CN113081949A - 一种复方葡萄糖酸钙口服凝胶制剂及其制备方法 - Google Patents
一种复方葡萄糖酸钙口服凝胶制剂及其制备方法 Download PDFInfo
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- A—HUMAN NECESSITIES
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Abstract
本发明公开一种复方葡萄糖酸钙口服凝胶制剂,该制剂包括如下原料:葡萄糖酸钙,乳酸钙,乳酸,黄原胶,山梨酸钾等;本发明在葡萄糖酸钙溶液中加入助溶剂乳酸钙,同时乳酸钙亦作为一种优质的钙补充剂,两者协同增效,相互提高自身溶解度,有效提高制剂钙元素含量及稳定性;另外,加入适量凝胶基质制备为凝胶制剂,能够缓冲因需要矫正原料药本身带有的金属异味而加入大量甜味剂所带来的强烈味蕾冲击,因此其能够在提高吸收方面的同时有效改善口感、提高制剂对于不同糖度耐受能力人群的顺应性,且工艺合理可行,制备简单,成本较低,适合工业化生产。
Description
技术领域
本发明涉及一种凝胶制剂,特别涉及一种复方葡萄糖酸钙口服凝胶制剂及其制备方法。
技术背景
微量元素是维持人类正常生理机能不可缺少的一部分,微量元素在人体内的含量不到人体总质量的万分之一,微量元素缺乏引起多种疾病。因此,有效预防和治疗微量元素的缺乏,是临床上的一种必要措施。而钙是人类生命元素之一,不仅是构成骨骼的主要物质,而且是保持神经、肌肉功能所必须的,对维持正常的心肺和凝血功能,以及细胞膜和毛细血管的通透性起着重要作用。近年来,临床上使用的钙制剂就有近百个品种,葡萄糖酸钙所含钙参与骨骼的形成与骨折后骨组织的再建以及肌肉收缩、神经传递、凝血随着科技的进步,所含钙为体内许多酶的重要组成成份,具有促进生长发育、改善味觉等作用,抑制,并降低毛细血管的通透性;缺乏时,生长停滞、生殖无能、伤口不易愈合、机体衰弱,还可发生结膜炎、口腔炎、舌炎、食欲缺乏、慢性腹泻、味觉丧失以及神经症状等。除此之外葡萄糖酸钙还具有抗过敏作用、镁中毒和氟中毒的解救以及心脏疾病复苏时应用,是临床上较为常用的一种制剂。目前,葡萄糖酸钙有多种剂型,片剂、口服液、注射剂等。
由于葡萄糖酸钙饱和溶解度低,目前市售的葡萄糖酸钙口服液制剂虽为一种使用方便的钙制剂,但因其系葡萄糖酸钙的过饱和溶液,在放置过程中亦有不稳定,易于结晶、沉淀的问题,药品要求具有安全性、有效性、稳定性和均一性,产品质量不仅是产品本身的优劣,更关乎人民的健康,由于不同药品生产企业的生产条件差异,所采用的的设备、原辅料、生产工艺、关键参数都会有所差异,产品的质量也会有差异;市售葡萄糖酸钙注射液中的可见异物和结晶析出现象尤为常见,在洁净区生产环境因素、生产设备、人员等因素的影响下,葡萄糖酸钙注射液的合格率较低,而且葡萄糖酸钙注射液在室温条件下存放一段时间后,其可见异物项目检查会出现结晶析出,这种情况严重影响葡萄糖酸钙注射液的产品质量,也影响患者的用药安全;而其市售葡萄糖酸钙片的片剂制剂,服用时需用水冲服,在体内仍需崩解后方能吸收,且片剂较大,对于儿童及吞咽困难者,临床顺应依从性较差。因此如何同时提高葡萄糖酸钙口服制剂的稳定性、顺应性是本领域技术人员一直想解决的问题,其具有重要意义。
发明内容
本发明是通过如下技术方案实现的:一种复方葡萄糖酸钙口服凝胶制剂,该制剂包括如下原料:
加水至1000体积份;
优选配比为:
加水制成1000体积份。
本发明凝胶制剂还可以加入蔗糖或甜味剂:
蔗糖150-250重量份,安赛蜜或三氯蔗糖0.3-0.4重量份;
该制剂制备方法为:
(1)A液:30%配方量经煮沸处理的纯化水,加入配方量抑菌剂山梨酸钾,搅拌溶解后加入配方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入约50%配方量经煮沸处理的纯化水,依次加入配方量量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,加入或不加入甜味剂,搅拌溶解,最后加入或不加入适量的香精,搅拌均匀,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至配方量量,搅拌均匀,降至室温,分装,即得。
本发明所述重量份与体积份的关系为g/ml。
本发明在葡萄糖酸钙溶液中加入助溶剂乳酸钙,同时乳酸钙亦作为一种优质的钙补充剂,两者协同增效,相互提高自身溶解度,有效提高制剂钙元素含量及稳定性;另外,加入适量凝胶基质制备为凝胶制剂,能够缓冲因需要矫正原料药本身带有的金属异味而加入大量甜味剂所带来的强烈味蕾冲击,因此其能够在提高吸收方面的同时有效改善口感、提高制剂对于不同糖度耐受能力人群的顺应性,且工艺合理可行,制备简单,成本较低,适合工业化生产。
本发明凝胶制剂中含有复方制剂的主成分葡萄糖酸钙及乳酸钙外,仍可以加入适量的凝胶基质、甜味剂、pH调节剂(缓冲剂)、芳香剂及抑菌剂。
实验例1凝胶基质的筛选
在试验案例中,各种凝胶基质辅料采用常用量,加40%处方量经煮沸处理的纯化水,搅拌溶胀适宜时间后制成空白凝胶基质;另外,称取处方量的葡萄糖酸钙、乳酸钙和乳酸加入50%处方量经煮沸处理的纯化水中煮沸溶解,之后将药液缓慢加入至凝胶基质中,搅拌,观察其性状。各处方如下:
表1:空白凝胶基质的筛选处方
处方1/2/4/5工艺:
(1)A液:40%处方量经煮沸处理的纯化水,加入处方量抑菌剂山梨酸钾,搅拌溶解后加入处方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%处方量经煮沸处理的纯化水,依次加入处方量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至处方量,搅拌均匀,降至室温,即得。
处方3工艺:
(1)A液:40%处方量经煮沸处理的纯化水,加入处方量抑菌剂山梨酸钾,搅拌溶解后加入处方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%处方量经煮沸处理的纯化水,依次加入处方量葡萄糖酸钙、乳酸钙及乳酸,继续加热煮沸至完全溶解后,加入胶凝剂氯化钾,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至处方量,搅拌均匀,降至室温,即得。
处方6工艺:
(1)A液:40%处方量经煮沸处理的纯化水,加入处方量抑菌剂山梨酸钾,搅拌溶解后加入处方量凝胶基质,搅拌、溶胀至均匀状态,之后加入处方量的胶凝剂,搅拌均匀后备用;
(2)B液:加入50%处方量经煮沸处理的纯化水,依次加入处方量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至处方量,搅拌均匀,降至室温,即得。
按照处方工艺中方法制得的各样品,终获得产品性状结果如下表2:
表2:凝胶基质的筛选结果
由表2可知,所考察的黄原胶、魔芋粉、卡拉胶、琼脂、海藻酸钠、卡波姆几种基质作为本制剂中凝胶基质与原料药的相容性试验中,黄原胶作为凝胶基质,相较其他基质,与原料药混合后,所制备凝胶剂均匀、细腻,无分层、渗水状态,制备形成的凝胶剂外观较为适宜,且据悉黄原胶是全世界规模最大球用途最广泛的微生物多糖,由野油菜黄单胞杆菌以碳水化合物为主要原料(如玉米淀粉)发酵生产的一微生物胞外多糖,黄原胶自身引起良好的水溶性、独特的流变性、对热和酸碱的稳定性、以及与盐类良好的相容性,在食品、石油、医药等20多个行业中被用作增稠剂、悬浮剂、乳化剂、以及稳定剂。
实验例2不同凝胶基质比例的考察
在试验案例中添加不同比例的黄原胶进行增稠,对比考察其凝胶质地情况,处方如表3:
表3:不同比例的凝胶基质
物料名称 | 处方7 | 处方8 | 处方9 |
葡萄糖酸钙 | 50g | 50g | 50g |
乳酸钙 | 50g | 50g | 50g |
乳酸 | 4g | 4g | 4g |
黄原胶 | 10g | 5g | 20g |
蔗糖 | 200g | 200g | 200g |
山梨酸钾 | 1g | 1g | 1g |
草莓香精 | q.s | q.s | q.s |
加水至 | 1000ml | 1000ml | 1000ml |
处方工艺:
(1)A液:40%处方量经煮沸处理的纯化水,加入处方量抑菌剂山梨酸钾,搅拌溶解后加入处方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%处方量经煮沸处理的纯化水,依次加入处方量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至处方量,搅拌均匀,降至室温,即得。
按照处方工艺中方法制得的各样品,终获得产品性状结果如下表4:
表4:不同比例凝胶基质的筛选结果
由表2可知,黄原胶作为凝胶基质,其1%浓度比例制备形成果昔状的凝胶剂较为适宜,口感润滑,适口,且产品质量稳定,暂定1%的黄原胶浓度比例作为凝胶剂的基质。
实验例3(有糖型)不同甜味剂添加量的考察
本品为口服凝胶制剂,本身为一种药物与辅料形成的稠厚液体,在保证其应有的疗效和稳定性的前提下,应注意其口味,提高病人顺应性。蔗糖作为一种天然甜味剂,其甜味纯正、稳定、回味良好,给人以愉悦的感觉,而且在人食用后分解为二氧化碳和水,经几百年人类的食用证明,蔗糖是安全的食品,其在制剂中亦是首选的营养型甜味剂。以下根据矫正制剂口味情况考察了蔗糖的不同比例添加,处方如表5:
表5:蔗糖不同用量情况考察
物料名称 | 处方10 | 处方11 | 处方12 |
葡萄糖酸钙 | 50g | 50g | 50g |
乳酸钙 | 50g | 50g | 50g |
乳酸 | 4g | 4g | 4g |
黄原胶 | 10g | 10g | 10g |
蔗糖 | 200g | 50g | 300g |
山梨酸钾 | 1g | 1g | 1g |
草莓香精 | q.s | q.s | q.s |
加水至 | 1000ml | 1000ml | 1000ml |
按照处方工艺中方法制得的各样品,终获得产品,口味顺应性考察结果如下表6:
表6:不同蔗糖添加量的考察结果
由表中可知,蔗糖添加量为20%左右较为适宜,此时凝胶制剂在有效矫正其不良口味外,又能使其保持适宜的甜度,提高患者对药物制剂的顺应性。
实验例4无糖型制剂的开发
考虑到蔗糖含量较高,可能致儿童蛀牙、妊娠期高血糖及老年性糖尿病,并不能适用于更广范围的患者,另外从生产工艺方面考虑,蔗糖在高温40℃以上不稳定,容易导致溶液变色,提高因辅料带入的安全风险,而且溶液粘度较大,微孔滤膜过滤速度缓慢,生产效率低,为增加患者更多的选择及提高生产效益,同时开发无糖型产品。进行无糖型不同类型甜味剂添加比例的考察,处方如表7:
表7:不同类型甜味剂及用量考察
按处方工艺制备制得的各样品,终获得产品,口味顺应性考察结果如下表8:
表8:不同类型甜味剂及用量考察结果
由表中可知在葡萄糖酸钙乳酸钙药液中加入适量的三氯蔗糖、阿司帕坦、安赛蜜的一种或几种矫味剂,制备的处方工艺从性状、适口性亦均能符合要求,可以作为无糖型处方,木糖醇制备无糖型制剂口感适宜,用量亦较大,暂不做考虑。
实验例5不同类型芳香剂的考察
在口服制剂中甜味剂矫正口味必需,另外在气味中增加芳香性能够进一步增加小儿患者的顺应性,试验中分别用草莓香精、水蜜桃香精、樱桃香精及甜橙香精等多种果味香精进行果味香精的气味性的考察,考察不同芳香剂的可接受程度:
表9:不同类型芳香剂的考察
物料名称 | 处方21 | 处方22 | 处方23 | 处方24 |
葡萄糖酸钙 | 50g | 50g | 50g | 50g |
乳酸钙 | 50g | 50g | 50g | 50g |
乳酸 | 4g | 4g | 4g | 4g |
黄原胶 | 10g | 10g | 10g | 10g |
蔗糖 | 200g | 150g | 150g | 250g |
山梨酸钾 | 1g | 1g | 1g | 1g |
草莓香精 | q.s | - | - | - |
水蜜桃香精 | - | q.s | - | - |
樱桃香精 | - | - | q.s | - |
甜橙香精 | - | - | - | q.s |
加水至 | 1000ml | 1000ml | 1000ml | 1000ml |
按处方工艺制备制得的各样品,终获得产品,口味顺应性考察结果如下表10:
表10:不同类型香精的添加考察结果
根据以上结果,按表制备的各样品气味均较好,根据儿童的气味试验,筛选出实施例的草莓香精及水蜜桃香精为较好口味。
实验例6不同类型的包装、使用的对比
目前多种市售复方葡萄糖酸钙口服液包装采用玻璃管制口服液体瓶包装,玻璃瓶本身虽化学稳定性良好、阻隔性优良、价格低廉,但其容器自重与容量之比大,质脆易碎,大大增加了药物的包装成本与运输成本,同时,服用时另需额外配备聚丙烯(PP)吸管,增加用药操作,不方便;然而根据本凝胶制剂的特性,选择使用铝塑复合袋(PET/NY/AL/CPP)作包装,其本身不透明、呈银白色、亚光,不仅具有良好的阻隔性、热封性、遮光性、耐高温、耐低温、耐油性、保香性、无毒无味、柔软性等特点外,而且其重量小,减小包装成本与运输成本,另外易撕开使用易提高患者用药的方便性,患者可以以任意方便的方式进行服药,外出期间亦可方便携带、进食该品。
制备复方葡萄糖酸钙口服凝胶制剂分装进行低温及冻融-热循环试验,来验证其运输或使用过程中的稳定性。具体方法如下:(1)低温试验应包括三次循环,每次循环应在2~8℃条件下2天,然后在40℃加速条件下考察2天,取样检测。(2)冻融试验应包括三次循环,每次循环应在-10~-20℃条件下2天,然后在40℃加速条件下考察2天,取样检测。
表11:凝胶剂冻融-热循环试验结果
依处方工艺制备的复方葡萄糖酸钙口服凝胶稳定性良好,在冻融和热循环试验过程中未出现凝胶分层以及凝胶剂溶液中钙析出现象,颜色也未发生变化,各项指标检查均符合规定,应能耐受运输及贮藏期间的温度变化。
实施例1-4:样品制备及评价
表12:实施例样品制备处方
物料名称 | 实施例1 | 实施例2 | 实施例3 | 实施例4 |
葡萄糖酸钙 | 50g | 50g | 50g | 50g |
乳酸钙 | 50g | 50g | 50g | 50g |
乳酸 | 4g | 4g | 4g | 4g |
黄原胶 | 10g | 10g | 10g | 10g |
蔗糖 | 200g | - | - | 200g |
三氯蔗糖 | - | 0.4g | - | - |
阿司帕坦 | - | - | 0.3g | - |
安赛蜜 | - | - | 0.3g | - |
山梨酸钾 | 1g | 1g | 1g | 1g |
草莓香精 | q.s | q.s | q.s | - |
水蜜桃香精 | - | - | - | q.s |
加水至 | 1000ml | 1000ml | 1000ml | 1000ml |
制成 | 100支 | 100支 | 100支 | 100支 |
制备方法:
(1)A液:30%处方量经煮沸处理的纯化水,加入处方量抑菌剂山梨酸钾,搅拌溶解后加入处方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%处方量经煮沸处理的纯化水,依次加入处方量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,加入处方量的蔗糖或甜味剂,搅拌溶解,最后加入适量的香精,搅拌均匀,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至处方量,搅拌均匀,降至室温,分装,即得。
表13:实施例制备得到的口服凝胶的评价指标
实施例5
(1)A液:30%配方量经煮沸处理的纯化水,加入配方量抑菌剂山梨酸钾,搅拌溶解后加入配方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%配方量经煮沸处理的纯化水,依次加入配方量量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,搅拌溶解,搅拌均匀,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至配方量量,搅拌均匀,降至室温,分装,即得凝胶制剂。
实施例6
蔗糖150g,加水至1000ml;
制法同实施例1-4。
实施例7
加水至1000ml;
制法同实施例5。
实施例8
安赛蜜或三氯蔗糖0.3-0.4重量份,加水至1000ml;
制法同实施例1-4。
实施例9
加水至1000ml;
制法同实施例5。
本发明所有配方与实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限制。在上述基础上可做出其他任意不同形式的变化或变动。
Claims (6)
3.如权利要求1或2所述复方葡萄糖酸钙口服凝胶制剂,该制剂原料加入蔗糖:
蔗糖 150-250重量份。
4.如权利要求1或2所述复方葡萄糖酸钙凝胶制剂,该制剂原料加入甜味剂:
安赛蜜或三氯蔗糖 0.3-0.4重量份。
5.如权利要求1或2所述复方葡萄糖酸钙凝胶制剂的制备方法,该方法为:
(1)A液:30%配方量经煮沸处理的纯化水,加入配方量抑菌剂山梨酸钾,搅拌溶解后加入配方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%配方量经煮沸处理的纯化水,依次加入配方量量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,搅拌溶解,搅拌均匀,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至配方量量,搅拌均匀,降至室温,分装,即得凝胶制剂。
6.如权利要求3或4所述复方葡萄糖酸钙口服凝胶制剂的制备方法,该方法为:
(1)A液:30%配方量经煮沸处理的纯化水,加入配方量抑菌剂山梨酸钾,搅拌溶解后加入配方量凝胶基质,搅拌、溶胀至均匀状态,备用;
(2)B液:加入50%配方量经煮沸处理的纯化水,依次加入配方量量葡萄糖酸钙及乳酸钙及乳酸,继续加热煮沸至完全溶解后,加入甜味剂,搅拌溶解,最后加入适量的香精,搅拌均匀,趁热过滤;
(3)将过滤后的B液加入至A液中,加入经煮沸处理的纯化水定量至配方量量,搅拌均匀,降至室温,分装,即得。
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