CN107106485A - 甲氨蝶呤制剂 - Google Patents
甲氨蝶呤制剂 Download PDFInfo
- Publication number
- CN107106485A CN107106485A CN201580059139.6A CN201580059139A CN107106485A CN 107106485 A CN107106485 A CN 107106485A CN 201580059139 A CN201580059139 A CN 201580059139A CN 107106485 A CN107106485 A CN 107106485A
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- CN
- China
- Prior art keywords
- composition
- buffer
- methotrexate
- mtx
- hydroxybenzoate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 description 2
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Classifications
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Abstract
液体药物组合物包含甲氨蝶呤游离酸和缓冲剂,其中组合物的pH的范围为6.5至8.2。还描述了用于制备液体药物组合物的方法。液体药物组合物可用于治疗。
Description
发明领域
本发明涉及用于口服施用的新型液体甲氨蝶呤组合物。
发明背景
甲氨蝶呤(methotrexate)或4-氨基-N10-甲基蝶酰谷氨酸是抗增殖剂和免疫抑制剂。甲氨喋呤用于治疗严重的顽固性银屑病(包括不能充分响应其它形式的治疗的银屑病关节炎)、类风湿性关节炎以及治疗广泛的肿瘤病况,如滋养细胞肿瘤、急性淋巴细胞性白血病、脑膜白血病的预防、非霍奇金淋巴瘤、成骨肉瘤、乳腺癌、头颈癌、绒毛膜癌和类似的滋养细胞疾病、膀胱癌以及各种其它病况。
甲氨蝶呤在英国以2.5mg和10mg的片剂的形式市售。一些患者群体,如儿科患者或老年患者可能经受吞咽固体片剂制剂困难。甲氨蝶呤在英国还作为2.5mg/ml、25mg/ml、50mg/ml或100mg/ml注射液进行销售。虽然儿科群体可以接受注射,但可能需要干扰技术和局部麻醉来减轻疼痛以鼓励合作。此外,儿童的肌肉质量是变化的,这使得如果没有选择适当的进针位置、针头尺寸和注射角度,在进行肌内注射时,可能会导致神经损伤或其它并发症。
目前,可用于儿童的制剂是有限的。由于难以准确地破碎片剂且难以试图将片剂或片剂块溶解于饮品中,处理成人药物使其适于向儿童施用会导致不准确的给药。因此,需要比目前可用的制剂更安全且更方便的治疗。
甲氨蝶呤游离酸的化学结构由式I表示。甲氨蝶呤游离酸含有具有二羧酸官能度的谷氨酸基团。羧酸基团的pKa值为2.15和3.84。
甲氨蝶呤几乎不溶于水、乙醇、氯仿和***,且据报道,其易溶于碱性溶液并微溶于盐酸。对于药物溶液,在产品的整个保存期限内治疗剂和赋形剂均存在于溶液中是必要的。当治疗剂的水溶性有限时,这一点尤其具有挑战性。
此外,甲氨蝶呤具有一定程度的化学不稳定性,尤其是在非常低和非常高的pH值下。
对于制剂科学家而言,主要挑战是获得对于最终组合物的化学稳定性最优的pH,同时也获得活性药物成分的可接受的溶解度。当评估口服剂型的口服生物利用度时,水溶性是考虑的关键因素之一。口服生物利用度低的最常见原因是溶解性差。
本发明的制剂的另一考虑是赋形剂的选择,其对于用于儿科制剂必须被认为是可接受的且安全的。
各种研究表明,甲氨蝶呤的溶解度是pH依赖性的。对基于甲氨蝶呤的制剂的报道追溯到20世纪80年代,当时Vaidyanathan等人研究了增加pH对甲氨蝶呤的50%(v/v)丙二醇:水制剂的溶解度的影响。pH5.29时的溶解度明显高于pH 4时的溶解度,并且将媒介物pH提高到6.34,进一步增加了药物的溶解度。已表明,通常用于防止pH偏移的缓冲剂催化甲氨蝶呤游离酸的水解和光解,其中降解速率随着缓冲体系离子强度的增加而增加。因此,当配制甲氨蝶呤游离酸的溶液时,需要仔细考虑pH和缓冲强度。
用于增加难溶性药物的溶解度的多种技术是已知的,这包括处理颗粒尺寸,成盐以及表面活性剂、水溶性聚合物和环糊精的使用。US6309663公开了包含表面活性剂组合的组合物;US6383471公开了包含表面活性剂和甘油三酯的组合物,以及US5925669公开了包含具有高水平的二十二碳六烯酸的甘油酯的油(glyceridic oil)的组合物。US5472954公开了环糊精-甲氨蝶呤药物复合物;US4474752公开了包含热胶凝聚合物的延长释放组合物,以及US5770585公开了用于将甲氨蝶呤施用至肺部的水性全氟化合物分散液。
使用药物的盐形式是在药物开发以及重制已知药物中的常见做法。这是因为已知药物盐具有优等性质。已知的优点包括改善的稳定性、溶解性以及改善的处理性能。因此,在稳定制剂的开发中,通常优选盐。像许多其它药物一样,甲氨蝶呤以盐形式出售,并且可以获得多种盐形式。许多市售产品含有甲氨蝶呤的钠盐,选择甲氨蝶呤的钠盐是因为其与游离酸相比具有更高的溶解度。EP2614814A公开了含有甲氨蝶呤的药学上可接受的盐(尤其是二钠盐)的口服液体制剂。US2005101605也公开了液体甲氨蝶呤制剂。此外,所有实例均使用二钠盐。
pH和缓冲剂浓度也影响存在于最终制剂中的药学上可接受的赋形剂(如防腐剂)的稳定性和溶解度。因此,最终产品的最终pH不但是活性成分的稳定性和溶解度的关键,也必须对其进行谨慎选择,以免对稳定性和防腐剂的功效有不利影响。相对较少的防腐剂被批准用于儿科药物。对羟基苯甲酸乙酯和对羟基苯甲酸甲酯是合适的,尽管已显示这些防腐剂的功效随pH的增加而降低。据报道,对羟基苯甲酸酯具有4至8的有效pH范围,并且已表明组合时更有效。
为了成功销售儿科液体制剂,重要的是在液体制剂中掩盖药物的味道。据报道,甲氨蝶呤具有苦味,这进一步增加了将该治疗剂配制成美味的口服溶液的挑战。当将液体替代物配制成口服固体剂型时,获得可接受的味道、气味和质感常常是一个挑战。儿科药物中通常优选的调味剂是柑橘(citrus)调味剂或浆果调味剂。已知使用柠檬酸盐缓冲剂来改善口服剂型的口味。已表明,钠盐降低了用于小儿的液体形式的药物的苦味(Mennella JA,Beauchamp GK,“Optimizing oral drugications for children”,Clin Ther.2008;30:2120-32)。
发明概述
令人惊奇地发现,包含甲氨蝶呤游离酸和缓冲剂的液体组合物,其中pH范围为6.5至8.2,克服了先前报道的甲氨蝶呤液体制剂的溶解度和稳定性的问题。这一发现部分基于本文所报道的研究,其表明pH为6.8的甲氨蝶呤游离酸组合物比pH为6.2的组合物化学上和物理上更稳定。
根据本发明的第一方面,提供了包含甲氨蝶呤游离酸和缓冲剂的液体药物组合物,其中组合物的pH为6.5至8.2。
根据本发明的第二方面,如上所述的液体制剂适合于口服施用。
根据本发明的第三方面,如上所述的液体制剂可用于治疗,其中通过口服途径施用。
根据本发明的第四方面,用于制备如上所述的液体药物组合物的方法包括将缓冲剂添加到甲氨蝶呤游离酸中以将pH调节至6.5至8.2。
根据本发明的第五方面,向需要治疗的患者施用氨甲蝶呤的方法包括向患者口服施用治疗有效量的如上所述的液体药物组合物。
优选实施方案的描述
如本文所用,术语“药学上可接受的”是指当施用于个体时,不产生不利的、过敏性的或其它不良或不希望的反应的任何分子实体或组合物。如本文所用,术语“药学上可接受的组合物”与“药物组合物”同义。本发明的药物组合物可用于人和兽医学应用。在本发明的优选实施方案中,将本发明的组合物施用于人,最优选施用于儿童。本文公开的药物组合物可以单独或与其它活性成分组合施用于个体。
本文使用的术语“儿童”或“儿科患者”是指18岁以下的患者。优选地,儿童是0至16岁。更优选地,儿童是0至12岁。
本文使用的术语共溶剂是指液体制剂中存在的增加物质溶解度的任何溶剂。共溶剂可提高甲氨蝶呤游离酸的溶解度。
在本发明中,组合物的pH的范围为6.5至8.2。
在优选的实施方案中,组合物的pH的范围为6.5至8.2或6.5至8.0或6.5至7.0。在另一个优选的实施方案中,组合物的pH的范围为6.6至8.2或6.6至8.0或6.6至7.0。在优选的实施方案中,pH为6.6、6.7、6.8或6.9。在更优选的实施方案中,pH为6.7或6.8。在又一优选的实施方案中,pH为6.8。在另一个更优选的实施方案中,pH为7。
在特别优选的实施方案中,pH为6.8且缓冲强度为0.05M。在另一个特别优选的实施方案中,pH为7.0且缓冲强度为0.02M。
可以使用多种缓冲剂来制备本发明的药物组合物,只要所获得的制备物是药学上可接受的。此类缓冲剂包括但不限于乙酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂、中性缓冲盐水、磷酸盐缓冲盐水和硼酸盐缓冲剂。应当理解,可以根据需要,使用酸或碱调节组合物的pH。在优选的实施方案中,缓冲剂是柠檬酸钠缓冲剂。在更优选的实施方案中,柠檬酸钠缓冲剂包含柠檬酸三钠、柠檬酸和纯水。在另一个优选的实施方案中,缓冲剂是磷酸盐缓冲剂。
优选地,缓冲强度的范围为0.01至0.1M或0.01至1M。更优选地,缓冲强度为0.01M至0.06M。在又一优选的实施方式中,缓冲强度为0.02M至0.06M,更优选为0.02M至0.05M,最优选为0.02M或0.05M。令人惊讶的是,形成的稳定的组合物具有如此低的缓冲强度。
活性成分和/或赋形剂可以是可溶性的,或者可以作为悬浮物递送到所需的载体或稀释剂中。在本发明的优选实施方案中,液体药物组合物是溶液。
在优选的实施方案中,使用一种或多种防腐剂。所使用的防腐剂可以是对羟基苯甲酸乙酯或对羟基苯甲酸甲酯或其药学上可接受的盐,或本领域已知的任何合适的防腐剂。在更加优选的实施方案中,使用对羟基苯甲酸乙酯和对羟基苯甲酸甲酯。在更加优选的实施方案中,使用对羟基苯甲酸乙酯和对羟基苯甲酸甲酯的钠盐。
优选地,使用调味化合物和/或甜味剂。所使用的调味剂可以是本领域已知的任何合适的调味剂。优选地,调味剂是橙味调味剂或浆果调味剂。所使用的甜味剂可以是本领域已知的任何合适的甜味剂。在优选的实施方案中,甜味剂是三氯蔗糖。在更优选的实施方案中,本发明的组合物包含橙味调味剂和三氯蔗糖。发现这提高了适口性。据信,本发明的缓冲剂与橙味和三氯蔗糖协同作用以产生改良的口味。
在本发明中,制剂中可以存在一种或多种共溶剂。
在优选的实施方案中,使用甘油。这对味道也有积极影响。优选地,所使用的甘油是 G 99。
在本发明的另一个优选实施方案中,制剂中存在聚乙二醇。更优选地,聚乙二醇是PEG 400。可以认为,聚乙二醇增强了甲氨蝶呤游离酸的溶解度。
在特别优选的实施方案中,制剂中存在甘油和聚乙二醇。
优选地,本发明的组合物包含(并且优选由以下组成)甲氨蝶呤游离酸、一种或多种防腐剂、一种或多种共溶剂、调味剂、甜味剂和缓冲剂。
更优选地,本发明的组合物包含甲氨蝶呤游离酸、聚乙二醇、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯的钠盐、甘油、橙味调味剂、三氯蔗糖和柠檬酸钠缓冲剂。
根据本发明,本发明组合物中甲氨蝶呤游离酸的量的范围为0.4mg/ml至20mg/ml。优选地,甲氨蝶呤游离酸以1mg/ml至10mg/ml的浓度存在。更优选地,甲氨蝶呤游离酸以1mg/ml至5mg/ml的浓度存在。
由于成人可接受的药物赋形剂可能不一定以相同的方式在儿童中代谢或消除,因而谨慎选择赋形剂(包括调味剂、共溶剂、缓冲剂组分和防腐剂)确保符合欧洲药品管理局关于用于儿科用途的药物的药学开发的指南(European Medicines Agency’s guidelineson pharmaceutical development of medicines for paediatric use)。
在一个方面,提供了制备本发明的液体药物组合物的方法,其包括将缓冲剂添加到甲氨蝶呤游离酸中以将pH调节至6.5至8.2。在该方法中,技术人员会知道,为了制备本发明的优选组合物,需要什么附加步骤,例如添加缓冲剂或者添加稳定剂或防腐剂。技术人员会知道用于制备此类组合物的常规程序和条件。
根据本发明的药物组合物可以任选地包括有利于将活性成分加工成药学上可接受的组合物的药学上可接受的载体。如本文所用,术语“药理学上可接受的载体”是指当施用时基本上不具有长期或永久的有害作用的任何载体。可以使用技术人员已知的任何药学上可接受的载体,这包括但不限于水性介质(如水)、溶剂、共溶剂、稀释剂等。可以添加其它赋形剂、佐剂或调味剂等。如果药理学上可接受的载体、赋形剂、佐剂或调味剂等与活性成分相容,则考虑其在药学上可接受的组合物中的用途。
本发明的组合物优选适于口服给药。优选用于治疗,其中通过口服途径进行给药。本发明的组合物可以是任何类型的口服液体,包括溶液、糖浆、酏剂和悬浮液。
本发明的组合物可用于治疗脊椎关节病、全身性皮肌炎、严重的顽固性银屑病(包括不能充分响应其它形式的治疗的银屑病关节炎)、类风湿性关节炎、血清阴性关节炎、成人类风湿性关节炎全身性皮肌炎、克罗恩病、多发性硬化症、多关节型重度阳性幼年特发性关节炎(polyarthritic forms of severe,active juvenile idiopathic arthritis)、抗性幼年类风湿性关节炎、移植物抗宿主病、狼疮、硬斑病(也被称为局部性硬皮病)、强直性脊柱炎和其它自身免疫疾病,以及用于治疗广泛的肿瘤病况,如蕈样真菌病、造血组织增生、滋养细胞肿瘤、急性淋巴细胞性白血病、脑膜白血病的预防、非霍奇金淋巴瘤、成骨肉瘤、乳腺癌、头颈癌、绒毛膜癌和类似的滋养细胞疾病、肺癌、膀胱癌、成人软组织肉瘤以及各种其它恶性肿瘤或患者需要甲氨蝶呤治疗的任何其它病况。
根据本发明的治疗通常可以按已知的方式进行,这取决于多种因素,如患者的性别、年龄或状况,以及是否存在一种或多种相伴治疗。
优选地,患者是人类患者。但是,本发明的制剂也可用于兽医用途。
制剂应在技术人员已知的适当条件下储存,例如储存在III型琥珀色玻璃烧瓶、小瓶或瓶中。
本发明所述的甲氨蝶呤液体口服制剂和制备方法示于以下实施例。这些实施例仅作为说明提供,且不应被解释为对本发明的限制。
实施例
实施例1:
根据下表制备4种口服液体制剂:
制剂具有如下不同的缓冲强度/pH:
制剂1:0.05M柠檬酸钠缓冲剂,pH 6.8
制剂2:0.05M柠檬酸钠缓冲剂,pH 6.2(对比)
制剂3:0.1M柠檬酸钠缓冲剂,pH 6.8
制剂4:0.1M柠檬酸钠缓冲剂,pH 6.2(对比)
测试
在储存于ICH稳定性条件下之前,将制剂储存在琥珀色玻璃瓶中并用儿童防护件进行密封。定期观察制剂的化学和物理稳定性。
结果
根据本发明的所有制剂,在25℃和40℃储存三个月后,外观或pH未显示出变化。这样的数据示出,在所评估的条件下,低缓冲剂浓度足以维持制剂的pH。
相关物质的数据(杂质测试)显示,对于储存于40℃下的所有样品而言,总相关物质的增加不依赖于制剂组成。然而,与将pH调节至6.8的制剂大约3.5%至4.5%的总相关物质的增加相比,将pH调节至6.2的制剂显示出约5%的总相关物质的更大的增加。
在储存3个月后,制剂1显示出最低的杂质水平。该体系似乎比3种替代的体系提供了更高的化学稳定性。
在储存1个月后,制剂1和3是清澈的,而制剂2和4(对比)显示出沉淀。这表明pH6.8的溶液比pH 6.2的制剂更稳定。
制剂1显示出比其它制剂更少的降解。pH 6.8的制剂比pH 6.2的制剂具有更低的降解。
在适口性测试中,发现橙味调味剂比浆果调味剂更美味,这表明橙味调味剂、三氯蔗糖和缓冲剂之间可能具有协同作用。
Claims (30)
1.液体药物组合物,其包含甲氨蝶呤游离酸和缓冲剂,其中所述组合物的pH的范围为6.5至8.2。
2.如权利要求1所述的组合物,其中所述组合物的pH为6.6、6.7、6.8、6.9或7。
3.如权利要求1或权利要求2所述的组合物,其中所述pH为6.8。
4.如权利要求1或权利要求2所述的组合物,其中所述pH为7。
5.如前述权利要求中任一项所述的组合物,其中缓冲强度的范围为0.01M至1M。
6.如前述权利要求中任一项所述的组合物,其中缓冲强度的范围为0.01M至0.1M。
7.如前述权利要求中任一项所述的组合物,其中缓冲强度为0.01M至0.06M。
8.如前述权利要求中任一项所述的组合物,其中缓冲强度为0.02M至0.05M。
9.如前述权利要求中任一项所述的组合物,其中缓冲强度为0.05M。
10.如前述权利要求中任一项所述的组合物,其中缓冲强度为0.02M。
11.如前述权利要求中任一项所述的组合物,其中所述缓冲剂是柠檬酸钠缓冲剂。
12.如前述权利要求中任一项所述的组合物,其中所述缓冲剂是磷酸盐缓冲剂。
13.如前述权利要求中任一项所述的组合物,其中所述液体组合物是溶液或悬浮液。
14.如权利要求13所述的组合物,其中所述液体是溶液。
15.如前述权利要求中任一项所述的组合物,其中所述组合物还包含一种或多种防腐剂。
16.如权利要求15所述的组合物,其中所述一种或多种防腐剂包括对羟基苯甲酸乙酯和/或对羟基苯甲酸甲酯。
17.如权利要求15或16所述的组合物,其中所述对羟基苯甲酸甲酯是对羟基苯甲酸甲酯的钠盐。
18.如前述权利要求中任一项所述的组合物,其中所述组合物还包含一种或多种调味化合物和/或甜味剂。
19.如权利要求18所述的组合物,其中所述一种或多种调味化合物和/或甜味剂包括橙味调味剂或浆果调味剂和/或三氯蔗糖。
20.如前述权利要求中任一项所述的组合物,其中所述组合物还包含一种或多种共溶剂。
21.如前述权利要求中任一项所述的组合物,其中所述组合物包含甘油。
22.如前述权利要求中任一项所述的组合物,其中所述组合物包含聚乙二醇。
23.如权利要求22所述的组合物,其中所述聚乙二醇是PEG 400。
24.如前述权利要求中任一项所述的组合物,其包含:
0.4-20mg/ml的甲氨蝶呤游离酸;
PEG 400;
对羟基苯甲酸乙酯;
对羟基苯甲酸甲酯的钠盐;
甘油;
橙味调味剂;
三氯蔗糖;和
柠檬酸钠缓冲剂或磷酸盐缓冲剂。
25.如前述权利要求中任一项所述的液体药物组合物,其用于口服施用。
26.制备前述权利要求中任一项所述的液体药物组合物的方法,其包括向甲氨蝶呤游离酸添加缓冲剂以将pH调节至6.5-8.2。
27.如权利要求1至25中任一项所述的组合物,其用于治疗,其中施用经口服途径。
28.向需要治疗的患者施用甲氨蝶呤的方法,其包括向患者口服施用治疗有效量的权利要求1至25中任一项所述的液体药物组合物。
29.如权利要求1至25中任一项所述的组合物或权利要求28所述的方法,其中治疗用于银屑病、银屑病关节炎、全身性皮肌炎、血清阴性关节炎、成人类风湿性关节炎、抗性幼年类风湿性关节炎、多关节型阳性幼年特发性关节炎(JIA)、移植物抗宿主病、蕈样真菌病、脊椎关节病、脊椎关节病、强直性脊柱炎、肿瘤、急性淋巴细胞性白血病、脑膜白血病的预防、乳腺癌、膀胱癌、头癌、颈癌、非霍奇金淋巴瘤、成骨肉瘤、成人软组织肉瘤、绒毛膜癌或肺癌、造血组织增生,或甲氨蝶呤所对症的任何其它恶性肿瘤或病况。
30.如权利要求27至29中任一项所述的方法,其中所述患者是儿童。
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GB2591681A (en) * | 2018-08-29 | 2021-08-04 | Ftf Pharma Private Ltd | Methotrexate pharmaceutical composition |
AU2022320525A1 (en) * | 2021-07-30 | 2024-02-15 | Epygenix Therapeutics, Inc. | Clemizole formulation |
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