WO2016082413A1 - Dexibuprofen pharmaceutical composition for injection and preparation method thereof - Google Patents

Dexibuprofen pharmaceutical composition for injection and preparation method thereof Download PDF

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WO2016082413A1
WO2016082413A1 PCT/CN2015/075844 CN2015075844W WO2016082413A1 WO 2016082413 A1 WO2016082413 A1 WO 2016082413A1 CN 2015075844 W CN2015075844 W CN 2015075844W WO 2016082413 A1 WO2016082413 A1 WO 2016082413A1
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dextroprofen
concentration
tromethamine
injection
composition
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PCT/CN2015/075844
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French (fr)
Chinese (zh)
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林金平
宋华先
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北京蓝丹医药科技有限公司
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Publication of WO2016082413A1 publication Critical patent/WO2016082413A1/en

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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
    • A61K9/08—Solutions
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • the present invention relates to the field of pharmacy, and in particular to a dextroprofen composition and a process for the preparation thereof.
  • Non-steroidal anti-inflammatory drugs have good anti-inflammatory, antipyretic and analgesic effects.
  • Ibuprofen was first marketed in the UK in 1968. It has been widely used because of its remarkable efficacy in antipyretic and analgesic effects, and its low toxicity, superior to aspirin and paracetamol. Despite its many advantages, one of the main drawbacks of ibuprofen is its poor solubility in water.
  • WO 03/039532 and WO 2005/065674 describe liquid pharmaceutical compositions of ibuprofen comprising an amino acid, such as arginine, for increasing the solubility of ibuprofen.
  • Ibuprofen injection was marketed in the United States in 2009, in which the concentration of ibuprofen was 100 mg/ml, and the molar ratio of the cosolvent arginine to ibuprofen was 0.92:1.
  • concentration of ibuprofen in the ibuprofen injection is 8 mg/ml, and the concentration of tromethamine is 6.04 mg/ml.
  • the ibuprofen injection is not suitable for high temperature sterilization, but can only be used. Sterile filtration is carried out to increase production costs.
  • a low concentration of ibuprofen injection is disclosed in CN102892410A, wherein the concentration of ibuprofen is 2-6 mg/ml, and the concentration of tromethamine is 1.8-5.8 mg/ml.
  • Dextroprofen is the S-(+)-isomer of ibuprofen, very soluble in ethanol, acetone, chloroform and diethyl ether, but almost insoluble in water.
  • CN102362857A discloses a dextroprofen injection comprising dextroprofen, meglumine, citric acid and trisodium citrate, wherein the concentration of dextroprofen is 50 mg/ml.
  • CN103720647A also discloses a dextroprofen injection, wherein the concentration of dextroprofen is 100 mg/ml, and the molar ratio of dextroprofen to arginine is 1:0.8-1.4, preferably 1 : 1.3. Since arginine will decompose during the sterilization process, it will not produce For the foreseeable impurities, we chose tromethamine in combination with dextroprofen.
  • the present invention provides a dextroprofen composition, which is an aqueous solution containing dextroprofen and tromethamine, wherein dextrozole
  • concentration of phenanthrene is 2-4 mg/ml
  • concentration of tromethamine is 1.0-3.4 mg/ml.
  • the present invention provides a method of preparing a dextroprofen composition according to the present invention, the method comprising:
  • the above-mentioned dextroprofen composition provided by the present invention has no significant change in the content before and after filtration, and can withstand high temperature sterilization.
  • the present invention provides a dextroprofen composition, which is an aqueous solution containing dextroprofen and tromethamine, wherein the concentration of dextroprofen is 2-4 mg/ml, the concentration of tromethamine is 1.0-3.4 mg/ml.
  • the concentration of dextroprofen is 2.5-3.5 mg/ml, and the concentration of tromethamine is 1.8. -3.0 mg/ml.
  • the concentration of the dextroprofen is 2 mg/ml, and the concentration of the tromethamine is 1.0 to 1.4 mg/ml, particularly preferably the tromethamine
  • concentration of the alcohol is 0.7-1.4 mg/ml; or
  • the concentration of dextroprofen is 3 mg/ml
  • the concentration of tromethamine is 1.5-2.7 mg/ml
  • the concentration of tromethamine is 1.5. -1.8mg/ml
  • the concentration of dextroprofen is 4 mg/ml, and the concentration of tromethamine is 2.4-3.4 mg/ml; preferably, the concentration of tromethamine is 2.4. -3.0 mg/ml.
  • the dextroprofen composition further contains a pH adjusting agent and an osmotic pressure adjusting agent (also referred to as an isotonicity adjusting agent).
  • the pH adjusting agent is sodium hydroxide and has a pH in the range of 6.5 to 8.5.
  • the isotonicity adjusting agent is sodium chloride.
  • the present invention provides a method of preparing a dextroprofen composition according to the present invention, the method comprising:
  • the dextroprofen composition of the present invention has no significant change in content before and after filtration, and can withstand high temperature sterilization.
  • the above-mentioned dextroprofen composition provided by the present invention can maintain stability and is not easily deteriorated in filtration, high temperature sterilization, and long-term storage.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the dextroprofen combination prepared in the above examples and comparative examples was determined by HPLC method.
  • the content of dextroprofen in the product is shown in Table 1:
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
  • the glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.

Abstract

Disclosed is a dexibuprofen composition comprising dexibuprofen and tromethamine, wherein the concentration of the dexibuprofen is 2-4 mg/ml, and the concentration of the tromethamine is 1.0-3.4 mg/ml.

Description

一种用于注射的右旋布洛芬药物组合物及其制备方法Dextroprofen pharmaceutical composition for injection and preparation method thereof 技术领域Technical field
本发明涉及制药领域，具体地，涉及一种右旋布洛芬组合物及其制备方法。The present invention relates to the field of pharmacy, and in particular to a dextroprofen composition and a process for the preparation thereof.
背景技术Background technique
非甾体类抗炎药具有较好的消炎解热镇痛作用。布洛芬最早是1968年在英国上市，由于解热镇痛方面的疗效显著，而且毒性低，优于阿司匹林和扑热息痛，已被广泛的应用。尽管有许多优势，但是布洛芬的主要缺点之一是它在水中的溶解性差。WO03/039532和WO2005/065674记载了布洛芬的液体药物组合物，该组合物中包括用于提高布洛芬溶解性的氨基酸，如精氨酸。布洛芬注射液于2009年在美国上市，其中布洛芬的浓度为100mg/ml，助溶剂精氨酸与布洛芬的摩尔比为0.92∶1。而DE19912436A中公开了布洛芬注射液中布洛芬浓度为8mg/ml，氨丁三醇的浓度为6.04mg/ml，然而，该布洛芬注射液不适合高温灭菌，而仅能采用无菌过滤进行制备，从而增加了生产成本。为了解决高温灭菌问题，CN102892410A中公开了一种低浓度的布洛芬注射液，其中布洛芬的浓度为2-6mg/ml，氨丁三醇的浓度为1.8-5.8mg/ml。Non-steroidal anti-inflammatory drugs have good anti-inflammatory, antipyretic and analgesic effects. Ibuprofen was first marketed in the UK in 1968. It has been widely used because of its remarkable efficacy in antipyretic and analgesic effects, and its low toxicity, superior to aspirin and paracetamol. Despite its many advantages, one of the main drawbacks of ibuprofen is its poor solubility in water. WO 03/039532 and WO 2005/065674 describe liquid pharmaceutical compositions of ibuprofen comprising an amino acid, such as arginine, for increasing the solubility of ibuprofen. Ibuprofen injection was marketed in the United States in 2009, in which the concentration of ibuprofen was 100 mg/ml, and the molar ratio of the cosolvent arginine to ibuprofen was 0.92:1. In DE19912436A, the concentration of ibuprofen in the ibuprofen injection is 8 mg/ml, and the concentration of tromethamine is 6.04 mg/ml. However, the ibuprofen injection is not suitable for high temperature sterilization, but can only be used. Sterile filtration is carried out to increase production costs. In order to solve the problem of high temperature sterilization, a low concentration of ibuprofen injection is disclosed in CN102892410A, wherein the concentration of ibuprofen is 2-6 mg/ml, and the concentration of tromethamine is 1.8-5.8 mg/ml.
右旋布洛芬是布洛芬的S-(+)-异构体，极易溶解于乙醇、丙酮、氯仿和乙醚中，但是几乎不溶于水。CN102362857A中公开了一种右旋布洛芬注射液，该注射液由右旋布洛芬、葡甲胺、柠檬酸和柠檬酸三钠组成，其中，右旋布洛芬的浓度为50mg/ml。CN103720647A也公开了一种右旋布洛芬注射液，其中，右旋布洛芬的浓度为100mg/ml，右旋布洛芬与精氨酸的摩尔比为1∶0.8-1.4，优选为1∶1.3。由于精氨酸在灭菌过程中会分解，产生不 可预见的杂质，我们选择氨丁三醇与右旋布洛芬组合。Dextroprofen is the S-(+)-isomer of ibuprofen, very soluble in ethanol, acetone, chloroform and diethyl ether, but almost insoluble in water. CN102362857A discloses a dextroprofen injection comprising dextroprofen, meglumine, citric acid and trisodium citrate, wherein the concentration of dextroprofen is 50 mg/ml. . CN103720647A also discloses a dextroprofen injection, wherein the concentration of dextroprofen is 100 mg/ml, and the molar ratio of dextroprofen to arginine is 1:0.8-1.4, preferably 1 : 1.3. Since arginine will decompose during the sterilization process, it will not produce For the foreseeable impurities, we chose tromethamine in combination with dextroprofen.
研究中意外发现，采用右旋布洛芬与氨丁三醇组合时，氨丁三醇较高浓度时，过滤前后含量下降明显，为此，我们在现有技术基础上，提供一种更优选的右旋布洛芬与氨丁三醇组合物。It was unexpectedly found in the study that when dextroprofen was combined with tromethamine, the concentration of tromethamine was significantly decreased before and after filtration. For this reason, we provide a more preferable method based on the prior art. The composition of dextroprofen and tromethamine.
发明内容Summary of the invention
本发明的目的是提供一种新的右旋布洛芬组合物，该右旋布洛芬组合物能够克服现有技术的缺陷，在过滤和高温灭菌以及长期保存中均能够维持稳定而不易变质。It is an object of the present invention to provide a novel dextroprofen composition which overcomes the deficiencies of the prior art and which is stable and stable during filtration and high temperature sterilization as well as long-term storage. Deterioration.
为了实现上述目的，一方面，本发明提供一种右旋布洛芬组合物，该右旋布洛芬组合物为含有右旋布洛芬和氨丁三醇的水溶液，其中，右旋布洛芬的浓度为2-4mg/ml，氨丁三醇的浓度为1.0-3.4mg/ml。In order to achieve the above object, in one aspect, the present invention provides a dextroprofen composition, which is an aqueous solution containing dextroprofen and tromethamine, wherein dextrozole The concentration of phenanthrene is 2-4 mg/ml, and the concentration of tromethamine is 1.0-3.4 mg/ml.
另一方面，本发明还提供了一种制备本发明所述的右旋布洛芬组合物的方法，该方法包括：In another aspect, the present invention provides a method of preparing a dextroprofen composition according to the present invention, the method comprising:
(1)将氨丁三醇和氢氧化钠以及任选的氯化钠加入注射用水中；(1) adding tromethamine and sodium hydroxide and optionally sodium chloride to water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入活性炭，加热搅拌；(3) adding activated carbon, heating and stirring;
(4)过滤，注射用水加至足量，调节pH值；(4) Filtration, adding water for injection to a sufficient amount to adjust the pH value;
(5)灌封、灭菌。(5) Potting and sterilization.
本发明提供的上述右旋布洛芬组合物在过滤前后含量无明显变化，能耐受高温灭菌。The above-mentioned dextroprofen composition provided by the present invention has no significant change in the content before and after filtration, and can withstand high temperature sterilization.
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。Other features and advantages of the invention will be described in detail in the detailed description which follows.
具体实施方式detailed description
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描 述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。Specific embodiments of the present invention will be described in detail below. It should be understood that the description here The specific embodiments described are only intended to illustrate and explain the present invention and are not intended to limit the invention.
一方面，本发明提供了一种右旋布洛芬组合物，该右旋布洛芬组合物为含有右旋布洛芬和氨丁三醇的水溶液，其中，右旋布洛芬的浓度为2-4mg/ml，氨丁三醇的浓度为1.0-3.4mg/ml。In one aspect, the present invention provides a dextroprofen composition, which is an aqueous solution containing dextroprofen and tromethamine, wherein the concentration of dextroprofen is 2-4 mg/ml, the concentration of tromethamine is 1.0-3.4 mg/ml.
根据本发明的一种优选的具体实施方式，在本发明所述的右旋布洛芬组合物中，右旋布洛芬的浓度为2.5-3.5mg/ml，氨丁三醇的浓度为1.8-3.0mg/ml。According to a preferred embodiment of the present invention, in the dextroprofen composition of the present invention, the concentration of dextroprofen is 2.5-3.5 mg/ml, and the concentration of tromethamine is 1.8. -3.0 mg/ml.
在本发明所述的右旋布洛芬组合物中，更优选所述右旋布洛芬的浓度为2mg/ml，氨丁三醇的浓度为1.0-1.4mg/ml，特别优选氨丁三醇的浓度为0.7-1.4mg/ml；或者In the dextroprofen composition according to the present invention, it is more preferred that the concentration of the dextroprofen is 2 mg/ml, and the concentration of the tromethamine is 1.0 to 1.4 mg/ml, particularly preferably the tromethamine The concentration of the alcohol is 0.7-1.4 mg/ml; or
在本发明所述的右旋布洛芬组合物中，右旋布洛芬的浓度为3mg/ml，氨丁三醇的浓度为1.5-2.7mg/ml；优选氨丁三醇的浓度为1.5-1.8mg/ml；或者In the dextroprofen composition of the present invention, the concentration of dextroprofen is 3 mg/ml, the concentration of tromethamine is 1.5-2.7 mg/ml; preferably the concentration of tromethamine is 1.5. -1.8mg/ml; or
在本发明所述的右旋布洛芬组合物中，右旋布洛芬的浓度为4mg/ml，氨丁三醇的浓度为2.4-3.4mg/ml；优选氨丁三醇的浓度为2.4-3.0mg/ml。In the dextroprofen composition of the present invention, the concentration of dextroprofen is 4 mg/ml, and the concentration of tromethamine is 2.4-3.4 mg/ml; preferably, the concentration of tromethamine is 2.4. -3.0 mg/ml.
根据本发明所述的右旋布洛芬组合物，所述右旋布洛芬组合物中还含有pH值调节剂和渗透压调节剂(也称为等渗调节剂)。According to the dextroprofen composition of the present invention, the dextroprofen composition further contains a pH adjusting agent and an osmotic pressure adjusting agent (also referred to as an isotonicity adjusting agent).
在本发明所述的右旋布洛芬组合物中，所述pH值调节剂为氢氧化钠，pH值范围为6.5-8.5。In the dextroprofen composition of the present invention, the pH adjusting agent is sodium hydroxide and has a pH in the range of 6.5 to 8.5.
在本发明所述的右旋布洛芬组合物中，所述等渗调节剂为氯化钠。In the dextroprofen composition of the present invention, the isotonicity adjusting agent is sodium chloride.
另一方面，本发明还提供了一种制备本发明所述的右旋布洛芬组合物的方法，该方法包括：In another aspect, the present invention provides a method of preparing a dextroprofen composition according to the present invention, the method comprising:
(1)将氨丁三醇和氢氧化钠以及任选的氯化钠加入注射用水中；(1) adding tromethamine and sodium hydroxide and optionally sodium chloride to water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入活性炭，加热搅拌；(3) adding activated carbon, heating and stirring;
(4)过滤，注射用水加至足量，调节pH值； (4) Filtration, adding water for injection to a sufficient amount to adjust the pH value;
(5)灌封、灭菌(121℃，F0＞12)，即得到本发明所述的右旋布洛芬组合物。(5) Potting and sterilization (121 ° C, F0 > 12), that is, the dextroprofen composition of the present invention is obtained.
本发明所述的右旋布洛芬组合物在过滤前后含量无明显变化，能耐受高温灭菌。The dextroprofen composition of the present invention has no significant change in content before and after filtration, and can withstand high temperature sterilization.
另外，本发明提供的上述右旋布洛芬组合物在过滤和高温灭菌以及长期保存中均能够维持稳定而不易变质。In addition, the above-mentioned dextroprofen composition provided by the present invention can maintain stability and is not easily deteriorated in filtration, high temperature sterilization, and long-term storage.
以下将通过实施例和对比例对本发明的技术方案及其效果进行详细描述。以下实施例和对比例中，所使用的各种原料均来自商购。在以下实施例和对比例中，在没有特别说明的情况下，所述浓度均为重量浓度。The technical solutions of the present invention and the effects thereof will be described in detail below by way of examples and comparative examples. In the following examples and comparative examples, various raw materials used were commercially available. In the following examples and comparative examples, the concentrations are all by weight unless otherwise specified.
对比例1Comparative example 1
处方：prescription:
Figure PCTCN2015075844-appb-000001
Figure PCTCN2015075844-appb-000001
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％注射用水中；(1) adding tromethamine and sodium hydroxide to 80% water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.7；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.7;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例1Example 1
处方：prescription:
Figure PCTCN2015075844-appb-000002
Figure PCTCN2015075844-appb-000002
Figure PCTCN2015075844-appb-000003
Figure PCTCN2015075844-appb-000003
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.6；；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.6;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例2Example 2
处方：prescription:
Figure PCTCN2015075844-appb-000004
Figure PCTCN2015075844-appb-000004
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.8；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.8;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例3Example 3
处方：prescription:
Figure PCTCN2015075844-appb-000005
Figure PCTCN2015075844-appb-000005
Figure PCTCN2015075844-appb-000006
Figure PCTCN2015075844-appb-000006
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.7；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.7;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例4Example 4
处方：prescription:
Figure PCTCN2015075844-appb-000007
Figure PCTCN2015075844-appb-000007
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.6；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.6;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例5Example 5
处方： Prescription:
Figure PCTCN2015075844-appb-000008
Figure PCTCN2015075844-appb-000008
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.7；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.7;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例6Example 6
处方：prescription:
Figure PCTCN2015075844-appb-000009
Figure PCTCN2015075844-appb-000009
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.5％的活性炭(w/v)，40℃下加热搅拌30分钟；(3) adding 0.5% of activated carbon (w/v) in a liquid volume, and heating and stirring at 40 ° C for 30 minutes;
(4)过滤，注射用水加至足量，测量pH值为6.7；(4) Filtration, water for injection is added to a sufficient amount, and the pH is measured to be 6.7;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
测试实施例1Test Example 1
采用HPLC法测定上述实施例和对比例中制备得到的右旋布洛芬组合 物中的右旋布洛芬的含量，结果列于表1中：The dextroprofen combination prepared in the above examples and comparative examples was determined by HPLC method. The content of dextroprofen in the product is shown in Table 1:
表1Table 1
Figure PCTCN2015075844-appb-000010
Figure PCTCN2015075844-appb-000010
结果表明，对比例1中的氨丁三醇用量过高，而且，对比例1中制备右旋布洛芬组合物的过滤过程中右旋布洛芬含量显著下降。The results showed that the amount of tromethamine in Comparative Example 1 was too high, and the content of dextroprofen was significantly decreased during the filtration of the dextroprofen composition prepared in Comparative Example 1.
实施例7Example 7
处方：prescription:
Figure PCTCN2015075844-appb-000011
Figure PCTCN2015075844-appb-000011
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠、氯化钠加入80％注射用水中；(1) adding tromethamine and sodium hydroxide, sodium chloride to 80% water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.1％的活性炭(w/v)，60℃下加热搅拌30分钟；(3) adding 0.1% of activated carbon (w/v) in a liquid volume, and heating and stirring at 60 ° C for 30 minutes;
(4)过滤(过滤后含量下降0.4％)，注射用水加至足量，pH值为7.3；(4) Filtration (the content after filtration decreased by 0.4%), the water for injection was added to a sufficient amount, and the pH was 7.3;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例8Example 8
处方：prescription:
Figure PCTCN2015075844-appb-000012
Figure PCTCN2015075844-appb-000012
Figure PCTCN2015075844-appb-000013
Figure PCTCN2015075844-appb-000013
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠、氯化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide and sodium chloride to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.1％的活性炭(w/v)，60℃下加热搅拌30分钟；(3) adding 0.1% of activated carbon (w/v) in a liquid volume, and heating and stirring at 60 ° C for 30 minutes;
(4)过滤(过滤后含量下降0.3％)，注射用水加至足量，测量pH值为8.5；(4) Filtration (the content after filtration decreased by 0.3%), the amount of water for injection was added to a sufficient amount, and the pH was measured to be 8.5;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。(5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
实施例9Example 9
处方：prescription:
Figure PCTCN2015075844-appb-000014
Figure PCTCN2015075844-appb-000014
制备方法：Preparation:
(1)将氨丁三醇和氢氧化钠、氯化钠加入80％的注射用水中；(1) adding tromethamine and sodium hydroxide and sodium chloride to 80% of water for injection;
(2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
(3)加入液体体积0.1％的活性炭(w/v)，60℃下加热搅拌30分钟；(3) adding 0.1% of activated carbon (w/v) in a liquid volume, and heating and stirring at 60 ° C for 30 minutes;
(4)过滤(过滤后含量下降0.5％)，注射用水加至足量，测量pH值为7.8；(4) Filtration (the content after filtration decreased by 0.5%), the water for injection was added to a sufficient amount, and the pH was measured to be 7.8;
(5)玻璃瓶灌封、灭菌(121℃，F0＞12)，即得右旋布洛芬组合物。 (5) The glass bottle is potted and sterilized (121 ° C, F0>12), that is, the dextroprofen composition is obtained.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solutions of the present invention within the scope of the technical idea of the present invention. These simple variants All fall within the scope of protection of the present invention.
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。It should be further noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention has various possibilities. The combination method will not be described separately.
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。 In addition, any combination of various embodiments of the invention may be made as long as it does not deviate from the idea of the invention, and it should be regarded as the disclosure of the invention.

Claims (11)

  1. 一种右旋布洛芬组合物，该右旋布洛芬组合物为含有右旋布洛芬和氨丁三醇的水溶液，其特征在于，右旋布洛芬的浓度为2-4mg/ml，氨丁三醇的浓度为1.0-3.4mg/ml。A dextroprofen composition, the dextroprofen composition being an aqueous solution containing dextroprofen and tromethamine, characterized in that the concentration of dextroprofen is 2-4 mg/ml The concentration of tromethamine is 1.0-3.4 mg/ml.
  2. 根据权利要求1所述的右旋布洛芬组合物，其中，右旋布洛芬的浓度为2.5-3.5mg/ml，氨丁三醇的浓度为1.8-3.0mg/ml。The dextroprofen composition according to claim 1, wherein the concentration of dextroprofen is 2.5-3.5 mg/ml, and the concentration of tromethamine is 1.8-3.0 mg/ml.
  3. 根据权利要求1所述的右旋布洛芬组合物，其中，右旋布洛芬的浓度为2mg/ml，氨丁三醇的浓度为1.0-1.4mg/ml。The dextroprofen composition according to claim 1, wherein the concentration of dextroprofen is 2 mg/ml and the concentration of tromethamine is 1.0 to 1.4 mg/ml.
  4. 根据权利要求3所述的右旋布洛芬组合物，其中，氨丁三醇的浓度为1.0-1.2mg/ml。The dextroprofen composition according to claim 3, wherein the concentration of tromethamine is 1.0 to 1.2 mg/ml.
  5. 根据权利要求1所述的右旋布洛芬组合物，其中，右旋布洛芬的浓度为3mg/ml，氨丁三醇的浓度为1.5-2.7mg/ml。The dextroprofen composition according to claim 1, wherein the concentration of dextroprofen is 3 mg/ml and the concentration of tromethamine is 1.5 to 2.7 mg/ml.
  6. 根据权利要求5所述的右旋布洛芬组合物，其中，氨丁三醇的浓度为1.5-1.8mg/ml。The dextroprofen composition according to claim 5, wherein the concentration of tromethamine is 1.5 to 1.8 mg/ml.
  7. 根据权利要求1所述的右旋布洛芬组合物，其中，右旋布洛芬的浓度为4mg/ml，氨丁三醇的浓度为2.4-3.4mg/ml。The dextroprofen composition according to claim 1, wherein the concentration of dextroprofen is 4 mg/ml and the concentration of tromethamine is 2.4 to 3.4 mg/ml.
  8. 根据权利要求7所述的右旋布洛芬组合物，其中，氨丁三醇的浓度为2.4-3.0mg/ml。 The dextroprofen composition according to claim 7, wherein the concentration of tromethamine is 2.4 to 3.0 mg/ml.
  9. 根据权利要求1至8任意一项所述的右旋布洛芬组合物，其中，含有pH值调节剂。The dextroprofen composition according to any one of claims 1 to 8, which comprises a pH adjuster.
  10. 根据权利要求1至8任意一项所述的右旋布洛芬组合物，其中，含有等渗调节剂。The dextroprofen composition according to any one of claims 1 to 8, which comprises an isotonicity adjusting agent.
  11. 制备权利要求1-10中任意一项所述的右旋布洛芬组合物的方法，其特征在于，该方法包括：A method of preparing a dextroprofen composition according to any one of claims 1 to 10, the method comprising:
    (1)将氨丁三醇和氢氧化钠以及任选的氯化钠加入注射用水中；(1) adding tromethamine and sodium hydroxide and optionally sodium chloride to water for injection;
    (2)加入右旋布洛芬，搅拌至溶解；(2) adding dextroprofen, stirring until dissolved;
    (3)加入活性炭，加热搅拌；(3) adding activated carbon, heating and stirring;
    (4)过滤，注射用水加至足量，调节pH值；(4) Filtration, adding water for injection to a sufficient amount to adjust the pH value;
    (5)灌封、灭菌。 (5) Potting and sterilization.
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