CN1674886A - 软胶囊制剂 - Google Patents
软胶囊制剂 Download PDFInfo
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- CN1674886A CN1674886A CNA038196271A CN03819627A CN1674886A CN 1674886 A CN1674886 A CN 1674886A CN A038196271 A CNA038196271 A CN A038196271A CN 03819627 A CN03819627 A CN 03819627A CN 1674886 A CN1674886 A CN 1674886A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
本发明公开了一种软胶囊制剂。该软胶囊制剂有遮光性胶囊壳，其中封入了分散在植物油中的(2E，4E，6E，10E)－3，7，11，15－四甲基－2，4，6，10，14－十六戊酮酸。表面活性剂优选使用含单油酸聚氧化乙烯山梨糖醇酐及甘油一硬脂酸酯等；植物油优选使用豆油、芝麻油或它们的混合物等。
Description
技术领域
本发明涉及对抑制肝癌复发有作用的药品，含有(2E，4E，6E，10E)-3，7，11，15-四甲基-2，4，6，10，14-十六戊酮酸(ヘキサデカペンタェン酸)的长期稳定软胶囊制剂。
背景技术
肝癌被认为是治疗后年复发率为25％的预后极差的疾病。因此，在肝癌的早期发现和早期治疗的同时，预防肝癌的复发也被列为今后的重要课题。聚异戊二烯类化合物中的一种(2E，4E，6E，10E)-3，7，11，15-四甲基-2，4，6，10，14-十六戊酮酸(下面，在本说明书中有时简略为“NIK-333”)被认为是有延缓肝癌治疗后的复发乃至预防肝癌效果的化合物。据武藤等人的报告，把NIK-333给治疗后的肝癌患者口服1年后，证明本化合物具有高的安全性，抑制了肝癌的复发，提高了患者的生存率(New Eng.J.Med.，334，1561，1996；New Eng.J.Med.，340，1046，1999)。
但是，由于NIK-333对于光、热、或氧气是不稳定的容易氧化，所以当制造制剂时需要想各种的办法。我们知道脂溶性维生素以及脂溶性药物中有许多是对于光和热不稳定，容易氧化的，当制造这些化合物制剂时有种种稳定化的技巧。关于NIK-333，在特公昭63-32058号公报中公开了把聚异戊二烯类化合物溶解在花生油中调制成溶液的方法；在特开平10-167960号公报中公开了把NIK-333和花生油一起封入胶囊的制剂。但是，用这些方法获得的制剂目前还存在稳定性方面的问题，还达不到实用标准。
发明内容
本发明的课题是提供一种含有NIK-333的、长期稳定的软胶囊制剂。
本发明者们经过提供长期稳定的NIK-333软胶囊制剂的各种研究，发现把NIK-333分散在植物油中，并且把其分散物封入有遮光性的软胶囊中，可以解决上述问题。本发明是基于上述见解而完成的。
也就是说，本发明提供一种软胶囊制剂，该制剂有遮光性胶囊壳(剤皮)，其中封入了分散在植物油中的(2E，4E，6E，10E)-3，7，11，15-四甲基-2，4，6，10，14-十六戊酮酸。
按照本发明的适宜状态，可以提供以下的上述软胶囊制剂：上述分散物包含表面活性剂的上述软胶囊制剂；植物油为碘价超过100的植物油的上述软胶囊制剂；植物油为豆油或芝麻油的上述软胶囊制剂；有遮光性胶囊壳是含有遮光剂的胶囊壳的上述软胶囊制剂；遮光剂为氧化钛及/或黄色三氧化二铁的上述软胶囊制剂；胶囊壳为琥珀化凝胶的上述软胶囊制剂；以及表面活性剂为选自甘油-硬脂酸酯、倍半油酸山梨糖醇酐、单油酸聚氧化乙烯山梨糖醇酐及蔗糖脂肪酸酯中的一种或两种或以上的表面活性剂的上述软胶囊制剂。
具体实施方式
(2E，4E，6E，10E)-3，7，11，15-四甲基-2，4，6，10，14-十六戊酮酸是特公昭63-32058号公报及J.Chem.Soc.(c)，2154，1966中记载的普遍熟悉的物质，是从事该行业者容易获得的物质。
植物油除了可以使用天然的植物油以外，还可以使用天然植物油的改性油，或者具有类似天然的植物油或改性油特性的合成油。典型的植物油可举出：豆油、棉籽油、玉米油、红花油、芝麻油、椰子油、橄榄油、菜籽油等。植物油中，碘价超过100的植物油，优选碘价为104或以上的植物油、半干性油(碘价超过100，不到130的)或干性油(碘价为130或以上的)。NIK-333在不干性油(碘价100以下)中有时不十分稳定。碘价可以根据，例如日本药典的油脂试验法中记载的Wijs法求出。植物油的比重，可以是例如0.914或以上，优选0.917或以上的。比重的上限是例如0.922。可以优选使用豆油或芝麻油。也可以混合使用两种或以上的植物油。
把NIK-333分散在植物油中调制分散物时，可以使用表面活性剂。通常，最好使用表面活性剂。表面活性剂可以举出，如低HLB表面活性剂有甘油一硬脂酸酯或倍半油酸山梨糖醇酐、高HLB表面活性剂有单油酸聚氧化乙烯山梨糖醇酐、蔗糖脂肪酸酯类等。可以优选使用低HLB表面活性剂和高HLB表面活性剂的组合。例如可以优选单油酸聚氧化乙烯山梨糖醇酐和甘油一硬脂酸酯的组合。不一定拘泥于什么特定的理论，低HLB表面活性剂有助于赋与增粘性及悬浮稳定性，高HLB表面活性剂有助于口服时在消化道内形成分散。
还可以进一步使用悬浮剂。悬浮剂可举出，如蜂蜡、白蜡、甘油脂肪酸酯或硬化油等。
软胶囊的胶囊壳可举出，如明胶、琥珀化凝胶等，优选使用琥珀化凝胶。
有遮光性的胶囊壳，可以由在明胶、琥珀化凝胶等构成的普通的胶囊壳上添加阻碍紫外线等光吸收的遮光剂等方法获得。
遮光剂可以使用氧化钛等普通的遮光剂。单独用氧化钛遮光性不充分的情况下，最好配合使用其它的遮光剂(例如着色剂)。遮光剂必须选择与NIK-333没有相互作用的，以及不向软胶囊中的分散物转移的。
遮光剂可以举出，如氧化钛之外有黄色三氧化二铁、食用黄色4号、食用黄色5号、食用红色3号、食用红色102号、食用红色105号、食用红色106号、或三氧化二铁等以往作为遮光剂或着色剂使用的。本发明中特别优选使用氧化钛和黄色三氧化二铁的组合。
另外，本发明中，胶囊壳上的增塑剂常常优选添加浓甘油、D-山梨糖醇。
软胶囊中包含的分散物各种成分的比例没有特别的限制，但通常使用以下范围内的。
植物油与NIK-333(1重量份)的比例为0.5～10重量份，优选使用0.7～3重量份。表面活性剂对应于1重量份植物油为0.005～0.4重量份，优选使用0.02～0.2重量份的。遮光剂可以使用几乎能够阻碍全部紫外线等光吸收的量，通常，对应于1重量份胶囊壳使用0.0005～0.05重量份，优选使用0.001～0.01重量份的。分散物中的NIK-333的粒径没有特别限制，例如为30至50μm。
本发明的软胶囊制剂，采用普通的方法在胶囊的胶囊壳中填充含有NIK-333的分散物，再经密封，就能容易地制造。
实施例
下面举几个本发明包含的具代表性的实施例，对本发明进一步加以具体说明。但本发明的范围并不限定于下面的实施例。
实施例1(稳定性试验)
把NIK-333装入密封的瓶中，再装入铝袋中。把这个试样在25℃条件下保存0、1或3个月后，测定其过氧化物的价。结果如表1所示。
表1
| 保存时间(月) | 0 | 1 | 3 |
| 过氧化物的价(meq/kg) | 0.4 | 6.2 | 14.4 |
实施例2(在各种油中的稳定性试验)
把NIK-333分别分散在豆油、芝麻油、花生油、中链脂肪酸三甘油酸酯(MCT)(33w/w％)中，分装在褐色的管瓶中。这时候管瓶内部用氩气置换。把这种分散物在25或40℃的条件下存放0、2或4周后用HPLC确认其纯度。结果如表2及表3所示。
表2
在25℃条件保存(NIK-333残存率(％))
| 保存期间(周) | |||
| 0 | 2 | 4 | |
| 豆油芝麻油花生油.MCT | 100.0100.0100.0100.0 | 100.0100.199.967.7 | 100.099.497.117.5 |
表3
在40℃条件保存(NIK-333残存率(％))
| 保存期间(周) | |||
| 0 | 2 | 4 | |
| 豆油芝麻油花生油MCT | 100.0100.0100.0100.0 | 98.299.898.054.4 | 99.298.563.30.0 |
实施例3(分散物的调制)
NIK-333 150mg
单油酸聚氧化乙烯山梨糖醇酐 15mg
甘油一硬脂酸酯 6mg
豆油 204mg
把上述处方的豆油、单油酸聚氧化乙烯山梨糖醇酐及甘油一硬脂酸酯加温溶解后，冷却，把NIK-333混合、分散后，再脱泡，调制出分散物。
实施例4(软胶囊胶囊壳的调制)
琥珀化凝胶 134mg
浓甘油 27mg
D-山梨糖醇液 27mg
氧化钛 1.3mg
加入上述处方的浓甘油、70％D-山梨糖醇液、氧化钛及水，并搅拌，获得分散物。在此分散物中添加加温至60℃的琥珀化凝胶溶液，搅拌，使其溶解。把混合物减压脱泡后，用蒸馏水调整粘度，获得软胶囊胶囊壳。
实施例5(软胶囊胶囊壳的调制)
琥珀化凝胶 134mg
浓甘油 27mg
D-山梨糖醇液 27mg
氧化钛 0.7mg
黄色三氧化二铁 0.5mg
除了使用了黄色三氧化二铁以外，用和实施例4同样的方法，调制了胶囊壳。
实施例6(光稳定性试验)
用胶囊成型机(伦勒(ラィナ一)公司制的旋转式填充机)把实施例3的分散物分别封入用实施例4及实施例5所得到软胶囊胶囊壳中。对得到的软胶囊制剂进行光稳定性试验(总照度120万Lux·hr)，用HPLC测定NIK-333的含量，求出残存率。
表4
光稳定性(NIK-333残存率(％))
| 光照射前 | 光照射后 | |
| 实施例4实施例5 | 100.0100.0 | 98.3100.0 |
实施例7(药品组成物的调制)
NIK-333 75mg
单油酸聚氧化乙烯山梨糖醇酐 8mg
甘油-硬脂酸酯 3mg
豆油 102mg
按上述处方，用和实施例3同样的方法进行了调制。
实施例8(软胶囊胶囊壳的调制)
琥珀化凝胶 78mg
浓甘油 16mg
D-山梨糖醇液 16mg
氧化钛 0.4mg
黄色三氧化二铁 0.3mg
按上述处方，用和实施例5同样的方法进行了调制。进而，用和实施例6同样的方法，获得了软胶囊制剂。
实施例9(稳定性试验)
把由实施例8获得的软胶囊制剂，在25℃、湿度60％(60％RH)、40℃湿度75％(75％RH)的条件下保存，测定其含量及过氧化物的价。NIK-333的含量、过氧化物的价分别如表5和表6所示。
表5
NIK-333含量(％)
| 保存条件 | 保存时间(月) | |||||
| 0 | 1 | 6 | 12 | 18 | 24 | |
| 25℃，60％RH40℃，75％RH | 102.5102.5 | 100.5101.1 | 100.8101.5 | 100.2- | 101.2- | 100.8- |
表6
过氧化物的价(meq/kg)
| 保存条件 | 保存时间(月) | |||||
| 0 | 1 | 6 | 12 | 18 | 24 | |
| 25℃，60％RH40℃，75％RH | 0.30.3 | 0.50.7 | 0.51.1 | 0.6- | 0.7- | 0.8- |
工业上利用的可能性
尽管NIK-333是极不稳定的物质，但是本发明的软胶囊制剂，即使长期保存也是稳定的。
Claims (9)
1、一种软胶囊制剂，其软胶囊含有遮光性胶囊壳，在软胶囊中封入了分散在植物油中的(2E，4E，6E，10E)-3，7，11，15-四甲基-2，4，6，10，14-十六戊酮酸。
2、根据权利要求1所述的软胶囊制剂，其特征在于：所述的分散物含有一种或两种以上的表面活性剂。
3、根据权利要求2所述的软胶囊制剂，其特征在于：所述的表面活性剂是选自甘油一硬脂酸酯、倍半油酸山梨糖醇酐、单油酸聚氧化乙烯山梨糖醇酐及蔗糖脂肪酸酯中的一种或两种以上的表面活性剂。
4、根据权利要求2所述的软胶囊制剂，其特征在于：所述的表面活性剂含有单油酸聚氧化乙烯山梨糖醇酐及甘油一硬脂酸酯。
5、根据权利要求1至4所述的软胶囊制剂，其特征在于：所述的植物油是碘价超过100的植物油或它们的混合物。
6、根据权利要求1至5所述的软胶囊制剂，其特征在于：所述的植物油是豆油、芝麻油或它们的混合物。
7、根据权利要求1至6所述的软胶囊制剂，其特征在于：所述的有遮光性胶囊壳是含有遮光剂的胶囊壳。
8、根据权利要求7所述的软胶囊制剂，其特征在于：所述的遮光剂是氧化钛、黄色三氧化二铁或它们的组合。
9、根据权利要求1至8所述的软胶囊制剂，其特征在于：所述的胶囊壳是琥珀化凝胶。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103562212A (zh) * | 2011-04-27 | 2014-02-05 | 兴和株式会社 | 膦酰基丁烯酸衍生物的制造方法 |
| CN103976951A (zh) * | 2014-06-03 | 2014-08-13 | 深圳万乐药业有限公司 | 一种培维a酸自微乳组合物 |
| CN103976951B (zh) * | 2014-06-03 | 2016-06-08 | 深圳万乐药业有限公司 | 一种培维a酸自微乳组合物 |
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| US20060141022A1 (en) | 2006-06-29 |
| ES2448830T3 (es) | 2014-03-17 |
| EP1547588A1 (en) | 2005-06-29 |
| JP4398862B2 (ja) | 2010-01-13 |
| EP1547588A4 (en) | 2008-09-17 |
| KR20060066665A (ko) | 2006-06-16 |
| KR100956404B1 (ko) | 2010-05-06 |
| WO2004017958A1 (ja) | 2004-03-04 |
| EP1547588B1 (en) | 2013-12-11 |
| JPWO2004017958A1 (ja) | 2005-12-08 |
| AU2003257550A1 (en) | 2004-03-11 |
| CN1303993C (zh) | 2007-03-14 |
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