CN102137663A - 抑制变色的稳定的药物制剂 - Google Patents
抑制变色的稳定的药物制剂 Download PDFInfo
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- CN102137663A CN102137663A CN2009801342323A CN200980134232A CN102137663A CN 102137663 A CN102137663 A CN 102137663A CN 2009801342323 A CN2009801342323 A CN 2009801342323A CN 200980134232 A CN200980134232 A CN 200980134232A CN 102137663 A CN102137663 A CN 102137663A
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- polyvinyl alcohol
- acid
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- ascorbic acid
- solid pharmaceutical
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract 3
- 238000002845 discoloration Methods 0.000 title abstract 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 64
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 55
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 55
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 31
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 31
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims description 40
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 16
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims description 13
- 229960004172 pyridoxine hydrochloride Drugs 0.000 claims description 13
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 claims description 13
- 239000011764 pyridoxine hydrochloride Substances 0.000 claims description 13
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 12
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 claims description 12
- 229960002079 calcium pantothenate Drugs 0.000 claims description 12
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- 229940055726 pantothenic acid Drugs 0.000 claims description 6
- 235000019161 pantothenic acid Nutrition 0.000 claims description 6
- 239000011713 pantothenic acid Substances 0.000 claims description 6
- 235000008160 pyridoxine Nutrition 0.000 claims description 6
- 239000011677 pyridoxine Substances 0.000 claims description 6
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 6
- 235000013878 L-cysteine Nutrition 0.000 claims description 3
- 239000004201 L-cysteine Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 22
- 238000009472 formulation Methods 0.000 abstract description 9
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 abstract 2
- 229960000401 tranexamic acid Drugs 0.000 abstract 2
- 238000002360 preparation method Methods 0.000 description 27
- 239000008187 granular material Substances 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 18
- 229920002678 cellulose Polymers 0.000 description 18
- 239000001913 cellulose Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 12
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- 229960003943 hypromellose Drugs 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
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- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 239000007921 spray Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
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- 229920001223 polyethylene glycol Polymers 0.000 description 4
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
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- 206010008570 Chloasma Diseases 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
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- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010040829 Skin discolouration Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- HHCCNQLNWSZWDH-UHFFFAOYSA-N n-hydroxymethanimine oxide Chemical compound O[N+]([O-])=C HHCCNQLNWSZWDH-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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Classifications
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Abstract
本发明提供一种包含凝血酸和抗坏血酸的内服用固体药物制剂,其不发生变色且稳定性极好。该内服用固体药物制剂的特征在于,通过向包含凝血酸和抗坏血酸的制剂中添加聚乙烯醇共聚物和/或部分皂化的聚乙烯醇而组成该制剂。
Description
技术领域
本发明涉及一种口服用固体药物制剂,该制剂即使包含凝血酸和抗坏血酸时也不太可能发生变色。
背景技术
凝血酸具有抗出血(作为抗纤溶酶)、抗过敏和抗炎症等作用,被广泛用作处方药,并且也被配合在OTC药品中。1979年报道了将凝血酸给予慢性荨麻疹病患时,与荨麻疹同时出现在该病患中的黄褐斑消失了,此后,开始将凝血酸用于治疗黄褐斑的处方(参见,例如非专利文献1)。
很久之前就已经知道,抗坏血酸抑制黑色素的产生,并且因为抗坏血酸对已经积累的黑色素的分解作用,它还抑制色素沉着。就OTC药品而言,在含有维生素C作为基本成分的制剂的已核准适应症中,包括有黑点、雀斑、由晒伤或皮疹引起的色素沉着(参见非专利文献2)。
此外,已经公开了用于治疗色素沉着的含有凝血酸和抗坏血酸的制剂,并且报道了,与将凝血酸或抗坏血酸作为单一药物给予的情况相比,该制剂显示出对色素沉着的改善程度更好(参见专利文献1)。
此外,本发明人公开了含有凝血酸、抗坏血酸和L-半胱氨酸的皮肤美白组合物,并且发现与同时使用凝血酸和抗坏血酸相比,色素沉着进一步被抑制(参见专利文献2)。在专利文件2的制剂例中,公开了一种片剂,其除了上述三种组分作为有效成分外,还包含结晶纤维素、玉米淀粉、低取代水平的羟丙基纤维素、羟丙基纤维素、硬脂酸镁、羟丙甲纤维素、聚乙二醇、滑石粉和氧化钛作为添加剂。
此外,在专利文献3的制剂例中,公开了一种片剂,其除了凝血酸、抗坏血酸、L-半胱氨酸、吡哆醇盐酸盐和泛酸钙作为有效成分外,还包含结晶纤维素、玉米淀粉、低取代水平的羟丙基纤维素、羟丙基纤维素、硬脂酸镁、羟丙甲纤维素、聚乙二醇、滑石粉和氧化钛作为药物添加剂(参见专利文献3)。
另一方面,随着牛海绵状脑变(BSE)问题的出现,已经将聚乙烯醇与可聚合乙烯单体通过共聚合反应获得的聚乙烯醇共聚物(PVA共聚物)用作无明胶的胶囊材料(参见,例如专利文献4)。除胶囊以外,公开了PVA共聚物作为片剂或颗粒剂的包衣剂(专利文献5)或作为药物粘合剂(专利文献6)的医药用途。
此外,通过聚醋酸乙烯酯的皂化作用获得的部分皂化的聚乙烯醇具有78至96mol%的皂化度。至于医药应用,将部分皂化的聚乙烯醇用作片剂或颗粒剂的包衣剂、药物粘合剂或类似物(参见,例如非专利文献3)。
然而,目前还没有公开含有凝血酸、抗坏血酸等作为有效成分,并且进一步含有聚乙烯醇作为添加剂的制剂,更没有公开进一步含有聚乙烯醇共聚物和/或部分皂化的聚乙烯醇作为额外添加剂的制剂。
[现有技术文献]
[专利文献]
[专利文献1]:JP-A-4-243825
[专利文献2]:JP-A-2004-217655
[专利文献3]:JP-A-2005-314403
[专利文献4]:JP-A-2007-091670
[专利文献5]:JP-A-2007-022938
[专利文献6]:WO2005/019286
[非专利文献]
[非专利文献1]:Pharmacia Vol.44,No.5,2008,pp.437-442
[非专利文献2]:Ippan-yo Iyakuhin Seizo(Yunyu)Shonin Kijun(Approval Standards for Manufacturing of Non-Prescription Drugs(Import)),Jiho,2008
[非专利文献3]:Iyakuhin Tenkabutsu Jiten(Japanese Pharmaceutical Excipients Directory)2005,Yukuji Nippo Limited,2005
发明内容
[要解决的技术问题]
本发明人实际上是在试验基础上生产了专利文献1的实施例1中公开的含有凝血酸与抗坏血酸的颗粒剂,并意识到该颗粒剂在经历长期保存时逐渐变色(赤变)(在温度为40℃,相对湿度为75%的加速试验中)的问题。
也就是说,本发明的目的是提供一种口服用固体制剂,其包含凝血酸和抗坏血酸,并且稳定性极好,不发生变色。
[解决问题的手段]
为了解决上述问题,本发明人反复试验进行了广泛研究以找出哪种添加剂对包含凝血酸和抗坏血酸作为有效成分的制剂的稳定性做出的贡献最大。
结果,本发明人发现一个惊人的事实,当将聚乙烯醇共聚物和/或部分皂化的聚乙烯醇添加到包含凝血酸和抗坏血酸的制剂中时,可以显著防止该制剂的变色。
此外,本发明人发现,当将聚乙烯醇共聚物和/或部分皂化的聚乙烯醇作为造粒粘合剂用于本发明的制剂中时,可以显著防止该制剂的变色,由此完成本发明。
也就是说,本发明涉及:
(1)一种包含凝血酸和抗坏血酸的口服用固体药物制剂,其特征在于,所述固体药物制剂进一步包含聚乙烯醇共聚物和/或部分皂化的聚乙烯醇,并且本发明的优选实施方式如下所示:
(2)(1)中所述的口服用固体药物制剂,其特征在于,进一步包含L-半胱氨酸;
(3)(1)或(2)中所述的口服用固体药物制剂,其特征在于,进一步包含泛酸和/或吡哆醇;
(4)(3)中所述的口服用固体药物制剂,其中所述吡哆醇为吡哆醇盐酸盐;以及
(5)(3)或(4)中所述的口服用固体药物制剂,其中所述泛酸为泛酸钙。
[发明的效果]
本发明的制剂是稳定的并且有益的,因为即使其中加入有凝血酸和抗坏血酸,也能防止变色。而且,本发明是有益的,因为它可以用于获得稳定的制剂,其中即使该制剂中进一步加入有诸如L-半胱氨酸、吡哆醇盐酸盐和泛酸钙的有效成分,也能防止变色。
具体实施方式
本发明中的“吡哆醇”包括吡哆醇及其盐,并且优选为吡哆醇盐酸盐。
本发明中的“泛酸”包括泛酸及其盐,并且优选为泛酸钙。
本发明中的凝血酸、抗坏血酸、泛酸钙和吡哆醇盐酸盐分别列举在日本药典第15版中。
本发明中的L-半胱氨酸和部分皂化的聚乙烯醇列举在例如,日本药学辅料2003中。
本发明中的“部分皂化的聚乙烯醇”是通过醋酸乙烯酯的聚合反应获得的部分皂化的聚醋酸乙烯酯聚合物,并且通常具有78至96mol%的皂化度,并且优选地具有2至100mm2/S的粘度。
本发明中使用的部分皂化的聚乙烯醇是以商品名“Gosenol”(The Nippon Synthetic Chemical Industry Co.,Ltd)而商业可得的,因此可以容易地得到。
此外,包含部分皂化的聚乙烯醇的薄膜包衣基剂(base)是以商品名“Opadry II”(Colorcon Japan Limited)而商业可得的,因此可以容易地得到。
本发明的“聚乙烯醇共聚物”可以根据WO2005/19286或WO2002/17848中描述的方法生产,是通过将平均聚合度为100至2000的部分皂化的聚乙烯醇与至少一种可聚合乙烯单体以6∶4至9∶1的重量比进行共聚反应而获得的聚乙烯醇共聚物。所述共聚物在20℃,2%重量的溶液形式中具有10至300mPa·S的粘度。
优选地,聚乙烯醇共聚物是通过将平均聚合度为150至1000的部分皂化的聚乙烯醇与至少一种可聚合乙烯单体以6∶4至9∶1的重量比进行共聚反应而获得,并且在20℃,2%重量的溶液形式中具有10至250mPa·S的粘度。
至于使用的可聚合乙烯单体,优选的是丙烯酸、甲基丙烯酸、聚乙二醇等。
此外,也优选聚乙烯醇与缩乙二醇醚(聚乙二醇)的共聚物作为本发明使用的聚乙烯醇共聚物。
本发明中使用的聚乙烯醇共聚物是商业可得的,例如以商品名“POVACOAT”(Nisshin Kasei Co.,Ltd)或商品名“Kollicoat IR”(BASF),并且可以容易地得到。
在本发明的制剂中,对于凝血酸、抗坏血酸以及聚乙烯醇共聚物或部分皂化的聚乙烯醇的含量比,基于1重量份的凝血酸,抗坏血酸以及聚乙烯醇共聚物或部分皂化的聚乙烯醇的含量比分别为0.01至10重量份以及0.001至1重量份,优选分别为0.1至2重量份以及0.01至0.5重量份。
本发明的制剂包含凝血酸和抗坏血酸,并且这些组分可以混合物存在或者被界限隔开以免相互接触。然而,凝血酸和抗坏血酸优选地作为分开的颗粒存在于该制剂中。
接着,以下将描述生产本发明的固体药物制剂的方法。
本发明的固体制剂指日本药典第15版中列举的颗粒剂、丸剂、散剂、片剂(包括多层片)、胶囊剂等。
本发明中,剂型优选为颗粒剂或片剂,其可以为糖包衣或薄膜包衣。
本发明的固体药物制剂可以用已知的技术生产。
在本发明的固体药物制剂的剂型为颗粒剂或片剂的情况下,可用已知的技术生产制剂。此外,这种颗粒剂或片剂也可以通过已知的方法用糖或薄膜包衣。
[实施例]
以下将描述实施例和比较例,以便更详细地说明本发明。
1.1铸型薄膜形式的比较试验
(比较例1:对照)
将仅仅羟丙甲纤维素(也称作“羟丙基甲基纤维素”)的8%的水性溶液用作对照。
(比较例2)
将0.5g凝血酸和0.2g抗坏血酸分散或溶解于57.5g 8%的羟丙甲纤维素的水性溶液中。
(实施例1)
将0.5g凝血酸和0.2g抗坏血酸分散或溶解于57.5g 8%的聚乙烯醇共聚物(商品名“POVACOAT”,由Nisshin Kasei Co.,Ltd,以下省略)的水性溶液中。
(实施例2)
将0.5g凝血酸和0.2g抗坏血酸分散或溶解于57.5g 50%的聚乙烯醇共聚物的乙醇水性溶液中。
(实施例3)
将0.5g凝血酸和0.2g抗坏血酸分散或溶解于57.5g 8%的含有部分皂化的聚乙烯醇的薄膜包衣基剂(商品名“Opadry II”)的水性溶液中。
(实施例4)
将0.5g凝血酸和0.2g抗坏血酸分散或溶解于57.5g 8%的部分皂化的聚乙烯醇的水性溶液中。
1.2试验方法
将实施例1至4和比较例1至2的各个样品取适量并涂布在白色板上,在50℃下放置一昼夜以制备铸型薄膜。目视观察每个制备的铸型薄膜的变色情况。根据以下标准进行变色评估:
1.3评估标准
A:无变色
B:轻微变色
C:有些变色
D:显著变色
1.4试验结果
试验结果如表1所示。从表中显示的结果可以看出,当使用聚乙烯醇共聚物和部分皂化的聚乙烯醇进行造粒时,可以防止变色。
[表1]
比较例1 | 比较例2 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | |
凝血酸 | ○ | ○ | ○ | ○ | ○ | |
抗坏血酸 | ○ | ○ | ○ | ○ | ○ | |
羟丙甲纤维素 | ○ | ○ | ||||
PVA共聚物 | ○ | ○ | ||||
部分皂化的PVA | ○ | ○ | ||||
目视评估 | A | D | A | B | B | A |
2.1造粒粘合剂的比较试验
(比较例3)
在流化床造粒机(Flow Coater FLO-5,Freund Corporation)中,投入2403.8g凝血酸、118.6g泛酸钙和适量的结晶纤维素并混合,然后喷射羟丙甲纤维素的水性溶液,由此制备的造粒粉为“颗粒a”。
此外,在流化床造粒机中,投入961.5g凝血酸、769.2g L-半胱氨酸、19.2g吡哆醇盐酸盐和适量的结晶纤维素投入并混合,然后喷射羟丙甲纤维素的水性溶液,由此制备的造粒粉为“颗粒b”。
将因此制备的颗粒a和b混合,由此制备造粒颗粒。将3651.3g造粒颗粒与205.1g结晶纤维素、102.6g交联羧甲纤维素钠以及41.0g硬脂酸镁混合,并将得到的混合物压片,由此获得作为中心核的素片。
(实施例5)
在流化床造粒机中,投入2403.8g凝血酸、769.2g L-半胱氨酸、118.6g泛酸钙、19.2g吡哆醇盐酸盐和适量的结晶纤维素并混合,然后喷射聚乙烯醇共聚物(POVACOAT)的水性溶液,由此制备的造粒粉为“颗粒a”。
此外,在流化床造粒机中,投入961.5g凝血酸和适量的结晶纤维素并混合,然后喷射聚乙烯醇共聚物(POVACOAT)的水性溶液作为粘合剂,由此制备的造粒粉为“颗粒b”。
将因此制备的颗粒a和b混合,由此制备造粒颗粒。将3651.3g造粒颗粒与205.1g结晶纤维素、102.6g交联羧甲纤维素钠以及41.0g硬脂酸镁混合,并将得到的混合物压片,由此获得作为中心核的素片。
(实施例6)
在流化床造粒机中,投入2403.8g凝血酸、118.6g泛酸钙和适量的结晶纤维素并混合,然后喷射聚乙烯醇共聚物(POVACOAT)的水性溶液,由此制备的造粒粉为“颗粒a”。
此外,在流化床造粒机中,投入961.5g凝血酸、769.2g L-半胱氨酸、、19.2g吡哆醇盐酸盐和适量的结晶纤维素并混合,然后喷射聚乙烯醇共聚物(POVACOAT)的水性溶液作为粘合剂,由此制备的造粒粉为“颗粒b”。
将因此制备的颗粒a和b混合,由此制备造粒颗粒。将3651.3g造粒颗粒与205.1g结晶纤维素、102.6g交联羧甲纤维素钠以及41.0g硬脂酸镁混合,并将得到的混合物压片,由此获得作为中心核的素片。
(实施例7)
在流化床造粒机中,投入2403.8g凝血酸、118.6g泛酸钙和适量的结晶纤维素并混合,然后喷射部分皂化的聚乙烯醇的水性溶液,由此制备的造粒粉为“颗粒a”。
此外,在流化床造粒机中,投入961.5g凝血酸、769.2g L-半胱氨酸、19.2g吡哆醇盐酸盐和适量的结晶纤维素并混合,然后喷射部分皂化的聚乙烯醇的水性溶液,由此制备的造粒粉为“颗粒b”。
将因此制备的颗粒a和b混合,由此制备造粒颗粒。将3651.3g造粒颗粒与205.1g结晶纤维素、102.6g交联羧甲纤维素钠以及41.0g硬脂酸镁混合,并将得到的混合物压片,由此获得作为中心核的素片。
(实施例8)
在流化床造粒机中,投入386.6g凝血酸、19.1g泛酸钙、20.6g烟酰胺、30.9g 50倍生育酚醋酸酯散粉和适量的结晶纤维素投入并混合,然后喷射聚乙烯醇共聚物(POVACOAT)的水性溶液,由此制备的造粒粉为“颗粒a”。
此外,在流化床造粒机中,投入255.5g凝血酸、204.4g L-半胱氨酸、10.2g吡哆醇盐酸盐和适量的结晶纤维素并混合,然后喷射聚乙烯醇共聚物(POVACOAT)的水性溶液,由此制备的造粒粉为“颗粒b”。
将因此制备的颗粒a和b混合,由此制备造粒颗粒。将741.4g造粒颗粒与30.5g结晶纤维素、20.0g交联羧甲纤维素钠以及8.1g硬脂酸镁混合,并将得到的混合物压片,由此获得作为中心核的素片。
2.2试验方法
将实施例5至8和比较例3的各样品各取60片包装在玻璃瓶(6K标准瓶)中,并在25℃、75%RH下保存4周。然后,目视观察其变色情况。根据以下标准进行变色评估。
2.3评估标准
以与1.3中相同的方式,根据四个标准进行评估:A:无变色;B:轻微变色;C:有些变色;以及D:显著变色。
2.4试验结果
试验结果如表2和表3所示。从表中显示的结果可以看出,当使用聚乙烯醇共聚物和部分皂化的聚乙烯醇进行造粒时,可以防止变色。
表2
表3
3.1使用已知制剂的比较试验
使用专利文献3的制剂例3.2中公开的片剂。即,每6片作为原料,将750mg凝血酸、300mg抗坏血酸、240mg L-半胱氨酸、24mg泛酸钙、6mg吡哆醇盐酸盐、适量的结晶纤维素以及适量的低取代羟丙甲基纤维素混合,将所得的混合物用羟丙甲纤维素水性溶液造粒。然后,在其中混合适量的硬脂酸镁,将混合物压片,由此获得作为中心核的素片。
(比较例4)
将素片粉碎,并将适量粉碎的片剂分散或溶解于羟丙甲纤维素水性溶液中。
(比较例5)
将素片粉碎,并将适量粉碎的片剂分散或溶解于羟丙甲纤维素溶液(水∶乙醇=8∶2)中。
(实施例9)
将素片粉碎,并将适量粉碎的片剂分散或溶解于聚乙烯醇共聚物溶液(水∶乙醇=8∶2)中。
3.2试验方法
将实施例9以及比较例4和5的各个样品取适量并涂布在白色板上,并在50℃下放置一昼夜以制备铸型薄膜。目视观察每个制备的铸型薄膜的变色情况。根据以下标准进行变色评估。
3.3评估标准
以与1.3中相同的方式,根据四个标准进行评估:A:无变色;B:轻微变色;C:有些变色;以及D:显著变色。
3.4试验结果
试验结果如表4所示。从表中显示的结果可以看出,当使用聚乙烯醇共聚物时,可以防止变色。
表4
比较例4 | 比较例5 | 实施例9 | |
凝血酸 | ○ | ○ | ○ |
抗坏血酸 | ○ | ○ | ○ |
L-半胱氮酸 | ○ | ○ | ○ |
吡哆醇盐酸盐 | ○ | ○ | ○ |
羟丙甲纤维素 | ○ | ○ | |
PVA共聚物 | ○ | ||
目视评估 | C | D | A |
Claims (5)
1.一种包含凝血酸和抗坏血酸的口服用固体药物制剂,其特征在于,所述固体药物制剂进一步包含聚乙烯醇共聚物和/或部分皂化的聚乙烯醇。
2.根据权利要求1所述的口服用固体药物制剂,其特征在于,进一步包含L-半胱氨酸。
3.根据权利要求1或2所述的口服用固体药物制剂,其特征在于,进一步包含泛酸和/或吡哆醇。
4.根据权利要求3所述的口服用固体药物制剂,其中所述吡哆醇为吡哆醇盐酸盐。
5.根据权利要求3或4所述的口服用固体药物制剂,其中所述泛酸为泛酸钙。
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CN110573153A (zh) * | 2017-04-28 | 2019-12-13 | 安斯泰来制药有限公司 | 含有恩杂鲁胺的口服给药用药物组合物 |
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JP2013049671A (ja) * | 2011-08-04 | 2013-03-14 | Fancl Corp | アスコルビン酸製剤 |
JP6245786B2 (ja) * | 2011-10-17 | 2017-12-13 | 大同化成工業株式会社 | 医薬用結合剤及び該結合剤を用いた製剤 |
JP6657949B2 (ja) | 2014-07-25 | 2020-03-04 | 三菱ケミカル株式会社 | ポリビニルアルコール微粒子、それを用いた医薬用結合剤、医薬錠剤、徐放性医薬錠剤及びポリビニルアルコール微粒子の製造方法 |
JP2019081757A (ja) * | 2017-10-31 | 2019-05-30 | 武田コンシューマーヘルスケア株式会社 | 固形製剤の製造方法 |
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CN110573153A (zh) * | 2017-04-28 | 2019-12-13 | 安斯泰来制药有限公司 | 含有恩杂鲁胺的口服给药用药物组合物 |
CN110573153B (zh) * | 2017-04-28 | 2023-04-04 | 安斯泰来制药有限公司 | 含有恩杂鲁胺的口服给药用药物组合物 |
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