WO2021031791A1 - 一种右布洛芬脂肪乳注射液及其制备方法 - Google Patents

一种右布洛芬脂肪乳注射液及其制备方法 Download PDF

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WO2021031791A1
WO2021031791A1 PCT/CN2020/103928 CN2020103928W WO2021031791A1 WO 2021031791 A1 WO2021031791 A1 WO 2021031791A1 CN 2020103928 W CN2020103928 W CN 2020103928W WO 2021031791 A1 WO2021031791 A1 WO 2021031791A1
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fat emulsion
emulsion injection
dexibuprofen
chain fatty
injection
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曹青日
钱一忖
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苏州大学
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    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the invention relates to the field of pharmaceutical preparations, in particular to a dexibuprofen fat emulsion injection and a preparation method thereof.
  • Ibuprofen is an antipyretic and analgesic non-steroidal anti-inflammatory drug. It is commonly used for fever caused by colds and also used to relieve various mild and moderate pains. Dexibuprofen is the pure spatial counterpart of ibuprofen, and its activity is 160 times that of L-form and 1.6 times that of racemate. Dexbuprofen not only has good pharmacological activity, but also has low gastrointestinal adverse reactions and liver and kidney toxicity. At present, the dosage forms of dexibuprofen clinically used in China mainly include tablets, suppositories, capsules and suspensions, which have poor solubility and slow efficacy, and there is no injection on the market.
  • Dexprofen is insoluble in water.
  • Chinese invention patent CN102362857 A discloses a dextroibuprofen injection and its preparation method. The method uses meglumine, citric acid, and trisodium citrate as cosolvents to promote Ibuprofen forms a salt in an aqueous solution, thereby solving the solubility problem.
  • the stability of this formulation solution is poor, and the solubility of dextroprofen salt will change with the change of the pH of the solution.
  • Fat emulsion as a carrier can increase the solubility of dextroprofen and other poorly soluble drugs, improve drug stability and bioavailability, reduce drug irritation, and make the drug targetable and has good safety.
  • Chinese invention patent CN104546706 A discloses a dextroibuprofen injection emulsion and its preparation method.
  • the oil-phase adjuvant uses only soybean oil, which often causes injection pain in clinical applications; in addition, the process uses poloxamer as an emulsifier In clinical applications, adverse reactions such as hemolysis, vascular stimulation, and allergic reactions will occur, and there are certain safety issues.
  • the purpose of the present invention is to provide a dextroprofen fat emulsion injection and a preparation method thereof.
  • the present invention uses a highly safe injection solubilizer 15-hydroxystearate polyethylene glycol ester ( Kolliphor HS15), avoid the use of conventional solubilizers polysorbate and poloxamer, effectively improve safety and avoid various adverse reactions.
  • Kolliphor HS15 highly safe injection solubilizer 15-hydroxystearate polyethylene glycol ester
  • the prepared dextroprofen fat emulsion injection also has high drug loading, stable solution and The characteristics of clinical compatibility and safety.
  • One aspect of the present invention provides a method for preparing dexibuprofen fat emulsion injection, which comprises the following steps:
  • the emulsifier is a phospholipid compound
  • the long-chain fatty acid is soybean oil; 50-150 g of long-chain fatty acid is added to each 1000 mL of dextroprofen fat emulsion injection.
  • the medium-chain fatty acid is a medium-chain triglyceride; 50-150 g of medium-chain fatty acid is added to every 1000 mL of dexiprofen fat emulsion injection.
  • the phospholipid compound is egg yolk lecithin; 6-18 g of emulsifier is added to every 1000 mL of dextroprofen fat emulsion injection.
  • the osmotic pressure regulator is glycerin; 25 g of the osmotic pressure regulator is added to every 1000 mL of dextroprofen fat emulsion injection.
  • the pH adjusting agent is sodium hydroxide or hydrochloric acid.
  • step (2) the number of homogenization is 3-8 times.
  • step (2) the homogenization temperature is 20-75°C.
  • step (2) before adjusting the pH, it also includes the step of adding water to the target volume.
  • the preparation method of dexibuprofen fat emulsion injection includes the following steps:
  • step (2) Add the solubilizer Kolliphor HS15 to the mixed solution obtained in step (1), and stir at room temperature to 75 degrees until all is dissolved;
  • step (3) Add dextroprofen to the mixed solution obtained in step (2), stir at room temperature to 75 degrees until all is dissolved, and serve as the oil phase for use;
  • step (6) The emulsion obtained in step (6) is homogenized by a high-pressure homogenizer, the homogenization pressure is 500-900 Bar, the homogenization times are 3-8 times, and water is added to make the volume to a specified volume before the last homogenization.
  • dexibuprofen fat emulsion injection with uniform particle size and stable quality is prepared, wherein the average particle size of milk particles is 160-320nm, and the proportion of milk particles larger than 5 ⁇ m (pFat5) is less than 0.05%;
  • step (7) The emulsion obtained in step (7) is filtered, potted, and sterilized by moist heat at 121 degrees for 15 minutes to obtain a finished product of dexibuprofen fat emulsion injection.
  • the present invention also provides a dexibuprofen fat emulsion injection prepared by the above-mentioned method, which contains the following components per 1000 mL of fat emulsion injection: dexibuprofen 2-100g, long-chain fatty acid 50 ⁇ 150g; medium-chain fatty acid 50 ⁇ 150g; polyethylene glycol-15 hydroxystearate 0.5 ⁇ 200g; phospholipid compound 6-18g; osmotic pressure regulator 25g; the balance is water and pH regulator, the right The pH of ibuprofen fat emulsion injection is 4.0-9.0.
  • every 1000mL fat emulsion injection includes the following components: 20-60g dextroprofen, 50-100g long-chain fatty acids; 50-100g medium-chain fatty acids; polyethylene glycol-15 hydroxystearate 2-50g; phospholipid compound 8-16g; osmotic pressure regulator 25g; the balance is water and pH regulator, the pH of the dexibuprofen fat emulsion injection is 4.0-9.0.
  • the present invention has at least the following features:
  • the present invention provides a dexiprofen fat emulsion injection with stable clinical compatibility.
  • the average particle size of the milk particles is 160-320nm, and the milk particles larger than 5 ⁇ m (pFat5) are less than 0.05%, which meets the requirements of USP41;
  • the present invention provides a dextroibuprofen fat emulsion injection with a drug loading amount of 2-100 mg/mL;
  • the present invention provides a dextroprofen fat emulsion injection.
  • Kolliphor HS15 a new type of high-safety solubilizer for injection, is used, avoiding the use of traditional solubilizers such as polysorbate and poloxamer, thereby effectively improving safety , Thereby reducing the occurrence of related adverse reactions;
  • the present invention provides a dextroibuprofen fat emulsion injection, which uses equal proportions of long-chain fatty acids and medium-chain fatty acids as the drug-carrying oil phase to increase the drug-loading amount of dex-ibuprofen and also effectively reduce the pain of drug injection ;
  • the dexibuprofen fat emulsion injection prepared by the method of the present invention has the characteristics of high drug loading, stable solution and safe clinical compatibility.
  • Figure 1 is the homogeneous pressure-particle size change curve of the dexibuprofen fat emulsion injection prepared in Examples 2-6;
  • Fig. 2 is a curve of homogenization times-particle size change of dextroprofen fat emulsion injection prepared in Examples 7-10;
  • Figure 3 is the different ratio-particle size variation curve of the dextroibuprofen fat emulsion injection Kolliphor HS15 prepared in Examples 9, 11-13;
  • Figure 4 is a homogeneous photograph of emulsions containing Kolliphor HS15 in different proportions prepared in Examples 13-14;
  • Figure 5 is a photo of the finished product of the dexibuprofen fat emulsion injection prepared in Example 9;
  • the homogenization pressure is 500Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 600Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 800Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 900Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 2 times.
  • the homogenization times are 2 times.
  • After the first homogenization add water to make the volume to 200mL.
  • the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization times are 4 times. After the third homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 8 times. After the 7th homogenization, add water to make the volume to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • the homogenization pressure is 700Bar, and the homogenization times are 6 times. After the 5th homogenization, add water to make the volume up to 200mL. After the homogenization, the solution was sterilized by moist heat at 121 degrees for 15 minutes to obtain the dexibuprofen fat emulsion injection.
  • Example 1 Take each dexibuprofen saturated solution prepared in Example 1, weigh an appropriate amount, prepare three test solutions, and determine the content by high performance liquid chromatography. The results are shown in Table 1. The results show that dexibuprofen has a high solubility in soybean oil and medium-chain triglycerides, and has a certain solubility in glycerol, but has a small solubility in water.
  • a proper amount of the dexibuprofen fat emulsion injection prepared under different homogenizing pressures in Examples 2-6 was used to determine the average particle size and the ratio of milk particles larger than 5 ⁇ m (pFat5) with a laser particle size analyzer. The results are shown in Table 2. The results show that the dextroibuprofen fat emulsion injection can achieve a relatively ideal particle size by using 700bar pressure homogenization.
  • Example 2 Homogeneous pressure Average particle size, nm pFat5,% Example 2 (500bar) 291 0.0004 Example 3 (600bar) 222 0.0077 Example 4 (700bar) 204 0.0051 Example 5 (800bar) 204 0.0056 Example 6 (900bar) 206 0.0095
  • Figures 4a and b are the dextroprofen fat emulsion injections prepared in Example 13 and Example 14, respectively. The results show that the dextroprofen fat emulsion injection without Kolliphor HS15 appears abnormal during the homogenization process, and there are a lot of solids. Precipitated ( Figure 4b).

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Abstract

一种右布洛芬脂肪乳注射液的制备方法，包括以下步骤：将右布洛芬溶于长链脂肪酸、中链脂肪酸和15-羟基硬脂酸聚乙二醇酯(KolliphorHS 15)中，加热、搅拌形成均一油相溶液；将乳化剂、渗透压调节剂和水混匀，形成水相溶液；将油水两相混合，在一定温度下搅拌并剪切乳化，后经高压均质、pH调节、过滤、灭菌等，即得到所述的右布洛芬脂肪乳注射液。该脂肪乳注射液采用新型注射用增溶剂KolliphorHS15，有效解决了临床使用中右布洛芬注射液的配伍稳定性及载药量问题，同时有望提高制剂的安全性。

Description

一种右布洛芬脂肪乳注射液及其制备方法 技术领域
本发明涉及药物制剂领域，尤其涉及一种右布洛芬脂肪乳注射液及其制备方法。
背景技术
布洛芬是解热镇痛类非甾体抗炎药，常用于感冒引起的发热，也用于缓解各种轻、中度疼痛。右布洛芬是布洛芬的纯空间对应体，其活性是左旋体的160倍，是消旋体的1.6倍。右布洛芬不仅药理活性好，而且胃肠道不良反应和肝肾毒性小。目前国内临床上应用的右布洛芬剂型，主要有片剂、栓剂、胶囊剂和混悬剂，溶解性差、药效慢，尚未有注射剂上市。2009年6月Cumberland公司研制的布洛芬注射液在美国获得FDA批准上市，该布洛芬注射液使用精氨酸作为增溶剂，临床用药中布洛芬容易析出。为此研制更加安全、有效、稳定的右布洛芬制剂十分必要。
右布洛芬在水中难溶，中国发明专利CN102362857 A公布了一种右旋布洛芬注射液及其制备方法，该方法采用葡甲胺、柠檬酸、柠檬酸三钠作为助溶剂来促进右布洛芬在水溶液中成盐，从而解决溶解度的问题。但此配方溶液稳定性较差，右布洛芬盐溶解度会随着溶液pH的变化而变化，在临床配伍使用中载药量、安全性仍然具有一定问题。
脂肪乳作为载体能增加右布洛芬此类难溶性药物的溶解度，提高药物稳定性和生物利用度，减小药物刺激性，使药物产生靶向性，具有很好的安全性。中国发明专利CN104546706 A公布了一种右旋布洛芬注射乳剂及其制备方法，油相辅料仅采用大豆油，临床应用中往往会引起注射疼痛；此外，该工艺采用泊洛沙姆为乳化剂，临床应用中会有溶血、血管刺激、过敏反应等不良反应发生，存在一定的安全问题。
发明内容
为解决上述技术问题，本发明的目的是提供一种右布洛芬脂肪乳注射液及其制备方法，本发明使用安全性高的注射用增溶剂15-羟基硬脂酸聚乙二醇酯(KolliphorHS15)，避免常规增溶剂聚山梨酯、泊洛沙姆的使用，有效提高安全性，避免各类不良反应，所制备的右布洛芬脂肪乳注射液同时兼备载药量高、溶液稳定及临床配伍安全的特性。
为了实现上述目的，本发明提供了如下的技术方案：
本发明一方面提供了一种右布洛芬脂肪乳注射液制备方法，包括以下步骤：
(1)将右布洛芬溶于所述长链脂肪酸、中链脂肪酸和增溶剂中，形成油相溶液；所述增溶剂为聚乙二醇-15羟基硬脂酸酯；
将所述乳化剂、渗透压调节剂和水混匀，形成水相溶液；所述乳化剂为磷脂类化合物；
(2)将所述油相溶液和水相溶液混匀，在20～75℃℃下搅拌并剪切乳化，在500～900bar压力下均质后加入pH调节剂调节pH至4.0～9.0，过滤、灭菌后得到所述右布洛芬脂肪乳注射液。
进一步地，在步骤(1)中，所述长链脂肪酸为大豆油；每1000mL右布洛芬脂肪乳注射液中加入长链脂肪酸50～150g。
进一步地，在步骤(1)中，所述中链脂肪酸为中链甘油三酸酯；每1000mL右布洛芬脂肪乳注射液中加入中链脂肪酸50～150g。
进一步地，在步骤(1)中，所述磷脂类化合物为蛋黄卵磷脂；每1000mL右布洛芬脂肪乳注射液中加入乳化剂6～18g。
进一步地，在步骤(1)中，所述渗透压调节剂为甘油；每1000mL右布洛芬脂肪乳注射液中加入渗透压调节剂25g。
进一步地，在步骤(2)中，所述pH调节剂为氢氧化钠或盐酸。
进一步地，在步骤(2)中，均质次数为3～8次。
进一步地，在步骤(2)中，均质温度为20～75℃。
进一步地，在步骤(2)中，调节pH前还包括加入水定容至目标体积的步骤。
在本发明一优选实施例中，右布洛芬脂肪乳注射液制备方法包括以下步骤：
(1)称取长链脂肪酸及中链脂肪酸，混合，搅拌备用；
(2)在步骤(1)得到的混合液中加入增溶剂KolliphorHS15，在室温～75度条件下搅拌直至全部溶解；
(3)在步骤(2)得到的混合液中加入右布洛芬，在室温～75度条件下搅拌直至全部溶解，作为油相，备用；
(4)取注射用水，加入乳化剂和渗透压调节剂，在室温～75度条件下碾磨，搅拌直至溶液均一，作为水相，备用；
(5)将步骤(3)和(4)得到的溶液混合，剪切乳化，并在室温～75度条件下搅拌直 至溶液均一，形成初乳液；
(6)使用NaOH或盐酸，调节初乳液pH值至4.0～9.0，搅拌均一，溶液温度维持在室温～75度；
(7)将步骤(6)得到的乳液采用高压均质机均质，均质压力500～900Bar，均质次数3～8次，最后一次均质前加水定容到规定体积。均质结束后制得粒径均一、质量稳定的右布洛芬脂肪乳注射液，其中的乳粒平均粒径在160～320nm，且大于5μm的乳粒占比(pFat5)小于0.05％；
(8)将步骤(7)得到的乳液过滤，灌封，121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液成品。
进一步地，在步骤(1)～(8)制备过程中在氮气保护下进行。
另一方面，本发明还提供了一种采用上述方法制备的右布洛芬脂肪乳注射液每1000mL脂肪乳注射液中包括以下质量的组分：右布洛芬2～100g，长链脂肪酸50～150g；中链脂肪酸50～150g；聚乙二醇-15羟基硬脂酸酯0.5～200g；磷脂类化合物6～18g；渗透压调节剂25g；余量为水和pH调节剂，所述右布洛芬脂肪乳注射液的pH为4.0～9.0。
优选地，每1000mL脂肪乳注射液中包括以下质量的组分：右布洛芬20～60g，长链脂肪酸50～100g；中链脂肪酸50～100g；聚乙二醇-15羟基硬脂酸酯2～50g；磷脂类化合物8～16g；渗透压调节剂25g；余量为水和pH调节剂，所述右布洛芬脂肪乳注射液的pH为4.0～9.0。
借由上述方案，本发明至少具有以下特点：
(1)本发明提供了一种右布洛芬脂肪乳注射液，临床配伍质量稳定，乳粒平均粒径在160～320nm，大于5μm的乳粒(pFat5)小于0.05％，符合USP41要求；
(2)本发明提供了一种右布洛芬脂肪乳注射液，载药量达到2～100mg/mL；
(3)本发明提供了一种右布洛芬脂肪乳注射液，首次使用新型安全性高的注射用增溶剂KolliphorHS15，避免使用传统增溶剂聚山梨醇、泊洛沙姆等，有效提高安全性，从而降低相关不良反应发生；
(4)本发明提供了一种右布洛芬脂肪乳注射液，使用等比例长链脂肪酸和中链脂肪酸为载药油相，增加右布洛芬载药量，同时也有效减轻药物注射疼痛；
(5)本发明的方法所制备的右布洛芬脂肪乳注射液同时兼备载药量高、溶液稳定及临床配伍安全的特性。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1为实施例2～6制备的右布洛芬脂肪乳注射液均质压力-粒径变化曲线；
图2为实施例7～10制备的右布洛芬脂肪乳注射液均质次数-粒径变化曲线；
图3为实施例9、11～13制备的右布洛芬脂肪乳注射液KolliphorHS15不同比例-粒径变化曲线；
图4为实施例13～14制备的含KolliphorHS15不同比例的乳液均质照片；
图5是实施例9制备的右布洛芬脂肪乳注射液的成品照片；
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
本发明以下制备右布洛芬脂肪乳注射液的实施例均在氮气保护条件下进行。
实施例1
分别取大豆油、中链甘油三酸酯、甘油、水适量，加入过量右布洛芬，室温振摇24小时，使形成饱和溶液，离心后取上清油层，测定右布洛芬溶解度。
实施例2
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为500Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例3
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为600Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例4
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例5
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为800Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例6
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为900Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例7
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数2次，第1次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例8
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数4次，第3次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例9
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例10
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 1.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数8次，第7次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例11
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 0.1g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例12
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 0.2g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例13
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入增溶剂KolliphorHS15 2.0g，加热至50度，搅拌直至全部溶解；加入右布洛芬10.0g，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
实施例14
称取大豆油及中链甘油三酸酯各20.0g，混合，搅拌；加入右布洛芬10.0g，加热至50度，搅拌直至全部溶解，作为油相；取注射用水100mL，加入甘油5.0g、精制蛋黄卵磷脂2.4g，加热至50度，碾磨，搅拌直至溶液均一，作为水相；将油相和水相混合，剪切，搅拌直至溶液均一，形成初乳液。采用高压均质机均质，均质压力为700Bar，均质次数6次，第5次均质后加水定容至200mL。均质结束后溶液121度湿热灭菌15分钟，得到右布洛芬脂肪乳注射液。
测试例1右布洛芬溶解度测试
取实施例1制备的各右布洛芬饱和溶液，称取适量，制备三份测试溶液，用高效液相色谱仪测定含量，结果见表1。结果表面，右布洛芬在大豆油及中链甘油三酸酯中溶解度很大，在甘油中也有一定的溶解度，但在水中溶解度很小。
表1 不同溶剂中的溶解度
溶剂 平均溶解度，mg/g
大豆油 237.50
中链甘油三酸酯 397.96
甘油 134.65
水 2.39
测试例2均质压力测试
取实施例2～6不同均质压力下制备的右布洛芬脂肪乳注射液适量，用激光粒度仪测定平均粒径及大于5μm乳粒的比例(pFat5)，结果见表2。结果表明，右布洛芬脂肪乳注射液采用700bar压力均质可以达到比较理想的粒径。
表2 不同均质压力的粒径
均质压力 平均粒径，nm pFat5，％
实施例2(500bar) 291 0.0004
实施例3(600bar) 222 0.0077
实施例4(700bar) 204 0.0051
实施例5(800bar) 204 0.0056
实施例6(900bar) 206 0.0095
测试例3均质次数测试
取实施例7～10不同均质次数下制备的右布洛芬脂肪乳注射液适量，用激光粒度仪测定平均粒径及大于5μm乳粒的比例(pFat5)，结果见表3。结果表明，右布洛芬脂肪乳注射液均质6次可以达到比较理想的粒径。
表3 不同均质次数的粒径
均质次数 平均粒径，nm pFat5，％
实施例7(2次) 477 0.2633
实施例8(4次) 262 0.0029
实施例9(6次) 186 0.0023
实施例10(8次) 307 0.0028
测试例4KolliphorHS15比例测试
分别取实施例9、11～13制备的右布洛芬脂肪乳注射液适量，并用激光粒度仪测定平均粒径及大于5μm乳粒的比例(pFat5)，结果见表4。结果表明，当KolliphorHS15比例在0.1％以下时，右布洛芬脂肪乳注射液平均粒径及pFat5均比较大；当比例达0.5％以上时，pFat5比较小，右布洛芬脂肪乳注射液均一稳定，且可以达到比较理想的粒径。
表4 不同KolliphorHS15比例的粒径
KolliphorHS15比例 平均粒径，nm pFat5，％
实施例11(0.05％) 294 0.0453
实施例12(0.1％) 260 0.0294
实施例9(0.5％) 197 0.0072
实施例13(1.0％) 200 0.0062
测试例5不含KolliphorHS15的测试
取实施例13～14制备的右布洛芬脂肪乳注射液适量，检查溶液外观，结果见图4。图4a、b分别为实施例13和实施例14所制备的右布洛芬脂肪乳注射液，结果表明，不含KolliphorHS15的右布洛芬脂肪乳注射液均质过程中出现异常，有大量固体析出(图4b)。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (10)

  1. 一种右布洛芬脂肪乳注射液制备方法，其特征在于，包括以下步骤：
    (1)将右布洛芬溶于所述长链脂肪酸、中链脂肪酸和增溶剂中，形成油相溶液；所述增溶剂为聚乙二醇-15羟基硬脂酸酯；
    将所述乳化剂、渗透压调节剂和水混匀，形成水相溶液；所述乳化剂为磷脂类化合物；
    (2)将所述油相溶液和水相溶液混匀，在20～75℃下搅拌并剪切乳化，在500～900bar压力下均质后加入pH调节剂调节pH至4.0～9.0，过滤、灭菌后得到所述右布洛芬脂肪乳注射液。
  2. 根据权利要求1所述的制备方法，其特征在于，在步骤(1)中，所述长链脂肪酸为大豆油；每1000mL右布洛芬脂肪乳注射液中加入长链脂肪酸50～150g。
  3. 根据权利要求1所述的制备方法，其特征在于，在步骤(1)中，所述中链脂肪酸为中链甘油三酸酯；每1000mL右布洛芬脂肪乳注射液中加入中链脂肪酸50～150g。
  4. 根据权利要求1所述的制备方法，其特征在于，在步骤(1)中，所述磷脂类化合物为蛋黄卵磷脂；每1000mL右布洛芬脂肪乳注射液中加入乳化剂6～18g。
  5. 根据权利要求1所述的制备方法，其特征在于，在步骤(1)中，所述渗透压调节剂为甘油；每1000mL右布洛芬脂肪乳注射液中加入渗透压调节剂25g。
  6. 根据权利要求1所述的制备方法，其特征在于，在步骤(2)中，所述pH调节剂为氢氧化钠或盐酸。
  7. 根据权利要求1所述的制备方法，其特征在于，在步骤(2)中，均质次数为3～8次。
  8. 根据权利要求1所述的制备方法，其特征在于，在步骤(2)中，均质温度为20～75℃。
  9. 一种权利要求1-8中任一项所述的制备方法所制备的右布洛芬脂肪乳注射液，其特征在于，每1000mL脂肪乳注射液中包括以下质量的组分：右布洛芬2～100g，长链脂肪酸50～150g；中链脂肪酸50～150g；聚乙二醇-15羟基硬脂酸酯0.5～200g；磷脂类化合物6～18g；渗透压调节剂25g；余量为水和pH调节剂，所述右布洛芬脂肪乳注射液的pH为4.0～9.0。
  10. 根据权利要求9所述的右布洛芬脂肪乳注射液，其特征在于，每1000mL脂肪乳注射液中包括以下质量的组分：右布洛芬20～60g，长链脂肪酸50～100g；中链脂肪酸50～100g；聚乙二醇-15羟基硬脂酸酯2～50g；磷脂类化合物8～16g；渗透压调节剂25g；余量为水和pH 调节剂，所述右布洛芬脂肪乳注射液的pH为4.0～9.0。
PCT/CN2020/103928 2019-08-19 2020-07-24 一种右布洛芬脂肪乳注射液及其制备方法 WO2021031791A1 (zh)

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