CN111372572B - 包含丹皮酚和罗布麻宁的液体制剂 - Google Patents
包含丹皮酚和罗布麻宁的液体制剂 Download PDFInfo
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- CN111372572B CN111372572B CN201880075175.5A CN201880075175A CN111372572B CN 111372572 B CN111372572 B CN 111372572B CN 201880075175 A CN201880075175 A CN 201880075175A CN 111372572 B CN111372572 B CN 111372572B
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- Prior art keywords
- apocynin
- paeonol
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- liquid
- excipient
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Abstract
提供了一种稳定的液体制剂。
Description
本发明涉及用于治疗人或动物的抗炎和/或镇痛制剂。该制剂还可以用于治疗神经变性疾病。
已知有效成分4-羟基-3-甲氧基苯乙酮(罗布麻宁，apocynin)和2-羟基-4-甲氧基苯乙酮(丹皮酚，paeonol)的组合形成用于抗炎的药物。一种这样的制剂被称为APPA，在犬骨关节炎的治疗中具有积极的结果。APPA制剂将活性成分与固体赋形剂组合在一起。在这些固体剂型如片剂中，在制粒过程中和/或在片剂压制过程中在片剂上引起的热可引起低熔点丹皮酚的瞬时熔化和随后活性成分的物理性质的不利转变。固相药物制剂也表现出比液体制剂差的生物利用度。
活性成分可以通过溶解或悬浮在适当的液体中而进入液相，然后将其包封，或者以必须由患者口服的标准化液体提取物的形式。这样的液相制剂具有降低的活性成分浓度。这导致需要服用的胶囊数量增加或必须喝的液体提取物的量增加。这是不希望的，因为该制剂味道不好，并且患者不希望服用大量的胶囊或喝大量不愉快味道的药物。这种易于服用的剂量和依从性问题在临床上较脆弱的患者群体(如患有神经变性疾病的患者)中尤其重要。
因此，需要具有高浓度活性成分的罗布麻宁和丹皮酚的液相制剂。
丹皮酚是2-羟基-4-甲氧基苯乙酮，由下式表示:
罗布麻宁是植物酚4-羟基-3-甲氧基苯乙酮，具有下式:
根据我们的研究，丹皮酚是一种具有约49.7℃的低熔点的固体。根据我们的研究，罗布麻宁是一种具有约114.6℃的更高熔点的固体。如上所述，APPA是丹皮酚和罗布麻宁的混合物。
已知当以约3.5丹皮酚:1罗布麻宁的比例(按重量计)混合时，该化合物可有效治疗炎性疾病。申请人惊奇地发现，以该比例(或接近该比例)形成低共熔混合物，导致组合熔点显著降低到44.7℃，比丹皮酚和罗布麻宁均要低。在所有混合比中，这是APPA系统可能的最低熔点。
申请人进一步发现，向低共熔APPA混合物中添加相对少量的赋形剂提供了在室温下稳定的液体形式的APPA。赋形剂可以是任何合适的低毒性的氧化化合物。许多赋形剂材料可能是合适的，包括乙二醇和乙二醇衍生物、多元醇、酯和醚。调查显示聚乙二醇400是最有效的。这被称为PEG400。
当将3.5丹皮酚:1罗布麻宁的混合物与2.5份PEG400组合时，会形成稳定的液体，该液体在约3℃的温度下储存时不会固化。
由于仅需要少量的赋形剂物质即可引起熔点的显著降低，因此所得液体制剂具有相对较高浓度的活性化合物。当将3.5丹皮酚:1罗布麻宁的混合物与2.5份PEG400组合时，所形成的稳定液体包含64.3重量％的APPA。由于液体具有1.1659g/ml的高密度，按单位体积的重量计，这相当于74.5％APPA。因此，本发明的液体制剂可以提供高度浓缩形式的APPA。
由APPA的低共熔混合物制成的这种高度浓缩的液体制剂的生产可被视为一项非凡的发现，可显著改善患者的服用量和依从性(除了其他方面)。
罗布麻宁和丹皮酚的异构体是本领域已知的。罗布麻宁和丹皮酚的异构体包括2-羟基-3-甲氧基苯乙酮“正乙酰香子兰酮”(CAS:703-98-0)、2-羟基-5-甲氧基苯乙酮(CAS:705-15-7)，3-羟基-4-甲氧基苯乙酮“异乙酰香子兰酮”(CAS:6100-74-9)和4-羟基-2-甲氧基苯乙酮“异丹皮酚”(CAS:493-33-4)。
根据本发明，提供了一种液体制剂，其包含活性化合物2-羟基-4-甲氧基苯乙酮(丹皮酚)或其异构体和4-羟基-3-甲氧基苯乙酮(罗布麻宁)或其异构体，其中丹皮酚与罗布麻宁的重量比为3:2到9:1。
根据本发明，进一步提供了一种液体制剂，其包含活性化合物2-羟基-4-甲氧基苯乙酮(丹皮酚)或其异构体和4-羟基-3-甲氧基苯乙酮(罗布麻宁)或其异构体，其中丹皮酚与罗布麻宁的重量比为3:2至9:1，所述制剂还包含至少一种赋形剂，其中总活性化合物(即丹皮酚和罗布麻宁的总重量)与赋形剂的重量比为2:3至19:1。优选地，总活性化合物与赋形剂的重量比为2:3至9:1。
优选地，所述液体制剂是由2-羟基-4-甲氧基苯乙酮(丹皮酚)或其异构体与4-羟基-3-甲氧基苯乙酮(罗布麻宁)或其异构体的低共熔混合物制得。
优选地，所述液体制剂包含活性化合物2-羟基-4-甲氧基苯乙酮(丹皮酚)和4-羟基-3-甲氧基苯乙酮(罗布麻宁)，其中丹皮酚与罗布麻宁的重量比为3:2至9:1，所述制剂进一步包含至少一种赋形剂，其中总活性化合物(即丹皮酚和罗布麻宁的总重量)与赋形剂的重量比为2:3至19:1。优选地，总活性化合物与赋形剂的重量比为2:3至9:1。
罗布麻宁和丹皮酚是彼此的异构体。应当理解，根据本发明，液体制剂包含两种不同的活性化合物(例如罗布麻宁本身和丹皮酚本身)。
赋形剂可以是任何合适的低毒性的氧化的化合物。应当理解，在本发明的上下文中，术语“低毒性”可以指其毒性适于与APPA一起给人长期口服而没有不利影响的物质。
优选地，赋形剂是乙二醇或乙二醇衍生物、多元醇或其酯和/或醚。优选地，赋形剂是乙二醇。优选地，赋形剂是聚乙二醇。更优选地，赋形剂是聚乙二醇400。优选制剂的丹皮酚或其异构体与罗布麻宁或其异构体的重量比为80:20至77.7:22.3。优选地，总活性化合物与赋形剂的重量比为64:36。
优选地，所述制剂在室温(15至25℃)下是稳定的液体。
高浓度的APPA制剂可在单个软凝胶胶囊中包含可接受的剂量。例如，3.5丹皮酚:1罗布麻宁与2.5份PEG400的0.533ml的混合物包含400mg APPA。这是活性化合物的药学有效剂量，其体积小到足以装入单个软凝胶胶囊中。此外，3.5丹皮酚:1罗布麻宁与2.5份PEG400的1.07ml的混合物包含800mgAPPA。这也是活性化合物的药学有效剂量，其体积小到足以装入单个软凝胶胶囊中。
根据本发明，提供了一种由低共熔混合物制成的液体制剂，其包含活性化合物丹皮酚或其异构体和罗布麻宁或其异构体。
根据本发明，进一步提供了由包含活性化合物丹皮酚或其异构体和罗布麻宁或其异构体的低共熔混合物制得的液体制剂，所述液体制剂还包含至少一种赋形剂。
优选地，所述液体制剂由包含活性化合物丹皮酚和罗布麻宁的低共熔混合物制得，所述液体制剂还包含至少一种赋形剂。
罗布麻宁和丹皮酚是彼此的异构体。应当理解，根据本发明，液体制剂包含两种不同的活性化合物(例如罗布麻宁本身和丹皮酚本身)。
赋形剂可以是任何合适的低毒性的氧化化合物。应当理解，在本发明的上下文中，术语“低毒性”可以指其毒性适于与APPA一起给人长期口服而没有不利影响的物质。
优选地，赋形剂是乙二醇或乙二醇衍生物、多元醇或其酯和/或醚。优选地，赋形剂是乙二醇。优选地，赋形剂是聚乙二醇。更优选地，赋形剂是聚乙二醇400。
优选制剂的总活性化合物与赋形剂的重量比为2:3至19:1。优选地，总活性化合物与赋形剂的重量比为2:3至9:1。优选地，总活性化合物与赋形剂的重量比为64:36。
优选地，所述制剂在室温(15至25℃)下是稳定的液体。
罗布麻宁存在于植物物质和植物提取物中，例如存在于植物胡黄连(picrorrhizakurroa)、apocynum cannabinium、罗布麻(apocynum venatum)、美国茶叶花(apocynumandrosaemifolium)和香草种(例如香子兰(Vanilla planifolia))的提取物中。
本发明的制剂和制品包括2-羟基-4-甲氧基苯乙酮(罗布麻宁)。优选地，罗布麻宁被合成或从植物中提取并纯化。这可以称为分离的罗布麻宁。本文描述的量和比例是指分离的罗布麻宁。
罗布麻宁可以作为例如上述植物的直接提取物(例如，作为未纯化的植物或根提取物形式的未溶解的化合物混合物的一部分)存在于本发明的制剂或制品中。这些将被称为“天然形式的”罗布麻宁或“天然罗布麻宁”。例如，以胡黄连形式存在于根据本发明的制品中的罗布麻宁被称为“天然罗布麻宁”。术语“天然罗布麻宁”或“天然形式的”罗布麻宁还包括罗布麻宁的糖苷，例如在其中发现有罗布麻宁的植物物种中发现的糖苷。这样的糖苷包括例如雄素和其他环烯醚萜糖苷。
所述制剂可以包含罗布麻宁，其为未纯化的植物或根提取物形式的未溶解的化合物混合物的一部分:“天然”罗布麻宁。胡黄连是基于标准化环烯醚醚萜糖苷部分的标准化形式；这样的形式是众所周知的。标准化形式的胡黄连包括标准化为“Kutkin min 4％”的胡黄连。Kutkin是通过结晶获得的，由比例为1:2的葡糖苷胡黄连苷I(picroside I)和kutoside以及其他少量的糖苷组成(Sing和Rastogi，1972；Ansari等，1988)。
与天然罗布麻宁相比，分离的罗布麻宁具有更一致的罗布麻宁质量。它也可以以比天然罗布麻宁更大规模生产。因此，本发明中优选使用分离的罗布麻宁。
如上所述，所述制剂可以包含天然形式的罗布麻宁，尽管这是不太优选的。如果使用天然罗布麻宁，技术人员将容易理解如何调节比例以生产本发明的制剂。但是，如果是这种情况，可能有必要限制胡黄连的量以防止副作用(例如因胡黄连中的其他植物化学物质而引起的胃部不适)。但是，应注意的是，大多数人类受试者每天最多可以服用2,000mg胡黄连(Kutkin min 2％)，而不会感到不适。
丹皮酚可能存在于植物物质和植物提取物中。例如丹皮酚可以发现于牡丹(Paeonia suffruticosa)、芍药(Paeonia lactiflora)、川赤芍(Paeonia veitchii)、草芍药(Paeonia obovata)、掌叶大黄(Rheum palmatum)(根茎)和黄岑(Scutellariabaicalensis)(根)。本发明的制剂和制品包括2-羟基-4-甲氧基苯乙酮(丹皮酚)。
优选地，丹皮酚被合成或从植物中提取并纯化。这可以称为分离的丹皮酚。本文描述的数量和比例是指分离的丹皮酚。不太优选地，丹皮酚可以作为来自植物的直接提取物存在于本发明的制品中(即，作为未纯化的植物或根提取物形式的未溶解的化合物混合物的一部分)。这些将被称为“天然形式”的丹皮酚或“天然丹皮酚”。例如，以牡丹形式存在于本发明的制品中的丹皮酚被称为“天然丹皮酚”。术语“天然形式的”丹皮酚或“天然丹皮酚”包括丹皮酚的糖苷，例如在其中发现丹皮酚的植物物种中发现的糖苷。这样的糖苷包括例如甲基花青苷(paeonin)、牡丹酚原甙(paeonolide)和丹皮苷(paeonoside)。如果使用天然丹皮酚，技术人员将容易理解如何调节比例以提供本发明的制剂。
与天然丹皮酚相比，分离的丹皮酚可提供更一致的丹皮酚质量。它也可以以比天然丹皮酚更大规模生产。因此，本申请中优选使用分离的丹皮酚。本发明的制剂可以用于治疗炎性疾病。本发明的制剂还可用于治疗神经变性疾病。
根据本发明，提供了一种液体制剂的生产方法，该液体制剂包含活性化合物丹皮酚或其异构体和罗布麻宁或其异构体，所述方法包括(a)形成活性化合物丹皮酚或其异构体和罗布麻宁或其异构体的低共熔混合物。
根据本发明，进一步提供了一种制备包含活性化合物丹皮酚或其异构体和罗布麻宁或其异构体的液体制剂的方法，所述方法包括:(a)形成活性化合物丹皮酚或其异构体和罗布麻宁或其异构体的低共熔混合物；(b)添加赋形剂(例如乙二醇)。
根据本发明，提供了一种由包含活性化合物丹皮酚或其异构体和罗布麻宁或其异构体的低共熔混合物制成的制剂。优选地，所述制剂是液体。
现在将参考以下实施例详细描述本发明。
实施例1
为了生产在室温下为稳定液体的1000mg APPA制剂，将777.8mg丹皮酚与222.2mg罗布麻宁混合。加热混合物，并在搅拌混合物的同时添加555.6mg PEG400。产生了稳定的混合物，该混合物在约3℃下储存过夜时不会固化。
实施例2-400mg APPA胶囊
为了生产包含约400mg APPA的制剂，将311.1mg丹皮酚与88.9mg罗布麻宁混合。加热混合物，并在搅拌混合物的同时添加222.2mg PEG400。这产生了0.533ml的丹皮酚和罗布麻宁的液体制剂，其在室温下是稳定的。可以通过本领域已知的方法将其封装在软凝胶胶囊中，以提供胶囊形式的药物产品。
实施例3-800mg APPA胶囊
为了制备含有约800mg APPA的制剂，将622.2mg丹皮酚与177.8mg罗布麻宁混合。加热混合物，并在搅拌混合物的同时添加444.4mg PEG400。这产生了1.07ml的丹皮酚和罗布麻宁的液体制剂，其在室温下是稳定的。可以通过本领域已知的方法将其封装在软凝胶胶囊中，以提供胶囊形式的药物产品。
Claims (6)
1.液体制剂，其由活性化合物丹皮酚、罗布麻宁和聚乙二醇400组成，其中丹皮酚与罗布麻宁的重量比为3.5:1，总活性化合物与聚乙二醇400的重量比为64:36。
2.根据权利要求1的制剂，其中所述制剂在室温下是稳定的。
3.根据权利要求1至2中任一项的制剂在制备治疗炎性疾病和/或神经变性疾病的药物中的用途。
4.一种生产根据权利要求1至2中任一项所述的液体制剂的方法，该方法包括:(a)将活性化合物丹皮酚和罗布麻宁混合并加热混合物，并在搅拌混合物的同时加入聚乙二醇400，其中丹皮酚与罗布麻宁的重量比为3.5:1，总活性化合物与聚乙二醇400的重量比为64:36。
5.由权利要求4的方法制得的制剂。
6.根据权利要求5的制剂，其中所述制剂是液体。
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| CN1053010A (zh) * | 1989-05-16 | 1991-07-17 | 梅迪斯化学药物工厂普特两合股份公司 | 药物制剂 |
| GB0507208D0 (en) * | 2005-04-08 | 2005-05-18 | Larkins Nicholas J | Anti-inflammatory formulation |
| CN1736368A (zh) * | 2004-08-18 | 2006-02-22 | 上海佰加壹医药有限公司 | 一种丹皮酚软胶囊及其制备方法和用途 |
| WO2013037843A1 (en) * | 2011-09-12 | 2013-03-21 | Akl Inflammatory Limited | Formulation for the treatment of benign prostate hyperplasia |
| WO2017137767A1 (en) * | 2016-02-11 | 2017-08-17 | Akl Research & Development Ltd | Anti-neurodegenerative disease formulation containing apocynin and paeonol |
| US20170296510A1 (en) * | 2014-09-25 | 2017-10-19 | Prosonix Limited | Method of forming concentrated solution |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2463080A (en) * | 2008-09-02 | 2010-03-03 | Nicholas John Larkins | Pharmaceutical preparation |
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2017
- 2017-11-23 GB GB1719464.8A patent/GB2568698A/en not_active Withdrawn
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2018
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- 2018-11-22 HU HUE18810956A patent/HUE057595T2/hu unknown
- 2018-11-22 WO PCT/EP2018/082178 patent/WO2019101842A1/en unknown
- 2018-11-22 DK DK18810956.5T patent/DK3713546T3/da active
- 2018-11-22 US US16/765,627 patent/US11701325B2/en active Active
- 2018-11-22 CN CN201880075175.5A patent/CN111372572B/zh active Active
- 2018-11-22 EP EP21209333.0A patent/EP4019005A1/en active Pending
- 2018-11-22 RS RS20220135A patent/RS62923B1/sr unknown
- 2018-11-22 JP JP2020545869A patent/JP7314157B2/ja active Active
- 2018-11-22 CA CA3082945A patent/CA3082945A1/en active Pending
- 2018-11-22 ES ES18810956T patent/ES2906761T3/es active Active
- 2018-11-22 LT LTEPPCT/EP2018/082178T patent/LT3713546T/lt unknown
- 2018-11-22 MX MX2020005313A patent/MX2020005313A/es unknown
- 2018-11-22 PL PL18810956T patent/PL3713546T3/pl unknown
- 2018-11-22 AU AU2018371165A patent/AU2018371165B2/en active Active
- 2018-11-22 EP EP18810956.5A patent/EP3713546B1/en active Active
- 2018-11-22 KR KR1020207018001A patent/KR20200090858A/ko not_active Application Discontinuation
- 2018-11-22 HR HRP20220303TT patent/HRP20220303T1/hr unknown
- 2018-11-22 CN CN202310468972.2A patent/CN116999417A/zh active Pending
- 2018-11-22 PT PT188109565T patent/PT3713546T/pt unknown
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2020
- 2020-07-13 MX MX2022008551A patent/MX2022008551A/es unknown
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2022
- 2022-02-10 CY CY20221100119T patent/CY1124986T1/el unknown
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2023
- 2023-05-12 JP JP2023079234A patent/JP2023104963A/ja active Pending
- 2023-06-01 US US18/327,202 patent/US20230330017A1/en active Pending
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2024
- 2024-05-27 AU AU2024203514A patent/AU2024203514A1/en active Pending
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| CN1053010A (zh) * | 1989-05-16 | 1991-07-17 | 梅迪斯化学药物工厂普特两合股份公司 | 药物制剂 |
| CN1736368A (zh) * | 2004-08-18 | 2006-02-22 | 上海佰加壹医药有限公司 | 一种丹皮酚软胶囊及其制备方法和用途 |
| GB0507208D0 (en) * | 2005-04-08 | 2005-05-18 | Larkins Nicholas J | Anti-inflammatory formulation |
| WO2013037843A1 (en) * | 2011-09-12 | 2013-03-21 | Akl Inflammatory Limited | Formulation for the treatment of benign prostate hyperplasia |
| US20170296510A1 (en) * | 2014-09-25 | 2017-10-19 | Prosonix Limited | Method of forming concentrated solution |
| WO2017137767A1 (en) * | 2016-02-11 | 2017-08-17 | Akl Research & Development Ltd | Anti-neurodegenerative disease formulation containing apocynin and paeonol |
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|---|---|
| RS62923B1 (sr) | 2022-03-31 |
| WO2019101842A1 (en) | 2019-05-31 |
| GB2568698A (en) | 2019-05-29 |
| LT3713546T (lt) | 2022-03-10 |
| EP3713546A1 (en) | 2020-09-30 |
| CA3082945A1 (en) | 2019-05-31 |
| KR20200090858A (ko) | 2020-07-29 |
| AU2018371165B2 (en) | 2024-02-29 |
| CN111372572A (zh) | 2020-07-03 |
| SI3713546T1 (sl) | 2022-04-29 |
| HRP20220303T1 (hr) | 2022-05-13 |
| US20230330017A1 (en) | 2023-10-19 |
| MX2020005313A (es) | 2020-08-17 |
| JP7314157B2 (ja) | 2023-07-25 |
| PL3713546T3 (pl) | 2022-05-02 |
| MX2022008551A (es) | 2022-08-10 |
| AU2018371165A1 (en) | 2020-05-21 |
| CY1124986T1 (el) | 2023-01-05 |
| PT3713546T (pt) | 2022-02-02 |
| CN116999417A (zh) | 2023-11-07 |
| US20200297628A1 (en) | 2020-09-24 |
| JP2021504461A (ja) | 2021-02-15 |
| EP3713546B1 (en) | 2021-12-08 |
| EP4019005A1 (en) | 2022-06-29 |
| HUE057595T2 (hu) | 2022-05-28 |
| DK3713546T3 (da) | 2022-01-31 |
| ES2906761T3 (es) | 2022-04-20 |
| AU2024203514A1 (en) | 2024-06-20 |
| US11701325B2 (en) | 2023-07-18 |
| JP2023104963A (ja) | 2023-07-28 |
| GB201719464D0 (en) | 2018-01-10 |
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