CN113082051B - 一种复方维生素和微量元素口服溶液及其制备方法 - Google Patents
一种复方维生素和微量元素口服溶液及其制备方法 Download PDFInfo
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- CN113082051B CN113082051B CN202110334334.2A CN202110334334A CN113082051B CN 113082051 B CN113082051 B CN 113082051B CN 202110334334 A CN202110334334 A CN 202110334334A CN 113082051 B CN113082051 B CN 113082051B
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- Prior art keywords
- vitamin
- gluconate
- oral solution
- sodium
- acid
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Abstract
本发明涉及一种复方维生素和微量元素口服溶液及其制备方法,涉及保健品制剂制备技术领域。本发明的复方维生素和微量元素口服溶液包括了人体必需的主要微量元素、脂溶性维生素和水溶性维生素,还含有适量氨基酸。本发明提供了所述复方维生素和微量元素口服溶液的制备方法,通过本发明方法制得的口服液,稳定性良好,提高了各维生素、微量元素的生物利用度,改善机体营养状态,具有良好的保健效果。
Description
技术领域
本发明涉及保健品制剂制备技术领域,具体地,涉及一种复方维生素和微量元素口服溶液及其制备方法。
背景技术
维生素(Vitamin)是维持人体正常生理功能所必需的一类低分子有机化合物,它们是人体所需要的微量营养成分,而一般又无法由人体自己生产,需要通过饮食等手段获得由外源供给。维生素对人体的新陈代谢起调节作用。根据维生素的溶解性将其分为两大类,脂溶性和水溶性维生素。脂溶性包含维生素A、D、E、K1,不溶于水,可溶于脂肪和有机溶剂中。水溶性维生素包括B族维生素(维生素B1、维生素B2、烟酰胺(维生素B3)、泛酸(维生素B5)、维生素B6、叶酸(维生素B9)、维生素B12、生物素(维生素H)等)和维生素C,它们可溶于水却不溶于脂肪和有机溶剂。
人体所必须的微量元素有14种,分别是铁(Fe)、铜(Cu)、锌(Zn)、锡(Su)、硒(Se)、锰(Mu)、碘(I)、钴(Co)、铬(Cr)、钼(Mo)、钒(V)、镍(Ni)、氟(F)、硅(Si)。微量元素在人体内含量虽然极微小,但具有强大的生物学作用,它们参与酶、激素维生素和核酸的代谢过程,其生理功能主要表现为协助输送宏量元素;作为酶的组成成分或激活剂;在激素和维生素中起独特作用;影响核酸代谢等。
赖氨酸是人类和哺乳动物的必需氨基酸之一,机体不能自身合成,必须从食物中补充。赖氨酸在促进人体生长发育、增强机体免疫力、抗病毒、促进脂肪氧化、缓解焦虑情绪等方面都具有积极的营养学意义,同时也能促进某些营养素的吸收,能与一些营养素协同作用,更好的发挥各种营养素的生理功能。
目前含有赖氨酸的多种维生素和微量元素胃肠营养制剂,特别是适用于大手术、严重感染、各种烧伤、癌症等病人的产品常为片剂和注射剂,例如冻干粉针剂,使用时以静脉滴注的方式给药,但这种补充方式由于需要静脉注射,增加了患者疼痛感和接受注射的时间。为满足临床需求,研究人员考虑将胃肠营养产品制备为方便摄取的口服溶液,但在研发过程中,往往由于水溶性维生素和脂溶性维生素的不兼容性、对溶液的整体环境有较苛刻的要求,以及微量元素在液体环境下稳定性差、无机来源的微量元素吸收性差等原因,导致难以出现理想的既能保持各成分良好稳定性、又利于机体充分吸收丰富微量元素、维生素的口服液。比如,亚铁离子容易被氧化,铁离子和锌离子、钙离子共存情况下,导致机体对锌离子、钙离子的吸收能力降低;锌离子影响机体对铜离子的吸收;维生素C在酸性溶液中稳定存在,但烟酰胺在中性溶液中稳定存在,两种维生素对液体环境的pH值有不同的要求;维生素C容易还原一些金属微量元素,从而产生沉淀等等,使得在制备口服溶液过程中,需要研究人员兼顾各种维生素的特性和各个微量元素的特点,确保它们在共存体系下,能够最大限度保证溶液体系中各组分的稳定性,为机体提供必要且充分的丰富的维生素、微量元素。
因此开发一种适用于成人或手术病人,烧伤、癌症患者的胃肠内营养补充口服制剂很有必要。
发明内容
本发明的目的是提供一种稳定性好,富含维生素、微量元素和氨基酸的适用于成人或手术病人,烧伤、癌症患者的胃肠内营养补充口服制剂,及其制备方法。
本发明提供的一种复方维生素和微量元素口服溶液,每30ml口服溶液中含有以下:
(1)水溶性维生素:维生素C 50mg~250mg、维生素B1 1.2mg~10mg、维生素B21.4mg~3.6mg、维生素B6 1mg~6mg、烟酰胺15mg~60mg、泛酸5mg~20mg、叶酸150μg~600μg、生物素20μg~80μg;
(2)脂溶性维生素:维生素A 2000IU~4000IU、维生素D3 200IU~600IU;
(3)微量元素:葡萄糖酸亚铁4.32mg~12.96mg、葡萄糖酸锌38.98mg~116.94mg、葡萄糖酸铜1.7mg~5.1mg、葡萄糖酸锰0.8105mg~2.4315mg、葡萄糖酸钴6μg~18μg、氟化钠1.6mg~4.8mg、碘化钠0.9μg~2.7μg、亚硒酸钠117μg~351μg、七钼酸铵23μg~69μg、氯化铬38.5μg~115.5μg;
(4)氨基酸:异亮氨酸、亮氨酸、盐酸赖氨酸、精氨酸、酪氨酸、牛磺酸中的一种或多种,所述氨基酸的总量为10-50mg。
优选地,本发明提供的复方维生素和微量元素口服溶液,每30ml口服溶液中含有以下:
(1)水溶性维生素:维生素C 100mg~200mg、维生素B1 1.5mg~6mg、维生素B21.5mg~3.0mg、维生素B6 1mg~4mg、烟酰胺20mg~40mg、泛酸8mg~16mg、叶酸250μg~400μg、生物素40μg~60μg;
(2)脂溶性维生素:维生素A 2500IU~3500IU、维生素D3 300IU~500IU;
(3)微量元素:葡萄糖酸亚铁4.32mg~12.96mg、葡萄糖酸锌38.98mg~116.94mg、葡萄糖酸铜1.7mg~5.1mg、葡萄糖酸锰0.8105mg~2.4315mg、葡萄糖酸钴6μg~18μg、氟化钠1.6mg~4.8mg、碘化钠0.9μg~2.7μg、亚硒酸钠117μg~351μg、七钼酸铵23μg~69μg、氯化铬38.5μg~115.5μg;
(4)氨基酸:异亮氨酸、亮氨酸、盐酸赖氨酸、精氨酸、酪氨酸、牛磺酸中的一种或多种,所述氨基酸的总量为20-50mg。
本发明的所述口服溶液中还含有:助溶剂、pH调节剂、抑菌剂、增稠剂、甜味剂、芳香剂、溶剂。
所述助溶剂为聚山梨酯80、丙二醇、聚乙二醇300-400、山梨醇、十二烷基磺酸钠中的一种或两种组合物,优选为聚山梨酯80和丙二醇;或
所述pH调节剂为枸橼酸、枸橼酸钠、盐酸、氢氧化钠、磷酸二氢钠、磷酸氢二钠中的一种或两种组合物,优选为枸橼酸、枸橼酸钠组成的缓冲对;或
所述抑菌剂为羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯、苯甲酸、苯甲酸钠中的一种或两种组合物,优选为苯甲酸钠;或
所述增稠剂为黄原胶、羧甲纤维素钠、甲基纤维素、羟乙基纤维素中的一种或两种组合物,优选为羟乙基纤维素;或
所述甜味剂为蔗糖、安赛蜜、阿司帕坦、三氯蔗糖中的一种或两种组合物,优选为三氯蔗糖和安赛蜜;或
所述溶剂为纯化水;或
所述氨基酸为盐酸赖氨酸。
进一步地,所述聚山梨酯80用量为0.20%~0.50%,所述丙二醇用量为1.0%~3.0%,此处%含量是指溶质质量与口服溶液的体积百分含量,以g/100ml计;或
所述pH调节剂枸橼酸用量为0.24%~0.50%、枸橼酸钠用量为0.25%~0.55%的二者组合物,此处%含量是指pH调节剂质量与口服溶液的体积百分含量,以g/100ml计。
水溶性维生素是一类能溶于水的有机营养分子,包括在酶的催化中起着重要作用的B族维生素以及维生素C等,B族维生素主要有维生素B1、维生素B2、维生素B6、维生素B12、烟酰胺、泛酸、叶酸、生物素。
维生素B1又称硫铵素,缺乏硫胺素会导致糖代谢障碍,使血液中丙酮酸和乳酸含量增多,影响神经组织供能。维生素B1具有保持循环、消化、神经和肌内正常功能、调整胃肠道的功能,其作为脱羧酶的辅酶,参加糖的代谢,能预防脚气病。
维生素B2又称核黄素。是体内许多重要辅酶类的组成成分,这些酶能在体内物质代谢过程中传递氢,它还是蛋白质、糖、脂肪酸代谢和能量利用与组成所必需的物质。能促进生长发育,保护眼睛、皮肤的健康。
烟酰胺又称维生素B3、烟酸、尼克酸,可构成辅酶A,是酰基转移酶的辅酶。也可构成酰基载体蛋白(CAP),是脂肪酸合成酶复合体的成分。可抗应激、抗寒冷、抗感染、防止某些抗生素的毒性,消除术后腹胀。目前含有维生素B3的产品常为片剂和注射剂,用于防治口炎,舌炎,以及用于治疗冠心病、病毒性心肌炎、风湿性心脏病及少数洋地黄中毒等伴发的心律失常。烟酰胺还具有修复性功效,刺激皮肤产生神经酰胺和其他脂质,从而改善皮肤的屏障功能。
泛酸又称维生素B5,遍多酸,泛酸与头发、皮肤的营养状态密切相关,当头发缺乏光泽或变得较稀疏时,多补充泛酸可见其效;制造抗体也是泛酸的作用之一,能帮助人体抵抗传染病,缓和多种抗生素副作用及毒性,减轻过敏症状。泛酸缺乏易引起血液及皮肤异常,产生低血糖等症。泛酸溶于水和醋酸,在水溶液中显中性或弱碱性反应,在中性溶液中对温热、氧化及还原都比较稳定,但易被酸、碱和干热(2~6天)破坏,在pH5~7的水溶液遇热可被破坏。
叶酸又称维生素B9,叶酸对蛋白质、核酸的合成及各种氨基酸的代谢有重要作用,是人体在利用糖分和氨基酸时的必要物质,是机体细胞生长和繁殖所必需的物质。叶酸参与嘌呤和胸腺嘧啶的合成,进一步合成DNA和RNA;叶酸参与氨基酸代谢,在甘氨酸与丝氨酸、组氨酸和谷氨酸、同型半胱氨酸与蛋氨酸之间的相互转化过程中充当一碳单位的载体;叶酸还参与血红蛋白及甲基化合物如肾上腺素、胆碱、肌酸等的合成。叶酸在空气中稳定,但受紫外光照射即分解失去活力。其在酸性溶液中对热不稳定,在中性和碱性环境中十分稳定。
生物素又称维生素H、辅酶R,是水溶性维生素,也属于维生素B族,B7。它是合成维生素C的必要物质,参与维生素B12、叶酸、泛酸的代谢;促进尿素合成与排泄,是脂肪和蛋白质正常代谢不可或缺的物质。是一种维持人体自然生长、发育和正常人体机能健康必要的营养素,是多种羧化酶的辅酶,在羧化酶反应中起CO2载体的作用,具有维持上皮组织结构完整,增强机体免疫反应和抵抗力、维持机体正常发育的作用。生物素在中等强度的酸及中性溶液中可稳定数日,在碱性溶液中稳定性较差。在普通温度下相当稳定,但高温和氧化剂可使其丧失活性。
脂溶性维生素包括维生素A、维生素D、维生素E、维生素K。维生素A是脂溶性物质,它的消化与吸收需要矿物质和脂肪。维生素D具有促进钙吸收、抗佝偻病的作用,与脂肪一起吸收,吸收部位主要在空肠与回肠。
葡萄糖酸亚铁易吸收,对消化系统无刺激、无副作用,并且对食品的感官性能和风味无影响,同时可作为药物有治疗贫血的功能。葡萄糖酸锌存在于众多的酶系中,如碳酸酐酶,呼吸酶,乳酸脱氢酸,超氧化物歧化酶,碱性磷酸酶,DNA和RNA聚中酶等中,为核酸,蛋白质,碳水化合物的合成和维生素A的利用所必需。铁在酸性环境易吸收。体内铁的代谢非常旺盛,体内每天约有1/120的红细胞需要更新,衰老红细胞释放的血红素铁约90%倍重新利用,供给新生红细胞合成血红蛋白,这部分铁约有数十毫克。机体每天从胃肠道吸收补充到血液中的铁仅1毫克,葡萄糖酸亚铁进入血液后,立刻氧化为三价铁离子,并与血浆中转铁蛋白结合,成血浆铁,并以转铁蛋白为载体转运到肝,脾,骨等组织,以铁蛋白形式贮存即可满足生理需要。低价铁比高价铁更易被吸收。
葡萄糖酸锌口服后主要由小肠吸收,血清锌浓度于1小时后达高峰,约2小时开始下降。能广泛分布于肝,肠,脾,胰,心,肾,肺,肌肉及中枢神经系统,骨骼等内。葡萄糖酸锌主要用于治疗因缺锌引起的生长发育迟缓,营养不良,厌食症,复发性口腔溃疡,皮肤痤疮等症,具有促进生长发育,改善味觉的作用。
葡萄糖酸铜是一种铜的微生物可运用方式,而身体正常作用需要少量铜,因而,铜也被称作少量矿物,但机体内缺铜会影响心脏心率和血压,缺铜会提升静脉血栓,并造成心脏病发病。因而,摄入充足的铜对维持心脏作用很重要。
葡萄糖酸锰是一种很好的营养强化剂,锰可激活大量的酶,参与机体代谢活动,促进人体生长和正常的成骨作用,缺乏时可引起生长迟缓,生殖功能变阻,主要用作营养品、膳食添加剂,可预防皮肤炎、关节痛等疾病。
本发明采用的葡萄糖酸钴、氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬均为本领域内常用的营养强化剂,营养补充剂。
金属元素主要经十二指肠和空肠吸收,十二指肠对锌的吸收能力最强。锰元素主要在十二指肠被吸收,钴元素在空肠被吸收。三价铬最易被吸收的部位是空肠,其次是回肠和十二指肠。碘在整个胃肠道均可被吸收,但在胃和小肠吸收迅速,空腹时1-2小时可完全吸收。机体对碘、氟、硒无内稳态调节机制,不存在吸收调节机制,摄入量增加,吸收量也增加,吸收率达到70-90%以上。水溶性氟可全部吸收,碘可完全吸收。硅虽经饮食摄入较多,但吸收率1%。葡萄糖耐量因子形式的铬,吸收率为无机铬的100倍。
虽然有报道将上述微量元素制成多种微量元素注射剂,可供应锌、锰、铜、磷、铁、钴等微量元素的正常每日需要量,用作多种氨基酸注射液和葡萄糖注射液的添加剂,但将这些微量元素与维生素混合制得复方维生素和微量元素口服液,由于各个组分对溶液酸碱度适应性不同,各组分间发生反应,或竞争,导致微量元素、维生素和必要的氨基酸不能充分发挥各种电解质、微量元素、维生素特有作用,不能满足机体内有关生化反应的正常进行。
本发明实验发现,由于维生素B3需要几乎中性的pH才能保持稳定,相反,维生素C需要较低的pH才能保持稳定,即在酸性pH环境下稳定存在。当在高温下,维生素C与维生素B3会发生反应,生成一种称为烟碱酸的物质,从而影响机体对维生素C和维生素B3的吸收。实验说明维生素C和维生素B3需要在不同的pH条件才能保持每种成分的理想的稳定状态。如果把他们加入同一配方将导致配伍禁忌,特定的pH值会导致其中的一种维生素降解,失去其特性,功能和有效性。
本发明前期摸索实验还发现,一定剂量的维生素C会导致铜离子被还原为一些黑色素沉淀,使口服溶液不澄清。以及,维生素B2有氧化性,维生素C有还原性,两者共存容易发生氧化还原后起不到应有的营养价值。
另外,考虑到某一种微量元素过多可干扰机体对另一元素的吸收。比如锌的存在构成了机体对铜的吸收抑制,是由于锌可诱导肠粘膜细胞合成金属硫蛋白,后者对铜的亲和力明显高于锌,进入细胞的铜更易与之结合,从而减少了铜的吸收。本发明结合机体对各种微量元素的吸收特点,不断进行用量的调整和筛选,确定了锌元素和铜元素的用量,利用氨基酸能够影响铁铜的生物利用率,来促进机体对铁和铜的吸收。
本发明通过大量反复实验进行研究和摸索,探索了得到一种复方维生素和微量元素口服溶液的制备方法,采用本发明的方法制得的口服溶液,不仅含有有效剂量的微生物、微量元素和氨基酸,还保证了各成分的稳定性,口服摄取后能在机体充分发挥各种电解质、微量元素、维生素特有生理生化作用。
具体来说,本发明的复方维生素和微量元素口服溶液的制备方法包括以下步骤:
(1)称取处方量70%的纯化水,加热至75±5℃,先加入增稠剂、抑菌剂,搅拌至溶解;
(2)依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,水温始终保持在75±5℃,搅拌至溶解,将水温降至25~35℃;
本发明试验发现,水温在75±5℃能够在最短时间实现葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴在同一溶剂体系下快速溶解,若水温低于75±5℃,溶解速度减缓,若水温高于75±5℃,
(3)依次加入维生素C、维生素B1、维生素B2、维生素B6、烟酰胺、泛酸、叶酸、生物素,搅拌至溶解;
(4)再依次加入氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬,搅拌至溶解;再加入氨基酸、甜味剂和芳香剂;
(5)另行取处方量5%的纯化水,水温为25~35℃,加入助溶剂,再依次加入维生素A、维生素D3,搅拌至溶解;
(6)将步骤(5)的混合溶液加入步骤(4)获得的溶液中,用pH调节剂调节pH至4.0~5.0,加纯化水定容至处方量;过滤,灌封。
步骤(1)中,所述增稠剂为羟乙基纤维素,其用量为0.1%~0.5%,优选为0.2%~0.4%,此处%含量是指溶质质量与口服溶液的体积百分含量,以g/100ml计。
优选使用羟乙基纤维素的原因在于,羧甲基纤维素与铁、锌等盐溶液有配伍禁忌,而羟乙基纤维素能够很好地在酸性环境下与金属离子溶液共存。
所述步骤(4)中氨基酸为盐酸赖氨酸,其用量为每30ml口服溶液中含盐酸赖氨酸12.5mg~50mg,能够满足机体每日生长需要,增强免疫力。
本发明提供了上述制备方法制得的复方维生素和微量元素口服溶液。
本发明提供了上述制备方法在制备稳定性好的营养补充口服溶液中的应用。
本发明的有益效果在于:本发明结合机体对各种微量元素的吸收特点,不断进行用量的调整和筛选,确定了维生素和微量元素的用量和添加方式,利用氨基酸能够影响铁铜的生物利用率,来促进机体对铁和铜的吸收。维生素C作为还原剂促进三价铁还原成二价铁,作为络合剂与铁结合成可溶性复合物,通过有效增加维生素C的用量来增加机体对口服溶液中铁的吸收率。本发明充分考虑到多种微量元素与多种水溶性维生素、脂溶性维生素共存下,一些微量元素会互相影响,不同维生素的最佳稳定态对溶液的浓度、pH值、存在其他离子的要求各有侧重,平衡各组分的特点,选择了最合适的配方,采用本发明的方法制得的复方口服溶液,稳定性好,经长期放置,各维生素、微量元素的含量均在合格范围内,无析出、无沉淀、有效组分无降解。临床动物实验证实本发明的复方口服液生物利用度高,具有良好的保健功能。
具体实施方式
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的,并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下,可以对本发明进行各种修改和替换。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1复方维生素和微量元素口服溶液的制备(1)
(1)处方组成
(2)制备工艺为:
①配液:称取处方量70%的纯化水至配液罐中,加热纯化水温度至75±5℃,先加入羟乙基纤维素、苯甲酸钠,搅拌20min使溶解;
②依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,水温度维持在80℃,搅拌10min,使溶解,全部溶解后,将水温降至25~35℃,开始投料:开启搅拌,依次处方量的维生素C、维生素B1、维生素B2、维生素B6、烟酰胺、泛酸、叶酸、生物素,搅拌15min,使溶解;
③再依次加入氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬,搅拌10min,使溶解。
④再加入盐酸赖氨酸、三氯蔗糖、安赛蜜和香精;
⑤称取5%的纯化水至不锈钢桶中,水温为25~35℃,加入处方量的聚山梨酯80、丙二醇,搅拌15min,依次加入维生素A、维生素D3,搅拌15min,使溶解,将脂溶性维生素混合溶液加入至配液罐中,继续搅拌15min,用枸橼酸和枸橼酸钠调节pH至4.0~5.0,加纯化水定容至处方量;
⑥过滤:将药液过10μm滤芯;
⑦灌封:将药液灌装至30ml棕色玻璃口服液瓶中,压盖。
实施例2复方维生素和微量元素口服溶液的制备(2)
(1)处方组成
(2)制备工艺为:
①配液:称取处方量70%的纯化水至配液罐中,加热纯化水温度至75±5℃,先加入羟乙基纤维素、苯甲酸钠,搅拌20min使溶解;
②依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,水温度维持在75℃左右,搅拌10min,全部溶解后,将水温降至25~35℃,开始投料:开启搅拌,依次处方量的维生素C、维生素B1、维生素B2、维生素B6、烟酰胺、泛酸、叶酸、生物素,搅拌15min,使溶解;
③再依次加入氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬,搅拌10min,使溶解。
④再加入盐酸赖氨酸、三氯蔗糖、安赛蜜和香精;
⑤称取5%的纯化水至不锈钢桶中,水温为25~35℃,加入处方量的聚山梨酯80、丙二醇,搅拌15min,依次加入维生素A、维生素D3,搅拌15min,使溶解,将脂溶性维生素混合溶液加入至配液罐中,继续搅拌15min,用枸橼酸和枸橼酸钠调节pH至4.0~5.0,加纯化水定容至处方量;
⑥过滤:将药液过10μm滤芯;
⑦灌封:将药液灌装至30ml棕色玻璃口服液瓶中,压盖。
实施例3复方维生素和微量元素口服溶液的制备(3)
(1)A瓶处方组成
(2)制备工艺为:
①配液:称取处方量70%的纯化水至配液罐中,加热纯化水温度至75±5℃,先加入羟乙基纤维素、苯甲酸钠,搅拌20min使溶解;
②依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,水温度维持在70℃,搅拌10min,使溶解,全部溶解后,将水温降至25~35℃,开始投料:开启搅拌,依次处方量的维生素C、维生素B1、维生素B2、维生素B6、烟酰胺、泛酸、叶酸、生物素,搅拌15min,使溶解;
③再依次加入氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬,搅拌,使溶解。
④再加入盐酸赖氨酸、三氯蔗糖、安赛蜜和香精;
⑤称取5%的纯化水至不锈钢桶中,水温为25~35℃,加入处方量的聚山梨酯80、丙二醇,搅拌15min,依次加入维生素A、维生素D3,搅拌15min,使溶解,将脂溶性维生素混合溶液加入至配液罐中,继续搅拌15min,用枸橼酸和枸橼酸钠调节pH至4.0~5.0,加纯化水定容至处方量;
⑥过滤:将药液过10μm滤芯;
⑦灌封:将药液灌装至30ml棕色玻璃口服液瓶中,压盖。
对比例1聚山梨酯80和丙二醇用量对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例1(其中,聚山梨酯80用量为0.5%,丙二醇用量为1.0%)的区别在于,聚山梨酯80用量为0.5%,丙二醇用量为0.5%,“%”含量是指溶质质量与口服溶液的体积百分含量,以g/100ml计。其他配方均与实施例1相同,制备方法参照实施例1的方法进行。
对比例2聚山梨酯80和丙二醇用量对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例2(其中,聚山梨酯80用量为0.2%,丙二醇用量为2.0%)的区别在于,聚山梨酯80用量为0.1%,丙二醇用量为2.0%;“%”含量是指溶质质量与口服溶液的体积百分含量,以g/100ml计。其他配方均与实施例2相同,制备方法参照实施例2的方法进行。
对比例3微量元素用量对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例2(实施例2中,葡萄糖酸亚铁用量为8.64mg,葡萄糖酸锌用量为77.96mg,葡萄糖酸铜用量为3.4mg)的区别在于,葡萄糖酸亚铁用量为17.28mg,葡萄糖酸锌用量为155.92mg,葡萄糖酸铜用量为6.8mg。其他配方均与实施例2相同,制备方法参照实施例2的方法进行。
对比例4制备方法对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例2的区别在于制备方法不一致;主要表现在步骤①配液步骤中,未添加羟乙基纤维素、苯甲酸钠,直接将葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴加入加热的纯化水中,具体为:
①配液:称取处方量70%的纯化水至配液罐中,加热纯化水温度至75±5℃;
②依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,搅拌20min,使溶解,全部溶解后,将水温降至25~35℃,
此时发现当水温下降至40℃后配液罐中有沉淀析出。而实施例1-3在进行至步骤③时,溶液匀质澄清,未有沉淀析出。
对比例5制备方法对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例2的区别在于制备方法的步骤⑤不一致;
①配液:称取处方量70%的纯化水至配液罐中,加热纯化水温度至75±5℃,先加入羟乙基纤维素、苯甲酸钠,搅拌20min使溶解;
②依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,搅拌20min,使溶解,全部溶解后,将水温降至25~35℃,开始投料:开启搅拌,依次处方量的维生素C、维生素B1、维生素B2、维生素B6、烟酰胺、泛酸、叶酸、生物素,搅拌,使溶解;
③再依次加入氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬,搅拌,使溶解。
④再加入盐酸赖氨酸、三氯蔗糖、安赛蜜和香精;
⑤在配液罐中直接加入处方量的聚山梨酯80、丙二醇,搅拌15min,依次加入维生素A、维生素D3,搅拌15min,使溶解,用枸橼酸或枸橼酸钠调节pH至4.0~5.0,加纯化水定容至处方量;
⑥过滤:将药液过10μm滤芯;
⑦灌封:将药液灌装至30ml棕色玻璃口服液瓶中,压盖。
本实施例中,由于在步骤⑤中,脂溶性维生素未单独溶解,导致脂溶性维生素直接加入体系中溶解不完全。
对比例6制备方法对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例2的区别在于采用盐酸和氢氧化钠调节药液pH至4.0~5.0。
对比例7制备方法对比例
本对比例提供一种复方维生素和微量元素口服溶液的制备方法,其处方与实施例2的区别在于采用枸橼酸和枸橼酸钠调节药液pH至6.0~7.0。试验发现当pH至6.0~7.0,维生素C不能稳定存在。
实验例
以下实验例的含量测定:维生素B1,维生素B6,烟酰胺和维生素B2避光操作。照高效液相色谱法(中国药典2020年版四部通则0512)测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂;以0.03mol/L磷酸二氢钾-甲醇(98:2),用10%磷酸溶液pH值至3.7为流动相A,甲醇为流动相B;按下表进行梯度洗脱。柱温35℃,总流速1.0ml/min,检测波长为280nm。维生素B1,维生素B6,烟酰胺和维生素B2峰之间的分离度应符合规定。
表1
时间(min) | A(%) | B(%) |
0 | 100 | 0 |
9 | 100 | 0 |
10 | 70 | 30 |
15 | 70 | 30 |
16 | 60 | 40 |
24 | 60 | 40 |
25 | 100 | 0 |
35 | 100 | 0 |
测定法量取本品15ml,置200ml棕色量瓶中,精密称定,用流动相A稀释至刻度,摇匀,超声数分钟,经0.45μm滤膜滤过,弃去初滤液,精密量取续滤液20μl,注入液相色谱仪,记录色谱图;另分别取对照品维生素B1约15mg,维生素B6约23mg,烟酰胺65mg,维生素B2约26mg,精密称定,置100ml棕色量瓶中,加流动相A溶解并稀释至刻度,摇匀,精密量取该溶液5ml置50ml棕色量瓶中,用流动相A稀释至刻度,摇匀,作为对照品溶液,同法测定,按外标法以峰面积计算,即得。
盐酸赖氨酸:参照高效液相色谱法(《中国药典》2020年版(四部)通则0512)试验,用氨基键合硅胶为填充剂;以0.05mol/L磷酸二氢钾溶液-乙腈溶液[乙腈-水(10:1)](18:80)为流动相;按外标法以峰面积计算盐酸赖氨酸含量;
对照品溶液的配制:取盐酸赖氨酸对照品约60mg,精密称定,置50ml量瓶中,加水5ml,超声数分钟,用混合溶剂[取0.05mol/L磷酸二氢钾溶液20份与乙腈-水溶液(100:12)80份混合,加热至室温,即得]定容至刻度,摇匀,作为对照品溶液。
供试品溶液的配制:取本品3g,精密称定,置50ml量瓶中,超声数分钟,加入流动相30ml,加入磁芯,置磁力搅拌器上搅拌30分钟,取出磁芯,用混合溶剂冲洗磁芯,洗液并入量瓶中,并用混合溶剂定容至刻度,摇匀,经0.45μm滤膜滤过,弃去初滤液,作为供试品溶液。
维生素D3:用内容量移液管精密量取本品适量,加正己烷溶解并定量稀释制成每1ml中约含维生素D3 0.225mg的溶液,精密量取5ml,置50ml棕色量瓶中,用正己烷稀释至刻度,摇匀,作为供试品溶液。除精密称取维生素D3对照品22.5mg外,照维生素D测定法(《中国药典》2020年版(四部)通则0722第一法)测定,即得。
维生素A:按照《中国药典》2020年版(四部)通则0721第二法测定。
实验例1长期稳定性试验
稳定性考察,取实施例1-3和对比例1-3,5-7的样品置于温度25℃±2℃条件下放置,在放置0个月、3个月、6个月取样分析,测定并计算放置后样品中各组分含量,结果见表2~表4。
表2实施例1-3和对比例1~3-5~7稳定性结果
注:表2中%为标示量的百分比
表3实施例1-3和对比例1~3、5~7稳定性结果(%)
表4实施例1-3和对比例1~3,5~7稳定性结果(mg/30ml)
实验例2加速稳定性试验
稳定性考察,取实施例1-4和对比例1-3,5-7的样品置于温度40℃±2℃条件下放置,在放置0个月、3个月、6个月取样分析,测定并计算放置后样品中各各组分含量,结果见表5~表7。
表5实施例1-3和对比例1~3,5~7稳定性结果
注:表4中%为标示量的百分比
表6实施例1-3和对比例1~3,对比例5~7稳定性结果(%)
表7实施例1-3和对比例1~3-5~7稳定性结果(mg/30ml)
稳定性实验结果表明:实施例1-3采用的聚山梨酯80和丙二醇用量、pH调节剂种类和pH范围、制备工艺等制备的样品经加速6个月和长期6个月稳定性结果表明,结果均合格,与对比例1~7比较,稳定性更好,有效成分含量不降低,不析出。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (8)
1.一种复方维生素和微量元素口服溶液,其特征在于,每30ml口服溶液中含有以下:
(1)水溶性维生素:维生素C 50 mg ~250mg、维生素B1 1.2 mg ~10 mg、维生素B2 1.4mg ~3.6mg、维生素B6 1 mg ~6 mg、烟酰胺15 mg ~60mg、泛酸 5mg~20mg、叶酸150μg ~600μg、生物素20μg ~80μg;
(2)脂溶性维生素:维生素A 2000 IU ~4000 IU、维生素D3 200 IU ~600IU;
(3)微量元素:葡萄糖酸亚铁4.32 mg ~12.96mg、葡萄糖酸锌38.98 mg ~116.94 mg、葡萄糖酸铜1.7 mg ~5.1 mg、葡萄糖酸锰0.8105 mg ~2.4315 mg、葡萄糖酸钴6μg ~18 μg、氟化钠1.6 mg ~4.8 mg、碘化钠0.9 μg ~2.7 μg、亚硒酸钠117μg ~351μg、七钼酸铵23 μg ~69 μg、氯化铬38.5μg ~115.5 μg;
(4)氨基酸:异亮氨酸、亮氨酸、盐酸赖氨酸、精氨酸、酪氨酸、牛磺酸中的一种或多种,所述氨基酸的总量为10-50 mg;
还含有助溶剂、pH调节剂、抑菌剂、增稠剂、甜味剂、芳香剂、溶剂;
所述助溶剂为聚山梨酯80、丙二醇,所述聚山梨酯80用量为0.20%~0.50%,所述丙二醇用量为1.0%~3.0%,此处%含量是指溶质质量与口服溶液的体积百分含量,以g/100ml计;所述pH调节剂为枸橼酸和枸橼酸钠的组合;所述pH调节剂中枸橼酸用量为0.24%~0.50%、枸橼酸钠用量为0.25%~0.55%的二者组合物,此处%含量是指pH调节剂质量与口服溶液的体积百分含量,以g/100ml计;
所述抑菌剂为羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯、苯甲酸、苯甲酸钠中的一种或两种组合物;
所述增稠剂为黄原胶、羧甲纤维素钠、甲基纤维素、羟乙基纤维素中的一种或两种组合物;
所述甜味剂为蔗糖、安赛蜜、阿司帕坦、三氯蔗糖中的一种或两种组合物;
所述溶剂为纯化水。
2.根据权利要求1所述的复方维生素和微量元素口服溶液,其特征在于,每30ml口服溶液中含有以下:
(1)水溶性维生素:维生素C 100 mg ~200mg、维生素B1 1.5 mg ~6 mg、维生素B2 1.5mg ~3.0mg、维生素B6 1 mg ~4 mg、烟酰胺20 mg ~40mg、泛酸 8mg~16mg、叶酸250μg ~400μg、生物素40μg ~60μg;
(2)脂溶性维生素:维生素A 2500 IU ~3500 IU、维生素D3 300 IU ~500IU;
(3)微量元素:葡萄糖酸亚铁4.32 mg ~12.96mg、葡萄糖酸锌38.98 mg ~116.94 mg、葡萄糖酸铜1.7 mg ~5.1 mg、葡萄糖酸锰0.8105 mg ~2.4315 mg、葡萄糖酸钴6μg ~18 μg、氟化钠1.6 mg ~4.8 mg、碘化钠0.9 μg ~2.7 μg、亚硒酸钠117μg ~351μg、七钼酸铵23 μg ~69 μg、氯化铬38.5μg ~115.5 μg;
(4)氨基酸:异亮氨酸、亮氨酸、盐酸赖氨酸、精氨酸、酪氨酸、牛磺酸中的一种或多种,所述氨基酸的总量为20-50 mg。
3.根据权利要求1或2所述的复方维生素和微量元素口服溶液,其特征在于,
所述抑菌剂为苯甲酸钠;
所述增稠剂为羟乙基纤维素;
所述甜味剂为三氯蔗糖和安赛蜜。
4.权利要求1-3任一所述的复方维生素和微量元素口服溶液的制备方法,其特征在于,包括以下步骤:
(1)称取处方量70%的纯化水,加热至75±5℃,先加入增稠剂、抑菌剂,搅拌至溶解;
(2)依次加入葡萄糖酸亚铁、葡萄糖酸锌、葡萄糖酸铜、葡萄糖酸锰、葡萄糖酸钴,水温始终保持在75±5℃,搅拌至溶解,将水温降至25~35℃;
(3)依次加入维生素C、维生素B1、维生素B2、维生素B6、烟酰胺、泛酸、叶酸、生物素,搅拌至溶解;
(4)再依次加入氟化钠、碘化钠、亚硒酸钠、七钼酸铵、氯化铬,搅拌至溶解;再加入氨基酸、甜味剂和芳香剂;
(5)另行取处方量5%的纯化水,水温为25~35℃,加入助溶剂,再依次加入维生素A、维生素D3,搅拌至溶解;
(6)将步骤(5)的混合溶液加入步骤(4)获得的溶液中,用pH调节剂调节pH至4.0~5.0,加纯化水定容至处方量;过滤,灌封。
5.根据权利要求4所述的制备方法,其特征在于,所述增稠剂为羟乙基纤维素,其用量为0.1%~0.5%;此处%含量是指溶质质量与口服溶液的体积百分含量,以g/100ml计。
6.根据权利要求4所述的制备方法,其特征在于,所述步骤(4)中氨基酸为盐酸赖氨酸,其用量为每30ml口服溶液中含盐酸赖氨酸12.5 mg~50 mg。
7.根据权利要求4-6任一所述的制备方法制得的复方维生素和微量元素口服溶液。
8.根据权利要求4-6任一所述的制备方法在制备稳定性好的营养补充口服溶液中的应用。
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