丁质载体析出,再经由0.22μm滤膜过滤,取得澄清溶液后利用高效能液相层析仪(HPLC)来测其溶液中肽浓度,侦测方法如实施例六所示,经浓度换算及计算总释放量,并计算各时间取样的累计释放率,各样本测得数据如表二所示。其累计释放率公式如下:
表一具传递作用的高分子基质配方表
配方 | 1 | 2 |
脱乙酰几丁质酸溶液(1.25%) | 800mL | 800mL |
胸腺五肽分子水溶液(10%) | 100mL | 100mL |
氨基酸螯合矿物质溶液(2%) | 天冬氨酸钙溶液90mL | 谷氨酸钙溶液90mL |
表二具传递作用的高分子基质产物分析
由表二具传递作用的高分子基质产物分析结果显示,本发明所制备出的平均粒径皆小于500nm之间,且经由氨基酸钙与脱乙酰几丁质的离子性架桥后(编号1~16),其粒径皆比未架桥的样品小许多(编号17),以样品编号3的粒径为最小。样本1~8对胸腺五肽包覆率约为72~94%,样本9~16对胆囊收缩素八肽包覆率约为81~54%,其中以样品编号3经过24hr的作用后累积释放率为59%,其胸腺五肽累积释放率最缓慢,具有较佳的缓释能力,样品编号11经过24hr的作用后累积释放率为60%,其胆囊收缩素八肽累积释放率最缓慢,具有较佳的缓释能力。此研究结果未见于国内外相关文献报导中。本发明所使用的两种氨基酸钙可由结果观察到,利用谷氨酸钙(编号2、4、6、10、12、14)与脱乙酰几丁质进行架桥的包覆率比天冬氨酸钙(编号1、3、5、9、11、13)较佳,但其缓释能力就比较差。本发明所使用的两种氨基酸镁可由结果观察到,利用谷氨酸镁(编号8、16)与脱乙酰几丁质进行架桥的包覆率比天冬氨酸镁(编号7、15)较佳,且其缓释能力比较佳。
本发明所使用的两种酸溶液可由结果观察到,利用乙酸(编号1、2、3、4、7、8、9、10、11、12、15、16)来溶解脱乙酰几丁质其粒径、包覆率及累积释放能力皆比使用甲酸溶剂好(编号5、6、13、14)。而样品编号17为对照组并未添加氨基酸盐,其粒径大于2微米,且对胸腺五肽的包覆率仅有21%,在胸腺五肽累积释放率的实验里也发现其在1小时就有79%的释放率,可视其并无任何释放控制的能力。
综合以上所述,本发明以氨基酸螯合矿物质与脱乙酰几丁质进行离子性架桥制备成高分子基质粒径小,且具有良好的包覆率,同时也拥有较佳的缓释能力,其制备方法简单特殊,而结果均能达到预期的效果,且工艺质量稳定、成本低、无化学反应参与。
Claims (10)
1.一种具传递作用的高分子基质的制备方法,其特征在于,首先将脱乙酰几丁质溶解在酸液中制成脱乙酰几丁质的酸水溶液,另分别将被传递分子及氨基酸螯合矿物质溶解于水中,然后,先将适量的被传递分子水溶液与脱乙酰几丁质的酸水溶液充分混合,接着将氨基酸螯合矿物质水溶液在高速均质下,快速加入混合溶液中,此时溶液呈弱酸性,再加入pH值为7的缓冲液,就可形成已包覆及具传递作用的高分子基质胶体溶液;其中,所用的氨基酸螯合矿物质为具负电荷性的天冬氨酸(aspartate)及谷氨酸(glutamate)盐。
2.如权利要求1所述的制备方法,其特征在于,脱乙酰几丁质的去乙酰度为50%至99.9%,数均分子量1000至1500000,配制成浓度为0.01至5%(w/v)的水溶液使用。
3.如权利要求1所述的制备方法,其特征在于,所用的酸液为乙酸、甲酸、氢氯酸、丙酸、磷酸、乳酸、苹果酸、琥珀酸、硝酸、草酸、己二酸等有机及无机酸,其浓度为0.1~10%(w/v)。
4.如权利要求1所述的制备方法,其特征在于,被传递分子为短链肽分子,其氨基酸重复单位数为2至30个分子,将其溶于水中,其中被传递分子在水溶液中之浓度为0.01~20%(w/v)。
5.如权利要求1所述的制备方法,其特征在于,所用的氨基酸螯合矿物质的阴离子为天冬氨酸根及谷氨酸根,阳离子为金属阳离子。
6.如权利要求5所述的方法,其特征在于,所用的金属为镁、钙、锶、锌、铜、铁、银、铝、硼及钛离子。
7.如权利要求1所述的方法,其特征在于,氨基酸螯合矿物质在水溶液中之浓度为0.1~5%(w/v)。
8.如权利要求1所述的制备方法,其特征在于,被传递分子水溶液以1∶1至1∶10比例加入脱乙酰几丁质酸溶液中。
9.如权利要求1所述的制备方法,其特征在于,氨基酸螯合矿物质水溶液以1∶1至1∶10比例加入脱乙酰几丁质酸溶液与被传递分子混合液中。
10.如权利要求1所述的制备方法,其特征在于,生成的胶体溶液粒径大小为20纳米(nm)至500纳米(nm)。
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CN1106820A (zh) * | 1993-10-30 | 1995-08-16 | 默克专利股份有限公司 | 脱乙酰壳多糖水溶液和凝胶的制备方法 |
CN1114146A (zh) * | 1994-06-25 | 1996-01-03 | 大连水产学院 | 复合氨基酸螯合盐和水解蛋白的制备方法 |
CN1931828A (zh) * | 2006-09-29 | 2007-03-21 | 华侨大学 | 氨基酸螯合钙的制备方法 |
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CN1106820A (zh) * | 1993-10-30 | 1995-08-16 | 默克专利股份有限公司 | 脱乙酰壳多糖水溶液和凝胶的制备方法 |
CN1114146A (zh) * | 1994-06-25 | 1996-01-03 | 大连水产学院 | 复合氨基酸螯合盐和水解蛋白的制备方法 |
CN1931828A (zh) * | 2006-09-29 | 2007-03-21 | 华侨大学 | 氨基酸螯合钙的制备方法 |
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