CN1893938A - 普瑞巴林组合物 - Google Patents
普瑞巴林组合物 Download PDFInfo
- Publication number
- CN1893938A CN1893938A CNA2004800374979A CN200480037497A CN1893938A CN 1893938 A CN1893938 A CN 1893938A CN A2004800374979 A CNA2004800374979 A CN A2004800374979A CN 200480037497 A CN200480037497 A CN 200480037497A CN 1893938 A CN1893938 A CN 1893938A
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- CN
- China
- Prior art keywords
- pharmaceutical compositions
- liquid pharmaceutical
- lyrica
- acid
- described liquid
- 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.)
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 53
- 239000000203 mixture Substances 0.000 title abstract description 32
- 229960001233 pregabalin Drugs 0.000 title abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 54
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 46
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 229940009697 lyrica Drugs 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
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- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical group OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 11
- 229940085605 saccharin sodium Drugs 0.000 claims description 11
- 230000002421 anti-septic effect Effects 0.000 claims description 8
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 8
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 8
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- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 8
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 8
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 7
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- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical class C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- YAZDSTCFFRZJLW-UHFFFAOYSA-N 2-hydroxyicosa-2,4,6,8-tetraenoic acid Chemical compound CCCCCCCCCCCC=CC=CC=CC=C(O)C(O)=O YAZDSTCFFRZJLW-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 1
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- 239000004475 Arginine Substances 0.000 description 1
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Abstract
本发明提供一种化学和物理学稳定的、可口服给药的含普瑞巴林的水性药物组合物。该液体组合物包括至少一种防腐剂、至少一种矫味剂、以及可选的粘度调节剂。该液体药物组合物的pH至少为5.5但不超过7.0。
Description
技术领域
本发明涉及含有普瑞巴林(pregabalin)的液体药物组合物，其适合口服给药。
背景技术
可口服给药的液体药物组合物是备受关注的治疗儿童和老年患者的剂型。液体药物组合物易于吞咽，如果配方合适，可具有令人愉快的口味，改善患者对处方给药方案的依从性。另外，与固体剂型相比，液体药物制剂可提供更好的个性化给药方式，在治疗如儿童和老年人的不同患者群体时可能是重要的。
普瑞巴林，或(S)-(+)-3-氨甲基-5-甲基-己酸，与钙离子通道α-2-δ-(α2δ)亚单位结合，与内源性抑制性神经递质γ-氨基丁酸(GABA)有关，其参与调节大脑神经元的活动。普瑞巴林显示有抗癫痫发作活性，如R.B.Silverman等人的美国专利第5,563,175号中的讨论，它被认为可用于治疗疼痛、与精神运动性兴奋剂相关的生理状态、炎症、胃肠损害、酒精中毒、失眠、以及各种精神疾患，包括躁狂和双相性精神障碍(bipolardisorder)。
含有普瑞巴林的口服液体药物组合物给制剂专家提出了众多挑战。普瑞巴林有很强烈的苦味。因此，任何儿科制剂都可能需要矫味。但普瑞巴林很高的水溶性(32.1mg/mL)使矫味很困难。而且，类似加巴喷丁(gabapentin)，普瑞巴林是γ-氨基酸，在正常储存条件下以及有水存在时，会发生分子内环化形成内酰胺，4-异丁基-吡咯烷-2-酮。参见例如，WO 99/10186和WO 99/59573，均属于A.Aomatsu。尽管已知该组合物的非活性成分可影响内酰胺的形成，但很难预料何种赋形剂或佐剂可能会引起不需要的内酰胺形成。
发明内容
本发明提供了一种稳定的可口服给药的液体药学组合物。该组合物包含普瑞巴林或普瑞巴林的药学可接受的配合物或盐。该液体药学组合物也包括水、至少一种防腐剂、至少一种矫味剂、以及可选的粘度调节剂。该液体药学组合物的pH为至少5.5但不超过7.0。
具体实施方式
除非另外说明，本内容使用下面的定义。
“药学可接受的”是指在合理的医学判断范围内，适合用于接触患者的组织而没有不适当的毒性、刺激性、过敏反应、和类似情况，具有合理的收益/风险比，并有效用于其预期用途的物质。
“治疗(treating)”是指逆转、缓解、抑制该术语适用的疾患或病症的进展、或预防该疾患或病症、或防止该疾患或病症的一种或多种症状。
“治疗(treatment)”是指上面刚定义的“治疗(treating)”的行为。
“大约”，当用于连接可测量的数字变量时，是指该变量的指示值，以及在该指示值的实验误差范围内的变量的所有值(例如，在均数的95％置信区间内)或在该指示值的10％范围内中较大的一个。
“溶剂合物”描述了含有普瑞巴林以及化学计量的一种或多种药学可接受的溶剂分子(例如，乙醇)的分子配合物。
“水合物”描述了含有普瑞巴林和化学计量的水的溶剂合物。
如上所述，口服的液体药学组合物含有可溶解或分散在水中的普瑞巴林，并含有至少一种防腐剂、至少一种矫味剂、以及一种或多种可选的粘度调节剂。普瑞巴林通常在液体药学组合物中的浓度为至少大约10mg/mL，更典型的浓度为至少大约15mg/mL。
普瑞巴林可使用公知的方法制备。在其中一些方法中，合成了外消旋的3-氨甲基-5-甲基-己酸，随后拆分为R-和S-对映体。这些方法在R.B.Silverman等人的美国专利第5,563,175号、T.M.Grote等人的美国专利第6,046,353号、T.M.Grote等人的美国专利第5,840,956号、T.M.Grote等人的美国专利第5,637,767号、B.K.Huckabee & D.M.Sobieray的美国专利第5,629,447号和B.K.Huckabee & D.M.Sobieray的美国专利第5,616,793号中描述。在这些方法的每一种方法中，外消旋物与手性酸(拆分剂)反应形成一对非对映异构的盐，其可通过公知的技术分离，如分步结晶和色谱。在其它方法中，普瑞巴林使用手性助剂(4R，5S)-4-甲基-5-苯基-2-噁唑烷酮直接合成。参见，例如美国专利第6,359,169、6,028,214、5,847,151、5,710,304、5,684,189、5,608,090、和5,599,973号，均属于Silverman等人。在另一些方法中，普瑞巴林的制备是通过氰取代的链烯烃的不对称氢化作用，以产生(S)-3-氨甲基-5-甲基己酸的手性氰基前体，随后被还原产生普瑞巴林。参见Burk等人的美国专利申请2003/0212290 A1。
当制备口服的液体药学组合物时，可以使用普瑞巴林的任何药学可接受的形式，包括但不限于，其游离形式(两性离子)、以及其药学可接受的配合物、盐、溶剂合物、水合物、和多形体。盐类包括但不限于酸加成盐和碱加成盐，包括半盐(hemisalts)。药学可接受的酸加成盐包括来自盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸、亚磷酸等之类的无机酸的无毒盐类，以及来自如脂肪族单羟酸和二羟酸、苯基取代的链烷酸、羟基链烷酸、链烷双酸、芳香酸、脂肪族和芳香族磺酸等等之类的有机酸的无毒盐类。潜在可用的盐类包括醋酸盐、天冬氨酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、苯磺酸盐(besylate)、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、焦硫酸盐、亚硫酸氢盐、亚硫酸盐、硼酸盐、右旋樟脑磺酸盐、辛酸盐、柠檬酸盐、乙二磺酸盐(edisylate)、乙磺酸盐(esylate)、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡萄糖酸盐、葡糖醛酸盐、六氟磷酸盐、羟苯酰苯酸盐(hibenzate)、盐酸盐、氯化物、氢溴酸盐、溴化物、氢碘化物、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、naphthylate、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、邻苯二甲酸盐、丙酸盐、糖酸盐、癸二酸盐、硬脂酸盐、辛二酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐、三氟醋酸盐和类似物。
药学可接受的碱性盐可包括来自碱类的无毒盐类，该碱类包括碱或碱土金属阳离子之类的金属阳离子、和胺。潜在可用的盐类的例子包括但不限于铝、精氨酸、N，N’-二苄基乙二胺、钙、氯普鲁卡因、胆碱、二乙醇胺、二乙胺、二环己基胺、乙二胺、甘氨酸、赖氨酸、镁、N-甲基葡胺、乙醇胺(olamine)、钾、普鲁卡因、钠、缓血酸胺、锌和类似物。对于可用的酸加成和碱盐类的讨论，参见S.M.Berge等人，J.of Pharm.Sci.，66：1-19(1977)；另见Stahl和Wermuth，Handbook of PharmaceuticalSalts：Properties，Selection，and Use(2002)。
普瑞巴林的药学可接受的盐的制备可通过将其游离(两性离子)形式与所需的酸或碱反应；从普瑞巴林适当的前体中去除酸-或碱-不稳定保护基团；使用所需的酸或碱将合适的环状(内酰胺)前体开环；或通过与合适的酸或碱反应或与合适的离子交换柱接触，将普瑞巴林的一种盐转变为另一种盐。所有这些转化作用都可典型地在溶剂中进行。得到的盐可被沉淀出来，并通过过滤收集或通过蒸发溶剂而回收。得到的盐中离子化的程度可从完全离子化至几乎未离子化。
普瑞巴林可能以未溶剂化和溶剂化形式，作为除盐类之外的其他配合物类型存在。可用的配合物包括笼形包合物或药物-主体包合配合物(drug-host inclusion complex)，与溶剂合物相比，药物和主体是以化学计量或非化学计量存在的。可用的普瑞巴林配合物也可含有化学计量或非化学计量的两种或更多种有机、无机、或有机和无机组分。得到的配合物可被离子化、部分离子化、或非离子化。对于这种配合物的综述，参见J.K.Haleblian，J.Pharm.Sci.64(8)：1269-88(1975)。
普瑞巴林的可用形式包括其所有的多形体和晶体惯态，以及其R-对映体和普瑞巴林的外消旋混合物和其R-对映体。
普瑞巴林的可用形式也包括药学可接受的同位素标记的化合物，其中一个或多个原子被具有相同原子序数，但原子质量或质量数与天然占优势的原子质量或质量数不同的原子而置换。适合在普瑞巴林中包含的同位素的实例包括氢的同位素(2H和3H)，碳的同位素(11C、13C和14C)，和氮的同位素(13N和15N)。普瑞巴林同位素标记的形式通常可通过本领域技术人员所知的常规技术来制备的。
如上所述，液体药学组合物的pH范围是大约5.5至大约7.0(包含端值)，优选的范围是大约5.5至大约6.5(包含端值)，更优选的范围是大约5.8至大约6.2(包含端值)。在制备液体组合物的过程中，以及在ICH条件(25℃在60％RH，30℃在60％RH，以及40℃在75％RH)下和冷藏条件(2℃至8℃，包含端值)下储存该组合物达2年的过程中，这样的pH范围似乎可减少或防止内酰胺的形成。在低于大约5.5或高于大约7.0的pH下，组合物中的内酰胺形成似乎是不可接受的(即，超过大约0.5重量％)；维持pH在大约5.8和大约6.2之间(包含端值)似乎可以使内酰胺的形成最少化。在制备液体组合物的过程中，可加入药学可接受的酸或碱将pH调整至所需的值，也可加入常规的缓冲液(例如，柠檬酸盐缓冲液)将pH维持在上述所需的范围内。
口服的液体药学组合物包含一种或多种防腐剂以减少或防止多倍剂量容器中的微生物生长。防腐剂的选择根据许多标准。所需的特性包括但不限于，在pH 5.5和7.0之间足够的抗微生物活性；对组合物pH的影响最小；对口味的不良影响最小；适合口服递送；在2℃至8℃储存中有足够的可溶性；不与普瑞巴林反应；不与其它的制剂成分反应；以及在ICH条件下稳定两年。除了抗微生物特性外，这些标准也应用于该液体药物制剂中的其他赋形剂。
如在实施例中所见，许多普通的防腐剂不能满足这些标准。例如，将山梨酸与普瑞巴林一起使用会引起溶液变色，以及不可接受的pH转变至5.0，其似乎将利于内酰胺的形成。如在实施例中提到，甘油不能满足欧洲药典(European Pharmacopoeia)现行版本的要求(第五版，2004)。其它的普通防腐剂如乙醇，不适合用于儿科制剂中。
尽管许多更普通的防腐剂不可接受，然而各种对羟基苯甲酸酯发现可用作含普瑞巴林的口服液体药学组合物中的抗微生物剂。可用的对羟基苯甲酸酯包括对羟基苯甲酸甲酯和对羟基苯甲酸乙酯，单独或联合使用，其中例如，对羟基苯甲酸甲酯存在的浓度为至少大约2mg/mL，对羟基苯甲酸乙酯存在的浓度为至少大约0.5mg/mL。可用的对羟基苯甲酸酯组合包括，其中基于重量，对羟基苯甲酸甲酯的量为对羟基苯甲酸乙酯的量的至少约3倍，但不超过对羟基苯甲酸乙酯的大约5倍。
口服液体药学组合物还包含至少一种矫味剂。矫味剂包括甜味剂和香精，可单独或联合使用。尽管儿科制剂通常要避免使用生龋齿的糖类作为甜味剂，但通常不生龋齿的糖类木糖醇和甘油在5℃的储存条件下会从溶液中沉淀出来，使其不适合用在液体药物制剂中。随后的测试表明，在5℃时糖精钠仍存在于溶液中，与制剂中的其它组分相容。糖精钠在液体药物组合物中存在的浓度可为至少大约0.5mg/mL，不过更典型地的存在浓度为至少大约2mg/mL。
除了甜味剂以外，液体药学组合物可含有香精以掩盖普瑞巴林的苦味。可用的香精包括各种果味香精(例如，橙、樱桃、草莓、葡萄等)和薄荷香精，其类似于防腐剂，在液体药学组合物的制备过程中或储存中不会与普瑞巴林反应。惰性的香精包括缺少羰基(即，醛和酮基)的香精。因此可用的香精包括购自HAARMANN & REIMER的StrawberryFlavor 207420、和购自DRAGOCO的Orange Flavor 9/055600。
液体药学组合物可任选地包含粘度调节剂以提高组合物的粘度。增加粘度可改善组合物的处理，似乎可以改善药学制剂的味道。可用的粘度调节剂包括羟乙基纤维素、黄原胶和类似物，其可单独或联合使用。粘度调节剂使用的浓度为至少大约2mg/mL直至大约5mg/mL。
含有普瑞巴林的口服液体药学组合物可如下面实施例6至9中所述进行制备。得到的浆样的药学组合物可注入单次剂量或多次剂量容器内。含有两份一半剂量的双囊包被铝箔可用作单次剂量容器。多次剂量容器允许可变的体积剂量，并可提供适当的辅助用量装置(例如，有刻度的杯子或吸管)。多次剂量容器可以是装有儿童防护盖的玻璃瓶或塑料瓶。可用的盖子包括以聚乙烯泡沫为衬垫的盖子。
实施例
下面实施例的目的是说明性和非限制性的，并代表了本发明的特定
实施方式。
实施例1至实施例5
表1列举了对含有普瑞巴林和包括山梨酸、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯和甘油的各种防腐剂的液体药学组合物检测抗微生物效果的代表性结果。在表1中显示的所有实施例中，普瑞巴林的浓度为15mg/mL，加入足量的纯水得到所示的批量。在表1中，注释“满足欧洲药典”和“未通过欧洲药典”是指实验结果是否满足或未通过欧洲药典现行版本(第五版，2004)所规定的微生物限度检测：1000细菌/g(最大值)；100酵母和霉菌/g(最大值)；以及没有大肠杆菌。
实施例6至实施例9
表2列举了经过稳定性检测的代表性的含普瑞巴林的液体药学组合物。在表2中显示的所有实施例中，加入足量的纯水得到5L的批量。实施6和实施例7使用的香精不同，但其他相同。实施例8和实施例9与实施例6相似，除了通过分别加0.1N HCl和0.1N NaOH将pH调整为5.5和7.0。
对于实施例6至9的每一个，将纯净和无菌的水(大约4.5L)置于装备有搅拌器的温控容器中。将容器内容物加热至80℃。将对羟基苯甲酸甲酯(10g)和对羟基苯甲酸乙酯(2.5g)搅拌入热水中。获得清亮的溶液后，加入糖精钠(5g)。下一步，在强力搅拌下分小份加入羟乙基纤维素(45g)，避免成块。得到的液体混合物冷却至30℃，在搅拌下分小份加入普瑞巴林(75g)。普瑞巴林完全溶解后，继续冷却，并在25℃至30℃加入香精(10g Strawberry Flavor或5g Orange Flavor)。混合物搅拌至少10分钟使每种香精均匀分散。使用MILLIPORE膜滤器(醋酸纤维素，孔径10μm)过滤溶液。加入纯水以及0.1NHCl或0.1NNaOH(实施例8和9)使总批量为5L。得到的液体药学组合物储存在密封的容器内。
对实施例6至9中的每种口服液体普瑞巴林制剂进行稳定性测试。对组合物的初始制剂进行稳定性测试，预先确定在5℃、25℃和60％RH、及30℃和60％RH下储存1、3、6、12、18和24个月后进行实验。稳定性实验方案包括检查液体组合物的外观和颜色，以及检测普瑞巴林和降解物浓度、溶液pH、以及抗微生物活性(仅在25℃)。
储存6个月后，制剂清亮或稍微有些不透明，且无色或稍微有些黄色。另外，储存6个月后，所有批次的内酰胺形成基于重量都不超过0.1％，pH在5.4和7.0之间，不管其初始pH是否被调整。最后，所有批次均满足现行版本欧洲药典所提出的微生物限度。
表1.普瑞巴林水性液体药学组合物的抗微生物活性
| 实施例 | 体积L | 成分1 | mg/mL | 储存2月数 | 结果 | 备注 |
| 12345 | 45555 | 山梨酸木糖醇C NF对羟基苯甲酸乙酯对羟基苯甲酸甲酯糖精钠对羟基苯甲酸乙酯对羟基苯甲酸甲酯糖精钠羟乙基纤维素250HHX甘油min.99％糖精钠0.1N HCl(mL)对羟基苯甲酸乙酯对羟基苯甲酸甲酯糖精钠羟乙基纤维素250HHX草莓香精 | 22000.31.20.50.41.60.534000.60.010.52132 | 03013010136 | 未测定满足欧洲药典未通过欧洲药典(A.niger)满足欧洲药典满足欧洲药典未通过欧洲药典(A.niger)未通过欧洲药典(A.niger，C.albicans)未通过欧洲药典(A.niger，C.albicans)满足欧洲药典满足欧洲药典满足欧洲药典满足欧洲药典 | pH变化，未溶解的颗粒，粉红色霉菌 |
1.加入纯水得到指定的批量体积；普瑞巴林浓度为15mg/mL。
2.在25℃和相对湿度60％(RH)下储存。
表2.水性普瑞巴林组合物1
| 成分 | 实施例 | |||
| 6 | 7 | 82 | 93 | |
| 普瑞巴林对羟基苯甲酸甲酯对羟基苯甲酸乙酯糖精钠羟乙基纤维素250 HHXStrawberry Flavor 207420 H&ROrange Flavor 9/055600 DRAGOCO | 1520.5132 | 1520.5131 | 1520.5132 | 1520.5132 |
1.加入纯水得到5L的批量。
2.加入0.1N HCl调整pH至5.5。
3.加入0.1N NaOH调整pH至7.0。
应该注意的是，如在本说明书和所附的权利要求中所使用的，单数物品如“一个(a、an)”和“该”，如果文中没有另外清晰地标明，可指一个物体或多个物体。因此，例如，就含有“化合物”的组合物而言，它可包括一种化合物或两种或多种化合物。
要理解的是上述的描述是说明性的，不是限制性的。对于本领域技术人员通过阅读上述说明，许多实施方案将是显而易见的。因此本发明范围的确定不涉及上面的说明，而应该参考所附的权利要求，以及这些权利要求所授权的同等物的整个范围而确定。所有文章和参考资料的内容，包括专利、专利申请和出版物，为了所有目的而完全引入本文以供参考。
Claims (15)
1.一种口服给药的液体药学组合物，包括：
普瑞巴林或其药学可接受的盐或配合物；
水；
至少一种防腐剂；
至少一种矫味剂；和
可选的粘度调节剂；
其中所述的液体药学组合物的pH至少为5.5，但不超过7.0。
2.如权利要求1所述的液体药学组合物，其中所述的液体药学组合物的pH至少为5.5但不超过6.5。
3.如权利要求2所述的液体药学组合物，其中所述的液体药学组合物的pH至少为5.8但不超过6.2。
4.如权利要求1至3所述的液体药学组合物，其中普瑞巴林在所述液体药学组合物中的存在浓度为至少10mg/mL。
5.如权利要求4所述的液体药学组合物，其中普瑞巴林在所述的液体药学组合物中的存在浓度为至少15mg/mL。
6.如权利要求1至5所述的液体药学组合物，其中所述的防腐剂包括一种或多种对羟基苯甲酸酯。
7.如权利要求1至5所述的液体药学组合物，其中所述的防腐剂包括对羟基苯甲酸甲酯和对羟基苯甲酸乙酯。
8.如权利要求7所述的液体药学组合物，其中对羟基苯甲酸甲酯在所述的液体药学组合物中的存在浓度为至少2mg/mL。
9.如权利要求8所述的液体药学组合物，其中对羟基苯甲酸乙酯在所述的液体药学组合物中的存在浓度为至少0.5mg/mL。
10.如权利要求1所述的液体药学组合物，其中所述的矫味剂包括甜味剂。
11.如权利要求10所述的液体药学组合物，其中所述的甜味剂是糖精钠。
12.如权利要求11所述的液体药学组合物，其中糖精钠在所述的液体药学组合物中的存在浓度为至少0.5mg/mL。
13.如权利要求11所述的液体药学组合物，其中糖精钠在所述的液体药学组合物中的存在浓度为至少2mg/mL。
14.如权利要求1至13所述的液体药学组合物，其中所述的矫味剂包括香精，所述香精的特征为没有羰基基团。
15.如权利要求1至13所述的液体药学组合物，其中所述的粘度调节剂为羟乙基纤维素。
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| JP (1) | JP2007514728A (zh) |
| KR (1) | KR100841893B1 (zh) |
| CN (1) | CN1893938A (zh) |
| AU (1) | AU2004308747A1 (zh) |
| BR (1) | BRPI0417585A (zh) |
| CA (1) | CA2549599A1 (zh) |
| IL (1) | IL176129A0 (zh) |
| MX (1) | MXPA06006811A (zh) |
| MY (1) | MY143561A (zh) |
| NO (1) | NO20063178L (zh) |
| RU (1) | RU2352333C2 (zh) |
| SG (2) | SG143257A1 (zh) |
| TW (1) | TWI279230B (zh) |
| WO (1) | WO2005063229A1 (zh) |
| ZA (1) | ZA200604656B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998074A (zh) * | 2017-12-13 | 2018-05-08 | 广州大光制药有限公司 | 普瑞巴林口服溶液及其制备方法 |
| CN112107537A (zh) * | 2019-06-19 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | 一种普瑞巴林口服溶液及其制备方法 |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL126999A (en) | 1996-07-24 | 2002-03-10 | Warner Lambert Co | Pharmaceutical preparations containing isobutylgaba and its history for use in the treatment of pain |
| DE102007019071A1 (de) * | 2007-04-23 | 2008-10-30 | Ratiopharm Gmbh | Stabilisierte pharmazeutische Zusammensetzung enthaltend Pregabalin |
| EP2246044A1 (en) * | 2009-04-21 | 2010-11-03 | Pierre Fabre Dermo-Cosmétique | Paediatric solutions comprising a beta-blocker |
| WO2010150221A1 (en) | 2009-06-25 | 2010-12-29 | Wockhardt Research Centre | Taste masked pharmaceutical compositions of pregabalin |
| HU230031B1 (hu) | 2010-03-01 | 2015-05-28 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Pregabalint és izomaltot tartalmazó stabilizált gyógyszerkészítmény |
| TR201005241A1 (tr) * | 2010-05-25 | 2012-01-23 | Sanovel �La� San. Ve T�C. A.�. | Kontrollü salım sağlayan pregabalin solüsyon formülasyonu. |
| EA017542B1 (ru) * | 2011-05-24 | 2013-01-30 | Плива Кроэйша Лтд. | Стабильная фармацевтическая композиция, содержащая прегабалин, капсула, ее содержащая, способ получения и применение |
| EA020558B1 (ru) * | 2012-03-20 | 2014-12-30 | ООО "Эн.Си. ФАРМ" | Фармацевтический состав, обладающий нейропротекторной, антиамнестической, антиоксидантной, противогипоксической, нейрометаболической, противоишемической активностью (варианты) |
| US9937153B2 (en) | 2013-08-30 | 2018-04-10 | Merck Sharp & Dohme Ltd. | Oral pharmaceutical formulation of omarigliptin |
| GR1009462B (el) * | 2017-10-05 | 2019-02-15 | Laboserve Φαρμακευτικη Βιομηχανια Α.Ε. | Ποσιμο φαρμακευτικο διαλυμα με συγκαλυμμενη γευση |
| CN110693820A (zh) * | 2018-07-10 | 2020-01-17 | 北京万全德众医药生物技术有限公司 | 普瑞巴林口服溶液及其制备方法 |
| CN113631150A (zh) | 2019-03-26 | 2021-11-09 | 奥赖恩公司 | 普瑞巴林制剂及其用途 |
| CN111855828B (zh) * | 2020-02-28 | 2022-07-01 | 中国人民解放军军事科学院军事医学研究院 | 一种同时测定普瑞巴林以及羟苯酯类抑菌剂含量的方法 |
| CN113616591B (zh) * | 2021-09-03 | 2023-05-23 | 贝克诺顿(浙江)制药有限公司 | 一种普瑞巴林口服溶液及制备方法 |
| GB2624861A (en) | 2022-11-28 | 2024-06-05 | Orbit Pharma Ltd | Sustained release pharmaceutical compositions comprising pregabalin or pharmaceutically acceptable salts thereof |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6197819B1 (en) * | 1990-11-27 | 2001-03-06 | Northwestern University | Gamma amino butyric acid analogs and optical isomers |
| US5616793A (en) * | 1995-06-02 | 1997-04-01 | Warner-Lambert Company | Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
| US5637767A (en) * | 1995-06-07 | 1997-06-10 | Warner-Lambert Company | Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
| HRP980342A2 (en) * | 1997-06-25 | 1999-02-28 | Warner Lambert Co | Anti-inflammatory method |
| WO1999066920A1 (en) * | 1998-06-22 | 1999-12-29 | American Biogenetic Sciences, Inc. | The use of valproic acid analog for the treatment and prevention of migraine and affective illness |
| AP2002002501A0 (en) * | 1999-10-07 | 2002-06-30 | Warner Lambert Co | Synergistic combinations of an NK1 receptor antagonist and a gaba structural analog. |
| AU777046B2 (en) * | 2000-01-27 | 2004-09-30 | Warner-Lambert Company Llc | Asymmetric synthesis of pregabalin |
| PT1395242E (pt) * | 2001-05-25 | 2006-11-30 | Warner Lambert Co | Composição farmacêutica líquida |
| US6818787B2 (en) * | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| WO2003080588A1 (en) * | 2002-03-20 | 2003-10-02 | Xenoport | Cyclic 1-(acyloxy)-alkyl prodrugs of gaba analogs, compositions and uses thereof |
-
2003
- 2003-12-18 EP EP03029117A patent/EP1543831A1/en not_active Withdrawn
-
2004
- 2004-12-06 CA CA002549599A patent/CA2549599A1/en not_active Abandoned
- 2004-12-06 SG SG200803603-0A patent/SG143257A1/en unknown
- 2004-12-06 JP JP2006544577A patent/JP2007514728A/ja not_active Withdrawn
- 2004-12-06 MX MXPA06006811A patent/MXPA06006811A/es unknown
- 2004-12-06 EP EP04801336A patent/EP1722773A1/en not_active Withdrawn
- 2004-12-06 RU RU2006120946/15A patent/RU2352333C2/ru not_active IP Right Cessation
- 2004-12-06 BR BRPI0417585-9A patent/BRPI0417585A/pt not_active IP Right Cessation
- 2004-12-06 SG SG200705273-1A patent/SG136119A1/en unknown
- 2004-12-06 AU AU2004308747A patent/AU2004308747A1/en not_active Abandoned
- 2004-12-06 CN CNA2004800374979A patent/CN1893938A/zh active Pending
- 2004-12-06 KR KR1020067011926A patent/KR100841893B1/ko not_active IP Right Cessation
- 2004-12-06 WO PCT/IB2004/004029 patent/WO2005063229A1/en active Application Filing
- 2004-12-17 MY MYPI20045225A patent/MY143561A/en unknown
- 2004-12-17 US US11/016,511 patent/US20050171203A1/en not_active Abandoned
- 2004-12-17 TW TW093139422A patent/TWI279230B/zh not_active IP Right Cessation
-
2006
- 2006-06-05 IL IL176129A patent/IL176129A0/en unknown
- 2006-06-07 ZA ZA200604656A patent/ZA200604656B/xx unknown
- 2006-07-07 NO NO20063178A patent/NO20063178L/no not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998074A (zh) * | 2017-12-13 | 2018-05-08 | 广州大光制药有限公司 | 普瑞巴林口服溶液及其制备方法 |
| CN112107537A (zh) * | 2019-06-19 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | 一种普瑞巴林口服溶液及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2352333C2 (ru) | 2009-04-20 |
| IL176129A0 (en) | 2006-10-05 |
| SG143257A1 (en) | 2008-06-27 |
| BRPI0417585A (pt) | 2007-03-13 |
| KR20060103336A (ko) | 2006-09-28 |
| AU2004308747A1 (en) | 2005-07-14 |
| JP2007514728A (ja) | 2007-06-07 |
| MXPA06006811A (es) | 2006-08-23 |
| ZA200604656B (en) | 2007-10-31 |
| WO2005063229A1 (en) | 2005-07-14 |
| TWI279230B (en) | 2007-04-21 |
| RU2006120946A (ru) | 2008-01-27 |
| US20050171203A1 (en) | 2005-08-04 |
| CA2549599A1 (en) | 2005-07-14 |
| KR100841893B1 (ko) | 2008-06-26 |
| TW200520751A (en) | 2005-07-01 |
| MY143561A (en) | 2011-05-31 |
| NO20063178L (no) | 2006-06-19 |
| EP1543831A1 (en) | 2005-06-22 |
| SG136119A1 (en) | 2007-10-29 |
| EP1722773A1 (en) | 2006-11-22 |
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