CN100423709C - 包括芬太尼的鼻内递送用药物组合物 - Google Patents
包括芬太尼的鼻内递送用药物组合物 Download PDFInfo
- Publication number
- CN100423709C CN100423709C CNB200480002000XA CN200480002000A CN100423709C CN 100423709 C CN100423709 C CN 100423709C CN B200480002000X A CNB200480002000X A CN B200480002000XA CN 200480002000 A CN200480002000 A CN 200480002000A CN 100423709 C CN100423709 C CN 100423709C
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- China
- Prior art keywords
- fentanyl
- compositions
- pectin
- max
- officinal salt
- 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.)
- Expired - Lifetime
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Abstract
本发明提供了用于对动物鼻内给药芬太尼或其可药用盐的组合物,其包括(i)芬太尼或其可药用盐和(ii)可药用添加剂的水溶液,其中可药用添加剂选自(a)果胶和(b)泊洛沙姆和脱乙酰壳多糖或脱乙酰壳多糖的盐或衍生物;条件是当组合物包括果胶时,该组合物基本上不含二价金属离子;并且,与以同样剂量鼻内给药的芬太尼简单水溶液相比,本发明的组合物提供了以相同芬太尼剂量鼻内给药简单水溶液实现的血浆峰浓度(Cmax)的10%到80%的芬太尼血浆峰浓度(Cmax)。
Description
技术领域
本发明涉及用于芬太尼的鼻内给药的药物组合物。
背景技术
通过鼻路径递送药物可使药物的作用迅速产生并方便患者和/或护理人员。该路径可使药物被迅速吸收到血液循环中。有时可以实现几乎全部剂量的吸收并且其药代动力学类似于静脉内给药。这种迅速且有效的药物递送可用于紧急情况的治疗,如疼痛,包括爆发性疼痛、头痛和偏头痛(Nasal Systemic Drug Delivery,Chien等人(出版物),Dekker,New York,1987)。
芬太尼,(N-(1-苯乙基-4-哌啶基)-N-丙酰苯胺)为强效的鸦片样止痛剂,可用于治疗严重的急性疼痛和慢性疼痛。
已有报道说芬太尼被从鼻腔迅速且良好地吸收(Striebel等人,Brit.J.Anaesthesia,96,增刊1,第108页,1993)。另外,已经在许多研究中证明了鼻内给药芬太尼在患者止痛中的有效性(例如Striebel等人,Brit.J.Anaesthesia,96,增刊1,第108和109页,1993;Striebel等人,Anaesthesia,48,753-757,1993;Majushree等人,Can.J.Anesth.,49,190-193,2002;Toussaint等人,Can.J.Anesth.,47,299-302,2000)。在所有的这些研究中,看来似乎已经通过将市售的注射剂制剂(得自Janssen)滴到或喷雾到鼻中实现了芬太尼的鼻内给药。市售的芬太尼注射剂制剂在1ml氯化钠溶液中包含0.05mg的拘橼酸芬太尼,这需要鼻内给药大量的液体,以提供治疗有效剂量的药物。
目前也可以得到经皮贴片和经粘膜锭剂形式的芬太尼。经皮贴片(例如得自Janssen的)提供长时间、稳定的芬太尼血浆浓度,但不适合于迅速缓解剧烈疼痛如与绝症有关的爆发性疼痛或与创伤或术后有关的急性疼痛。经粘膜锭剂(Cephalon Inc)用于治疗爆发性疼痛,并且具有0.2到1.6mg的多种剂量范围。芬太尼从经粘膜制剂的吸收相对缓慢。已经报导了达到血浆峰浓度需要的时间(Tmax)为20到480分钟(Physician′s Desk Reference,第54版,第405-409页,Medical Economics company,Montvale,NJ,2000)。
因此,仍需要芬太尼的可替代的递送方式,如通过鼻内路径递送。
不应将本说明书中列举或讨论的在先公开的文献当然地理解为该文件是本领域的一部分或是普通常识。
发明内容
本发明提供了适合于芬太尼鼻内给药的组合物,其克服了一个或多个上述问题。
令人惊讶地,我们发现有可能以实用的剂量鼻内给药芬太尼并且提供迅速的吸收和相对于使用简单水溶液所提供的血浆峰浓度更低的血浆峰浓度以及延长的血浆浓度-时间曲线。我们发现可以实现这些优点,并同时保持与含芬太尼简单水溶液鼻内给药得到的生物利用度可比较的生物利用度。
可比较的生物利用度是指血浆浓度-时间曲线下的面积(AUC)相对于在同样剂量下鼻内给药芬太尼简单水溶液的血浆浓度-时间曲线下的面积(AUC)为至少50%,优选至少60%,最优选至少70%。
简单水溶液是指将芬太尼和使溶液等渗的成分,如甘露醇、葡萄糖或氯化钠,溶解于水中。简单水溶液可选择性地包含防腐剂如苯扎氯铵。这种简单水溶液的例子包括在水中的1.57mg/ml枸橼酸芬太尼、48mg/ml甘露醇和0.15mg/ml苯扎氯铵。
本发明提供用于对动物鼻内给药芬太尼或其可药用盐的组合物,其包括以下(i)和(ii)的水溶液,
(i)芬太尼或其可药用盐,和
(ii)可药用添加剂,可药用添加剂选自
(a)果胶,和
(b)泊洛沙姆和脱乙酰壳多糖或脱乙酰壳多糖的盐或衍生物;
条件是当组合物包括果胶时,其基本上不含引起果胶胶凝的试剂,如二价金属离子,特别是钙离子。
与在同样剂量下鼻内给药芬太尼简单水溶液相比,本发明的组合物提供了更低的芬太尼血浆峰浓度(Cmax)并选择性地提供了延长的血浆浓度-时间曲线。使用本发明的组合物实现的血浆峰浓度(Cmax)为在相同的芬太尼剂量下鼻内给药简单水溶液实现的血浆峰浓度(Cmax)的10%到80%,优选20%到75%,更优选30%到70%。这意味着,例如,如果芬太尼简单水溶液产生1000μg/ml的Cmax,则在给药相同剂量的芬太尼后产生的Cmax为100-800μg/ml,优选200-750μg/ml,更优选300-700μg/ml。
本发明的组合物鼻内给药达到血浆峰浓度的时间(Tmax)优选为5到60分钟,更优选为5到45分钟,最优选为5到30分钟。
优选芬太尼以可药用盐的形式使用。最优选使用枸橼酸芬太尼。
在本发明的组合物中,优选芬太尼或其盐的浓度为0.05到30mg/ml,更优选为0.1到20mg/ml,最优选为0.2到16mg/ml(以芬太尼碱表示)。
术语“可药用的”在本领域中可容易地理解并认为其包括可用于市售药物或食品中的物质和/或具有GRAS(通用安全)状态的物质和/或在药典如美国药典或欧洲药典中列举的物质。
一方面,本发明提供了用于芬太尼或其可药用盐鼻内给药的组合物,其包括芬太尼或其可药用盐和果胶的水溶液,其提供的血浆峰浓度(Cmax)为在相同的芬太尼剂量下鼻内给药简单水溶液实现的血浆峰浓度的10%到80%。
果胶为存在于所有植物组织的细胞壁中的多糖物质。商业上它们通常得自柑桔属水果外皮内部的稀酸提取物或得自苹果渣。果胶为非均质物质,其包括部分甲基化的聚半乳糖醛酸。
甲酯中的半乳糖醛酸部分的比代表酯化度(DE)。术语“DE”为本领域技术人员公知的,其可表示为被酯化的羧基总数的百分比,即,例如,如果五个羧基中的四个被酯化,则酯化度表示为80%,或者DE可表示为果胶的甲氧基含量。各自的最大理论值分别为100%和16%。本文中使用的DE是指被酯化的羧基的总百分比。天然发现的果胶的酯化度(DE)可以有很大的不同(60到90%)。
可以将果胶分为低酯化度(低甲氧基化程度)的果胶类或高酯化度(高甲氧基化程度)的果胶类。“低DE”或“LM”果胶的酯化度低于50%,而“高DE”或“HM”果胶的酯化度最低为50%。
可以通过果胶的浓度、果胶的类型、特别是半乳糖醛酸单元的酯化度、和加入的盐的存在控制果胶水溶液的胶凝性质。
优选在本发明的组合物中使用低DE果胶。更优选在本发明中使用酯化度低于35%的果胶,例如酯化度为5%到35%,优选7%到30%,例如约10%到约25%,例如15%到25%。
通常通过被提取果胶的脱脂作用制备低DE果胶,通常通过酶促方法以实验室规模制备或通过在醇的非均一介质中用酸或氨处理以工业规模制备。用氨处理生成所谓的低DE酰胺化果胶。如本文中使用的,术语“低DE果胶”包括酰胺化和未酰胺化的低DE果胶。
低DE果胶在水溶液中胶凝的主要机理为通过接触金属离子,例如在WO 98/47535中所述的鼻粘膜流体中发现的那些金属离子。
本发明的溶液在储存时不应胶凝。因此,含果胶的溶液基本上不含引起果胶胶凝的试剂,如二价金属离子,特别是钙离子。“基本上不含”二价金属离子是指多于97%,优选多于99%,更优选多于99.9%,特别优选多于99.99%不含二价金属离子。
当本发明的组合物包含果胶时,优选果胶的浓度为1到40mg/ml,更优选为2到30mg/ml,最优选为5到25mg/ml。
本发明较优选的含果胶的组合物包括0.2到16mg/ml的芬太尼(以芬太尼碱表示)和5到25mg/ml的DE值为7%到30%的果胶,并且该组合物的pH为3.4到5.0,重量克分子渗透浓度为0.25到0.35渗透压摩尔/千克。
在一个方面中,本发明提供了包括芬太尼或其可药用盐和泊洛沙姆以及脱乙酰壳多糖或其盐或衍生物的组合物。
泊洛沙姆为氧化乙烯和氧化丙烯的嵌段共聚物。它们的通式为HO(C2H4O)a(C3H6O)b(C2H4O)aH,其中a典型地为2到130,b典型地为15到67。泊洛沙姆具有多种药学应用,如粘度调节剂、增溶剂或乳化剂。它们可在本发明的组合物中用作增稠剂并用于控制和调节芬太尼向系统循环中的吸收,使得芬太尼血浆峰浓度(Cmax)可为以相同的芬太尼剂量鼻内给药简单水溶液实现的血浆峰浓度的10%到80%。
市售有多种得自供应商例如BASF的不同类型的泊洛沙姆,其根据分子量和氧化乙烯“a”单元和氧化丙烯“b”单元比例的改变而改变。适合在本发明中使用的泊洛沙姆典型地具有2,500到18,000Da的分子量,例如7,000到15,000Da。适合在本发明中使用的市售的泊洛沙姆的例子包括泊洛沙姆188,其在结构上包含80个“a”单元和27个“b”单元,并且其分子量为7680到9510;和泊洛沙姆407,其在结构上包含101个“a”单元和56个“b”单元,并且其分子量为9840到14600(Handbook of Pharmaceutical Excipients,编辑:A.H.Kippe,第三版,Pharmaceutical Press,London,UK,2000)。优选泊洛沙姆为泊洛沙姆188。
当本发明的组合物包括泊洛沙姆时,优选泊洛沙姆的浓度为50到200mg/ml,更优选为65到160mg/ml,最优选为80到120mg/ml。
包括泊洛沙姆的本发明的组合物也包括脱乙酰壳多糖或其盐或衍生物。
脱乙酰壳多糖为具有粘膜粘合性质的阳离子聚合物。认为粘膜粘合是由于带正电的脱乙酰壳多糖分子与粘液素上带负电的唾液酸基团之间的相互作用所致(Soane等人,Int.J.Pharm.,178,55-65,1999)。
术语“脱乙酰壳多糖”包括所有的壳多糖衍生物、或聚N-乙酰基葡糖胺,包括所有的聚葡糖胺和不同分子量的葡糖胺物质的低聚物,其中已经通过水解(脱乙酰作用)除去更大比例的N-乙酰基。优选地,脱乙酰壳多糖由壳多糖通过大于40%,优选50%到98%,更优选70%到90%的程度的脱乙酰生产。
优选本发明中使用的脱乙酰壳多糖、脱乙酰壳多糖衍生物或其盐的分子量为至少4,000Da,优选10,000到1,000,000Da,更优选为15,000到750,000Da,最优选为50,000到300,000Da。
脱乙酰壳多糖的盐适合于在本发明中使用。适合的盐包括但不限于硝酸盐、磷酸盐、谷氨酸盐、乳酸盐、拘橼酸盐、盐酸盐、和醋酸盐。优选的盐为谷氨酸脱乙酰壳多糖和盐酸脱乙酰壳多糖。
脱乙酰壳多糖衍生物也适合于在本发明中使用。适合的脱乙酰壳多糖衍生物包括但不限于与脱乙酰壳多糖的羟基而不是与脱乙酰壳多糖的氨基结合酰基/或烷基,形成的酯、醚、或其它衍生物。例子为脱乙酰壳多糖的O-烷基醚和脱乙酰壳多糖的O-酰基酯。可在本发明中使用改性的脱乙酰壳多糖如结合于聚乙二醇的那些。
适合在本发明中使用的低粘度和中粘度的脱乙酰壳多糖可得自多种来源,包括NovaMatrix,Drammen,Norway;Seigagaku America Inc.,MD,USA;Meron(India)Pvt,Ltd.,India;Vanson Ltd,VA,USA;和AMS Biotechnology Ltd.,UK。适合的衍生物包括在Roberts,ChitinChemistry,MacMillan Press Ltd.,London(1992)中公开的那些。
可提及的特别优选的脱乙酰壳多糖化合物包括得自NovaMatrix,Drammen,Norway的“ProtosanTM”型。
优选地,脱乙酰壳多糖或其盐或衍生物为水溶性的。
可通过将脱乙酰壳多糖碱或脱乙酰壳多糖碱的衍生物溶解于可药用无机酸或有机酸中制备脱乙酰壳多糖的水溶液,无机酸或有机酸例如盐酸、乳酸、拘橼酸或谷氨酸,或通过将脱乙酰壳多糖盐或脱乙酰壳多糖衍生物的盐溶解于水中制备脱乙酰壳多糖的水溶液。
当本发明的组合物包括脱乙酰壳多糖、脱乙酰壳多糖盐或脱乙酰壳多糖衍生物时,优选脱乙酰壳多糖的浓度为0.1到20mg/ml,更优选为0.5到15mg/ml,最优选为1到10mg/ml(以脱乙酰壳多糖碱表示)。
优选的含泊洛沙姆和脱乙酰壳多糖的本发明的组合物包括0.2到16mg/ml的芬太尼(以芬太尼碱表示),80到130mg/ml的分子量为7,000到15,000Da的泊洛沙姆,和1到10mg/ml(以脱乙酰壳多糖碱表示)的分子量为50,000到300,000Da的脱乙酰壳多糖或其盐或衍生物,并且该组合物的pH为3.0到5.0,重量克分子渗透浓度为0.4到0.7渗透压摩尔/千克。
可以调节本发明的组合物的pH。例如,可以使用缓冲水溶液。或者,可使用与本发明组合物的其它组分相容的任何可药用酸化剂或碱化剂调节本发明的组合物的pH。适合的可药用酸化剂的例子包括但不限于盐酸、醋酸、拘橼酸、甲磺酸、乳酸、酒石酸、富马酸、和苹果酸。可药用碱化剂的例子包括但不限于氢氧化钠、氢氧化钾、甲葡胺、氨基丁三醇、碳酸氢钠、单乙醇胺、二乙醇胺、和三乙醇胺。当本发明的组合物包含果胶时,为了防止不期望的胶凝,优选酸化剂或碱化剂不应包含碱金属或碱土金属离子,例如其不应该为氢氧化钠、氢氧化钾或碳酸氢钠。
通常优选本发明的组合物的pH为3到6。对于含果胶的本发明的组合物,更优选pH为3.2到5.5,最优选为3.4到5.0。对于含泊洛沙姆和脱乙酰壳多糖的本发明的组合物,更优选pH为3.0到5.5,最优选3.0到5.0。
当对鼻给药(例如当喷雾到鼻腔中)时,为了保证患者对本发明的组合物有良好的耐受性,优选其重量克分子渗透浓度接近于血浆的重量克分子渗透浓度。通常优选重量克分子渗透浓度为0.1到1.0渗透压摩尔/千克。对于含果胶的本发明的组合物,更优选重量克分子渗透浓度为0.2到0.8渗透压摩尔/千克,更优选为0.2到0.4渗透压摩尔/千克,最优选为0.25到0.35渗透压摩尔/千克。对于含泊洛沙姆和脱乙酰壳多糖的本发明的组合物,更优选重量克分子渗透浓度为0.2到0.9渗透压摩尔/千克,更优选为0.3到0.8渗透压摩尔/千克,最优选为0.4到0.7渗透压摩尔/千克。
可通过加入任何适当的试剂将本发明组合物的重量克分子渗透浓度调节为所需的值。通常使用金属离子的盐,特别是氯化钠用于调节药物制剂的重量克分子渗透浓度。然而,当本发明的组合物包括果胶时不适合使用金属离子,因为在金属离子的存在下果胶可能形成凝胶。还发现向含芬太尼和脱乙酰壳多糖的组合物中加入金属离子如氯化钠形式的钠离子,导致形成沉淀。因此,优选避免使用含金属离子的试剂。我们发现通过使用不含金属离子的化合物如多元醇如甘露醇或山梨糖醇,或糖如葡萄糖、蔗糖、或海藻糖调节重量克分子渗透浓度可以避免含果胶的芬太尼组合物中的凝胶形成和含脱乙酰壳多糖的芬太尼组合物中的沉淀形成。特别优选的用于调节重量克分子渗透浓度的试剂为甘露醇和葡萄糖,其浓度至多为50mg/ml。
本发明的组合物也可包含其它成分,如抗氧化剂(如焦亚硫酸钠)、鳌合剂(如乙二胺四乙酸或其盐中的一种)、防腐剂(如苯扎氯铵、山梨酸或其盐中的一种、苯乙醇和/或羟基苯甲酸丙酯)、甜味剂(如糖精或天冬酰苯丙氨酸甲酯)、调味剂(如胡椒薄荷)或通常用于药物液体试剂中并且本领域技术人员公知的其它试剂。
优选地,本发明的组合物包含防腐剂或经过灭菌。
优选地,本发明的组合物为无热源的。
可以以任何适合的形式将本发明的组合物给药到鼻腔中,例如以滴剂或喷雾剂的形式。
适合于对鼻腔给药组合物的方法为本领域技术人员公知的。可使用任何适当的方法。优选的给药方法是使用喷雾装置。喷雾装置可以是例如包括瓶、泵和致动器的单一(单位)剂量或多剂量系统,其可得自多种商业来源,包括Pfeiffer、Valois、Bespak和Becton-Dickinson。在US 5,655,517描述的静电喷涂装置也适合于本发明组合物的鼻内给药。
对于喷雾装置,在单一喷雾动作中液体的典型量为0.01到0.15ml。鼻喷雾制品的典型的剂量给药方案为喷雾到单个鼻孔中的一次喷雾和喷雾到两个鼻孔中的两次喷雾。
芬太尼或其盐中的一种的优选剂量为0.01到5.0mg(10到5000μg),更优选为0.015到4.0mg(15到4000μg),最优选为0.02到3.0mg(20到3000μg)。
本发明还提供了装有上述组合物的“喷雾装置”。
本发明还提供了制备上述组合物的方法。该方法包括在水中将组合物的各组分混合。可使用净化水,如注射用水。
本发明的组合物可用于治疗、控制或预防动物、包括人的急性和慢性疼痛。本发明的组合物可用于治疗、控制或预防多种疼痛状况的疼痛,如与损伤和事故外伤、绝症有关的那些疼痛,特别是爆发性疼痛、和术后疼痛。
本发明还提供了可药用添加剂在生产用于对需要的动物如人鼻内递送芬太尼或其可药用盐的药物中的应用,该药物适合于提供以相同的芬太尼剂量鼻内给药芬太尼简单水溶液所实现的芬太尼血浆峰浓度(Cmax)的10%到80%的芬太尼血浆峰浓度(Cmax),所述添加剂选自
(a)果胶,和
(b)泊洛沙姆和脱乙酰壳多糖或脱乙酰壳多糖的盐或衍生物。
具体地,本发明提供了可药用添加剂在生产用于对需要的动物如人鼻内递送芬太尼或其可药用盐、适用于治疗、预防或控制急性疼痛或慢性疼痛的药物中的应用,该药物适合于提供以相同的芬太尼剂量鼻内给药芬太尼的简单水溶液所实现的芬太尼血浆峰浓度(Cmax)的10%到80%的芬太尼血浆峰浓度(Cmax),所述添加剂选自
(a)果胶,和
(b)泊洛沙姆和脱乙酰壳多糖或脱乙酰壳多糖的盐或衍生物。
附图说明
在附图中:
图1表示将实施例7中得到的包括脱乙酰壳多糖的芬太尼溶液和不包含脱乙酰壳多糖的芬太尼溶液对绵羊给药后的芬太尼的平均血浆浓度曲线。
图2表示实施例8中得到的三种鼻内制剂和一种经粘膜制剂的芬太尼的血浆浓度曲线。
具体实施方式
本发明通过以下非限制性实施例说明。
实施例
实施例1-含1.57mg/ml枸橼酸芬太尼(相当于1mg/ml芬太尼碱)和10mg/ml果胶的溶液
将2g果胶(Slendid 100,CP Kelco,Denmark)在搅拌下溶解在180ml水中。向果胶溶液中加入1ml的苯乙醇(R.C.Treat,UK)和40mg羟基苯甲酸丙酯(Nipa Laboratories,UK)作为防腐剂。将314mg的枸橼酸芬太尼(MacFarlan Smith,Edinburgh,UK)和8.3g甘露醇(Sigma,Poole,UK)溶解于果胶溶液中,将溶液转移到200ml容量瓶中并用补充水到容积。溶液的pH为4.2,重量克分子渗透浓度为0.33渗透压摩尔/千克。
实施例2-含1.57mg/ml枸橼酸芬太尼和20mg/ml果胶的溶液
在搅拌下将4g果胶(Slendid 100)溶解在180ml水中。向果胶溶液中加入1ml的苯乙醇和40mg的羟基苯甲酸丙酯。将314mg的枸橼酸芬太尼和8.3g甘露醇溶解于果胶溶液中,将溶液转移到200ml容量瓶中并用补充水到容积。
将4ml溶液转移到5ml玻璃瓶中。为瓶子连接具有致动器(Valois,France)的Valois VP7喷射泵(0.1ml容积)。通过喷射数次而启动泵。当启动时,喷射设备递送包含0.157mg枸橼酸芬太尼(相当于0.1mg芬太尼碱)的0.1ml的液体喷雾。
实施例3-含1.57mg/ml枸橼酸芬太尼、100mg/ml泊洛沙姆188和5mg/ml谷氨酸脱乙酰壳多糖的溶液
通过在10ml容量瓶中称重300mg的50%苯扎氯铵水溶液(Albright& Wilson,UK)并将其分散在约8ml水中,然后用补充水到10ml制备15mg/ml的苯扎氯铵溶液。
将2.5ml的15mg/ml的苯扎氯铵溶液和200ml水加入到烧杯中的25g泊洛沙姆188中。将烧杯置于冰浴中并搅拌内容物直到泊洛沙姆溶解。在泊洛沙姆溶液中搅拌进1.25g的谷氨酸脱乙酰壳多糖(ProtasanUPG213,Pronova,Norway)和11.25g的甘露醇直到溶解。将393mg枸橼酸芬太尼溶解于约10ml水中并加入到泊洛沙姆溶液中。将溶液转移到250ml容量瓶中并用补充水到容积。
溶液的pH为3.3,其重量克分子渗透浓度为0.56渗透压摩尔/千克。
将0.123ml最终溶液的样品填充到单一剂量鼻喷雾装置(UnitdoseSystem,Pfeiffer,Germany)的玻璃小瓶中。用橡胶盖密封小瓶并装配到设备中。在喷射时,该设备放出含0.157mg剂量的枸橼酸芬太尼(相当于0.1mg芬太尼碱)的0.1ml的液体喷雾。
实施例4-含6.28mg/ml枸橼酸芬太尼(相当于4mg/ml芬太尼碱)和10mg/ml果胶的溶液
在搅拌下将2.5g果胶(Slendid 100)溶解在200ml水中。向果胶溶液中加入1.25ml的苯乙醇和50mg羟基苯甲酸丙酯。将1.58mg的枸橼酸芬太尼和9g的甘露醇溶解于果胶溶液中,将溶液转移到250ml容量瓶中并补充水到容积。
溶液的pH为3.8,其重量克分子渗透浓度为0.30渗透压摩尔/千克。
将0.123ml最终溶液的样品填充到单一剂量鼻喷雾装置(UnitdoseSystem,Pfeiffer,Germany)的玻璃小瓶中。用橡胶盖密封小瓶并装配到设备中。在喷射时,该设备放出含0.628mg剂量的枸橼酸芬太尼(相当于0.4mg芬太尼碱)的0.1ml的液体喷雾。
实施例5-含1.57mg/ml枸橼酸芬太尼的溶液的制备
将78.5mg枸橼酸芬太尼溶解于40ml水中。向芬太尼溶液中加入0.5ml的15mg/ml苯扎氯铵溶液和2.4g的甘露醇并搅拌直到所有成分溶解。将溶液转移到50ml容量瓶中并补充水到容积。
实施例6-含1.57mg/ml枸橼酸芬太尼和5mg/ml谷氨酸脱乙酰壳多糖的溶液的制备
将250mg谷氨酸脱乙酰壳多糖溶解于40ml水中,向脱乙酰壳多糖溶液中加入0.5ml的15mg/ml苯扎氯铵溶液和78.5mg枸橼酸芬太尼和2.4g甘露醇并搅拌直到所有成分溶解。将溶液转移到50ml容量瓶中并补充水到容积。
实施例7-芬太尼鼻内制剂在绵羊中的药代动力学性质
将实施例5和6中制备的溶液鼻内给药于绵羊。每组使用8只动物,各个体重为约60kg。随机交叉设计给药剂量,每只动物鼻内接受0.3ml的各种试验溶液(相当于0.3mg芬太尼碱)。通过将剂量在两个鼻孔之间平分剂量的喷雾装置进行鼻内给药。
收集血样并分离血浆。通过LC-MS-MS方法分析血浆样品的芬太尼含量。
两种鼻内试验溶液的平均血浆浓度-时间曲线如图1中所示。曲线基本上相同,表明在有和没有脱乙酰壳多糖的情况下芬太尼都被迅速地吸收。
实施例8-芬太尼鼻内和口服经粘膜制剂在人志愿者中的药代动力学性质
鼻内制剂如上述实施例1、3和6中所述制备。
研究为在18名健康的成年志愿者中的完全交叉试验。使用PferfferUnitdose设备给药鼻内剂量。各个受试者接受单次喷雾到一个鼻孔中以提供0.1mg的芬太尼剂量。制剂作为包含200μg(0.2mg)芬太尼的锭剂提供。通过在约15分钟的时间内将锭剂在口中溶解而给药。从受试者收集血浆样品并使用LC-MS-MS分析芬太尼含量。从血浆数据计算药代动力学参数。
三种鼻内制剂和一种经粘膜制剂的血浆浓度-时间曲线如图2中所示。在表1中提供药代动力学参数的总结。
表1.平均芬太尼药代动力学参数的总结
基于实施例7中所述的对绵羊的研究结果,可以认为脱乙酰壳多糖溶液在人志愿者中的药代动力学性质为芬太尼简单水溶液的代表。含果胶的鼻内制剂和含泊洛沙姆和脱乙酰壳多糖混合物的鼻内制剂能够将Cmax分别降低到相对于鼻内脱乙酰壳多糖溶液的52%和68%。
Claims (23)
1. 用于鼻内递送芬太尼或其可药用盐的组合物,其包括以下(i)和(ii)的水溶液:
(i)芬太尼或其可药用盐,和
(ii)酯化度DE值为30%或更低的果胶,条件是该组合物基本上不含二价金属离子;
并且,与在相同剂量下鼻内给药的芬太尼简单水溶液相比,该组合物的芬太尼血浆峰浓度Cmax是使用在相同的芬太尼剂量下鼻内给药的芬太尼简单水溶液所实现的芬太尼血浆峰浓度Cmax的10%到80%。
2. 权利要求1的组合物,与在相同剂量下鼻内给药的芬太尼简单水溶液相比,该组合物的芬太尼血浆峰浓度Cmax是使用在相同的芬太尼剂量下鼻内给药的芬太尼简单水溶液所实现的芬太尼血浆峰浓度Cmax的30%到70%。
3. 权利要求1的组合物,其包括芬太尼的可药用盐。
4. 权利要求3的组合物,其中芬太尼的可药用盐为枸橼酸芬太尼。
5. 权利要求1的组合物,其中果胶的DE值为5%-30%。
6. 权利要求5的组合物,其中果胶的DE值为7%到30%。
7. 权利要求6的组合物,其中果胶的DE值为10%到25%。
8. 权利要求1的组合物,其中果胶的浓度为1到40mg/ml。
9. 权利要求8的组合物,其中果胶的浓度为2到30mg/ml。
10. 权利要求9的组合物,其中果胶的浓度为5到25mg/ml。
11. 权利要求1的组合物,其至少99%不包含二价金属离子。
12. 权利要求1的组合物,其重量克分子渗透浓度为0.25到0.35渗透压摩尔/千克。
13. 权利要求1的组合物,其pH为3.4到5.0。
14. 权利要求1的组合物,其中芬太尼或其可药用盐的浓度以芬太尼碱表示为0.2到15mg/ml。
15. 用于鼻内递送芬太尼或其可药用盐的组合物,该组合物包括以下(i)和(ii)的水溶液:
(i)以芬太尼游离碱表示的0.2到16mg/ml的芬太尼或其可药用盐,和
(ii)5到25mg/ml的DE值为7%到30%的果胶;
并且该组合物的pH为3.4到5.0,重量克分子渗透浓度为0.25到0.35渗透压摩尔/千克;
条件是该组合物基本上不含二价金属离子;
并且,与在相同剂量下鼻内给药的芬太尼简单水溶液相比,该组合物的芬太尼血浆峰浓度Cmax是使用在相同的芬太尼剂量下鼻内给药的芬太尼简单水溶液所实现的芬太尼血浆峰浓度Cmax的10%到80%。
16. 前述权利要求中任一项的组合物,其以滴剂或作为喷雾剂的形式对鼻递送。
17. 酯化度DE值为30%或更低的果胶在生产用于对需要的患者鼻内递送芬太尼或其可药用盐的药物中的应用,该药物适合于提供在相同的芬太尼剂量下鼻内给药芬太尼简单水溶液所实现的芬太尼血浆峰浓度Cmax的10%到80%的芬太尼血浆峰浓度Cmax。
18. 权利要求17的应用,其中果胶的DE值为7%到30%。
19. 权利要求18的应用,其中果胶的DE值为10%到25%。
20. 权利要求17到19中任一项的应用,用于生产治疗或预防急性疼痛或慢性疼痛的药物。
21. 权利要求1到16中任一项的组合物在制备用于治疗或预防急性疼痛或慢性疼痛的药物中的应用。
22. 装载有权利要求1到16中任一项的组合物的喷雾装置。
23. 制备权利要求1到16中任一项的组合物的方法,该方法包括将芬太尼或其可药用盐与果胶在水中混合。
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US (5) | US20040166067A1 (zh) |
EP (2) | EP1635783B1 (zh) |
JP (1) | JP4827725B2 (zh) |
KR (3) | KR20050103275A (zh) |
CN (1) | CN100423709C (zh) |
AU (1) | AU2004204381B2 (zh) |
BR (1) | BRPI0406674B8 (zh) |
CA (1) | CA2511974C (zh) |
CY (1) | CY1115056T1 (zh) |
DK (1) | DK1635783T5 (zh) |
EA (1) | EA008500B1 (zh) |
ES (2) | ES2432119T3 (zh) |
FR (1) | FR14C0020I1 (zh) |
GB (1) | GB0300531D0 (zh) |
GE (1) | GEP20084340B (zh) |
HK (1) | HK1088555A1 (zh) |
IL (1) | IL169480A (zh) |
MX (1) | MXPA05007333A (zh) |
NO (1) | NO335127B1 (zh) |
NZ (1) | NZ541018A (zh) |
PL (1) | PL212950B1 (zh) |
PT (2) | PT2436375T (zh) |
SI (1) | SI1635783T1 (zh) |
UA (1) | UA85050C2 (zh) |
WO (1) | WO2004062561A2 (zh) |
ZA (1) | ZA200505274B (zh) |
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EP2057982A1 (en) | 2007-11-09 | 2009-05-13 | Archimedes Development Limited | Intranasal compositions |
GB2464282A (en) * | 2008-10-08 | 2010-04-14 | Archimedes Dev Ltd | A device for administering a dose of opioid analgesic |
CZ302789B6 (cs) | 2009-11-25 | 2011-11-09 | Zentiva, K. S. | Zpusob zvýšení rozpustnosti farmaceuticky aktivních látek a cílený (kontrolovaný) transport do streva |
LT2670674T (lt) | 2011-02-04 | 2016-11-10 | Archimedes Development Limited | Patobulinta tara |
CN107260672A (zh) | 2011-05-13 | 2017-10-20 | 欧洲凯尔特公司 | 包含纳洛酮的鼻内药物剂型 |
ES2748632T3 (es) | 2012-10-03 | 2020-03-17 | Proponent Biotech Gmbh | Composición farmacéutica que comprende ácido propiónico para uso en el tratamiento de infecciones víricas |
JP6820743B2 (ja) | 2013-09-05 | 2021-01-27 | エイビー2 バイオ ソシエテアノニム | 炎症性疾患におけるil−18結合タンパク質(il−18bp) |
US11135155B2 (en) | 2014-07-08 | 2021-10-05 | Hikma Pharmaceuticals Usa Inc. | Liquid naloxone spray |
MX2017010919A (es) | 2015-03-05 | 2017-12-07 | Ab2 Bio Sa | Proteina de union il-18 (il-18bp) y anticuerpos en enfermedades inflamatorias. |
US9650338B1 (en) | 2016-07-29 | 2017-05-16 | VDM Biochemicals, Inc. | Opioid antagonist compounds and methods of making and using |
EP3568126B1 (en) * | 2017-01-11 | 2023-11-01 | Torrent Pharmaceuticals Limited | Tapentadol nasal composition |
US11207309B2 (en) | 2019-07-19 | 2021-12-28 | Hikma Pharmaceuticals International Limited | Ready-to-administer fentanyl formulations |
US11160799B2 (en) * | 2019-10-22 | 2021-11-02 | Cessatech A/S | Pediatric combination |
US20230173021A1 (en) | 2020-05-06 | 2023-06-08 | Ab2 Bio Sa | IL-18 Binding Protein (IL-18BP) In Respiratory Diseases |
GB202007404D0 (en) | 2020-05-19 | 2020-07-01 | Nasser Syed Muhammad Tahir | Treatment for viral respiratory infections |
EP3943097A1 (en) | 2020-07-24 | 2022-01-26 | AB2 Bio SA | Car-t cell therapy |
WO2023067348A1 (en) | 2021-10-21 | 2023-04-27 | Biosirius Ltd | Treatment for virally-induced pneumonia |
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2003
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2004
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- 2004-01-12 WO PCT/GB2004/000057 patent/WO2004062561A2/en active Application Filing
- 2004-01-12 KR KR1020057012821A patent/KR20050103275A/ko active Search and Examination
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