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CN1376054A - 含环丙沙星和地塞米松的局部悬浮制剂 - Google Patents

含环丙沙星和地塞米松的局部悬浮制剂 Download PDF

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CN1376054A
CN1376054A CN00813262A CN00813262A CN1376054A CN 1376054 A CN1376054 A CN 1376054A CN 00813262 A CN00813262 A CN 00813262A CN 00813262 A CN00813262 A CN 00813262A CN 1376054 A CN1376054 A CN 1376054A
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O·N·辛格
H·G·柏翟特
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Abstract

公开了包含地塞米松和环丙沙星的悬浮制剂。该制剂包含非离子聚合物、非离子表面活性剂和离子性补强剂,但是物理稳定的且易于再分散。该制剂意欲局部施用于眼睛、耳朵或鼻子。

Description

含环丙沙星和地塞米松的局部悬浮制剂
发明背景
本发明涉及环丙沙星和地塞米松的可局部给药的眼用和耳用制剂。本发明的制剂是具有优异的物理稳定性且其特征在于其容易和快速再悬浮性的悬浮液。具体而言，本发明涉及环丙沙星和地塞米松的稳定悬浮制剂，其不含非离子补强剂如甘油或甘露糖醇。
西班牙专利申请2,065,846A1(1995年2月16日)公开了可局部给药的眼用和耳用抗生素/甾类组合产品。实施例1-3描述了含有某些与包括非离子聚合物和非离子表面活性剂在内的赋形剂组合的药物的眼用悬浮制剂。实施例1是氯氟美松铜和洛美沙星的制剂，其含有非离子补强剂(tonicity agent)(甘油)。实施例2是氟氢缩松和诺氟沙星的制剂，其含有离子性补强剂(氯化钠)。实施例3是环丙沙星和地塞米松的制剂，其含有非离子补强剂(甘露糖醇)。
美国专利5,540,930和5,747,061公开了可局部给药的甾类悬浮制剂，其含有非离子聚合物、非离子表面活性剂和非离子补强剂。这些专利涉及“粒度小于等于15微米的水不溶性甾类药物的稳定悬浮液，其保持该状态以使得在需要时即使在长期沉降之后仍能直接悬浮”(参见’061专利的摘要)。这些专利基于“出人意料的是，即使在低至1mM的浓度下，常规补强剂如含有0.9％NaCl、0.1％EDTA的水溶液或磷酸盐缓冲液不能用于提供皮质甾类如[loteprednoletabonate(LE)]的稳定含水悬浮液”(’061专利，第2栏第52-56行)这一发现。
’061专利的目的在于提供解决“可以无附聚地配制的皮质甾类如LE的含水悬浮液”(第2栏第57-59行)这一需要的制剂。’061专利的制剂含有(A)以优选具有低于约15微米的平均直径的颗粒存在的软甾类如LE，(B)作为悬浮剂的非离子聚合物，(C)非离子表面活性剂和(D)非离子补强剂。’061专利将“软”药物定义为生物活性化学组分，其特征在于在提供其治疗效果后其在体内可预计代谢为无毒衍生物。’061专利教导了“这些组分(A)-(D)必须尽可能是非离子的，因为现已发现离子的存在是结块的主要原因”(第3栏第51-53行)。非离子二醇如甘油或甘露糖醇“而不是常用的氯化钠”被确定为优选的补强剂(见第3栏第53-56行)。非离子补强剂优选的存在量为约0.5-10重量％。
发明概述
除非另有说明，以百分数提供的所有成分量均为以重量％为单位。
本发明的组合物是皮质甾类(地塞米松)的含水悬浮制剂，其没有附聚。除了皮质甾类外，这些制剂包含抗生素(环丙沙星)作为第二活性试剂。本发明的制剂含有离子性补强剂，但足够稳定以在需要时可以立即和容易地再悬浮。发明详述
本发明的制剂包含皮质甾类和抗生素。皮质甾类是地塞米松，抗生素是环丙沙星。地塞米松可以任何具有不良水溶性的可眼用或可耳用形式存在，以使所得制剂是悬浮制剂。地塞米松的合适形式包括地塞米松醇(dexamethasone alcohol)和乙酸地塞米松。地塞米松醇是地塞米松的优选形式。环丙沙星可以任何可眼用或可耳用形式存在，以使环丙沙星成分在最终制剂中呈溶液形式。环丙沙星的优选形式为一水合盐酸环丙沙星。
地塞米松成分在本发明制剂中占约0.01-0.5％，而环丙沙星成分占约0.1-0.4％。地塞米松和环丙沙星在本发明制剂中的优选量分别为0.1％和0.3％。
除了活性试剂外，本发明的制剂含有氯化钠作为离子性补强剂。NaCl的量取决于最终制剂所需的强度，但通常为0.1-0.9％。对于眼和耳的应用，本发明的悬浮制剂优选含有的NaCl量应足以使制剂具有约250-350mOsm的重量摩尔渗透压浓度。
本发明悬浮制剂还含有非离子聚合物。许多可眼用和可耳用非离子聚合物是已知的。这些聚合物包括羟乙基纤维素；羟丙基甲基纤维素；甲基纤维素；羧甲基纤维素；聚乙烯基吡咯烷酮和聚乙烯醇。优选的非离子聚合物是羟乙基纤维素。非离子聚合物在本发明制剂中的存在量为约0.1-0.5％。在羟乙基纤维素的情况下，非离子聚合物的优选浓度是0.2％。
本发明的制剂还含有非离子表面活性剂，其量为约0.01-0.2％。许多可眼用和可耳用非离子表面活性剂是已知的。合适的非离子表面活性剂包括四丁酚醛；聚氧乙烯脱水山梨醇酯，如聚山梨酸酯20，聚山梨酸酯60和聚山梨酸酯80；聚乙氧基化蓖麻油，如Cremaphor EL；聚乙氧基化氢化蓖麻油，如HCO-40；以及聚氧乙烯聚氧丙烯嵌段共聚物(poloxamer)。优选的表面活性剂是四丁酚醛。
若需要，制剂可以含有季铵盐卤化物作为防腐剂。合适的季铵盐卤化物包括聚季铵-1(polyquaternium-1)和卤苄烷铵(benzalkoniumhalide)。优选的卤苄烷铵是氯苄烷铵(“BAC”)和溴苄烷铵。通常而言，防腐剂成分的量为约0.005-0.3％。在其中防腐剂是BAC的优选情况下，优选的存在浓度是0.01％。
若需要，本发明的悬浮制剂中还可以存在螯合剂。合适的螯合剂包括乙二胺四乙酸二钠(“EDTA”)；乙二胺四乙酸三钠；乙二胺四乙酸四钠；以及五乙酸二亚乙基胺(diethyleneamine pentaacetate)。最优选的是EDTA。若存在，螯合剂通常以约0.001-0.1％的量存在。在EDTA情况下，螯合剂优选以0.01％的浓度存在。
在防腐的或多剂量制剂情况下，本发明的悬浮制剂可以含有0.1-1.5％的硼酸。
本发明的制剂具有的pH为3-5，优选4.5。pH可以用NaOH/HCl调节。用于本发明制剂的优选缓冲体系是乙酸钠和乙酸的组合。乙酸钠的浓度通常为0.015-0.06％，优选为约0.03％。乙酸的浓度通常为0.02-0.08％，优选为约0.04％。
地塞米松成分的平均粒度(平均体积基)应低于10微米以避免刺激或不适。平均粒度优选低于6微米且最优选低于3微米。地塞米松颗粒可以使用已知的技术如球磨、微流化和声处理分级。
本发明的悬浮制剂意欲用于对眼、耳或鼻进行局部给药。
下列实施例用于说明而不限制本发明。
                        实施例1
                          配方
    成分   A％(w/w)   B％(w/w)   C％(w/w)   D％(w/w)   E％(w/w)
一水合盐酸环丙沙星   0.35*   0.35   0.35   0.35   0.35
  地塞米松醇   0.1   0.1   0.1   0.1   0.1
羟乙基纤维素   0.2   0.2   0.2   0.2   0.2
  氯苄烷铵   0.01   0.01   0.01   0.01   0.01
乙酸钠(三水合物)   0.03   0.03   0.03   0.03   0.03
    乙酸   0.04   0.04   0.04   0.04   0.04
    氯化钠   0.25   0.25   0.80   0.53   ---
乙二胺四乙酸二钠   0.01   0.01   0.01   0.01   0.01
    四丁酚醛   0.05   0.05   0.05   0.05   0.05
    甘油   1.5   ---   ---   ---   2.35
    硼酸   ---   ---   ---   0.6   ---
    NaOH/HCl   适量pH4.5±0.2   适量pH4.5±0.2   适量pH4.5±0.2   适量pH4.5±0.2   适量pH4.5±0.2
    纯水   适量100   适量100   适量100   适量100   适量100
重量摩尔渗透压浓度(mOsm)   272   99   274   286   290
*等于0.3％环丙沙星基准
制剂A-E使用下列方法制备：(1) 对于500ml的制剂料量，通过在30ml聚丙烯研磨瓶中混合
75g3mm的锆珠、12g四丁酚醛的1.0％储液和0.5g地塞米松
醇形成浆料(使用的四丁酚醛占最终批料要求量的约48％)；(2) 对包括珠粒的浆料进行蒸汽灭菌(高压釜)；(3) 在50-55rpm下对灭菌的浆料进行无菌球磨；(4) 制备含有剩余量的四丁酚醛和要求量的所有剩余成分(例如
在制剂D情况下，剩余成分为一水合盐酸环丙沙星、氯苄烷
铵、乙酸钠、乙酸、氯化钠、羟乙基纤维素、硼酸、乙二胺
四乙酸二钠和纯水)的水溶液；(5) 对在步骤(4)中制备的水溶液进行蒸汽灭菌(高压釜)；(6) 通过将在步骤3中得到的无菌浆料通过无菌筛(以除去珠粒)
而无菌倾入在步骤5中得到的无菌溶液中，使该浆料与该溶
液混合；(7) 使用无菌过滤的纯水将制剂重量调节为批料重量的80-90％；(8) 检测最终的pH并若需要，通过无菌过滤的氢氧化钠或盐酸将
其调节为pH4.5±0.2；以及(9) 使用无菌过滤的纯水使制剂为批料重量的100％。
尤其是在地塞米松原料以满足所需粒度要求提供或得到时，另一制备制剂A-E的方法如下：(1) 对地塞米松原料进行干热灭菌(推荐条件：130-140℃(内部
粉末温度)下7-11小时)；(2) 制备含有批料要求量的四丁酚醛在纯水中的四丁酚醛溶液；(3) 通过使其通过0.2微米的过滤器而对四丁酚醛溶液进行灭菌；(4) 将灭菌的地塞米松与灭菌的四丁酚醛溶液无菌混合以形成无
菌浆料并搅拌直至均匀；(5) 制备含有要求量的剩余成分(例如在制剂D情况下，剩余成
分为一水合盐酸环丙沙星、氯苄烷铵、乙酸钠、乙酸、氯化
钠、羟乙基纤维素、硼酸、乙二胺四乙酸二钠和纯水)的水
溶液；(6) 对在步骤(5)中制备的水溶液进行蒸汽灭菌(高压釜)；(7) 将在步骤(4)中得到的无菌浆料与在步骤(6)中制备的灭
菌溶液无菌混合；(8) 使用无菌过滤的纯水将制剂重量调节为批料重量的80-90％；(9) 检测最终的pH并若需要，通过无菌过滤的氢氧化钠或盐酸将
其调节为pH4.5±0.2；以及(10)使用无菌过滤的纯水使制剂为批料重量的100％。
                    实施例2
测试制剂A-E在“加速”和“真实时间”沉降研究中的再悬浮时间。
加速沉降研究通过使用IEC CENTRA-7离心机将5g各制剂在单独的16×125mm圆底玻璃管中以3100rmp离心分离30分钟而进行。沉降材料的再悬浮性通过测量完全再悬浮该沉降物所需要的手腕振摇(wrist shaking)秒数而测定。
真实时间沉降研究通过使5g各制剂在16×125mm圆底玻璃管中进行自然沉降(在重力下)7天(制剂B例外，其在4天后测试)而进行。沉降材料的再悬浮性通过测量完全再悬浮该沉降物所需要的反转次数而测定。
                          表2
加速沉降 真实时间沉降
制剂 再悬浮时间(秒) 完全再悬浮的反转次数
A  111211  171619
 B*  67  1616
 C  131619  121311
 D  796  121311
 E  ＞60＞60＞60  182619
*制剂B在放置4天后测试；所有其他制剂在7天后测试。
                     实施例3防腐效力试验
根据美国药典(USP)和欧洲药典(Ph.Eur.)中所述的方法使用有机体侵染试验测定本发明聚合季铵化合物/硼酸组合的抗菌防腐效力。用已知水平的革兰氏阳性(金黄色葡萄球菌(Staphylococcusaureus)ATCC6538)和革兰氏阴性(Pseudomonas aeruginosaATCC9027和大肠杆菌(Escherichia coli)  ATCC8739)营养(vegetative)细菌、酵母(白假丝酵母(Candida albicans)ATCC10231)和霉菌(黑曲霉(Aspergillun niger)ATCC16404)接种样品并以特定间隔取样以确定抗菌防腐体系是否能够杀灭或抑制有意引入配方中的有机体的增殖。按USP和/或Ph.Eur.防腐剂效力标准测定眼用制剂的抗菌活性水平。
眼用制剂的简要防腐标准的要求如下：对于细菌：(金黄色葡萄球菌，Pseudomonas aeruginosa和大肠杆菌)
               有机体增殖的对数(Log)降低培养时间    USP      Ph.Eur.A(靶)    Ph.Eur.B(最小)6小时       -        2               -24小时      -        3               17天         -        -               314天        3        -               -28天       *NI     **NR           NI对于真菌：(白假丝酵母，黑曲霉)培养时间    USP        Ph.Eur.A(靶)    Ph.Eur.B(最小)7天         -          2               -14天        NI         -               128天        NI         NI              NI
*NI＝在该培养时或该培养后无增加
**NR＝未回收到有机体
-＝在该培养时未要求
对实施例1-4的制剂所进行的防腐侵染研究结果示于表3中。这些结果说明若需要，可以保存本发明的悬浮制剂以使其同时满足美国药典(USP)和欧洲药典(Ph.Eur.)对眼用和耳用制剂的最小防腐要求。
                          表3
    制剂
试验有机体   时间   A     B     C     D
  S.Aureus   开始6小时24小时7天14天28天   6.05.05.05.05.05.0   6.15.15.15.15.15.1   6.15.15.15.15.15.1   5.94.94.94.94.94.9
    P.Aeruginosa   开始6小时24小时7天14天28天   6.05.05.05.05.05.0   6.05.05.05.05.05.0   6.05.04.75.05.05.0   6.05.05.05.05.05.0
  E.Coli   开始6小时24小时7天14天28天   6.04.04.04.04.04.0   6.04.04.04.04.04.0   6.04.04.04.04.04.0   5.93.93.93.93.93.9
    C.Albicans   开始7天14天28天   6.05.05.05.0   6.15.15.15.1   6.14.75.15.1   6.15.15.15.1
  A.Niger   开始7天14天28天   6.11.82.02.5   5.90.90.81.5   5.90.91.01.5   6.11.81.94.3
  满足PET要求 USP和Ph.Eur.B 仅USP  USPPh.Eur.B   USPPh.Eur.B
表3所列的各制剂通过了对细菌和白假丝酵母的Ph.Eur.A防腐标准，但不含硼酸的制剂通过对黑曲霉的Ph.Eur.B防腐标准存在困难。硼酸与氯苄烷铵的组合改进了对黑曲霉的防腐活性且制剂易于满足Ph.Eur.B防腐效力标准。制剂B(不含硼酸)仅满足USP标准且不能满足Ph.Eur.的最小防腐要求。制剂C(不含硼酸)满足USP和Ph.Eur.B(最小)要求。制剂A最初满足Ph.Eur.B要求，但当在52周再试验时对黑曲霉的活性降低。制剂A的初始和52周结果示于表4中。
                          表4
试验有机体     时间   初始值 52周的值
S.Aureus     开始6小时24小时7天14天28天     6.05.05.05.05.05.0     6.05.05.05.05.05.0
    P.Aeruginosa     开始6小时24小时7天14天28天     6.05.05.05.05.05.0     6.15.05.05.05.05.0
   E.Coli     开始6小时24小时7天14天28天     6.04.04.04.04.04.0     6.04.04.04.04.04.0
 C.Albicans     开始7天14天28天     6.05.05.05.0     6.05.05.05.0
  A.Niger     开始7天14天28天     6.11.82.02.5     6.21.01.21.7
本发明已参照某些优选实施方案进行了描述，但应理解本发明可以在不背离其要旨或基本特征的情况下以其他特定形式或其变化实施。因此，在所有方面将上述实施方案看作说明性而非限制性的，本发明的范围由所附权利要求书而不是前述说明所显示。

Claims (10)

1.一种意欲施用于眼睛、耳朵或鼻子的可局部给药的悬浮组合物，包含：
a)0.01-0.5重量％的地塞米松；
b)0.1-0.4重量％的环丙沙星；
c)基本由NaCl组成的补强剂，其量足以使得该组合物具有约250-350mOsm的重量摩尔渗透压浓度；
d)0.1-0.5重量％非离子聚合物；
e)0.01-0.2重量％非离子表面活性剂；和
f)缓冲剂；其中该组合物具有的pH约为3-5。
2.权利要求1的组合物，其中地塞米松选自地塞米松醇和乙酸地塞米松；且环丙沙星为一水合盐酸环丙沙星。
3.权利要求1的组合物，其中地塞米松的存在浓度为0.1重量％且环丙沙星的存在浓度为0.3％。
4.权利要求1的组合物，其中非离子聚合物选自羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、羧甲基纤维素、聚乙烯基吡咯烷酮和聚乙烯醇。
5.权利要求1的组合物，其中非离子表面活性剂选自四丁酚醛、聚氧乙烯脱水山梨醇酯、聚乙氧基化蓖麻油、聚乙氧基化氢化蓖麻油和聚氧乙烯聚氧丙烯嵌段共聚物。
6.权利要求4的组合物，其中非离子聚合物为羟乙基纤维素，该羟乙基纤维素的存在浓度为0.2重量％，非离子表面活性剂为四丁酚醛且四丁酚醛的存在浓度为0.05重量％。
7.权利要求1的组合物，还包含0.005-0.3重量％的季铵盐卤化物；0.001-0.1重量％的螯合剂和0.1-1.5重量％的硼酸。
8.权利要求7的组合物，其中季铵盐卤化物选自聚季铵-1和卤苄烷铵；且螯合剂选自乙二胺四乙酸二钠、乙二胺四乙酸三钠、乙二胺四乙酸四钠和五乙酸二亚乙基胺。
9.权利要求8的组合物，其中季铵盐卤化物为氯苄烷铵且螯合剂为乙二胺四乙酸二钠。
10.一种意欲施用于眼睛、耳朵或鼻子的可局部给药的悬浮组合物，基本由如下成分组成：
a)0.1重量％的地塞米松醇；
b)0.35重量％的一水合盐酸环丙沙星；
c)NaCl，其量足以使得该组合物具有约250-350mOsm的重量摩尔渗透压浓度；
d)0.2重量％羟乙基纤维素；
e)0.05重量％四丁酚醛；
f)包含乙酸钠和乙酸的缓冲剂；
g)0.01重量％氯苄烷铵；
h)0.01重量％乙二胺四乙酸二钠；和
i)0.6重量％硼酸；其中该组合物具有的pH约为4.5。
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CN101317847B (zh) * 2007-06-06 2010-10-13 深圳市瑞谷医药技术有限公司 一种眼用或耳鼻用药物组合物及其用途
CN101970042A (zh) * 2008-02-25 2011-02-09 眼门药品公司 经由离子电渗法增强递送治疗药物至眼部组织
US9149525B2 (en) 2008-02-25 2015-10-06 Eyegate Pharmaceuticals, Inc. Delivery of corticosteroids through iontophoresis
US9820935B2 (en) 2008-02-25 2017-11-21 Eyegate Pharmaceuticals, Inc. Delivery of corticosteroids through iontophoresis
WO2013084194A1 (en) * 2011-12-09 2013-06-13 Lupin Limited Topical pharmaceutical compositions of anti-microbial agents and anti-inflammatory agents
CN103565816A (zh) * 2012-07-25 2014-02-12 天津金耀集团有限公司 妥布霉素地塞米松滴眼液
CN107970244A (zh) * 2016-10-21 2018-05-01 武汉武药科技有限公司 一种含有环丙沙星和地塞米松的组合物及其制备方法
CN107970244B (zh) * 2016-10-21 2020-07-14 武汉武药科技有限公司 一种含有环丙沙星和地塞米松的组合物及其制备方法
CN108403700A (zh) * 2018-06-12 2018-08-17 新疆生产建设兵团第师畜牧兽医工作站 一种牛呼吸道疾病治疗用复合注射液
CN111568906A (zh) * 2019-02-15 2020-08-25 诺华股份有限公司 4-(7-羟基-2-异丙基-4-氧代-4h-喹唑啉-3-基)-苄腈的配制品
CN111568906B (zh) * 2019-02-15 2023-09-01 诺华股份有限公司 4-(7-羟基-2-异丙基-4-氧代-4h-喹唑啉-3-基)-苄腈的配制品
CN113797162A (zh) * 2020-06-17 2021-12-17 成都瑞沐生物医药科技有限公司 一种滴眼给药治疗黄斑水肿、视神经炎和非感染性眼内炎的眼用制剂
CN113144207A (zh) * 2021-02-07 2021-07-23 山西利普达医药科技有限公司 一种包括聚季铵盐-1的组合物及其应用

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DE60006262D1 (de) 2003-12-04
BR0014203A (pt) 2002-05-21
PT1214056E (pt) 2004-02-27
US6359016B2 (en) 2002-03-19
AR025661A1 (es) 2002-12-11
DE60006262T2 (de) 2004-05-13
CN1158994C (zh) 2004-07-28
JP2011032293A (ja) 2011-02-17
MXPA02003130A (es) 2004-04-21
EP1214056A1 (en) 2002-06-19
AU776609B2 (en) 2004-09-16
PL201130B1 (pl) 2009-03-31
CA2379605C (en) 2007-06-26
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SA00210418B1 (ar) 2006-04-22
DK1214056T3 (da) 2004-02-09
US6284804B1 (en) 2001-09-04
JP2003510263A (ja) 2003-03-18
CA2379605A1 (en) 2001-04-05
KR20020069508A (ko) 2002-09-04
KR100722502B1 (ko) 2007-05-28
ES2207549T3 (es) 2004-06-01
TWI228423B (en) 2005-03-01
ATE252887T1 (de) 2003-11-15
ZA200201904B (en) 2003-05-28
AU7057000A (en) 2001-04-30

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