CN102341091A - 利鲁唑水性悬浮液 - Google Patents
利鲁唑水性悬浮液 Download PDFInfo
- Publication number
- CN102341091A CN102341091A CN2010800108923A CN201080010892A CN102341091A CN 102341091 A CN102341091 A CN 102341091A CN 2010800108923 A CN2010800108923 A CN 2010800108923A CN 201080010892 A CN201080010892 A CN 201080010892A CN 102341091 A CN102341091 A CN 102341091A
- Authority
- CN
- China
- Prior art keywords
- riluzole
- suspension according
- surfactant
- suspension
- consumption
- 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.)
- Granted
Links
- 229960004181 riluzole Drugs 0.000 title claims abstract description 86
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 239000007900 aqueous suspension Substances 0.000 title abstract description 5
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
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- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 9
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pain & Pain Management (AREA)
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Abstract
本发明涉及理化性质稳定的利鲁唑水性悬浮液及其制备方法。该水性悬浮液包含颗粒形式的利鲁唑,和至少一种润湿剂,优选表面活性剂形式。利鲁唑的用量在约0.1%至约20%w/v之间且平均粒径小于200μm;该悬浮液完全避免了利鲁唑已知的局部(嘴部)麻醉作用。
Description
技术领域
本发明涉及用于口服的理化性质稳定的口服利鲁唑水性悬浮液,该悬浮液对口腔几乎无麻醉作用或将麻醉作用最小化。
背景技术
利鲁唑(6-(三氟甲氧基)苯骈噻唑-2-胺)是具有如下结构式的化合物:
用于治疗肌萎缩性脊髓侧索硬化症(ALS,有时亦称作鲁格利克氏征、夏科氏征或运动神经元疾病)的药物——利鲁唑的常用口服剂量为50mg/12hs。对于依赖呼吸机或接受气管造口术的特定患者,其服药间隙还需延长。
肌萎缩性脊髓侧索硬化症是一种由于运动神经退化所导致的致命的渐行性神经退化症,以控制横纹肌运动的中枢神经***神经细胞的逐渐退化为表征。由于运动神经元退化,它们不能再向日常控制肌肉运动的肌纤维传递神经脉冲。肌萎缩性脊髓侧索硬化症的早期症状通常包括肌无力现象严重化,特别是手臂部、腿部及与言语、吞咽和呼吸有关的肌肉群。
利鲁唑已被美国和欧洲批准用于治疗肌萎缩性脊髓侧索硬化症。
美国专利US5527814公开了利鲁唑治疗肌萎缩性脊髓侧索硬化症的使用;该专利中所阐述的基于利鲁唑的药物剂型为片剂、硬质明胶胶囊及注射液。
美国专利US6432992公开了利鲁唑治疗肾上腺白质营养不良症的使用;该专利中所阐述的基于利鲁唑的药物剂型同样为片剂、硬质明胶胶囊及注射液。
市售的口服利鲁唑为含有50mg活性成分的白色胶囊状包衣片。目前尚无利鲁唑的液体制剂上市。
与片剂不同,存在吞咽障碍的肌萎缩性脊髓侧索硬化症患者在服用液体制剂时,会逐渐增加依从性。
利鲁唑的水溶性非常低,中性pH值条件下约为0.3mg/mL。虽然利鲁唑在酸性条件下溶解度会增加(pH值1.2时,其溶解度为约12mg/mL),但其化学稳定性却会急剧下降。因此,为了便于口服而采用水溶性酸溶液是不可行的。
然而,制备浓度介于0.25至10%w/v的利鲁唑水溶液是切实可行的,不但技术上可行(例如使用共溶剂或增溶剂以增加利鲁唑水溶性),而且其理化性质稳定。然而,这些溶液表现出较差的适口性,这归咎于药物自身固有特性引起的强烈且持久(持续时间超过20-30分钟)的口腔麻醉作用。
由于其亲脂性和低水溶性,利鲁唑是制备悬浮剂的优良候选物。
发明内容
悬浮液是分散的两相***,其中一相(“内”相)的颗粒分散在第二相(“连续”或“外”相)中。像这样,它们被定义为热力学不稳定并且通过例如聚集、沉淀、晶体成长或结块的方式趋向于恢复到能量更加稳定的状态。
悬浮液包含分散在流体或半固体介质中的固体颗粒。因为悬浮剂是热力学不稳定的,分散的颗粒趋向于聚集和/或沉淀以减少表面积。悬浮液制备的两项关键性要求是使分散颗粒沉淀最小化以及防止沉降颗粒结块。最常用的方法是可控的絮凝途径。絮凝是悬浮颗粒聚集形成结构松散的絮体的过程,这些絮体聚集在一起结成网络状结构。因此,絮凝的颗粒结合较弱。像这样,它们不形成块状物且易于再悬浮。然而,哪种赋形剂会成功使悬浮液稳定是不可预知的,并且从悬浮液的物理稳定性上讲,它们的选择是关键的。
在本发明中,我们惊奇地发现:使用某些特定的赋形剂可以得到口服的利鲁唑水性悬浮液。该悬浮液具有最小的或根本没有口腔麻醉作用,导致患者的依从性得到改善。
这些水性悬浮液的理化性质稳定,这是工业制备和相应药物制剂分送的基本要求。
另一方面,这些利鲁唑悬浮液的浓度可以有较大的范围,例如从0.1%至超过15%(w/v)。这为医生提供了不同剂量和给药方案,实现了个性化治疗,并因此改善了患者的依从性。
因此,本发明的第一个方面涉及包含利鲁唑的具有最小或没有口腔麻醉作用的稳定的水性悬浮液。本发明的悬浮液优选通过口服给药;然而,这种悬浮液可能会增加那些肌萎缩性脊髓侧索硬化症(ALS)患者(由于他们的活动性降低,因此需要额外的给养)的肠道营养。
本发明的第二个方面涉及所述利鲁唑悬浮液在ALS治疗中的用途。
本发明的第三个方面涉及利鲁唑悬浮液的制备方法。
因此,本发明的第一个实施方案涉及包含利鲁唑颗粒或其药学上可接受的盐或衍生物和至少一种润湿剂的水性悬浮剂。
优选地,利鲁唑或其药学上可接受的盐或衍生物的用量介于约0.1%至约20%w/v。在更优选的实施方案中,利鲁唑的用量介于约0.2%至约10%,更优选介于约0.3至约6%w/v。
本发明中“w/v”的表述方式是指所提及化合物的重量(以g计)与悬浮液总体积(每100ml)的比值。
优选地,利鲁唑的平均粒径应低于200μm。在更优选的实施方案中,粒径值介于约75μm至约25μm,更优选地,介于约50μm至约10μm。
本发明的术语“润湿剂”是指提供疏水物质适当的湿润度的物质,例如,通过降低表面张力和固体颗粒与液体载体间的接触角,正如H.A.Lieberman、M.M.Rieger和G.S.Banker在《药物剂型:分散系》第1卷中编辑并公开的内容(Pharmaceutical Dosage Forms,Disperse system,Volume 1,1988 by Marcel Dekker,New York and Basel)。
根据本发明优选的实施方案,润湿剂是至少一种表面活性剂,优先选自阴离子表面活性剂、非离子型表面活性剂和其组合。
优选地,润湿剂的用量介于约0.005%至约2%w/v,更优选介于约0.01%至约0.5%w/v。
本发明适宜的表面活性剂可选自羧化物、天然乳化剂(例如磷脂)、硫酸酯(例如烷基硫酸酯)、磺酸酯、非离子醚(例如脂肪醇***、丙氧基乙醇、乙氧基/丙氧基嵌段共聚物)。
优选地,表面活性剂选自十二烷基硫酸钠(SLS)、磺基丁二酸钠二辛酯(或多库酯钠,DSS)、聚乙二醇蓖麻油衍生物(以Cremophor商标出售)、聚乙二醇脂肪醚(或乙氧基脂肪醇,以Volpo商标出售)和泊洛沙姆。
根据实施方案,阴离子表面活性剂选自:
●十二烷基硫酸钠(用量介于约0.0001%至约1%w/v,优选介于约0.0005至约0.5%w/v,更优选介于约0.001至约0.1%w/v);
●多库酯钠(用量介于约0.0001%至约1%w/v,优选介于约0.0005至约0.5%w/v,更优选介于约0.001至约0.1%w/v)。
根据另外的实施方案,非离子表面活性剂是丙烯酸树脂油(polyoxylated oil)和/或聚乙二醇(PEG)醚;所述非离子表面活性剂优先选自:
●聚氧35蓖麻油,如CremophorEL,或聚氧40氢化蓖麻油,如CremophorRH 40(用量介于约0.01%至约2%w/v,优选介于约0.05至约0.75%w/v,更优选介于约0.1至约0.3%w/v);
本发明人惊奇地发现:即使利鲁唑的浓度低至0.5%w/v,乙氧基脂肪醇仍可产生稳定的悬浮液。令人吃惊的是,即使应用利鲁唑以外的活性成分,在其浓度低于1.0%w/v的条件下,通常也难以获得稳定的悬浮液。
因此,本发明的优选实施方案涉及包含至少一种选自乙氧基脂肪醇的表面活性剂和利鲁唑或其药学上可接受的盐或衍生物的利鲁唑稳定悬浮液,其中利鲁唑或其药学上可接受的盐或衍生物的用量低于1.0%w/v,优选介于0.3%至0.8%w/v。
另一方面,本发明人还惊奇地发现:两种不同表面活性剂(优选离子型表面活性剂和非离子型表面活性剂)组合的结果是物理稳定性得到改善的悬浮剂。令人吃惊的是,表面活性剂通常作为润湿剂,并且很明显只需最小量的湿润剂就足以使颗粒充分分散。相反,增加表面活性剂的浓度(例如通过添加第二种该类试剂)会对分散颗粒产生抗絮凝作用。
发明人由此发现:在两种不同表面活性剂(优选离子型表面活性剂和非离子型表面活性剂)存在的条件下,利鲁唑悬浮液具有高絮凝度,而并未经历如预期地由增加润湿剂浓度引发的抗絮凝过程。
因此,本发明中的优选实施方案涉及包含利鲁唑颗粒或其药学上可接受的盐或衍生物和至少两种表面活性剂(优选离子型表面活性剂和非离子型表面活性剂)的利鲁唑的稳定组合物。离子型表面活性剂优先选自十二烷基硫酸钠和多库酯钠,而非离子型表面活性剂优先选自聚乙二醇醚(也称作乙氧基脂肪醇)如PEG 25鲸蜡硬脂醇醚。当利鲁唑或其药学上可接受的盐或衍生物的用量低于10%w/v,优选低于5%w/v,更优选介于约0.3%至约4.0%w/v时,特别优选将两种不同的表面活性剂联合使用。
优选地,本发明中的悬浮液包括助悬剂。本发明的术语“助悬剂”是指增加粘度和/或充当保护胶体的可产生稳定分散体的物质,它们减缓了颗粒的沉淀和凝聚,正如H.A.Lieberman、M.M.Rieger和G.S.Banker在《药物剂型:分散系》第1卷中编辑并公开的内容(Pharmaceutical Dosage Forms,Disperse system,Volume 1,1988 byMarcel Dekker,New York and Basel)。
优选的助悬剂选自蒙脱石黏土、黄原胶、琼脂、海藻酸盐、黄耆胶、瓜尔豆胶,和其他天然树胶、微晶纤维素及其组合。
在更优选实施方案中,助悬剂选自:
●黄原胶(用量介于约0.1%至约3.0%w/v,优选介于约0.15%至约1.0%w/v),单独或与另外一种选自羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(NaCMC)、甲基纤维素(MC)和羟乙基纤维素(HEC)的悬浮剂(用量介于约0.025%至约4%w/v)混合使用;
●硅酸铝镁,例如Veegum(用量介于约0.2%至约5.0%w/v,优选介于约0.5至约2.0%w/v),单独或与另外一种选自羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(NaCMC)、甲基纤维素(MC)和羟乙基纤维素(HEC)的悬浮剂(用量介于约0.025%至约4%w/v)或黄原胶(用量介于约0.025%至约1.0%w/v)混合使用;
●黄耆胶(用量介于约0.2%至约5.0%w/v,优选介于约0.5%至约1.5%w/v)。
已足以获得高至减缓悬浮颗粒沉淀进程,但同时不会增加液体剂型分散难度的粘度的用量加入上述助悬剂中任何一种。优选地,本发明助悬剂的用量介于约0.1%至约5%w/v,优选介于约0.01%至约2.0%w/v。
助悬剂通常表现为可塑体、或假可塑体、或触变流体或其组合。这有益于物理稳定性,由于其具有相对较高的静态粘度,因此沉淀被减缓,和在相对较高的切变率下(例如搅拌)易于流动,因而易于从瓶子或管形小瓶中分散。这些***的粘度值从约200mPa·秒至约3000mPa·秒不等,取决于助悬剂的用量和物理等级。然而,比绝对粘度更加重要的是在温和的手动搅拌条件下***再悬浮能力的便利性以及即便延长储存周期也不会出现的结块效果。
本发明的发明人惊奇地发现:至少一种表面活性剂与至少一种助悬剂的特定组合将导致改善的物理稳定性,例如改善的絮凝作用。
因此,本发明中另外的优选实施方案涉及包含至少一种选自乙氧基脂肪醇和/或十二烷基硫酸钠的表面活性剂和至少一种选自黄原胶、硅酸铝镁、羟丙基甲基纤维素和/或羧甲基纤维素钠的助悬剂的利鲁唑的稳定悬浮剂。
本发明的悬浮剂还可以包括防腐剂。
防腐剂可以是任何药学上可接受的抗微生物药物。优先选自尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、苯甲酸、山梨酸、苯甲酸钠、苄醇、苯乙醇和其混合物。
在特别优选的实施方案中,防腐剂是尼泊金甲酯和尼泊金丙酯或苄醇的混合物。
应以足以获得可接受的抗菌能力的用量加入防腐剂。其用量优选介于约0.05%至约2%w/v。
本发明的悬浮液还包括至少一种下列赋形剂,其用量为本领域技术人员所知:
●密度调配剂(例如山梨醇、木糖醇等);
●甜味剂和/或矫味剂;
●润湿剂,如甘油或丙二醇;
●抗泡沫剂(例如二甲基硅油乳剂)。
按照现有技术中的任何已知过程均能制备本发明所述悬浮液。因此本发明包含生产本发明中利鲁唑悬浮液的任何方法。在本发明中特定的实施方案中,悬浮液可按照如下的步骤制备:
A)分散载体的制备
(a)在适合的容器中(例如配有搅拌器的包套不锈钢罐),搅拌条件下将防腐剂体系溶解在占纯净水所需总体积约60-90%的水中(如需要,可加热)。
(b)搅拌条件下加入规定量的助悬剂,给予原料充足的时间以进行水合,即均匀分散或溶解以获得胶态分散体或胶体溶液,提供所需的粘度。该步骤需要加热载体(例如40-90℃)以便促进水合过程。同理,润湿剂(例如甘油)也可以用来促进助悬剂的分散过程:首先要制备润湿剂和助悬剂的紧密均匀的混合物,然后将其加入到水性载体中。这促进了水合过程,因为“严格的”,高分子量的聚合物和润湿剂(高亲水性和水溶性)的紧密混合物暴露出对水性载体的亲水表面。
(c)若需要可以将密度调配剂加入其中,并搅拌至混合物溶解。
(d)将载体的温度调节至室温(若必需)。
根据可选择的实施方案,阶段(b)和(c)加料顺序可以颠倒(即助悬剂的水合过程可在包含密度调配剂的水性载体中完成)。
B)利鲁唑的预分散体(湿化剂)
(e)在适合的容器中,加入占纯净水所需总体积约5-30%的水,且搅拌条件下分散抗泡沫剂,然后同样在搅拌条件下加入润湿剂并持续搅拌直至溶解或完全分散;然后加入规定量的利鲁唑并搅拌直至获得均匀的、没有块状物的悬浮液。
C)最终悬浮液的制备
(f)在强力搅拌条件下,向分散载体中加入利鲁唑预分散体,持续搅拌直至获得均匀的分散体。
(g)若需要,在搅拌条件下加入甜味剂和/或矫味剂。
(h)加入适量纯净水至最终体积并搅拌。
(i)借助适合的匀浆器(例如胶体磨、活塞型、ultraturrax型等)对最终悬浮液进行匀浆。
(j)将规定体积的悬浮液分送至个体最初的容器(玻璃或塑料)和盖子中。
根据可选择的实施方案,能够制备全部载体(即包含除利鲁唑以外所有成分的水性载体),然后在搅拌条件下,将活性成分缓慢加入至载体中。
附加的实施例提供本发明提及的药学上可行的悬浮液,然其只为阐述而并非限制本发明。
具体实施方式
本实验测定伴有不同化学性质的赋形剂(单独或组合使用)的利鲁唑液体组成物的稳定性。
应用ultraturrax型匀浆器制备如上所述的悬浮液。
悬浮液的物理稳定性已被下列方法所证实:外观(通过视觉观察);絮凝度(通过测定沉淀体积,F,定义为最终/最后的沉淀体积Vu(或高度Hu)与悬浮液起始体积Vo(或高度Ho)的比值,沉淀前,F=Vu/Vo(或Hu/Ho);光学显微镜(用来检测粒径的分布以及确证是否会有晶体产生);再悬浮(通过温和的手动振摇);粘度(借助旋转流变仪)。悬浮液的化学稳定性经特定的能够说明稳定性的高效液相色谱(HPLC)法评估。
下列实施例用于说明本发明的适用范围,但并不仅限于此。
实施例1:
口服悬浮剂-利鲁唑5.5%(w/v)
制备方法:
(a)将约占纯净水所需总体积约60-90%的水加入到配有搅拌器的包套不锈钢罐中并加热至约70-90℃。加入防腐剂体系(尼泊金甲酯和尼泊金丙脂)并搅拌直至溶解。
(b)维持温度在70-90℃,搅拌条件下加入预先紧密分散于甘油中的黄耆胶。使胶体发生水合直至获得均匀体系。
(c)加入规定量的蔗糖,并在70-90℃的条件下持续搅拌直至溶解。
(d)搅拌条件下,将载体的温度调节至室温。
(e)在独立的适合容器中制备利鲁唑预分散体:搅拌条件下,将规定量的十二烷基硫酸钠加入到占纯净水所需总体积约5-30%的水中。直至溶解,搅拌条件下加入规定量的利鲁唑并持续搅拌直至获得均匀的、没有块状物的悬浮液。
(f)在强力搅拌条件下,向载体中加入利鲁唑预分散体,持续搅拌直至获得均匀的分散体。
(g)加入适量纯净水至最终体积并搅拌。
(h)借助适合的匀浆器(例如胶体磨、活塞型、ultraturrax型等)对最终悬浮液进行匀浆。
(i)将规定体积的悬浮液分送至个体最初的容器(玻璃或塑料)和盖子中。
稳定性:40℃条件下,该制剂可至少在1个月内保持理化性质稳定。
实施例2:
口服悬浮剂-利鲁唑5.5%(w/v)
稳定性:40℃条件下,该制剂可至少在1周内保持物理性质稳定。
实施例3:
口服悬浮液-利鲁唑2.75%(w/v)
稳定性:40℃条件下,该制剂至少在1周内保持理化性质稳定。
实施例4:
口服悬浮剂-利鲁唑2.75%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例5:
口服悬浮剂-利鲁唑2.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该试剂至少在1个月内保持理化性质稳定。
实施例6:
口服悬浮剂-利鲁唑2.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该试剂至少在1个月内保持理化性质稳定。
实施例7:
口服悬浮液-利鲁唑0.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例8:
口服悬浮液-利鲁唑0.5%
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例9:
口服悬浮剂-利鲁唑0.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例10:
口服悬浮剂-利鲁唑0.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持保持理化性质稳定。
实施例11:
口服悬浮液-利鲁唑0.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例12:
口服悬浮剂-利鲁唑0.5%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例13:
口服悬浮剂-利鲁唑2.75%(w/v)
稳定性:40℃条件下,该制剂至少在1周内保持理化性质稳定。
实施例14:
口服悬浮液-利鲁唑2.75%(w/v)
稳定性:温度40℃、相对湿度75%的条件下,该制剂至少在1个月内保持理化性质稳定。
实施例15:
通过对比包含尼泊金酯、薄荷味香料和聚乙二醇蓖麻油衍生物(CremophorRH40)作为增溶剂的利鲁唑水溶液,评价利鲁唑悬浮液(实施例6和7)的适口性。该实验还包括含有实施例7中除利鲁唑以外所有成分的安慰剂。
根据以下的交叉实验方案,3名科学家(相对于“猜谜者”)对每一种组合物的样品进行单盲评价:
-样品由单独的科学家制备,因此猜谜者不知道他们需要服用的是什么;
-给予每名猜谜者2ml或10ml每种待测物(对应50mg利鲁唑)。用施用剂量的药物漱口约5秒钟,然后从口中吐出;
-基于普通“口感”(即如甜、苦、涩等属性),在漱口过程中进行第一次评价。然后基于口腔感觉、口腔刺激和麻醉作用进行余味评价。使用任意的四级刻度(arbitrary four-point)(0至3)进行评价,“0”意味着没有麻醉作用而“3”表示最强麻醉作用。记录麻醉作用消失所需时间。
-在样品吐出后至少30分钟内,猜谜者不允许用矿泉水漱口。
-样品评价间提供有1小时的洗刷周期,每名猜谜者每天至多评价4个样品。
研究结果总结如下:
-2.5%利鲁唑悬浮液:较好的普通口感,温和的口腔刺激,温和的麻醉效果,持续约15分钟。
-2.5%利鲁唑溶液:较差的普通口感,伴有强烈的口腔刺激、灼唇感和麻醉效果(3级),至少持续20-30分钟,最长可达到60分钟的极值(其中1个案例)。
-0.5%利鲁唑悬浮液:较好的普通口感,无口腔刺激,非常温和的或无麻醉效果(0-1级)。2个案例中,猜谜者不能将其从安慰剂中辨认出来。
-0.5%利鲁唑溶液:较好的普通口感,温和的口腔刺激和麻醉效果(2级),至少持续15-20分钟。
-安慰剂:较好的普通口感,无麻醉效果(0级)。
通过对比利鲁唑溶液,这些结果描绘了本发明组合物的令人吃惊的顺利的适口性研究,显示出该技术领域内的显著进步,尤其是为萎缩性脊髓侧索硬化症患者提供有效的、具有高度患者依从性潜质的治疗方案。
实施例16:对比实施例
对比包含相同利鲁唑浓度(0.5%)的四种不同利鲁唑水性悬浮液(A-D),评价实施例11中利鲁唑悬浮液的适口性。
所述利鲁唑水溶液的组成如下所述:
A)利鲁唑悬浮于水中;
B)利鲁唑悬浮于含有0.1%羧甲基纤维素钠(NaCMC)的水中;
C)利鲁唑悬浮于含有0.5%甲基纤维素(MC)的水中;及
D)如实施例11所述的悬浮剂,其中硅酸铝镁和黄原胶被1%的羧甲基纤维素钠(NaCMC)替代。
根据实施例15所述的交叉实验方案,3名科学家(相对于“猜谜者”)对每一种悬浮液的样品进行单盲评价:
研究结果总结如下:
-实施例11:较好的普通口感,无口腔刺激,非常温和的或无麻醉效果(0-1级)。
-悬浮液A):较差的普通口感,伴有强烈的口腔刺激,麻醉效果(2-3级),持续30-40分钟。
-悬浮液B):较差的普通口感,温和的口腔刺激和强烈的麻醉效果(2-3级),持续30-40分钟。
-悬浮液C):较差的普通口感,温和的口腔刺激和麻醉效果(2-3级),持续30-40分钟。
-悬浮剂D):较好的普通口感,温和的口腔刺激、灼唇感和麻醉效果(2-3级),持续30-40分钟。
通过对比四种不同的利鲁唑悬浮液,这些结果描绘了本发明悬浮液的令人吃惊的顺利的适口性研究,显示出该技术领域内的显著进步,尤其是为萎缩性脊髓侧索硬化症患者提供有效的、具有高度患者依从性潜质的治疗方案。
此外,四种对比悬浮液均未显示出工业制备方面充分的物理稳定性。
Claims (19)
1.一种水性悬浮液,其包含利鲁唑或其药用盐或衍生物,至少一种表面活性剂和至少一种助悬剂,其中所述表面活性剂选自阴离子表面活性剂、非离子型表面活性剂或其混合物,并且所述助悬剂选自蒙脱石黏土、微晶纤维素、天然树胶或其混合物。
2.根据权利要求1所述的悬浮液,其特征在于天然树胶选自黄原胶、黄耆胶、瓜尔豆胶、琼脂、海藻酸盐或其混合物。
3.根据权利要求1所述的悬浮液,其特征在于所述蒙脱石黏土是硅酸铝镁。
4.根据权利要求1所述的悬浮液,其特征在于所述助悬剂的用量介于约0.1%至约5%w/v,优选介于约0.01%至约2.0%w/v。
5.根据权利要求1所述的悬浮液,其特征在于利鲁唑或其药用盐或衍生物的用量介于约0.1%至约20%w/v,优选介于约0.2%至约10%w/v,更优选介于约0.3%至约6%w/v。
6.根据权利要求1所述的悬浮液,其特征在于利鲁唑或其药用盐或衍生物以颗粒形式存在。
7.根据权利要求6所述的悬浮液,其特征在于利鲁唑或其药用盐或衍生物的平均粒径小于200μm。
8.根据权利要求7所述的悬浮液,其特征在于所述平均粒径介于约75μm至约25μm,更优选地介于约50μm至10μm。
9.根据权利要求1所述的悬浮液,其特征在于所述表面活性剂的用量介于约0.005%至约2%w/v,优选介于约0.01%至约0.5%w/v。
10.根据权利要求1所述的悬浮液,其特征在于所述表面活性剂选自羧化物、天然乳化剂、硫酸酯、磺酸酯和/或非离子醚。
11.根据权利要求1所述的悬浮液,其特征在于所述表面活性剂选自十二烷基硫酸钠、磺基丁二酸钠二辛酯(多库酯钠)、聚乙二醇蓖麻油衍生物、聚乙二醇脂肪醚和/或泊洛沙姆。
12.根据权利要求1所述的悬浮液,其特征在于所述阴离子表面活性剂选自十二烷基硫酸钠(用量介于约0.0001%至约1%w/v,优选介于约0.0005%至约0.5%w/v,更优选介于约0.001%至约0.1%w/v)和/或多库酯钠(用量介于约0.0001%至约1%w/v,优选介于约0.0005%至约0.5%w/v,更优选介于约0.001%至约0.1%w/v)。
13.根据权利要求1所述的悬浮液,其特征在于所述非离子型表面活性剂是丙烯酸树脂油和/或聚乙二醇醚。
14.根据权利要求1所述的悬浮液,其特征在于所述表面活性剂是乙氧基脂肪醇。
15.根据权利要求14所述的悬浮液,其特征在于利鲁唑或其药学上可接受的盐或衍生物的用量低于1.0%w/v,优选介于0.3%至0.8%w/v。
16.根据权利要求1所述的悬浮液,其特征在于所述表面活性剂由两种不同的表面活性剂组成,优选阴离子表面活性剂和非离子型表面活性剂。
17.根据权利要求15所述的悬浮液,其特征在于所述阴离子表面活性剂选自十二烷基硫酸钠和多库酯钠,且非离子型表面活性剂选自聚乙二醇醚,如PEG 25鲸蜡硬脂醇醚。
18.根据权利要求1所述的悬浮液,其特征在于利鲁唑或其药学上可接受的盐或衍生物的用量低于10%w/v,优选低于5%w/v,更优选介于约0.3%至约4.0%w/v。
19.根据上述权利要求任一项所述的悬浮液,其用于治疗萎缩性脊髓侧索硬化症。
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ITMI20061274A1 (it) * | 2006-06-30 | 2008-01-01 | Consiglio Nazionale Ricerche | Vettori nanoparticellari lipidici contenenti riluzolo e composizioni farmaceutiche che li contengono |
US9132071B2 (en) * | 2006-07-28 | 2015-09-15 | Santen Sas | Compositions containing quaternary ammonium compounds |
UA41879U (ru) * | 2009-02-03 | 2009-06-10 | Сергей Викторович Фурс | Инфракрасный обогревательный прибор |
-
2009
- 2009-03-13 EP EP09425101A patent/EP2228054A1/en not_active Withdrawn
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2010
- 2010-03-02 ES ES10706234T patent/ES2400349T3/es active Active
- 2010-03-02 JP JP2011553390A patent/JP5607083B2/ja active Active
- 2010-03-02 CN CN2010800108923A patent/CN102341091B/zh active Active
- 2010-03-02 CA CA2748856A patent/CA2748856C/en active Active
- 2010-03-02 PL PL10706234T patent/PL2405890T3/pl unknown
- 2010-03-02 PT PT107062341T patent/PT2405890E/pt unknown
- 2010-03-02 RU RU2011141422/15A patent/RU2498802C2/ru active
- 2010-03-02 US US13/138,047 patent/US8765150B2/en active Active
- 2010-03-02 PE PE2011001558A patent/PE20120649A1/es active IP Right Grant
- 2010-03-02 SI SI201030130T patent/SI2405890T1/sl unknown
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- 2010-03-02 KR KR1020117020162A patent/KR101680175B1/ko active Protection Beyond IP Right Term
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- 2010-03-02 EP EP10706234A patent/EP2405890B1/en active Active
- 2010-03-02 BR BRPI1006418A patent/BRPI1006418A2/pt not_active Application Discontinuation
- 2010-03-02 WO PCT/EP2010/052598 patent/WO2010102923A2/en active Application Filing
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2011
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- 2011-09-08 CL CL2011002217A patent/CL2011002217A1/es unknown
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2012
- 2012-03-14 HK HK12102552.2A patent/HK1161985A1/xx unknown
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2013
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105726477A (zh) * | 2016-03-01 | 2016-07-06 | 山东司邦得制药有限公司 | 一种小儿多潘立酮混悬液及其制备方法 |
CN105726477B (zh) * | 2016-03-01 | 2018-10-12 | 山东司邦得制药有限公司 | 一种小儿多潘立酮混悬液及其制备方法 |
CN111437256A (zh) * | 2019-01-17 | 2020-07-24 | 北京万全德众医药生物技术有限公司 | 一种利鲁唑缓释口服混悬液 |
CN115025056A (zh) * | 2022-06-27 | 2022-09-09 | 郑州大学第一附属医院 | 一种含有替加氟、吉莫斯特和奥替拉西钾的口腔崩解制剂 |
Also Published As
Publication number | Publication date |
---|---|
PT2405890E (pt) | 2013-02-20 |
RU2498802C2 (ru) | 2013-11-20 |
WO2010102923A2 (en) | 2010-09-16 |
EP2405890B1 (en) | 2012-11-28 |
WO2010102923A3 (en) | 2011-03-03 |
BRPI1006418A2 (pt) | 2016-11-29 |
US20120039953A1 (en) | 2012-02-16 |
KR101680175B1 (ko) | 2016-11-28 |
RU2011141422A (ru) | 2013-04-20 |
CA2748856A1 (en) | 2010-09-16 |
PL2405890T3 (pl) | 2013-04-30 |
CA2748856C (en) | 2017-01-03 |
CN102341091B (zh) | 2013-08-07 |
CY1113825T1 (el) | 2016-07-27 |
EP2405890A2 (en) | 2012-01-18 |
JP5607083B2 (ja) | 2014-10-15 |
MX2011008922A (es) | 2011-12-06 |
HRP20130021T1 (hr) | 2013-02-28 |
CL2011002217A1 (es) | 2012-03-09 |
HK1161985A1 (en) | 2012-08-17 |
US8765150B2 (en) | 2014-07-01 |
SMT201300022B (it) | 2013-03-08 |
KR20120003854A (ko) | 2012-01-11 |
DK2405890T3 (da) | 2013-02-04 |
PE20120649A1 (es) | 2012-06-07 |
EP2228054A1 (en) | 2010-09-15 |
ES2400349T3 (es) | 2013-04-09 |
CO6410281A2 (es) | 2012-03-30 |
SI2405890T1 (sl) | 2013-02-28 |
JP2012520254A (ja) | 2012-09-06 |
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