CN114129529A - 一种西那卡塞度骨化醇片及其制备方法 - Google Patents
一种西那卡塞度骨化醇片及其制备方法 Download PDFInfo
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- 229960000413 doxercalciferol Drugs 0.000 claims abstract description 60
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 claims abstract description 60
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
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Abstract
本发明公开了一种西那卡塞度骨化醇片及其制备方法,该片剂由西那卡塞颗粒和度骨化醇颗粒经过双层压片技术压制成的双层片芯,然后在双层片芯外包裹胃溶性包衣。本发明在制备度骨化醇颗粒时采用高浓度、高粘稠溶液进行制粒,使具有成膜性的粘合剂材料包裹在度骨化醇表面再通过双层压片,从而最大限度使度骨化醇与西那卡塞隔绝,增加两主药的稳定性;通过制备度骨化醇颗粒与西那卡塞联合作用,制得的西那卡塞度骨化醇片服用后,能更有效地降低血清PTH水平,并可大大降低不良反应的发生率。
Description
技术领域
本发明属于生物医药制剂技术领域,更具体涉及一种西那卡塞度骨化醇片及其制备方法。
背景技术
度骨化醇是一种具有生物活性的维生素D2类似物,可进一步形成维生素1α-D2,在肝脏中代谢,对骨骼和肠道的影响较小。度骨化醇主要作用于甲状旁腺,能有效地抑制全段甲状旁腺激素(iPTH)的分泌,不良反应常见高钙血症,因此其应用受到了限制。盐酸西那卡塞是由美国NPS Pharmaceuticals公司研发的一种拟钙剂(calcimimetics),西那卡塞能够激活甲状旁腺中的钙受体,从而降低甲状旁腺素(PTH)的分泌,调节甲状旁腺钙受体的行为,通过增强受体对血流中钙水平的敏感性,降低甲状旁腺激素、钙、磷和钙-磷复合物的水平。西那卡塞主要用于治疗进行透析的慢性肾病(CKD)患者的继发性甲状旁腺功能亢进症以及甲状旁腺癌患者的高钙血症。西那卡塞服用时,应整片吞服,不能掰开,才能保证药物的药性。西那卡塞的主要副作用是轻、中度恶心和呕吐,也有少数患者出现低血钙的副作用,出现低血钙的发生率占比约为5%。
目前临床上,将西那卡塞与活性维生素D联合应用,取得了相对好的治疗效果。但是临床上,很难控制西那卡塞、活性维生素D的用药剂量,即使联合使用,用药后的不良反应的发生率下降比例不大,往往会在患者出现不良反应后,再调整用药。
发明内容
为了解决上述问题,本发明提供了一种西那卡塞度骨化醇片及其制备方法,制成的西那卡塞度骨化醇片为复方制剂,可有效降低PTH水平,并可降低不良反应的发生率,通过双层片芯的结构将两种活性成分作用机理不同的药剂以分开的实体制成一个复方制剂,有更优的疗效,改善患者适应性。
根据本发明的一个方面,提供了一种西那卡塞度骨化醇片,由西那卡塞颗粒和度骨化醇颗粒经过双层压片技术压制成的双层片芯,双层片芯外具有包衣层。度骨化醇颗粒包括度骨化醇、粘合剂、表面活性剂、水溶性填充剂、水不溶性填充剂、崩解剂和润滑剂,西那卡塞颗粒包括西那卡塞、填充剂、粘合剂、崩解剂和润滑剂。
作为本发明的进一步改进,每1000片片芯的处方中,
度骨化醇颗粒按重量百分比的组分包含:
西那卡塞颗粒按重量百分比的组分包含:
作为本发明的进一步改进,粘合剂为选自羟丙纤维素、聚维酮K30和羟丙甲纤维素中的一种或几种。
作为本发明的进一步改进,润滑剂选自硬脂酸镁、滑石粉和微粉硅胶中的一种或几种。
作为本发明的进一步改进,西那卡塞颗粒的填充剂选自微晶纤维素、玉米淀粉、部分预胶化淀粉、乳糖、磷酸氢钙和磷酸二氢钙中的一种或几种。
根据本发明的另一个方面,提供了一种西那卡塞度骨化醇片的制备方法,包括以下步骤:
步骤一:准备原料:称取处方量的原料,分别过100目筛备用;
步骤二:制备度骨化醇颗粒:制备粘合剂溶液,在顶驱式制粒机中,将过筛后的度骨化醇、表面活性剂分散在粘合剂溶液中,加入水溶性填充剂,搅拌混合均匀,再加入水不溶性填充剂和崩解剂,制成湿颗粒,干燥,整粒,加入润滑剂,得到度骨化醇颗粒;
步骤三:制备西那卡塞颗粒:将过筛后的西那卡塞、填充剂、粘合剂、崩解剂混合均匀,采用干法制粒,然后加入润滑剂,得到西那卡塞颗粒;
步骤四:将度骨化醇颗粒和西那卡塞颗粒分别置于不同饲料斗中,在双层压片机上压制成上下两层的双层片芯;
步骤五:包衣,在双层片芯外形成包衣层,得到西那卡塞度骨化醇片。
作为本发明的进一步改进,所述步骤二中制成的湿颗粒需要过40~60目筛,所述步骤三中通过干法制粒后得到的颗粒需要过40~60目筛。
作为本发明的进一步改进,步骤二中,制备粘合剂溶液的溶剂为乙醇水溶液。
作为本发明的进一步改进,粘合剂溶液为聚维酮K30的乙醇水溶液,用于制备粘合剂溶液的乙醇水溶液中乙醇的质量百分比为90%,聚维酮K30在粘合剂溶液中的质量百分比为20%。
作为本发明的进一步改进,包衣层为胃溶性包衣层。
本发明的优点是:本发明的制备方法中,制备度骨化醇颗粒时,先将主药度骨化醇和表面活性剂分散在粘合剂溶液中,将主药用粘合剂材料充分包裹,此时物料状态为溶液,再加入水溶性填充剂充分混匀,然后再加入水不溶性填充剂和其它辅料进行制粒,能有效提高度骨化醇在颗粒中的均匀分布,且采用高浓度、高粘稠溶液进行制粒,使具有成膜性的粘合剂材料包裹在度骨化醇表面再通过双层压片,从而最大限度使度骨化醇与西那卡塞隔绝,增加两主药的稳定性;本发明制备的度骨化醇颗粒与西那卡塞联合作用,能更有效地降低血清PTH水平,并可大大降低不良反应的发生率。
具体实施方式
下面结合具体实施方式对本发明作进一步的说明。
本发明所述一实施方式的一种西那卡塞度骨化醇片,该片剂由西那卡塞颗粒和度骨化醇颗粒经过双层压片技术压制成双层片芯,且片芯外具有包衣层,度骨化醇颗粒包括度骨化醇、粘合剂、表面活性剂、水溶性填充剂、水不溶性填充剂、崩解剂和润滑剂,西那卡塞颗粒包括西那卡塞、填充剂、粘合剂、崩解剂和润滑剂。
度骨化醇颗粒制粒时,先将度骨化醇和表面活性剂分散在粘合剂溶液中,再加入水溶性填充剂混匀,然后加入其它辅料进行制粒。在度骨化醇颗粒制粒过程中,先将主药用粘合剂材料充分包裹,此时物料状态为溶液,然后在水溶性辅料中分散,然后再采用水不溶性辅料进行制粒,能有效提高度骨化醇在颗粒中的均匀分布和亲水性,从而提高其释放。
粘合剂为具有成膜性的高分子材料,粘合剂为选自羟丙纤维素、聚维酮K30和羟丙甲纤维素中的一种或几种。度骨化醇颗粒制备时的粘合剂溶液的溶剂为乙醇水溶液,粘合剂溶液优选为聚维酮K30的乙醇水溶液,进一步的用于制备粘合剂溶液的乙醇水溶液中乙醇的质量百分比为90%,聚维酮K30在粘合剂溶液中的质量百分比为20%,制备的粘合剂溶液为近似胶状溶液。
表面活性剂选用十二烷基硫酸钠。水溶性填充剂选自乳糖、蔗糖、甘露醇、山梨醇中的一种或几种。水不溶性填充剂选自淀粉、微晶纤维素中的一种或两种。崩解剂选自交联羧甲基纤维素钠、交联聚维酮中的一种或两种。润滑剂选自硬脂酸镁、滑石粉和微粉硅胶中的一种或几种。
西那卡塞颗粒的填充剂选自微晶纤维素、玉米淀粉、部分预胶化淀粉、乳糖、磷酸氢钙和磷酸二氢钙中的一种或几种。优选为微晶纤维素、玉米淀粉、部分预胶化淀粉、乳糖中的一种或者两种以上(含两种)。
实施例1
西那卡塞度骨化醇片,1000片片芯的处方中,
制备度骨化醇层的原料组分如下:
制备西那卡塞层的原料组分如下:
该西那卡塞度骨化醇片的制备方法,步骤如下:
步骤一:按照上述的处方比例,准备原料,并将固体原料,分别过100目筛备用;
步骤二:在顶驱式制粒机中,按照处方比例将度骨化醇、十二烷基硫酸钠、羟丙纤维素按比例高度分散在浓度20%聚维酮K30-90%乙醇水溶液中,加入水溶性填充剂,搅拌混合均匀,再加入微晶纤维素和崩解剂,制成40~60目的湿颗粒,60℃干燥60min,整粒过40目筛,加入硬脂酸镁混匀,制得度骨化醇颗粒;
步骤三:按照处方比例将西那卡塞、微晶纤维素、玉米淀粉、交联聚维酮和羟丙基纤维素混合均匀,采用干法制粒,粒度控制在40目~60目,然后加入适量的硬脂酸镁和滑石粉,制得西那卡塞颗粒;
步骤四:将制得的度骨化醇颗粒和西那卡塞颗粒分别置于不同饲料斗中,在双层压片机上压制成上下两层的双层片芯;
步骤五:包衣,在双层片芯外形成胃溶性包衣层,得到西那卡塞度骨化醇片。
实施例2
西那卡塞度骨化醇片,1000片片芯的处方中,
制备度骨化醇层的原料组分如下:
制备西那卡塞层的原料组分如下:
该西那卡塞度骨化醇片的制备方法,步骤如下:
步骤一:按照上述的处方比例,准备原料,并将固体原料,分别过100目筛备用;
步骤二:在顶驱式制粒机中,按照处方比例将度骨化醇、十二烷基硫酸钠、羟丙纤维素按比例高度分散在浓度20%聚维酮K30-90%乙醇水溶液中,加入水溶性填充剂,搅拌混合均匀,再加入微晶纤维素和崩解剂,制成40~60目的湿颗粒,60℃干燥60min,整粒过40目筛,加入硬脂酸镁混匀,制得度骨化醇颗粒;
步骤三:按照处方比例将西那卡塞、微晶纤维素、乳糖、交联羧甲基纤维素钠和羟丙基纤维素混合均匀,采用干法制粒,粒度控制在40目~60目,然后加入适量的硬脂酸镁,制得西那卡塞颗粒;
步骤四:将制得的度骨化醇颗粒和西那卡塞颗粒分别置于不同饲料斗中,在双层压片机上压制成上下两层的双层片芯;
步骤五:包衣,在双层片芯外形成胃溶性包衣层,得到西那卡塞度骨化醇片。
实施例3
西那卡塞度骨化醇片,1000片片芯的处方中,
制备度骨化醇层的原料组分如下:
制备西那卡塞层的原料组分如下:
该西那卡塞度骨化醇片的制备方法,步骤如下:
步骤一:按照上述的处方比例,准备原料,并将固体原料,分别过100目筛备用;
步骤二:在顶驱式制粒机中,按照处方比例将度骨化醇、表面活性剂、羟丙纤维素混合均匀,分散在浓度20%聚维酮K30-90%乙醇水溶液中,逐渐加入乳糖,搅拌混合均匀,再加入微晶纤维素和交联羧甲基纤维素钠,制成40~60目的湿颗粒,60℃干燥60min,整粒过40目筛,加入硬脂酸镁混匀,制得度骨化醇颗粒;
步骤三:将西那卡塞、微晶纤维素、乳糖、交联羧甲基纤维素钠和羟丙基纤维素混合均匀,采用干法制粒,粒度控制在40目~60目,然后加入适量的硬脂酸镁,制得西那卡塞颗粒;
步骤四:将制得的度骨化醇颗粒和西那卡塞颗粒分别置于不同饲料斗中,在双层压片机上压制成上下两层的双层片芯;
步骤五:包衣,在双层片芯外形成胃溶性包衣层,得到西那卡塞度骨化醇片。
实施例4
西那卡塞度骨化醇片,1000片片芯的处方中,
制备度骨化醇层的原料组分如下:
制备西那卡塞层的原料组分如下:
该西那卡塞度骨化醇片的制备方法,步骤如下:
步骤一:按照上述的处方比例,准备原料,并将固体原料,分别过100目筛备用;
步骤二:在顶驱式制粒机中,按照处方比例将度骨化醇、表面活性剂、羟丙纤维素混合均匀,分散在浓度20%聚维酮K30-90%乙醇水溶液中,逐渐加入乳糖,搅拌混合均匀,再加入微晶纤维素和交联羧甲基纤维素钠,制成40~60目的湿颗粒,60℃干燥60min,整粒过40目筛,加入硬脂酸镁混匀,制得度骨化醇颗粒;
步骤三:将西那卡塞、微晶纤维素、玉米淀粉、交联聚维酮和羟丙基纤维素混合均匀,采用干法制粒,粒度控制在40目~60目,然后加入适量的硬脂酸镁和滑石粉,制得西那卡塞颗粒;
步骤四:将制得的度骨化醇颗粒和西那卡塞颗粒分别置于不同饲料斗中,在双层压片机上压制成上下两层的双层片芯;
步骤五:包衣,在双层片芯外形成胃溶性包衣层,得到西那卡塞度骨化醇片。
本发明的制备方法中,制备度骨化醇颗粒时,先将主药度骨化醇和表面活性剂分散在粘合剂溶液中,将主药用粘合剂材料充分包裹,此时物料状态为溶液,再加入水溶性填充剂充分混匀,然后再加入水不溶性填充剂和其它辅料进行制粒,能有效提高度骨化醇在颗粒中的均匀分布。且采用高浓度、高粘稠溶液进行制粒,使具有成膜性的粘合剂材料包裹在度骨化醇表面再通过双层压片,从而最大限度使度骨化醇与西那卡塞隔绝,增加两主药的稳定性。本发明制备的度骨化醇颗粒并与西那卡塞联合作用,能更有效地降低血清PTH水平,并可大大降低不良反应的发生率。
以上所述的仅是本发明的一些实施方式,应当指出,对于本领域的普通技术人员来说,在不脱离本发明的创造构思的前提下,还可以做出其它变形和改进,这些都属于本发明的保护范围。
Claims (10)
1.一种西那卡塞度骨化醇片,其特征在于,由西那卡塞颗粒和度骨化醇颗粒经过双层压片技术压制成的双层片芯,所述双层片芯外具有包衣层,度骨化醇颗粒包括度骨化醇、粘合剂、表面活性剂、水溶性填充剂、水不溶性填充剂、崩解剂和润滑剂,所述西那卡塞颗粒包括西那卡塞、填充剂、粘合剂、崩解剂和润滑剂。
3.根据权利要求2所述的西那卡塞度骨化醇片,其特征在于,所述粘合剂为选自羟丙纤维素、聚维酮K30和羟丙甲纤维素中的一种或几种。
4.根据权利要求2所述的西那卡塞度骨化醇片,其特征在于,所述润滑剂选自硬脂酸镁、滑石粉和微粉硅胶中的一种或几种。
5.根据权利要求2所述的西那卡塞度骨化醇片,其特征在于,所述西那卡塞颗粒的填充剂选自微晶纤维素、玉米淀粉、部分预胶化淀粉、乳糖、磷酸氢钙和磷酸二氢钙中的一种或几种。
6.权利要求1至5任意一项所述的一种西那卡塞度骨化醇片的制备方法,其特征在于,包括以下步骤:
步骤一:准备原料:称取处方量的原料,分别过100目筛备用;
步骤二:制备度骨化醇颗粒:制备粘合剂溶液,在顶驱式制粒机中,将过筛后的度骨化醇、表面活性剂分散在粘合剂溶液中,加入水溶性填充剂,搅拌混合均匀,再加入水不溶性填充剂和崩解剂,制成湿颗粒,干燥,整粒,加入润滑剂,得到度骨化醇颗粒;
步骤三:制备西那卡塞颗粒:将过筛后的西那卡塞、填充剂、粘合剂、崩解剂混合均匀,采用干法制粒,然后加入润滑剂,得到西那卡塞颗粒;
步骤四:将度骨化醇颗粒和西那卡塞颗粒分别置于不同饲料斗中,在双层压片机上压制成上下两层的双层片芯;
步骤五:包衣,在双层片芯外形成包衣层,得到西那卡塞度骨化醇片。
7.根据权利要求6所述的西那卡塞度骨化醇片的制备方法,其特征在于,所述步骤二中制成的湿颗粒需要过40~60目筛,所述步骤三中通过干法制粒后得到的颗粒需要过40~60目筛。
8.根据权利要求6所述的西那卡塞度骨化醇片的制备方法,其特征在于,所述步骤二中,制备粘合剂溶液的溶剂为乙醇水溶液。
9.根据权利要求8所述的西那卡塞度骨化醇片的制备方法,其特征在于,所述粘合剂溶液为聚维酮K30的乙醇水溶液,用于制备所述粘合剂溶液的乙醇水溶液中乙醇的质量百分比为90%,聚维酮K30在粘合剂溶液中的质量百分比为20%。
10.根据权利要求6所述的西那卡塞度骨化醇片的制备方法,其特征在于,所述包衣层为胃溶性包衣层。
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