CN116265011A - 布瓦西坦口服液制备及其制备方法 - Google Patents
布瓦西坦口服液制备及其制备方法 Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明涉及布瓦西坦口服溶液，更特别地是涉及一种具有优良药学性质的布瓦西坦口服溶液。本发明的布瓦西坦口服溶液，其包括：布瓦西坦、酸碱调节剂、矫味剂、防腐剂、增稠剂和水。本发明布瓦西坦口服溶液不但具有优良的化学稳定性，而且具有优良的生物学效果，例如具有优良的口服吸收效果。
Description
技术领域
本发明属于医药技术领域，涉及一种用于神经系统疾病的药物，布瓦西坦口服液制备及其制备方法。
背景技术
布瓦西坦具有高度亲和力，可选择性的结合突触囊泡蛋白2A(SV2A)，是AED左乙拉西坦的作用位点。SV2A位于突触前膜，参与调解神经递质的释放和囊泡循环进而维持着突触囊泡的正常功能。ChemicalbookAED与SV2A结合可减少兴奋性神经递质的释放，并通过调节脑内兴奋性递质和抑制性递质的平衡达到控制癫痫发作的效果。布瓦西坦的亲和力是左乙拉西坦的15-30倍，使其使用剂量降低约10倍。此外，口服剂型的给药是许多药品的首选给药途径，因为它提供了方便、低成本的给药。然而，一些患者如儿童或老人在被要求吞咽固体制剂（如片剂或胶囊）时可能会有问题。因此，开发一种液体口服制剂是可取的，因为它能提高病人的依从性。
发明内容
本发明涉及一种布瓦西坦的稳定溶液，该溶液的pH值在4.5和6.5之间布瓦西坦口服溶液，其包括：布瓦西坦、酸碱调节剂、矫味剂、防腐剂、增稠剂和水。
本发明涉及的布瓦西坦口服溶液，其特征在于以下任一项或多项：
(1)其每100ml中布瓦西坦的量为100~1000mg ；
(2)其中酸碱调节剂选自：盐酸、醋酸、磷酸、枸橼酸、酒石酸、富马酸、氢氧化钠、三乙胺、精氨酸、苹果酸、马来酸、山梨酸、琥珀酸、乳酸、枸橼酸钠、酒石酸钠等等及其组合；
(3)其中酸碱调节剂的量是使所得述溶液的pH值达到4. 5~6. 5范围内的量，例如使pH 值达到5. 0~6.0范围内的量；
(4)其中调味剂选自：蔗糖、果糖、山梨糖醇、糖精钠、甜菊苷、蔗糖素(又称氯化蔗糖)、阿司巴甜、三氯蔗糖、香精例如水溶性香精(例如草莓香精、桔子香精、菠萝香精、苹果香精、薄荷香精、拧檬香精、巧克力香精等)等等及其组合；
(5)所述口服溶液每100ml中调味剂的量为5~5000mg,例如5~2000mg，例如5~1000mg ；
(6)其中防腐剂选自：苯甲酸及其盐例如苯甲酸钠、泥泊金类(例如泥泊金甲酯、泥泊金乙酯、泥泊金丙酯、泥泊金丁酯)、三氯叔丁醇、苯甲醇等等及其组合；
(7)所述口服溶液每100ml中防腐剂量通常为10~500mg，例如为20~500mg,例如为50~250mg。
(8)所述口服溶液每100ml中增稠剂量通常为500~2500mg；
(9)其中还可以包含选自下列的多羟基醇：甘油、丙二醇及其组合，每100ml中包含的多羟基醇的量可以10000~100000mg，例如是15000~80000mg ；
本发明涉及所述布瓦西坦口服溶液中的方法，其包括以下步骤：
(1)使布瓦西坦、调味剂、防腐剂、和任选的其它辅料加至处方量的约80%的水中，搅拌使溶解；
(2)向所得溶液中添加酸碱调节剂并监测溶液的pH值使其达到处方规定的pH值范围；
(3)补加水至全量，较验溶液的pH值，必要时再添加酸碱调节剂以使溶液达到处方规定的pH值范围，即得。
具体实施例
下面的例子说明了本发明，但不限制其范围。
实施例1
| 原辅料名称 | 剂量mg/ml |
| 布瓦西坦 | 5.000 |
| 羟苯甲酯 | 1.000 |
| 柠檬酸 | 0.895 |
| 二水合物柠檬酸钠 | 2.940 |
| 羧甲基纤维素钠 | 5.000 |
| 三氯蔗糖 | 4.00 |
| 山梨醇溶液 | 239.80 |
| 甘油 | 152.00 |
| 覆盆子香精 | 5.600 |
| 纯化水 | 加至1ml |
制备方法：
1.在一个不锈钢桶中，转移90%的甘油并加入羟苯甲酯，通过加热并搅拌溶解，得溶液1，备用。
2.在另一个不锈钢桶中，转移纯净水搅拌溶解柠檬酸及二水合柠檬酸钠，至完全溶解；向其中加入布瓦西坦原料药，搅拌至其完全溶解，再依次溶解其他辅料得溶液2。
3.将溶液1与溶液2混合。
4.将水量添加至最终体积，并将制剂均匀化。
5.用pH计控制pH值（pH=5.6±0.3）。
实施例2
| 原辅料名称 | 剂量mg/ml |
| 布瓦西坦 | 10.00 |
| 羟苯甲酯 | 1.000 |
| 柠檬酸 | 0.895 |
| 二水合物柠檬酸钠 | 2.940 |
| 羧甲基纤维素钠 | 5.000 |
| 三氯蔗糖 | 40.00 |
| 山梨醇溶液 | 239.80 |
| 甘油 | 152.00 |
| 覆盆子香精 | 5.600 |
| 纯化水 | 加至1ml |
制备方法同实施例1，用pH计控制pH值（pH=5.4+0.2）。
实施例3
| 原辅料名称 | 剂量mg/ml |
| 布瓦西坦 | 1.00 |
| 羟苯甲酯 | 1.000 |
| 柠檬酸 | 0.895 |
| 二水合物柠檬酸钠 | 2.940 |
| 羧甲基纤维素钠 | 5.000 |
| 三氯蔗糖 | 40.00 |
| 山梨醇溶液 | 239.80 |
| 甘油 | 152.00 |
| 覆盆子香精 | 5.600 |
| 纯化水 | 加至1ml |
制备方法同实施例1，用pH计控制pH值（pH=5.5+0.2）。
对比实施例1
| 原辅料名称 | 剂量mg/ml |
| 布瓦西坦 | 10.00 |
| 羟苯甲酯 | 1.000 |
| 柠檬酸 | 1.895 |
| 二水合物柠檬酸钠 | 1.940 |
| 羧甲基纤维素钠 | 5.000 |
| 三氯蔗糖 | 40.00 |
| 山梨醇溶液 | 239.80 |
| 甘油 | 152.00 |
| 覆盆子香精 | 5.600 |
| 纯化水 | 加至1ml |
制备方法同实施例1，用pH计控制pH值（pH=3.5+0.2）。
对比实施例2
| 原辅料名称 | 剂量mg/ml |
| 布瓦西坦 | 1.00 |
| 羟苯甲酯 | 1.000 |
| 柠檬酸 | 0.895 |
| 二水合物柠檬酸钠 | 3.940 |
| 羧甲基纤维素钠 | 5.000 |
| 三氯蔗糖 | 40.00 |
| 山梨醇溶液 | 239.80 |
| 甘油 | 152.00 |
| 覆盆子香精 | 5.600 |
| 纯化水 | 加至1ml |
制备方法同实施例1，用pH计控制pH值（pH=7.0+0.2）。
对上述实施例与对比实施例放稳定性研究进行对比，如下表1。
表1各实施例与对比实施例稳定性样品研究对比表
综上所述，实施例1、2、3的pH值、含量和有关物质，均优于对比实施例1、2，说明本发明布瓦西坦口服溶液不但具有优良的化学稳定性，而且具有优良的生物学效果，例如具有优良的口服吸收效果。
Claims (3)
1.本发明涉及一种布瓦西坦的稳定溶液，该溶液的pH值在4.5和6.5之间布瓦西坦口服溶液，其包括：布瓦西坦、酸碱调节剂、矫味剂、防腐剂、增稠剂和水。
2.权利要求1的布瓦西坦口服溶液，其特征在于以下任一项或多项：
(1)其每100ml中布瓦西坦的量为100~1000mg ；
(2)其中酸碱调节剂选自：盐酸、醋酸、磷酸、枸橼酸、酒石酸、富马酸、氢氧化钠、三乙胺、精氨酸、苹果酸、马来酸、山梨酸、琥珀酸、乳酸、枸橼酸钠、酒石酸钠等等及其组合；
(3)其中酸碱调节剂的量是使所得述溶液的pH值达到4. 5~6. 5范围内的量，例如使pH值达到5. 0~6.0范围内的量；
(4)其中调味剂选自：蔗糖、果糖、山梨糖醇、糖精钠、甜菊苷、蔗糖素(又称氯化蔗糖)、阿司巴甜、三氯蔗糖、香精例如水溶性香精(例如草莓香精、桔子香精、菠萝香精、苹果香精、薄荷香精、拧檬香精、巧克力香精等)等等及其组合；
(5)所述口服溶液每100ml中调味剂的量为5~5000mg,例如5~2000mg，例如5~1000mg ；
(6)其中防腐剂选自：苯甲酸及其盐例如苯甲酸钠、泥泊金类(例如泥泊金甲酯、泥泊金乙酯、泥泊金丙酯、泥泊金丁酯)、三氯叔丁醇、苯甲醇等等及其组合；
(7)所述口服溶液每100ml中防腐剂量通常为10~500mg，例如为20~500mg,例如为 50~250mg。
(8)所述口服溶液每100ml中增稠剂量通常为500~2500mg；
(9)其中还可以包含选自下列的多羟基醇：甘油、丙二醇及其组合，每100ml中包含的多羟基醇的量可以10000~100000mg，例如是15000~80000mg。
3.制备权利要求1-2任一项所述布瓦西坦口服溶液中的方法，其包括以下步骤：
(1)使布瓦西坦、调味剂、防腐剂、和任选的其它辅料加至处方量的约80%的水中，搅拌使溶解；
(2)向所得溶液中添加酸碱调节剂并监测溶液的pH值使其达到处方规定的pH值范围；
(3)补加水至全量，较验溶液的pH值，必要时再添加酸碱调节剂以使溶液达到处方规定的pH值范围，即得。
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