CN114557980A - 一种骨化三醇缓释微丸及其制备方法 - Google Patents
一种骨化三醇缓释微丸及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种骨化三醇缓释微丸及其制备方法,所述缓释微丸由含药丸芯和缓释包衣层组成,其中含药丸芯含有骨化三醇、羧甲基纤维素钠、填充剂、粘合剂;缓释包衣膜包含缓释骨架材料、遮光剂、增塑剂、润滑剂和纯化水。本发明所得缓释微丸所得制剂缓释效果好,能够保持核心组分在24h的缓慢释放,有效维持产品的血药浓度,显著提升患者对本产品的顺应度。
Description
技术领域
本发明属于医药制剂技术领域。具体涉及一种骨化三醇缓释微丸及其制备方法
背景技术
骨化三醇(Calcitriol)又名1,25-二羟维生素D3,为维生素D3经肝脏和肾脏羟化酶代谢为抗佝偻病活性最强的1,25-二羟代谢物。骨化三醇最早由瑞士罗氏公司生产,1978年上市,商品名为“Rocaltrol”,用于治疗绝经后骨质疏松、慢性肾功能低下、术后甲状腺功能低下、特发性甲状旁腺功能低下、假性甲状腺功能低下、维生素D依赖性佝偻病、低血磷性维生素D抵抗型佝偻病等。
骨化三醇的生物合成途径为7-脱氢胆固醇在皮肤内经紫外线照射后生成维生素D3,维生素D3在肝脏中经羟化酶系的作用形成25-羟胆钙化醇,继而经血液被转运到肾脏,肾脏近曲小管细胞中羟化酶被25-羟胆钙化醇羟化为骨化三醇。
目前市售的骨化三醇大多为口服固体制剂,其中以片剂应用最为广泛,口服本品,血浆药物浓度达峰值时间为3-6小时,7小时后尿钙水平会增加,生物反应与剂量有关,血浆半衰期为3.5-6小时。目前市场上的药片规格为0.25μg/片,一日服用两次,服用本品的群体以老年人居多,一日两次的用药常会导致患者适应性较差,并且药物不能按时服用。
此外,骨化三醇的稳定性较差,对光和空气十分敏感,产品不适合长时间储存,因此开发一种缓释效果好、适合长时间存储的骨化三醇缓释制剂十分必要。
发明内容
本发明提供一种骨化三醇缓释微丸及其制备方法,本发明通过构建缓释丸芯与缓释包衣二元体系提供一种缓释效果好,产品质量稳定的骨化三醇缓释制剂,其中通过研究发现在制备骨化三醇缓释制剂过程中包衣膜的存在会导致缓释效果下降,但是通过加入合适量的羧甲基纤维素钠可以有效的解决缓释效果差的问题,另外通过合理搭配缓释制剂与其他药用辅料的比例,有效实现缓释效果的呈现,具体的本发明采用如下技术方案:
一种骨化三醇缓释微丸,所述缓释微丸由含药丸芯和缓释包衣层组成,其中含药丸芯含有骨化三醇、羧甲基纤维素钠、填充剂、粘合剂;缓释包衣膜包含缓释骨架材料、遮光剂、增塑剂、润滑剂和纯化水。
进一步优选的,所述骨化三醇与羧甲基纤维素钠的质量百分比为1:2-15。
进一步优选的,所述骨化三醇与羧甲基纤维素钠的质量百分比为1:4。
进一步优选的,所述遮光剂为二氧化钛或氧化铁。
进一步优选的,所述填充剂选自甘露醇、淀粉、微晶纤维素中的一种或多种。
进一步优选的,所述缓释骨架材料为Eudragit NE30D、Eudragit RL 30D、Eudragit RS 30D、Eudragit RL-PO、Eudragit RS-PO一种或者多种。
进一步优选的,所述缓释微丸胶囊按质量百分含量组成如下:
丸芯处方:
缓释包衣膜处方:
进一步优选的,所述缓释微丸胶囊按质量百分含量组成如下:
丸芯处方:
缓释包衣膜处方:
进一步优选的,本发明还提供的一种骨化三醇缓释微丸主要通过如下方法制备,
1)将骨化三醇与羧甲基纤维素钠置于乙醇溶液中搅拌、喷雾干燥、将所得干燥后的骨化三醇与羧甲基纤维素钠的混合物与填充剂充分混匀,向混匀体系加入稀释后的粘合剂溶液制备软材;软材挤出滚圆得到微丸;
2)将缓释骨架材料、遮光剂、增塑剂、润滑剂混合均匀,加入适量纯化水,搅拌均匀制得包衣液;
3)滚圆后的微丸过筛,流化床干燥、流化床缓释包衣得到骨化三醇缓释微丸。本发明具有如下技术优势:
(1)本发明所制备的骨化三醇缓释微丸胶囊是由骨化三醇与羧甲基纤维素钠结合制成的多个小单元微丸组成,所得制剂缓释效果好,能够保持核心组分在24h的缓慢释放,有效维持产品的血药浓度,有效提升患者对本产品的顺应度。
(2)另外本发明所得制剂克服骨化三醇制剂稳定性差,对光不稳定的问题,有效延长所得制剂的货架期。
(3)本发明制备方法简单,采用的辅料价格低,工艺步骤少,适合大规模工业化生产。
附图说明
图1为实施例1-4与对比实施例1-5在不同时间点的释放度结果图;
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仪用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比率、比例或份数按重量计。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
实施例1:制剂处方
丸芯处方:
缓释包衣膜处方:
制备方法:
1)将骨化三醇与羧甲基纤维素钠置于乙醇溶液中搅拌、喷雾干燥、将所得干燥后的骨化三醇与羧甲基纤维素钠的混合物与填充剂充分混匀,向混匀体系加入稀释后的粘合剂溶液制备软材;软材挤出滚圆得到微丸;
2)将处方量缓释骨架材料、遮光剂、增塑剂、润滑剂混合均匀,加入适量纯化水,搅拌均匀制得包衣液;
3)滚圆后的微丸过筛,流化床干燥、流化床缓释包衣得到骨化三醇缓释微丸。
所得微丸经过制剂的常规加工可以进一步制备得到骨化三醇缓释微丸压制的片剂或者制备的胶囊。
实施例2:制剂处方
丸芯处方:
缓释包衣膜处方:
制备方法同实施例1实施例3:制剂处方
丸芯处方:
缓释包衣膜处方:
制备方法同实施例1
实施例4:制剂处方
丸芯处方:
缓释包衣膜处方:
对比实施例1:制剂处方
丸芯处方:
骨化三醇 5份
微晶纤维素 90份
30%乙醇溶液 5份
缓释包衣膜处方:
制备方法同实施例1
对比实施例2:制剂处方
丸芯处方:
缓释包衣膜处方:
制备方法同实施例1
对比实施例3:制剂处方
丸芯处方:
缓释包衣膜处方:
对比实施例4:制剂处方
丸芯处方:
缓释包衣膜处方:
对比实施例5
片芯处方
制备方法:
将骨化三醇、HPMC K4M、乳糖过筛、混合均匀,用95%的乙醇溶液润湿制软材,过筛、制粒,干燥;加入硬脂酸镁和滑石粉,混合均匀,将混合物压片得片芯,将醋酸纤维素、PEG6000以及骨化三醇加入适量水中制备包衣液,用包衣液包衣,干燥,即得。
二、稳定性考察
分别取实施例1-4余对比实施例1-5制备的骨化三醇缓释微丸,对其进行铝塑泡罩包装后,于高温(40±2℃)、高湿(RH75%±5%)、强光(4500lx±500lx)条件下分别放置0天、5天和10天的核有关物质的含量,其中有关物质的含量测定采用高效液相色谱法测定,其中HPLC的条件是:色谱;ODS-C18柱,以十八烷基硅烷键合硅胶为填充剂;流动相;乙腈-水(75:25);检测波长:265nm;流速:1.0mL/min;进样量;50μL。理论塔板数按骨化三醇峰计算应不低5000,骨化三醇峰与反式骨化三醇峰之间的分离度应大于1.0,采用外标法计算含量。图1实施例与对比实施例有关物质含量。
根据稳定性实验可以得出,本发明所得缓释微丸制剂的稳定性较高,在高温、高湿以及强光条件下均能保持较好的稳定性。
三.释放度测定实验
释放度测定法按照中国药典2020年版四部通则0931第二法测定。采用第二法装置,以0.1mol/L的盐酸溶液700ml为溶出介质,转速每分钟75转,依法操作,经1小时、2小时、4小时、8小时、12小时、16小时、24小时分别取样20ml。滤过,并及时在操作容器中补充相同温度的溶出介质20ml,精密量取续滤液5ml,置100ml量瓶中,用0.1mol/L的盐酸溶液稀释至刻度,作为待测溶液;在262nm的波长处分别测定实施例与对比实施例的吸收度,计算实施例1-4与对比实施例1-5在不同时间的释放量,具体释放结果见图1。
根据实施例1-4与对比实施例1-5的实验结果可以看出,本发明所得制剂的缓释效果好,药物释放速度均匀,并且缓释时间长,从缓释实验也可以得出在本发明中羧甲基纤维素钠的选择以及重量组成极为重要,该成分影响缓释效果的最终结果,对缓释的释放速率以及缓释时间至关重要。另外,本发明组分含量和各组分的配比对缓释效果也有重要影响。
Claims (9)
1.一种骨化三醇缓释微丸,其特征在于,所述缓释微丸由含药丸芯和缓释包衣层组成,其中含药丸芯含有骨化三醇、羧甲基纤维素钠、填充剂、粘合剂;缓释包衣层包含缓释骨架材料、遮光剂、增塑剂、润滑剂和纯化水。
2.如权利要求1所述的骨化三醇缓释微丸,其特征在于,所述骨化三醇与羧甲基纤维素钠的质量百分比为1:2-15。
3.如权利要求1所述的骨化三醇缓释微丸,其特征在于,所述骨化三醇与羧甲基纤维素钠的质量百分比为1:4。
4.如权利要求1所述的骨化三醇缓释微丸,其特征在于,所述遮光剂为二氧化钛或氧化铁。
5.如权利要求1所述的骨化三醇缓释微丸,其特征在于,所述填充剂选自甘露醇、淀粉、微晶纤维素中的一种或多种。
6.如权利要求1所述的骨化三醇缓释微丸,其特征在于,所述缓释骨架材料为EudragitNE 30D、Eudragit RL 30D、Eudragit RS 30D、Eudragit RL-PO、Eudragit RS-PO一种或者多种。
9.一种制备权利要求1-7所述骨化三醇缓释微丸的制备方法,其特征在于所述方法依次包括如下步骤:
1)将骨化三醇与羧甲基纤维素钠置于乙醇溶液中搅拌、喷雾干燥、将所得干燥后的骨化三醇与羧甲基纤维素钠的混合物与填充剂充分混匀,向混匀体系加入稀释后的粘合剂溶液制备软材;软材挤出滚圆得到微丸;
2)将缓释骨架材料、遮光剂、增塑剂、润滑剂混合均匀,加入适量纯化水,搅拌均匀制得包衣液;
3)滚圆后的微丸过筛,流化床干燥、流化床缓释包衣得到骨化三醇缓释微丸。
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CN110934853A (zh) * | 2019-12-30 | 2020-03-31 | 鲁南制药集团股份有限公司 | 一种枸橼酸莫沙必利缓释微丸胶囊及其制备方法 |
CN111544418A (zh) * | 2020-05-20 | 2020-08-18 | 正大制药(青岛)有限公司 | 一种帕立骨化醇胶囊剂 |
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CN110934853A (zh) * | 2019-12-30 | 2020-03-31 | 鲁南制药集团股份有限公司 | 一种枸橼酸莫沙必利缓释微丸胶囊及其制备方法 |
CN111544418A (zh) * | 2020-05-20 | 2020-08-18 | 正大制药(青岛)有限公司 | 一种帕立骨化醇胶囊剂 |
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