CN111346060A - 一种释药速度可控的乙基纤维素掩味微球及其制备 - Google Patents
一种释药速度可控的乙基纤维素掩味微球及其制备 Download PDFInfo
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- CN111346060A CN111346060A CN202010206771.1A CN202010206771A CN111346060A CN 111346060 A CN111346060 A CN 111346060A CN 202010206771 A CN202010206771 A CN 202010206771A CN 111346060 A CN111346060 A CN 111346060A
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Classifications
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Abstract
本发明提供了一种释药速度可控的乙基纤维素掩味微球及其制备方法，所述体系包括一种或几种不同分子量乙基纤维素的一定比例混合物和疏水性药物。其中未使用致孔剂等其他赋形剂调控释药，以简易混合同一聚合物不同型号材料调控药物释放速度，并通过形成物理屏障延缓药物释放，避免苦味感知，从而达到掩味效果。本发明提供了上述微球的处方与制备方法。在实现掩味的同时，可根据需要调控药物释放，且微球载药量大、灵活性高、易于分剂量与吞咽，适用于儿童制剂研发。
Description
技术领域
本发明涉及一种释药速度可控的乙基纤维素掩味微球，其处方设计能够调控药物释放，并通过形成物理屏障达到掩味效果，属于药剂学领域。
背景技术
鉴于便利性、无侵入性和低成本，口服给药是最常用的药物递送途径。尽管口服制剂发展快速，其使用量日益增加，但是结合口感、胃肠道部位特点以及高分子材料性质使其制剂多样化具有一定研究价值和挑战。尤其是口服药物的不良口味掩盖与释药速度调控是其发挥疗效的关键。
微球是一种应用前景可期的包封递药系统，根据需要可制备成多种剂型，当采用适当的赋形剂与聚合物材料时，具有粒径范围小、服药顺应性高、载药量大、可提高药物稳定性、掩盖不良味道、能够控释与靶向等优势，因而可兼顾口服制剂存在的问题，发展迅速。掩盖不良味道是口服微球的重要应用，可以采用脂质材料、pH敏感材料、天然植物胶(如阿拉伯胶)、多糖类以及纤维素类为载体或包衣材料制备微球，通过形成物理屏障延缓苦味药物释放，避免苦味感知，从而达到掩味效果。Stagner等制备的载异烟肼微球中，交联壳聚糖载体不仅充当物理屏障，还通过形成氢键发挥掩味作用(Stagner WC,Iyer M,Rathod V,etal.Human volunteer,in vitro,and molecular level evaluation of an optimizedtaste-masked isoniazid-chitosan spray-dried microparticle matrix[J].Int JPharm,2019)。目前，常采用可降解、生物相容性良好且能够缓控释材料乙基纤维素为载体制备微球。专利CN201710550821.6公开的肺部用微球以乙基纤维素和白蛋白为载体，载药量达15％；专利CN201210087607.9采用65-75wt％的乙基纤维素与25-35wt％聚氨基甲基丙烯酸酯为缓释材料制备微球；专利CN201210042031.4采用乙基纤维素与释药调节剂达到缓释调控作用。现所制备的乙基纤维素微球还需添加其他载体材料和释药调节剂，除良溶剂外还包含架桥剂乙酸乙酯等，运用辅料多，涉及有机溶剂种类多，载药量不大。
本发明乙基纤维素微球处方工艺简单，采用辅料少，以简易混合同一聚合物不同型号材料调控药物释放速度，并具有掩味作用，可以根据临床需要制备不同释放要求的制剂，而且其载药量大，制剂灵活性高，可适用于给药剂量大并具有不同给药方案的药物。
发明内容
本发明的目的是提供一种释药可控的乙基纤维素掩味微球，所制备微球释药可控、具有掩味效果、载药量大、易于吞服、剂量灵活性高，可提高儿童等吞咽困难患者的服药顺应性。
本发明的另一目的是提供一种适用于疏水性药物的掩盖不良口感和释药可控的微球制备方法。采用价廉易得，少量辅料，以简单的处方设计和制备工艺达到不同释药行为，且通过延缓药物释放具有掩味效果，能够掩盖阿奇霉素等药物不良口感，提高患者服药顺应性。
本发明通过调整乙基纤维素型号与混合比例达到不同释药目的，采用低分子量型号乙基纤维能够达到0.5h内释放80％以上药物，实现速释；采用较高分子量型号乙基纤维素或混合应用不同分子量乙基纤维素达到缓释3h以上，从而调控药物释放。可根据药物临床需求，即可设计快速起治疗效果的制剂，也可设计缓慢释放，提高生物利用度，减少毒副作用的制剂。
为实现本发明目的，采用如下技术方案：
本发明提供一种释药可控的乙基纤维素掩味微球，由一种或几种不同分子量乙基纤维素的一定比例混合物和疏水性药物组成，所述疏水性药物与乙基纤维素载体的质量比例为(0.05～3):1，优选(0.2～3):1，更优选1:1或1:3或2:1或3:1或1:1.2或0.4:1或0.2:1,。
本发明所述乙基纤维素选自Aqualon TM系列乙基纤维素中的一种或多种，重均分子量75000～215000，优选规格T10、N7、N10、N14、N22、N50和N100Pharm。
本发明所述乙基纤维素选自T10、N22或N50；或N22/T 10混合乙基纤维素，混合比例为(1～10)/(0～10)，优选(5～10)/(1～5)，更优选7/3或9/1或6/4；或N22/N50/T 10混合乙基纤维素，混合比例为(1～10)/(0～10)/(0～10)，优选(1～6)/(1～3)/(1～6)，更优选6/1/3或2/3/5或5/3/2或8/1/1或5/2/3或1/3/6。
本发明所述疏水性药物选自阿奇霉素、克拉霉素、红霉素、罗红霉素、阿莫西林、头孢呋辛酯、蒿甲醚、洛哌丁胺、吲哚美辛、萘普生、尼美舒利、洛伐他丁、卡马西平、尼莫地平、硝苯地平、阿立哌唑等中的一种或多种药学活性药物。
本发明所述乙基纤维素微球，采用O/W乳化溶剂挥发法制备而成，所述O/W乳化溶剂挥发法具体操作为：将一种或几种乙基纤维素混合均匀后溶于有机溶剂，再加入药物得到油相，将油相匀速滴入高速搅拌中的含表面活性剂水相内，乳化搅拌一定时间后，抽滤洗涤微球，烘干收集既得所述微球。
本发明所述乙基纤维素微球制备的制剂，所述制剂选自微型片剂、微型胶囊、常规片剂、常规胶囊、口腔速崩片、分散片或干混悬剂。
本发明所述乙基纤维素微球的制备方法，采用O/W乳化溶剂挥发法制备而成，所述O/W乳化溶剂挥发法具体操作为：将一种或几种乙基纤维素混合均匀后溶于有机溶剂，再加入药物得到油相，将油相匀速滴入高速搅拌中的含表面活性剂水相内，乳化搅拌一定时间后，抽滤洗涤微球，烘干收集既得所述微球；其中乙基纤维素油相内质量浓度为5-10％(w/v)，所述的高速搅拌或乳化搅拌包含转速范围于800rpm-20000rpm内，所述的高速搅拌或乳化搅拌可以采用高速剪切分散、机械搅拌、磁力搅拌、超声破碎、高压匀质、高压过膜及其联用方式。
本发明所述有机溶剂为与水不混溶的常温下易挥发有机溶剂；优选二氯甲烷、氯仿、丙酮、醋酸异丙酯、乙酸乙酯；所述的表面活性剂选自易溶于水的阴离子型或非离子型表面活性剂，
所述的表面活性剂选自下列之一：SDS、SLS、Tween 80、Tween 60、PVA、泊洛沙姆188。
所述表面活性剂浓度为溶于水中形成质量浓度0.05％～2％的溶液，所述油相与水相体积比为1:(6～20)，优选1:10或1:8或1:18。
本发明提供一种乙基纤维素微球，由一种或几种不同分子量乙基纤维素的一定比例混合物和疏水性药物组成，其中所述乙基纤维素质量浓度范围为5％～10％(w/v)，所述疏水性药物与乙基纤维素载体比例为(0.2～3):1。
所述的乙基纤维素选择卡乐康AqualonTM系列乙基纤维素中的一种或多种，重均分子量75000～215000，优选规格T10、N7、N10、N14、N22、N50和N100 Pharm，更优选T10、N22和N50。所述混合乙基纤维素为上述规格乙基纤维素的两种或两种以上混合，其混合比例为(1～10)：(0～10)：(0～10)。
所述的药物包括：阿奇霉素、克拉霉素、红霉素、罗红霉素、阿莫西林、头孢呋辛酯、蒿甲醚、洛哌丁胺、吲哚美辛、萘普生等苦味药物或美沙拉嗪、洛伐他丁、司他夫定、卡马西平、尼莫地平、硝苯地平、阿立哌唑等中的一种或几种。
进一步的，本发明所述乙基纤维素微球是采用O/W乳化溶剂挥发法制备而成，所述O/W乳化溶剂挥发法具体操作为：将一种或几种乙基纤维素混合均匀后加入至油相内溶解完全，再将上述一种或几种药物组合溶解分散于油相；再将油相匀速滴入高速搅拌中的含表面活性剂水相内，乳化搅拌一定时间后，抽滤洗涤微球，烘干收集既得所述微球。
本发明所述的乙基纤维素微球粒径为30～200μm，优选为75～154μm。
所述的油相包括与水不混溶的常温下易挥发有机溶剂，所述油相与水相体积比为1:(6～20)，所述与水不混溶常温下易挥发有机溶剂包括但不限于二氯甲烷、氯仿、丙酮、醋酸异丙酯、乙酸乙酯等。
所述的表面活性剂包括易溶于水的阴离子型或非离子型表面活性剂，上述表面活性剂可选自下列之一：SDS、SLS、Tween 80、Tween 60、PVA、泊洛沙姆188，所述表面活性剂浓度为溶于水中形成质量浓度0.05％～2％溶液。
所述的高速搅拌，转速范围在于800rpm-20000rpm内。
所述的乳化搅拌可以采用涡旋、高速剪切分散、机械搅拌、磁力搅拌、高压匀质、高压过膜等方式。
所述的乙基纤维素微球，可以进一步制备成微型片剂、微型胶囊、常规片剂、常规胶囊、口腔速崩片、分散片、干混悬剂或其他可能的剂型，便于患者服用。
与现有的技术相比，本发明的有益效果在于：
本发明通过O/W乳化溶剂挥发法制备得到粒径分布窄、形态圆整、微球表面无药物晶体析出，口感良好而且其具有释药速度可控，掩味效果良好的优点。
本发明未使用释药调节剂如致孔剂和架桥剂等，所用辅料少且价廉易得，通过简易混合不同分子量乙基纤维素达到不同释药行为和掩味目的。
本发明乙基纤维素微球载药量能够高达70％，能够减少药物总给药剂量，而且其剂量灵活性高，适用于给药剂量大和具有不同给药方案的药物，可以减少给药总制剂的量并且灵活调整给药方案或者方便于协同给药。
本发明乙基纤维素微球粒径小，易于吞服，其需水量与口腔残留量少，适用于儿童等吞咽困难患者。
本发明乙基纤维素制剂灵活性高，可进一步制备成微型片剂、微型胶囊、常规片剂、常规胶囊、口腔速崩片、分散片、干混悬剂或其他可能的剂型，便于患者服用。
具体实施方式
下面对本发明技术方案以具体实施例进一步说明，但本发明的保护范围不限于此：
实施例1：乙基纤维素微球制备方法为：取载体乙基纤维素溶于相应溶剂中，再加入一定量的药物溶解完全得到油相，将上述油相匀速滴入高速搅拌中的含表面活性剂水相内，乳化搅拌后，抽滤、用去离子水洗涤产品、烘干得到乙基纤维素微球。不同药物乙基纤维素微球制备的用量与条件见表1。
表1乙基纤维素微球的制备条件
实施例2：取实施例1中的乙基纤维素微球，在相应检测方法下，分别测定其载药量，其检测方法与结果如表2所示，其中HPLC流速均为1mL/min。
表2乙基纤维素微球检测方法及载药量
实施例3：取实施例1中的乙基纤维素微球适量加入饮用水配为能够品尝的样品。由11位19-25岁健康成人志愿者组成的小组进行苦味评价测试，其中以相应原料药为苦味对照。要求志愿者以纯净水漱口后取适量样品含至口腔中，并将舌头左右前后转动至溶液与舌苔充分接触，30s后吐掉并用纯净水漱口数次。志愿者对不同浓度AZI溶液的苦味意见根据苦味量表评分，苦味量表由0＝无味、1＝微苦、2＝中苦和3＝强烈苦味四种标准组成。
表3乙基纤维素微球苦味评价
实施例4：以实施例1中的F1、F3、F4、F5为例，5mL经脱气处理的新鲜配制pH 7.4磷酸氢二钠为模拟口腔pH的释放介质，介质温度为37℃±0.5℃，设恒温振荡器转速50rpm，于1min，3min和5min取点检测，其中以相应原料药为对照。
表4乙基纤维素微球在模拟口腔pH介质内的释放量
实施例5：取一定量药物与载体溶于二氯甲烷得到油相，将油相匀速滴入以1500rpm转速搅拌中的0.1％100mL SDS水溶液内乳化搅拌后，抽滤洗涤烘干制得不同型号与混合比例乙基纤维素为载体的载药微球，并采用相应检测方法测定其载药量，其中F10-F15选择甲醇-0.05mol/L磷酸氢二钾(75:25)为流动相，210nm条件下HPLC法检测；F16-F18以乙腈-0.01mol/L磷酸氢二钠(45:55)为流动，在399nm条件下HPLC法检测；F19-F21采用甲醇与盐酸为溶剂，在285nm条件下UV法检测。药物和载体种类以及载药量结果如表5所示。
表5乙基纤维素微球载体信息及其载药量
实施例6：取实施例1和5中的乙基纤维素微球，在相应释放介质内于0.5h、1h、3h、6h、8h取点考察药物释放情况。其中，F3-F5、F10-F15以0.1mol/L pH 6.0磷酸二氢钠缓冲液为释放介质，F16-F18以pH8.8磷酸盐缓冲液为释放介质，F19-F21以稀盐酸(盐酸24ml加水至1000ml)为释放介质进行考察。
表6乙基纤维素微球释放情况
本发明实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种释药可控的乙基纤维素掩味微球，其特征在于，由一种或几种不同分子量乙基纤维素的混合物和疏水性药物组成，所述疏水性药物与乙基纤维素载体的质量比例为(0.05～3):1。
2.根据权利要求1所述的乙基纤维素微球，其特征在于乙基纤维素选自Aqualon TM系列乙基纤维素中的一种或多种，重均分子量75000～215000，优选规格T10、N7、N10、N14、N22、N50和N100 Pharm。
3.根据权利要求1或2所述乙基纤维素微球，其特征在于乙基纤维素选自T10、N22或N50；或N22/T10混合乙基纤维素；或N22/N50/T10混合乙基纤维素。
4.根据权利要求1所述乙基纤维素微球，其特征在于所述疏水性药物选自阿奇霉素、克拉霉素、红霉素、罗红霉素、阿莫西林、头孢呋辛酯、蒿甲醚、洛哌丁胺、吲哚美辛、萘普生、尼美舒利、洛伐他丁、卡马西平、尼莫地平、硝苯地平、阿立哌唑等中的一种或多种药学活性药物。
5.根据权利要求1-4任一项中所述乙基纤维素微球，其特征在于采用O/W乳化溶剂挥发法制备而成，所述O/W乳化溶剂挥发法具体操作为：将一种或几种乙基纤维素混合均匀后溶于有机溶剂，再加入药物得到油相，将油相匀速滴入高速搅拌中的含表面活性剂水相内，乳化搅拌一定时间后，抽滤洗涤微球，烘干收集既得所述微球。
6.根据权利要求1-5任一项所述的乙基纤维素微球制备的制剂，其特征在于所述制剂选自微型片剂、微型胶囊、常规片剂、常规胶囊、口腔速崩片、分散片或干混悬剂。
7.权利要求1所述乙基纤维素微球的制备方法，其特征在于：采用O/W乳化溶剂挥发法制备而成，所述O/W乳化溶剂挥发法具体操作为：将一种或几种乙基纤维素混合均匀后溶于有机溶剂，再加入药物得到油相，将油相匀速滴入高速搅拌中的含表面活性剂水相内，乳化搅拌一定时间后，抽滤洗涤微球，烘干收集既得所述微球；其中乙基纤维素油相内质量浓度为5-10％(w/v)，所述的高速搅拌或乳化搅拌包含转速范围于800rpm-20000rpm内，所述的高速搅拌或乳化搅拌可以采用高速剪切分散、机械搅拌、磁力搅拌、超声破碎、高压匀质、高压过膜及其联用方式。
8.根据权利要求7所述的制备方法，其特征在于，所述有机溶剂为与水不混溶的常温下易挥发有机溶剂；优选二氯甲烷、氯仿、丙酮、醋酸异丙酯、乙酸乙酯；所述的表面活性剂选自易溶于水的阴离子型或非离子型表面活性剂。
9.根据权利要求8所述的制备方法，其特征在于，所述的表面活性剂选自下列之一：SDS、SLS、Tween 80、Tween 60、PVA、泊洛沙姆188。
10.根据权利要求7所述的制备方法，其特征在于，所述表面活性剂浓度为溶于水中形成质量浓度0.05％～2％的溶液，所述油相与水相体积比为1:(6～20)。
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