CN115379861A - 缓释性主剂 - Google Patents
缓释性主剂 Download PDFInfo
- Publication number
- CN115379861A CN115379861A CN202180027671.5A CN202180027671A CN115379861A CN 115379861 A CN115379861 A CN 115379861A CN 202180027671 A CN202180027671 A CN 202180027671A CN 115379861 A CN115379861 A CN 115379861A
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- China
- Prior art keywords
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- polyvinyl alcohol
- agent
- sustained
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- 238000013268 sustained release Methods 0.000 title claims abstract description 33
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 33
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 68
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 38
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 21
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 19
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims description 54
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 35
- 229920000642 polymer Polymers 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 25
- 238000006116 polymerization reaction Methods 0.000 claims description 24
- 238000009472 formulation Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 13
- 238000007127 saponification reaction Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- -1 Vinyl aromatic carboxylates Chemical class 0.000 description 23
- 238000000034 method Methods 0.000 description 21
- 239000000178 monomer Substances 0.000 description 18
- 229920001567 vinyl ester resin Polymers 0.000 description 17
- 238000004090 dissolution Methods 0.000 description 15
- 239000002585 base Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 239000003405 delayed action preparation Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 8
- 229920001290 polyvinyl ester Polymers 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 229920002689 polyvinyl acetate Polymers 0.000 description 7
- 239000011118 polyvinyl acetate Substances 0.000 description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 6
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 5
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 5
- 239000003999 initiator Substances 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
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- 150000003839 salts Chemical class 0.000 description 4
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- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 3
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- 229940124584 antitussives Drugs 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
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- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 3
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- 238000007907 direct compression Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
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- 239000003921 oil Substances 0.000 description 3
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- 239000000047 product Substances 0.000 description 3
- 229960002477 riboflavin Drugs 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000013076 target substance Substances 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 2
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 2
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- WYGWHHGCAGTUCH-UHFFFAOYSA-N 2-[(2-cyano-4-methylpentan-2-yl)diazenyl]-2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C WYGWHHGCAGTUCH-UHFFFAOYSA-N 0.000 description 2
- AHOUBRCZNHFOSL-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 2
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FDJCVHVKXFIEPJ-JCNFZFLDSA-N Delapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 FDJCVHVKXFIEPJ-JCNFZFLDSA-N 0.000 description 2
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明提供一种新型的缓释性主剂。将该缓释性主剂制成组合有聚乙烯醇系聚合物及低取代度羟丙基纤维素。
Description
技术领域
本发明涉及缓释性主剂等。
背景技术
缓释性制剂为在给药之后经长时间在体内逐步少量释放药物的制剂,与速释性制剂相比,其具有可减少给药次数的特征。因此,可期待减轻患者的负担并提高顺应性,因而,在国内外得以广泛应用。
作为用于缓释性制剂的主剂,使用有各种各样的聚合物,且存在使用了聚乙烯醇(以下简称为PVA)的实例。
例如专利文献1及专利文献2中公开了通过直接压缩PVA或PVA衍生物与微晶纤维素(以下简称为MCC)的混合物,可得到显示出优异成型性与缓释性的制剂。
现有技术文献
专利文献
专利文献1:日本专利第6629835号公报
专利文献2:日本特开2013-241341号公报
发明内容
本发明要解决的技术问题
本发明的目的在于提供一种新型的缓释性主剂。
本发明的另一目的在于提供一种新型的制剂。
本发明的又一目的在于提供一种新型的制剂的制备方法。
解决技术问题的技术手段
专利文献1及专利文献2中记载的制剂虽然成型性和缓释性得以提升,但其效果有时并不充分。
本申请的发明人为了解决上述技术问题进行了深入研究,结果发现,通过使PVA与低取代度羟丙基纤维素进行组合,能够发挥作为缓释性制剂的主剂的功能,并进一步进行反复研究,从而完成了本发明。
即,本发明涉及以下发明。
(1)一种缓释性主剂,其组合有聚乙烯醇系聚合物及低取代度羟丙基纤维素。
(2)一种固体制剂,其包含聚乙烯醇系聚合物及低取代度羟丙基纤维素。
(3)根据(2)所述的制剂,其为缓释性制剂。
(4)根据(2)或(3)所述的制剂,其为口服制剂。
(5)根据(2)~(4)中任一项所述的制剂,其中,制剂的对象物包含药物。
(6)根据(1)~(5)中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的按照JISK6726测定的4质量%水溶液粘度满足15.0mPa·s以上。
(7)根据(1)~(6)中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的平均皂化度为65.0~90.0摩尔%。
(8)根据(1)~(7)中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的平均聚合度为1000以上。
(9)根据(1)~(8)中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物:低取代度羟丙基纤维素的质量比为40:60~80:20。
(10)根据(1)~(9)中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的平均聚合度为1000以上,聚乙烯醇系聚合物:低取代度羟丙基纤维素的质量比为40:60~80:20。
(11)一种固体制剂的制备方法,其包括直接压缩混合物的工序,所述混合物包含(1)及(6)~(10)中任一项所述的剂及制剂的对象物。
(12)一种聚乙烯醇系聚合物与低取代度羟丙基纤维素的组合在缓释性主剂中的应用。
(13)一种提高固体制剂的缓释性的方法,其中,使用了聚乙烯醇系聚合物与低取代度羟丙基纤维素的组合。
发明效果
在本发明的一个方案中,能够提供一种新型的缓释性主剂。
在本发明的一个方案中,可提供一种可用于得到固体制剂的缓释性主剂。例如通过将包含本发明的缓释性主剂的混合物进行压片,可高效地提供一种在硬度及缓释性方面有利的固体制剂(片剂)。
根据本发明的一个方案的剂,可提供一种高硬度的固体制剂。这种制剂在成型后不易破碎,因此成型性优异。
在本发明的一个方案中,可提供一种新型的制剂(特别是固体制剂)。
在本发明的一个方案中,可提供一种新型的制剂的制备方法。
附图说明
图1为示出实施例1~8的溶出度的经时变化的图表。
图2为示出参考例1~2的溶出度的经时变化的图表。
具体实施方式
[缓释性主剂]
在本发明的缓释性主剂中,组合有聚乙烯醇系聚合物及低取代度羟丙基纤维素。
本发明的缓释性主剂组合有这两种成分即可,可以在单一的主剂中含有这两种成分,也可以为以作为多种主剂的组合整体含有这两种成分的方式组合而成的主剂。换言之,对于组合多种主剂而成的体系,可以为用于与低取代度羟丙基纤维素进行组合的、包含聚乙烯醇系聚合物的缓释性主剂。
(聚乙烯醇系聚合物)
聚乙烯醇系聚合物(有时称作PVA系聚合物、PVA等)通常可以为乙烯酯系聚合物(至少以乙烯酯作为聚合成分的聚合物)的皂化物。
为了容易抑制制剂中的低取代度羟丙基纤维素的崩解性的表现、或者从制剂更加容易发挥缓释性效果等角度出发,PVA系聚合物的平均皂化度例如可以为90.0摩尔%以下(例如89.5摩尔%以下),优选为89.0摩尔%以下(例如88.5摩尔%以下、88.0摩尔%以下)等。
此外,PVA系聚合物的平均皂化度的下限值例如可以为60.0摩尔%以上(例如62.0摩尔%以上),优选为65.0摩尔%以上(例如68.0摩尔%以上、70.0摩尔%以上、75.0摩尔%以上、80.0摩尔%以上)等。
另外,对于PVA系聚合物的平均皂化度,可以适当组合上述上限值与下限值而设定为适宜的范围(例如60.0摩尔%以上且90.0摩尔%以下等)内(其他也相同),其中包括上述上限值与下限值的所有组合。
另外,PVA系聚合物的平均皂化度没有特别限定,例如可通过JIS K6726中的皂化度测定方法等进行测定。
为了容易抑制制剂中的低取代度羟丙基纤维素的崩解性的表现、或者从制剂更加容易发挥缓释性效果等角度出发,PVA系聚合物的平均聚合度例如可以为800以上(例如900以上、1000以上、1100以上、1200以上、1300以上、1400以上),优选为1500以上(例如1600以上),更优选为2000以上(例如2100以上、2400以上)等。
此外,PVA系聚合物的平均聚合度的上限值例如可以为5000以下(例如4900以下),优选为4500以下(例如4400以下),更优选为3500以下(例如3400以下)等。
另外,对于PVA系聚合物的平均聚合度,可以适当组合上述上限值与下限值而设定为适宜的范围(例如1500以上且3500以下等)内(其他也相同),其中包括上述上限值与下限值的所有组合。
另外,PVA系聚合物的平均聚合度没有特别限定,例如可以通过JIS K6726中的平均聚合度测定方法等进行测定。
从制剂的缓释性等角度出发,PVA系聚合物的4质量%水溶液粘度(按照JIS K6726而测定)例如可以为6.0mPa·s以上(例如8.0mPa·s以上),优选为10.0mPa·s以上(例如12.0mPa·s以上),特别优选为15.0mPa·s以上(例如18.0mPa·s以上、20.0mPa·s以上)等。
此外,PVA系聚合物的4质量%水溶液粘度(按照JIS K6726而测定)的上限值例如可以为300mPa·s以下(例如280mPa·s以下),优选为240mPa·s以下(例如220mPa·s以下),更优选为100mPa·s以下(例如80mPa·s以下)等。
另外,对于PVA系聚合物的4质量%水溶液粘度,可以适当组合上述上限值与下限值而设定为适宜的范围(例如15mPa·s以上且240mPa·s以下等)内(其他也相同),其中包括上述上限值与下限值的所有组合。
PVA系聚合物可以使用一种或组合使用两种以上。
PVA系聚合物可以利用市售品,也可以使用合成的物质。作为PVA系聚合物的制备方法,可采用使包含乙烯酯系单体的聚合成分的聚合物(乙烯酯系聚合物)皂化等公知的方法。
乙烯酯系单体(乙烯酯系单量体)没有特别限定,例如可列举出脂肪酸乙烯酯[例如甲酸乙烯酯、乙酸乙烯酯、丙酸乙烯酯、丁酸乙烯酯、辛酸乙烯酯、叔碳酸乙烯酯、一氯乙酸乙烯酯等C1-20脂肪酸乙烯酯(例如C1-16烷酸-乙烯酯)等]、芳香族羧酸乙烯酯[例如苯甲酸乙烯酯等芳烃羧酸乙烯酯(例如C7-12芳烃羧酸-乙烯酯)等]等。
乙烯酯系单体可以使用一种或组合使用两种以上。
乙烯酯系单体优选至少包含脂肪酸乙烯酯(例如甲酸乙烯酯、乙酸乙烯酯、丙酸乙烯酯、丁酸乙烯酯等C1-10烷酸-乙烯酯等),从工业角度等出发,特别是可以包含乙酸乙烯酯。
乙烯酯系聚合物具有乙烯酯单元即可,也可以根据需要具有来自其他单体(能够与乙烯酯系单体进行共聚的单体)的单元(也可利用其他单体而改性)。
其他单体没有特别限定,例如可列举出α-烯烃类(例如乙烯、丙烯等)、(甲基)丙烯酸酯类[例如(甲基)丙烯酸甲酯、(甲基)丙烯酸乙酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸2-乙基己酯等(甲基)丙烯酸烷基酯]、不饱和酰胺类[例如(甲基)丙烯酰胺、双丙酮丙烯酰胺、N-羟甲基丙烯酰胺等]、不饱和酸类{例如不饱和酸[例如(甲基)丙烯酸、巴豆酸、马来酸、衣康酸、富马酸等]、不饱和酸酯[除(甲基)丙烯酸以外的不饱和酸的酯,例如烷基(甲基、乙基、丙基等)酯等]、不饱和酸酐(马来酸酐等)、不饱和酸的盐[例如碱金属盐(例如钠盐、钾盐等)、铵盐等]等}、含缩水甘油基单体[例如烯丙基缩水甘油醚、(甲基)丙烯酸缩水甘油酯等]、含磺酸基单体(例如2-丙烯酰胺-2-甲基丙磺酸、其盐类等)、含磷酸基单体[例如酸性磷氧基乙基(甲基)丙烯酸酯(Acid phosphoxyethyl(meth)acrylate)、酸性磷氧基丙基(甲基)丙烯酸酯等]、乙烯醚类(例如烷基乙烯醚类)、烯丙醇等,但并不特别限定于这些单体。
其他单体可以使用一种或组合使用两种以上。
另外,当聚合成分包含其他单体时,聚合成分中的其他单体的比例例如可以为50质量%以下、30质量%以下、20质量%以下、10质量%以下。
聚合成分中的乙烯酯系单体的比例例如可以为50质量%以上,优选为70质量%以上,进一步优选为90质量%以上,也可以为100质量%。
另外,PVA系聚合物的部分乙烯醇单元可通过缩醛化、醚化、乙酰乙酰化、阳离子化等反应而进行改性。
聚合成分(例如包含乙酸乙烯酯等乙烯酯系单体的聚合成分)的聚合方法没有特别限定,例如可列举出现有公知的本体聚合、溶液聚合、悬浮聚合、乳液聚合等,但工业上优选将甲醇用作溶剂的溶液聚合。该溶液聚合中能够使用过氧化物系、偶氮系等公知的引发剂,且能够通过改变聚合成分与甲醇的掺合比、聚合收率来调节乙烯酯系聚合物的聚合度。此外,作为用于得到PVA系聚合物的原料,还能够使用市售的乙烯酯系聚合物(聚乙酸乙烯酯树脂等)。
作为乙烯酯系聚合物(例如聚乙酸乙烯酯)的皂化方法,能够应用现有公知的使用碱催化剂或酸催化剂的皂化方法,其中,工业上优选以下方法:向乙烯酯系聚合物(例如聚乙酸乙烯酯)的甲醇溶液或乙烯酯系聚合物(例如聚乙酸乙烯酯)的甲醇、水、乙酸甲酯等的混合溶液中加入氢氧化钠等碱,一边搅拌混合,一边使乙烯酯系聚合物(例如聚乙酸乙烯酯)的酰基(例如乙酰基)醇解。
然后,粉碎所得到的块状物、凝胶状物或粒状物,对根据需要而添加的碱进行中和后,分离固体物质与液体部分,并将固体物质干燥,由此可得到PVA系聚合物。
低取代度羟丙基纤维素的取代度(醚化度)例如可以为0.05~1.0(例如0.07~0.8),优选为0.1~0.6(例如0.15~0.5)左右。
另外,取代度为低取代度羟丙基纤维素中的每个葡萄糖单元的被取代的羟基的平均数即可。
对于低取代度羟丙基纤维素中的羟基的取代基的含量(质量%),例如羟丙氧基含量可以为5~16质量%。
低取代度羟丙基纤维素可以使用一种或组合使用两种以上。
从制剂的缓释性和成型性等角度出发,本发明的缓释性主剂中的聚乙烯醇系聚合物与低取代度羟丙基纤维素的掺合比例,即聚乙烯醇系聚合物:低取代度羟丙基纤维素(质量比)例如可以为30:70~90:10(例如33:67~87:13),优选为35:65~85:15(例如40:60~80:20),更优选为43:57~78:22(例如45:55~75:25)左右。
本发明的缓释性主剂的对象物没有特别限定,例如可以为药品、准药物、食品、农药等。此外,对象物可以为有效成分、营养素(或营养成分)等,也可以为药物(原料药等)。
对象物可以为有机物、无机物中的任意一种,也可以为它们的混合物或有机-无机杂化物。
这种对象物中的药物乃至有效成分(或对象物中包含的药物乃至有效成分)没有特别限定。作为该药物,例如可列举出中枢神经系统药物、脑代谢改善剂、脑循环改善剂、抗癫痫药物、交感神经兴奋剂、循环系统药物、呼吸系统药物、消化系统药物、抗生素、止咳化痰药、抗过敏药物、抗组胺剂、牙科口腔用药物、强心剂、心律失常用药物、利尿药、解热镇痛抗炎药、自律神经作用药、抗抑郁药物、抗精神病药、抗焦虑药、催眠镇静药、血管舒张药、降压药、血管收缩药、周围血管舒张药、抗凝血剂、高脂血症用药物、利胆剂、抗疟药、止泻药、精神活性药物、化疗剂、糖尿病用药物、骨质疏松症用药物、骨骼肌松弛药、滋补保健药、镇痉剂、抗风湿药、激素剂、生物碱类麻醉药、磺胺类药物、痛风治疗药、抗癌剂等。
作为中枢神经系统药物,例如可列举出地西泮、艾地苯醌、阿司匹林、布洛芬、扑热息痛、萘普生、吡罗昔康、吲哚美辛、舒林酸、劳拉西泮、硝西泮、苯妥英、扑热息痛、乙氧苯酰胺、酮洛芬、氯氮卓、胞磷胆碱钠等。
作为脑代谢改善剂,例如可列举出盐酸甲氯芬酯等。
作为脑循环改善剂,例如可列举出长春西汀等。
作为抗癫痫药物,例如可列举出苯妥英、卡马西平、丙戊酸钠等。
作为交感神经兴奋剂,例如可列举出盐酸异丙肾上腺素等。
作为循环系统药物,例如可列举出吗多明、长春西汀、普萘洛尔、甲基多巴、双嘧达莫、呋塞米、氨苯蝶啶、硝苯地平、阿替洛尔、螺内酯、美托洛尔、吲哚洛尔、卡托普利、硝异梨醇、盐酸地拉普利、盐酸甲氯芬酯、盐酸地尔硫卓、盐酸依替福林、洋地黄毒甙、盐酸普萘洛尔、盐酸阿普洛尔等。
作为呼吸系统药物,例如可列举出止咳化痰药、呼吸兴奋药、支气管扩张药等。
作为止咳化痰药,例如可列举出盐酸那可汀、柠檬酸喷托维林、右美沙芬、氢溴酸右美沙芬、柠檬酸异米尼克、磷酸二甲啡烷、盐酸氯哌斯汀、氢溴酸右美沙芬、茶碱、愈创木酚磺酸钾、愈创甘油醚、愈创甘油醚磷酸可待因、盐酸氨溴索等。
作为呼吸兴奋药,例如可列举出酒石酸左洛啡烷等。
作为支气管扩张药,例如可列举出茶碱、沙丁胺醇、硫酸沙丁胺醇等。
作为消化系统药物,例如可列举出肠胃药、抑酸剂、抗溃疡药、消化酶药物、排便功能促进剂、止吐剂等。
作为肠胃药,例如可列举出健胃消化剂(例如淀粉酶、含糖胃蛋白酶、东莨菪萃取物、纤维素酶AP3、脂肪酶AP、桂皮油)、整肠剂(例如盐酸小檗碱、耐性乳酸菌、双歧杆菌)等。
作为抑酸剂,例如可列举出碳酸镁、碳酸氢钠、硅镁铝、合成水滑石、沉淀碳酸钙、氧化镁等。
作为抗溃疡药,例如可列举出5-氨基水杨酸、兰索拉唑、奥美拉唑、雷贝拉唑、西咪替丁、法莫替丁、雷尼替丁、盐酸雷尼替丁、盐酸哌仑西平、2-[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲基亚磺酰基]苯并咪唑及5-甲氧基-2-[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基亚磺酰基]苯并咪唑等具有抗溃疡作用的苯并咪唑类药物等。
作为消化酶药物,例如可列举出胰酶等。
作为排便功能促进剂,例如可列举出比沙可啶等。
作为止吐剂,例如可列举出盐酸地芬尼多、甲氧氯普胺等。
作为抗生素,例如可列举出头孢氨苄、阿莫西林、头孢克洛、盐酸匹美西林、头孢替安海替酯盐酸盐、头孢羟氨苄、头孢克肟、头孢妥仑匹酯、头孢特仑新戊酯及头孢泊肟酯等头孢烯类、氨苄青霉素、环青霉素、萘啶酸及依诺沙星等合成抗菌剂、卡芦莫南钠等单环菌素类、红霉素等大环内酯类、青霉烯类、碳青霉烯类抗生素等。
作为抗过敏药物,例如可列举出氨来占诺、塞曲司特等。
作为抗组胺剂,例如可列举出盐酸苯海拉明、异丙嗪、盐酸异丙嗪、盐酸氮异丙嗪、dl-马来酸氯苯那敏等。
作为牙科口腔用药物,例如可列举出土霉素、曲安奈德、盐酸氯己定、利多卡因等。
作为强心剂,例如可列举出地高辛、咖啡因等。
作为心律抗过敏药物,例如可列举出盐酸普鲁卡因胺、盐酸普萘洛尔、吲哚洛尔等。
作为利尿药,例如可列举出咖啡因、呋塞米、异山梨醇、氢氯噻嗪等。
作为解热镇痛抗炎药,例如可列举出扑热息痛、阿司匹林、布洛芬、乙氧苯酰胺、盐酸苯海拉明、dl-马来酸氯苯那敏、双氯芬酸钠、磷酸二氢可待因、水杨酰胺、氨基比林、那可汀、盐酸甲基麻黄碱、盐酸苯丙醇胺、舍雷肽酶、盐酸溶菌酶、托芬那酸、甲芬那酸、氟芬那酸、酮洛芬、吲哚美辛、布可隆、喷他佐辛、咖啡因、无水咖啡因、安乃近、盐酸二氢吗啡酮、盐酸他喷他多等。
作为自律神经作用药,例如可列举出磷酸二氢可待因及dl-盐酸甲基麻黄碱、硫酸阿托品、氯化乙酰胆碱、新斯的明等。
作为血管舒张药,例如可列举出硝苯地平、乙胺香豆素盐酸盐、吗多明、盐酸维拉帕米等。
作为降压药,例如可列举出卡托普利、盐酸地拉普利、盐酸肼屈嗪、盐酸拉贝洛尔、盐酸马尼地平、坎地沙坦酯、甲基多巴、培哚普利等。
作为血管收缩药,例如可列举出盐酸去氧肾上腺素等。
作为周围血管舒张药,例如可列举出桂利嗪等。
作为抗凝血剂,例如可列举出双羟香豆素等。
作为高脂血症用药物,例如可列举出西立伐他汀钠、辛伐他汀、普伐他汀钠、阿托伐他汀钙水合物等。
作为利胆剂,例如可列举出脱氢胆酸、曲匹布通等。
作为抗疟疾药,例如可列举出盐酸奎宁等。
作为止泻药,例如可列举出盐酸洛哌丁胺等。
作为精神活性药物,例如可列举出氯丙嗪、利血平等。
作为抗抑郁药物,例如可列举出安非他命、米帕明、盐酸马普替林、盐酸帕罗西汀等。
作为抗精神病药,例如可列举出帕利哌酮等。
作为抗焦虑药,例如可列举出地西泮、阿普唑仑、氯氮卓等。
作为催眠镇静药,例如可列举出艾司唑仑、地西泮、硝西泮、哌拉平、苯巴比妥钠等。
作为化疗剂,例如可列举出磺胺甲噻二唑等。
作为糖尿病用药物,例如可列举出格列嘧啶钠、格列吡嗪、盐酸苯乙双胍、盐酸丁福明、二甲双胍、盐酸二甲双胍、甲苯磺丁脲、伏格列波糖、盐酸吡格列酮、格列苯脲、曲格列酮等。
作为骨质疏松症用药物,例如可列举出依普黄酮等。
作为骨骼肌松弛药,例如可列举出美索巴莫等。
作为滋补保健药,例如可列举出维生素类及其衍生物[例如维生素A、维生素B1、呋喃硫胺、维生素B2(核黄素)、维生素B6、维生素B12、维生素C、维生素D、维生素E、维生素K、泛酸钙、氨甲环酸等]、矿物质(例如钙、镁、铁等)、蛋白质、氨基酸、低聚糖、草药等。
作为镇痉剂,例如可列举出盐酸美克洛嗪、茶苯醇胺、氢溴酸菪胺、盐酸苯海拉明、盐酸罂粟碱等。
作为抗风湿药,例如可列举出甲氨蝶呤、布西拉明等。
作为激素剂,例如可列举出碘塞罗宁钠、地塞米松磷酸钠、泼尼松龙、奥生多龙、醋酸亮丙瑞林等。
作为生物碱类麻醉药,例如可列举出鸦片、吗啡盐酸盐、吐根、盐酸羟可待酮、盐酸鸦片生物碱、盐酸古柯碱等。
作为磺胺类药物,例如可列举出磺胺二甲基异嘧啶、磺胺甲噻二唑等。
作为痛风治疗药,例如可列举出别嘌醇、秋水仙碱等。
作为抗癌剂,例如可列举出5-氟尿嘧啶、尿嘧啶、丝裂霉素等。
对象物也可以包含其他成分(例如赋形剂、崩解剂、润滑剂、抗凝聚剂、助溶剂等本领域中常用的各种添加剂)。
作为赋形剂,例如可列举出白糖、乳糖、甘露醇、葡萄糖等糖类、淀粉、结晶纤维素、磷酸钙、硫酸钙等,可优选列举出乳糖、甘露醇、结晶纤维素等。
作为崩解剂,例如可列举出羧甲基纤维素或其盐、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、结晶纤维素、结晶纤维素-羧甲基纤维素钠等。
作为润滑剂、抗凝聚剂,例如可列举出滑石、硬脂酸镁、硬脂酸钙、胶态二氧化硅、硬脂酸、腊类、硬化油、聚乙二醇类、苯甲酸钠等。
作为助溶剂,例如可列举出富马酸、琥珀酸、苹果酸、己二酸等有机酸等。
这些添加剂可使用一种或两种以上。其他成分(添加剂)的含量可根据药剂的种类等适当决定。
对象物可以单独使用或组合使用两种以上。
对象物在常温(例如10~40℃等)下可以为固体。
对象物的形状优选为粉末(或粉体)。这种粉末(散装产品、浸膏粉等)的大小没有特别限定,例如平均粒径可以为500μm以下(例如5~400μm),优选为300μm以下,进一步优选为100μm以下(例如10~80μm)左右。
另外,粉末的平均粒径可使用激光粒度分布测定装置等进行测定。
[固体制剂等]
本发明还含有包含聚乙烯醇系聚合物及低取代度羟丙基纤维素的固体制剂。另外,聚乙烯醇系聚合物及低取代度羟丙基纤维素可以为上述示例的聚乙烯醇系聚合物及低取代度羟丙基纤维素。此外,制剂的对象物可以为上述示例的对象物(缓释性主剂的对象物),通常可为粉体。
本发明的制剂例如可以为片剂、颗粒剂、胶囊剂等,但优选片剂。
本发明的制剂适宜用作口服制剂。
除了聚乙烯醇系聚合物及低取代度羟丙基纤维素(以及制剂的对象物)以外,本发明的制剂还可以包含其他成分。
作为其他成分,通常可以包含本领域中常用的添加剂(例如崩解剂、润滑剂、抗凝聚剂、助溶剂等)。
作为崩解剂,例如可列举出羧甲基纤维素或其盐、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、结晶纤维素、结晶纤维素-羧甲基纤维素钠等。
作为润滑剂或抗凝聚剂,例如可列举出滑石、硬脂酸镁、硬脂酸钙、胶态二氧化硅、硬脂酸、腊类、硬化油、聚乙二醇类、苯甲酸钠等。
作为助溶剂,例如可列举出富马酸、琥珀酸、苹果酸、己二酸等有机酸等。
这些添加剂可使用一种或两种以上。
此外,可根据制剂的成分的种类等适当决定这些添加剂的含量。
在制剂中,本发明的缓释性主剂的比例例如可以为40~99.5质量%(例如42~99质量%),优选为45~98.5质量%(例如50~98质量%),更优选为52~97.5质量%(例如55~97质量%)左右。
在制剂中,聚乙烯醇系聚合物的比例例如可以为20~60质量%(例如22~58质量%),优选为25~55质量%(例如27~52质量%),更优选为30~50质量%(例如33~48质量%)左右。
在制剂中,低取代度羟丙基纤维素的比例例如可以为5~60质量%(例如7~58质量%),优选为10~55质量%(例如12~52质量%),更优选为15~50质量%(例如33~48质量%)左右。
从制剂的缓释性和成型性等角度出发,制剂中的聚乙烯醇系聚合物与低取代度羟丙基纤维素的掺合比例,即聚乙烯醇系聚合物:低取代度羟丙基纤维素(质量比)例如可以为30:70~90:10(例如33:67~87:13),优选为35:65~85:15(例如40:60~80:20),更优选为43:57~78:22(例如45:55~75:25)左右。
另外,本发明的制剂的形状没有特别限定,当制剂为片剂时,片剂的形状例如可以为圆盘形、透镜形、竿形等中的任意一种。
此外,本发明的制剂的大小没有特别限定,特别是当制剂为片剂时,对于片剂的大小,例如直径(最大径)可以为3mm以上(例如4~15mm、5~12mm、8~11mm等)。
片剂能够通过将至少包含聚乙烯醇系聚合物、低取代度羟丙基纤维素及制剂的对象物(或者本发明的缓释性主剂及制剂的对象物)的混合物(压片粉末)进行压片而进行制备。
压片粉末也可以包含上述其他成分。
压片方法没有特别限定,可采用常规的压片方法,但特别优选直接压缩法(直接压片法)。直接压缩(直接压片)可通过直接使用压片机将压片粉末压缩成型来实施。
片剂可以在片剂表面具有包衣层。
在包衣片剂中,包衣层的构成成分没有特别限定,例如可列举出纤维素系树脂(例如羟丙基甲基纤维素、醋酸酯化丁二酸氢酯化的纤维素-2-羟基丙基甲基醚等)、聚乙烯醇系聚合物等树脂材料。
本发明的制剂可以为缓释性制剂。
对于本发明的缓释性制剂,虽然活性成分的溶出度达到80%以上(例如80%)时的时间(溶出时间)因活性成分(例如有效成分、营养素、药物等)的种类等而不同,但其至少可以为2小时以上,优选为3小时以上(例如可以为4小时以上、5小时以上、6小时以上、7小时以上等)。
在本发明的缓释性制剂中,活性成分的溶出度达到80%以上(例如80%)时的时间的上限值没有特别限定,例如可以为20小时以下、19小时以下、18小时以下、17小时以下、16小时以下、15小时以下等。
此外,对于本发明的缓释性制剂,虽然活性成分的溶出度达到50%时的时间因活性成分的种类等而不同,但其例如可以为20分钟以上、优选为30分钟以上(例如40分钟以上),更优选为60分钟以上(例如80分钟以上)等。
在本发明的缓释性制剂中,活性成分的溶出度达到50%时的时间的上限值没有特别限定,例如可以为20小时以下、19小时以下、18小时以下、17小时以下、16小时以下、15小时以下等。
此外,溶出时间的测定方法没有特别限定,例如可以使用日本药典溶出试验第二法(桨法)。日本药典溶出试验第二法(桨法)中,试验液可以为900mL蒸馏水、桨转速可以为50rpm。
实施例
以下,举出实施例对本发明进行具体的说明,但本发明并不限定于此。
另外,在以下的实施例及比较例中,在没有特别说明的情况下,“%”及“份”表示质量基准。
此外,各种条件等如下所示。
<平均皂化度、平均聚合度及4质量%水溶液粘度>
按照JIS K6726进行测定。
<压片条件>
使用装置:旋转压片机VIRGO(KIKUSUI SEISAKUSHO LTD.制造)
压片压力:15kN
转速:10rpm
片剂重量:200mg
<片剂硬度的评价>
使用片剂硬度测定仪(TBH125,ERWEKA制造)测定所得到的片剂的硬度。进行6次测定,将其平均值作为测定值。
<溶出度的评价>
在以下的试验条件下进行溶出试验。并且,测定并计算出溶出度达到80%时的时间。
试验方法:日本药典溶出试验第二法(桨法)
试验液:蒸馏水900mL
桨转速:50rpm
测定样本:实施例及比较例所示的片剂
检测波长:UV444nm(核黄素)
UV270nm(茶碱)
将以下的实施例及参考例中使用的各PVA系聚合物(PVA1~3)示于表1。
另外,表1中记载了产品名称的PVA为JAPAN VAM&POVAL CO.,LTD.制造。
此外,所有PVA系聚合物均进行了粉碎,并将平均粒径调节至约100μm。
[表1]
此外,PVA3的合成方法如下所示。
(合成例1)
事先向具备搅拌机、冷凝器、氮气导入口及引发剂进料口的反应槽中添加140份甲醇及860份乙酸乙烯酯单体,对体系内部进行氮气置换后,加热至60℃,并在发生回流的时刻添加2.0份作为引发剂的2,2’-偶氮双(2,4-二甲基戊腈)的1.5%甲醇溶液,引发聚合。在聚合过程中使体系保持在70℃,使氮气通入体系内并设为常压,进一步,在聚合开始经过15分钟后,添加2.0份2,2’-偶氮双(2,4-二甲基戊腈)的2%甲醇溶液。在聚合开始经过2.3小时后,当乙酸乙烯酯的反应收率达到52%时,冷却体系,结束聚合。一边向所得到的反应物中加入甲醇蒸汽,一边蒸馏去除残留的乙酸乙烯酯单体,得到聚乙酸乙烯酯的40%甲醇溶液。
然后,向500份上述工序中得到的聚乙酸乙烯酯的40%甲醇溶液中添加100份甲醇、6份水、6.3份氢氧化钠的5.2%甲醇溶液并充分混合,在40℃下进行40分钟皂化反应,将所得到的凝胶状物粉碎,并在进行中和后利用甲醇进行洗涤,然后进行干燥,得到皂化度为65.0摩尔%、平均聚合度为2400的PVA系聚合物3(PVA3)。
(实施例1)
以表2中记载的掺合比例,将除硬脂酸镁(St-Mg)以外的成分装入聚乙烯袋中,通入空气使袋鼓起后,混合100次(摇晃袋)。然后,向袋中添加St-Mg,并通入空气使袋鼓起后,混合30次(摇晃袋)。将所得到的混合物进行压片从而制备片剂。针对所得到的片剂,测定片剂硬度及溶出时间。将结果示于表2。另外,在表2中,L-HPC是指低取代度羟丙基纤维素。作为L-HPC,使用NBD-021(Shin-Etsu Chemical Co.,Ltd.)。
(实施例2~8)
除了使用表2中记载的PVA系聚合物,并将各成分的种类及掺合比例设为表2中记载的种类及比例以外,以与实施例1相同的方法实施压片,并测定片剂硬度及溶出时间。将结果示于表2。
此外,将实施例1~8的溶出度的经时变化示于图1。
(参考例1~2)
除了使用表2中记载的PVA系聚合物,并将各成分的种类及掺合比例设为表2中记载的种类及比例以外,以与实施例1相同的方法实施压片,并测定片剂硬度及溶出时间。将结果示于表2。另外,在表2中,Cl-PVP是指交联聚乙烯吡咯烷酮(Kollidon CL,BASFジャパン社)。此外,将参考例1~2的溶出度的经时变化示于图2。
[表2]
如表2所示,对于实施例,通过同时使用PVA系聚合物与低取代度羟丙基纤维素,能够制作兼顾了高成型性与优异缓释性的制剂。
工业实用性
本发明能够提供一种新型的缓释性主剂。这种主剂能够用于获得缓释性制剂等。
Claims (11)
1.一种缓释性主剂,其组合有聚乙烯醇系聚合物及低取代度羟丙基纤维素。
2.一种固体制剂,其包含聚乙烯醇系聚合物及低取代度羟丙基纤维素。
3.根据权利要求2所述的制剂,其为缓释性制剂。
4.根据权利要求2或3所述的制剂,其为口服制剂。
5.根据权利要求2~4中任一项所述的制剂,其中,制剂的对象物包含药物。
6.根据权利要求1~5中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的按照JISK6726测定的4质量%水溶液粘度满足15.0mPa·s以上。
7.根据权利要求1~6中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的平均皂化度为65.0~90.0摩尔%。
8.根据权利要求1~7中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的平均聚合度为1000以上。
9.根据权利要求1~8中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物:低取代度羟丙基纤维素的质量比为40:60~80:20。
10.根据权利要求1~9中任一项所述的剂或制剂,其中,聚乙烯醇系聚合物的平均聚合度为1000以上,聚乙烯醇系聚合物:低取代度羟丙基纤维素的质量比为40:60~80:20。
11.一种固体制剂的制备方法,其包括直接压缩混合物的工序,所述混合物包含权利要求1及6~10中任一项所述的剂及制剂的对象物。
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