CN1059276A - 氟化氯霉素药物组合物 - Google Patents

氟化氯霉素药物组合物 Download PDF

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CN1059276A
CN1059276A CN91108502A CN91108502A CN1059276A CN 1059276 A CN1059276 A CN 1059276A CN 91108502 A CN91108502 A CN 91108502A CN 91108502 A CN91108502 A CN 91108502A CN 1059276 A CN1059276 A CN 1059276A
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pyrrolidone
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polyethylene glycol
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CN1041793C (zh
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H·M·阿佩利安
D·科芬-比奇
A·S·哈格
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • A—HUMAN NECESSITIES
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    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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Abstract

公开了一种兽用注射药物组合物，它含有氟化氯 霉素、N-甲基-2-吡咯烷酮、聚乙二醇和减粘剂。该 组合物具有化学和物理稳定性，呈现恒定的血药浓 度，不产生不良副作用。

Description

本发明涉及含有氟化氯霉素（florfenicol）作为活性成分的药物组合物，特别是涉及含有高浓度氟化氯霉素的注射用组合物。
氟化氯霉素（D-（苏型）-1-对甲磺酰苯基-2-二氯乙酰氨基-3-氟-1-丙醇）是已知抗菌剂，可用于兽医学目的。当治疗大动物时，有时期望施用含有高浓度氟化氯霉素的组合物。那么，如此大剂量施用的氟化氯霉素最好应该能显示出恒定的血药浓度，并且在长时间内保持其活性。
氟化氯霉素水溶性差（约1.3mg/ml），由于按治疗剂量给药所需体积很大，要配制其浓缩水溶液注射液是不现实的。
在许多药用有机溶剂中，氟化氯霉素的溶解度也很低，这些溶剂的例子有1，2-丙二醇、甘油、苯甲醇等。
氟化氯霉素一般可溶于非质子性极性溶剂，例如N-甲基-2-吡咯烷酮或2-吡咯烷酮，然而，在用于肌肉注射时，这些溶剂的浓度高于30%时会引起注射部位发炎和组织损伤。
已发现利用包含下列组分的新组合物可提供稳定的氟化氯霉素注射用组合物：
10-50%（重量）氟化氯霉素;
10-65%（重量）吡咯烷酮类溶剂;
5-15%（重量）减粘剂;
5-40%（重量）聚乙二醇。
这种新组合物在长时间内保持恒定的血药浓度并且表现出良好的物理和化学稳定性。
图1解释单次肌肉注射20mg/kg的剂量之后，小牛血清中氟化氯霉素的浓度。
氟化氯霉素呈现抗菌活性，可用于兽药（Merk  Index，11th  Edition，No.4042）。美国专利4，235，892叙述了该化合物及其制备方法，该专利在此列为参考。
本发明制得了一种新组合物，在该组合物中，氟化氯霉素以较高的浓度存在于一种独特的有机溶剂系统中，该有机溶剂系统由一种吡咯烷酮类溶剂（例如2-吡咯烷酮、N-甲基-2-吡咯烷酮）、聚乙二醇和一种减粘剂组成。
本发明组合物可包含10-50%，优选20-40%（重量）的氟化氯霉素。
可用于本发明的吡咯烷酮类溶剂包括2-吡咯烷酮和N-甲基-2-吡咯烷酮。优选溶剂为N-甲基-2-吡咯烷酮。本发明组合物中吡咯烷酮类溶剂的重量可占组合物总重量的10-65%。在给牛进行肌肉注射时，N-甲基-2-吡咯烷酮溶剂含量超过30%（重量）的组合物会造成注射部位发炎和组织损伤。
本发明组合物所用的聚乙二醇包括平均分子量为200-400的聚乙二醇，优选聚乙二醇的平均分子量约为300，也称为PEG300。本发明组合物中聚乙二醇的量为5-45%，优选30-40%（重量）。
由于本发明组合物中固体氟化氯霉素含量高，需要加入减粘剂以制得一种可用于注射的产品。本发明所用减粘剂的例子包括乙醇和丙二醇，优选的减粘剂是丙二醇。本发明组合物中减粘剂的用量为组合物重量的5-15%，优选10-15%。
将吡咯烷酮类溶剂、减粘剂与约90%的聚乙二醇组分混合，然后将氟化氯霉素溶解在该溶液中，并用剩余的聚乙二醇调整体积，所得澄清溶液经过滤灭菌，由此很容易制得本发明组合物。
本发明组合物所显示出的理想特性可使氟化氯霉素以比较高的浓度施用。该组合物具有理想的粘度特征，因此可在很宽的温度范围保持良好的可注射性并易于处理，例如通过灭菌滤膜的流速适宜。该组合物还具有物理和化学稳定性，如，在2℃-30℃下贮存时，该组合物可稳定并保持其特性至少两年。该组合物可在长时间内提供有治疗作用的血药浓度，还表现出可接受的组织耐受性。
下列实施例详细阐述了本发明。在不偏离本公开的目的和意图的前提下，可以进行各种改进，这对本领域技术人员是显而易见的。
实施例1
由下列成分配制注射液：
成分  重量/ml
氟化氯霉素  300mg
N-甲基-2-吡咯烷酮  250mg
丙二醇  150mg
聚乙二醇300  加至1ml
该溶液按下述程序配制：将N-甲基-2-吡咯烷酮、丙二醇和占所需量约90%的聚乙二醇300充分混合，然后将氟化氯霉素溶解在该混合物中。用剩余的聚乙二醇300调整体积，并将澄清溶液过滤灭菌。
对牛以20mg/kg氟化氯霉素的单次剂量肌肉注射上述制剂，所得血清药物浓度如下：
浓度（最大）  3.86μg/ml
浓度（12小时）  1.94μg/ml
浓度（24小时）  1.03μg/ml
实施例2
由下列成分配制注射液：
成分  重量/ml
氟化氯霉素  300mg
N-甲基-2-吡咯烷酮  250mg
乙醇  100mg
聚乙二醇300  加至1ml
该溶液按下述程序配制：将N-甲基-2-吡咯烷酮、乙醇和占所需量约90%的聚乙二醇300充分混合，然后将氟化氯霉素溶解在该混合物中。用剩余的聚乙二醇300调整体积，将澄清溶液过滤灭菌。
实施例3
由下列成分配制注射液：
成分  重量/ml
氟化氯霉素  300mg
N-甲基-2-吡咯烷酮  350mg
丙二醇  150mg
聚乙二醇300  加至1ml
该溶液按实施例1所述方法配制。
对牛以20mg/kg氟化氯霉素的单次剂量肌肉注射上述制剂，所得血清药物浓度如下：
浓度（最大）  5.80μg/ml
浓度（12小时）  1.80μg/ml
浓度（24小时）  0.60μg/ml
实施例4
由下列成分配制注射液：
成分  重量/ml
氟化氯霉素  300mg
N-甲基-2-吡咯烷酮  350mg
乙醇  100mg
聚乙二醇300  加至1ml
该溶液按实施例2所述方法配制。

Claims (8)

1、一种制备兽医用药物组合物的方法，该组合物包含：
10-50%(重量)氟化氯霉素；
10-65%(重量)吡咯烷酮类溶剂；
5-15%(重量)减粘剂；
5-40%(重量)聚乙二醇；
该方法包括：将吡咯烷酮类溶剂和减粘剂与大约90%的聚乙二醇组分混合，然后将氟化氯霉素溶于所得到的混合物中，用其余的聚乙二醇调整体积，过滤灭菌。
2、权利要求1的方法，其中吡咯烷酮类溶剂选自2-吡咯烷酮和N-甲基-2-吡咯烷酮。
3、权利要求2的方法，其中吡咯烷酮类溶剂为N-甲基-2-吡咯烷酮。
4、权利要求1的方法，其中聚乙二醇的平均分子量在200和400之间。
5、权利要求4的方法，其中聚乙二醇的平均分子量为300。
6、权利要求1的方法，其中减粘剂选自乙醇和丙二醇。
7、权利要求6的方法，其中减粘剂为丙二醇。
8、权利要求1的方法，其中使用下列成分：
重量/ml  成分
300mg  氟化氯霉素
250mg  N-甲基-2-吡咯烷酮
150mg  丙二醇
加至1ml  聚乙二醇300
CN91108502A 1990-08-29 1991-08-28 氟化氯霉素药物组合物 Expired - Lifetime CN1041793C (zh)

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US07/574,430 US5082863A (en) 1990-08-29 1990-08-29 Pharmaceutical composition of florfenicol

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CN1829503B (zh) * 2003-07-31 2010-06-23 科鲁纳制药公司 含有氟苯尼考的兽用水性可注射悬浮液
CN102342925A (zh) * 2003-05-29 2012-02-08 先灵-普劳有限公司 用于治疗牛和猪传染病的组合物

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US4235892A (en) * 1979-02-05 1980-11-25 Schering Corporation, Patent Dept. 1-Aryl-2-acylamido-3-fluoro-1-propanols, methods for their use as antibacterial agents and compositions useful therefor
US4423040A (en) * 1980-04-04 1983-12-27 Nelson Research & Development Company Vehicle composition containing 1-substituted azacyclohexan-2-ones

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1060310C (zh) * 1994-12-04 2001-01-10 张长兴 一种防治病害的农药
CN102342925A (zh) * 2003-05-29 2012-02-08 先灵-普劳有限公司 用于治疗牛和猪传染病的组合物
CN1829503B (zh) * 2003-07-31 2010-06-23 科鲁纳制药公司 含有氟苯尼考的兽用水性可注射悬浮液

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CZ25793A3 (en) 1993-10-13
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UA27244C2 (uk) 2000-08-15
FI930844A0 (fi) 1993-02-25
PL171466B1 (pl) 1997-05-30
ZA916780B (en) 1993-03-01
WO1992004016A1 (en) 1992-03-19
FI930844A (fi) 1993-02-25
PT98790B (pt) 1999-01-29
HUT63558A (en) 1993-09-28
MX9100855A (es) 1992-04-01
MY106780A (en) 1995-07-31
KR960005705B1 (ko) 1996-05-01
NO930616D0 (no) 1993-02-22
DK0546018T3 (da) 1994-11-28
DE69104724T2 (de) 1995-02-16
DE69104724D1 (de) 1994-11-24
US5082863A (en) 1992-01-21
HU9300555D0 (en) 1993-05-28
IE913024A1 (en) 1992-03-11
FI101596B1 (fi) 1998-07-31
IE66925B1 (en) 1996-02-07
NO930616L (no) 1993-02-22
JPH0692299B2 (ja) 1994-11-16
JPH05506245A (ja) 1993-09-16
AU8436691A (en) 1992-03-30
IL99337A (en) 1995-05-26
AU655935B2 (en) 1995-01-19
ATE112959T1 (de) 1994-11-15
PT98790A (pt) 1992-07-31
EP0546018B1 (en) 1994-10-19
EP0546018A1 (en) 1993-06-16
CN1041793C (zh) 1999-01-27
IL99337A0 (en) 1992-07-15
CZ280541B6 (cs) 1996-02-14
HU213406B (en) 1997-06-30
RU2085191C1 (ru) 1997-07-27
NZ239559A (en) 1992-11-25
NO301746B1 (no) 1997-12-08
TW215054B (zh) 1993-10-21
CA2090422A1 (en) 1992-03-01
SK12993A3 (en) 1993-07-07
ES2065059T3 (es) 1995-02-01

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