CN104706590A - Clarithromycin fat emulsion concentrate and preparation method and use thereof - Google Patents

Clarithromycin fat emulsion concentrate and preparation method and use thereof Download PDF

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CN104706590A
CN104706590A CN201310686287.3A CN201310686287A CN104706590A CN 104706590 A CN104706590 A CN 104706590A CN 201310686287 A CN201310686287 A CN 201310686287A CN 104706590 A CN104706590 A CN 104706590A
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clarithromycin
fat emulsion
content
preferably
emulsion concentrate
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CN201310686287.3A
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杨杰
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天津迈迪瑞康生物医药科技有限公司
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Abstract

The invention relates to a clarithromycin fat emulsion concentrate and a preparation method and use thereof, and belongs to the field of medicine and pharmacy. The clarithromycin fat emulsion concentrate overcomes the defects of complex traditional fat milk preparation process and poor product stability. The clarithromycin fat emulsion concentrate is simple in preparation process only needing simple physical mixing without homogenization process. The product can be sterilized through a 0.22 mum millipore filter film, can spontaneously emulsify during clinical use by dilution with normal saline or glucose solution and other water solutions and slight oscillation, and under the optimal conditions, average particle size is about 0.2 mum, and fully shows injection fat milk properties. The clarithromycin fat emulsion concentrate product has good liquidity, and may not be hung on the wall, the appearance is single-phase, transparent and clear, clarity detection is acceptable, and after repeated freezing and thawing, preparation stratification phenomenon does not occur. The clarithromycin fat emulsion concentrate product is used for treatment of upper and lower respiratory tract and wound infections and other diseases caused by sensitive bacteria.

Description

一种克拉霉素脂肪乳浓缩液、其制备方法及用途 Clarithromycin fat emulsion concentrates, their preparation and use

技术领域 FIELD

[0001] 本发明属于药物学和制药学领域,涉及克拉霉素脂肪乳浓缩液、其制备方法及用途。 [0001] The present invention belongs to the field of pharmacology and pharmaceutics, it relates to clarithromycin fat emulsion concentrates, their preparation and use.

背景技术 Background technique

[0002] 克拉霉素(Clarithromycin)是第三代大环内酯类衍生物,1982年由日本大正公司开发成功,1991年10月获FDA批准定为IB类新药上市,1993年在中国香港上市,商品名为克拉仙,由于其优越的抗菌性和安全性,市场用量稳步增长,已成为大环内酯类抗生素的"重磅炸弹"。 [0002] Clarithromycin (Clarithromycin) is a third-generation macrolide derivative, developed in 1982 by the Japanese company Taisho success, in October 1991 approved by the FDA as Class IB drugs on the market in 1993, listed in Hong Kong China trade name klacid, due to its excellent antibacterial and security, the amount of steady growth in the market, has become a macrolide antibiotic "blockbuster." 1996年全球销售额已达11. 50亿美元,2000年的销售额为12. 41亿美元,2003 年销售额为12. 21亿美元。 In 1996 global sales reached $ 1.15 billion in 2000 sales of $ 1.241 billion, 2003 sales of $ 1.221 billion. 专家预测,该药将是未来20年世界畅销的抗菌药物之一。 Experts predict that the drug will be one of the next 20 years the world's best-selling antibiotics. 克拉霉素是非水溶、非油溶物质,为了解决其溶解性问题,法国雅培公司的克拉霉素粉针剂是用乳糖酸与克拉霉素成盐来提高其溶解度,但临床使用时发现注射部位疼痛及静脉炎的发生率较高,大大限制了其在临床上的应用。 Clarithromycin non-aqueous, non-oil-soluble substance, in order to solve the solubility problem, Abbott France clarithromycin powder is clarithromycin lactobionate and a salt to improve its solubility, injection site pain but found clinical use and a higher incidence of phlebitis, which greatly limits its application in clinical practice. 国内外制剂人员均在努力寻找更好的方法制备出局部刺激性更小、溶液稳定性更好的静脉注射制剂,采用的技术有包合技术,脂质体技术等等,但目前均处于实验室阶段,无法实现工业化生产。 Formulations were prepared persons abroad less local irritation, and better solution stability of the intravenous formulation trying to find a better way, there are techniques employed inclusion art, liposome technology, etc., but are currently in experimental room stage, not industrial production.

[0003] 脂肪乳,又称亚微乳或脂质微球,是目前医药领域发展较快的剂型,它主要是以脂肪油为软基质,将药物溶解在脂肪油里,通过磷脂乳化作用将其包裹于磷脂膜包封的乳球中。 [0003] fat milk, also known as the submicron emulsion or lipid microspheres, is the rapid development of the field of pharmaceutical dosage form, it mainly fatty oil soft matrix, dissolving the drug in a fatty oil, through the emulsification of phospholipids wrapped in a phospholipid membrane encapsulated milk balls. 能保护被包被的药物,可提高药物稳定性、延长药物作用时间、降低副作用等,具有一定的缓释性和靶向性,是一种理想的药物载体。 Can protect the coated drug, can increase the stability of the drug, prolonged drug action time, reduce side effects and the like, having a sustained-release and targeting, it is an ideal drug carrier.

[0004] 陆岩研究表明,维生素E作用油相,对克拉霉素有着良好的溶解性,并据此开发出克拉霉素亚微乳注射液(陆岩,(2008)沈阳药科大学,硕士学位论文)。 [0004] Lu Yan study shows that the role of vitamin E oil phase, clarithromycin has a good solubility, and accordingly developed clarithromycin microemulsion for injection (Lu Yan, (2008), Shenyang Pharmaceutical University, master's degree Thesis). 但这一亚微乳的制备过程,属于传统的脂肪乳制备,工艺复杂,需要严格控制,并且产品最终需要采用高压灭菌法。 However, this preparation process submicron emulsion prepared fat emulsion is a traditional, complex process requires strict control, and the final product need autoclaving.

[0005] 本技术领域技术人员所熟知的,脂肪乳在热力学及动力学上均属于不稳定体系, 工业生产中脂肪乳通过两步乳化法制备,涉及初乳制备、高压均质,制备过程对设备、工艺参数、辅料配比等有着严格的要求,温度、乳化时间、均质压力、循环次数和生产设备都对产品质量产生影响。 [0005] skilled in the art in the art, the fat emulsion on the thermodynamics and kinetics of the system belong to instability, industrial production by two-step emulsification fat emulsion, relates to the preparation of colostrum, high pressure homogenization, processes for the preparation of equipment, process parameters, and other accessories have strict requirements ratio, temperature, time of emulsification, homogenization pressure, number of cycles and equipment have an impact on product quality. 这是由于直接将脂肪乳的组成成分(磷脂、油、水等物料混合后,会发生油水分离现象,只有将这些物料,经过专用的均质设备处理,如高压均质机,才能形成稳定均一的乳液,在均质过程中,物料受到高频振动、空穴、剪切,以及冲击等协调作用,最终被打散或细化为液体中的不溶相颗粒Hiroko Shibata, et al. (2009) Int. J. Pharm. 378: 167-176 ;Dirk L. Teagarden, et al. (1996)Adv. Drug. Deliv. Rev. 20 :155-164)〇 This is due directly to the fat emulsion after mixing components (a phospholipid, an oil, water, and other materials, oil-water separation phenomenon occurs only will these materials, after special homogenizing processing apparatus, such as a high pressure homogenizer, to form a stable and homogeneous emulsion, in a homogeneous process, the material subjected to high frequency vibration coordinating role, a hole, cut, and shock, and ultimately broken up or refined to be insoluble in the liquid phase particles Hiroko Shibata, et al. (2009) . int J. Pharm 378: 167-176; Dirk L. Teagarden, et al (1996) Adv Drug Deliv Rev. 20:. 155-164) square....

[0006] -种理想的克拉霉素脂肪乳,是制备工艺简单、无需特殊设备,可以通过微孔滤膜方式除菌,以减低制备成本。 [0006] - idealization of clarithromycin fat emulsion, the preparation process is simple, no special equipment, microporous membrane can be sterilized by the way, to reduce the production cost. 同时,临床应用方便,加入生理盐水等注射溶液,经轻微振荡后能自发乳化,乳化后的制剂,平均粒径在〇. 2 μ m左右,保持典型的脂肪乳特性。 At the same time, applicable to clinical, physiological saline injectable solution was added, with gentle shaking after spontaneous emulsification, the formulation of the emulsion, the average particle size in square. About 2 μ m, retaining the typical fat emulsion characteristics.

发明内容 SUMMARY

[0007] 本发明人经过深入的研究和创造性的劳动,得到了一种克拉霉素脂肪乳浓缩液, 本发明人惊奇地发现,本发明的克拉霉素脂肪乳浓缩液,与水混合后,不经过均质手段,即可形成稳定的乳液,可以有效地克服油-水分离现象。 [0007] The present inventors have intensive studies and creative labor, to obtain clarithromycin fat emulsion a concentrate, the present inventors have surprisingly found that clarithromycin fat emulsion concentrates of the present invention, after mixing with water, without homogenization means, to form a stable emulsion can overcome the oil - water separation. 并且本发明产品能有效地克服不同辅料间的密度差而带来的制剂分层现象,由此获得单相、透明、稳定,遇水后能够自发乳化的克拉霉素脂肪乳浓缩液。 And the product of the present invention can effectively overcome the difference in density between the different excipients and formulation brought stratification, thereby obtaining a single-phase, transparent, stable, clarithromycin fat emulsion concentrate can be emulsified with water after spontaneous. 由此提供了下述发明: 本发明涉及一种克拉霉素脂肪乳浓缩液,其包含: 主药:克拉霉素, 油:中链脂肪酸甘油酯和维生素E, 助溶剂:1,2-丙二醇, 低HLB值表面活性剂(4 < HLB < 9):磷脂,和高HLB值表面活性剂(HLB > 12):聚乙二醇十二羟基硬脂酸酯和/或聚氧乙烯醚(35) 蓖麻油; 可选地,所述低HLB值表面活性剂还包含聚甘油油酸酯; 可选地,所述高HLB值表面活性剂还包含吐温80。 Thus the invention provides the following: The present invention relates to clarithromycin fat emulsion concentrates, comprising: a main agent: clarithromycin, oil: medium chain fatty acid glycerides and vitamin E, co-solvent: 1,2-propanediol lower HLB value surfactant (4 <HLB <9): phospholipids, and a high HLB value surfactant (HLB> 12): twelve polyethylene glycol hydroxy stearate and / or polyoxyethylene ethers (35 ) castor oil; alternatively, the low HLB value of a surfactant further comprises a polyglycerol oleate; alternatively, the high HLB value surfactant further comprises Tween 80.

[0008] 根据本发明任一项所述克拉霉素脂肪乳浓缩液,其特征在于如下的(1) 一(5)项中的任意一项或者多项: (1) 所述克拉霉素的含量为〇. 1 - 5% (w/w),优选为0. 2 - 2. 5% (w/w); (2) 所述油的含量为45 - 85% (w/w),优选为50 - 70% (w/w); (3) 所述助溶剂的含量为5 - 30% (w/w),优选为5 - 15% (w/w); (4) 所述低HLB值表面活性剂的含量为5% - 15% (w/w); (5) 所述高HLB值表面活性剂的含量为5% - 20% (w/w)。 [0008] According to the present invention, any one of clarithromycin fat emulsion concentrate, characterized in that any of the following (1) - (5) of the one or more of: (1) The clarithromycin content of square 1 - 5% (w / w), preferably 0. 2 - 2. 5% (w / w);. (2) content of the oil is 45 - 85% (w / w), preferably It is 50 - 70% (w / w); (3) the content of the co-solvent is 5 - 30% (w / w), preferably 5 - 15% (w / w); (4) a low HLB value of the surfactant content is 5% - 15% (w / w); content (5) of the high HLB value of the surfactant is 5% - 20% (w / w).

[0009] 根据本发明任一项所述的克拉霉素脂肪乳浓缩液,其特征在于如下的(1)一(9)项中的任意一项或者多项: (1) 所述克拉霉素的含量为〇. 2 - 2. 5% (w/w),优选为0. 6 - I. 2% (w/w); (2) 所述中链脂肪酸甘油酯的含量为40% - 60% (w/w),优选为45% - 55% (w/w); (3) 所述维生素E的含量为5% - 30% (w/w),优选为10 - 25% (w/w) (4) 所述1,2-丙二醇的含量为5% - 15% (w/w),优选为8% - 12% (w/w); (5) 所述磷脂的含量为5% - 15% (w/w),优选为7. 5% - 12% (w/w); (6) 所述聚甘油油酸酯的含量为0 - 8% (w/w),优选为0 - 5% (w/w); (7) 所述聚乙二醇十二羟基硬脂酸酯的含量为0 - 15% (w/w),优选为0 - 10% (w/ w); (8) 所述聚氧乙烯醚(35)菌麻油的含量为0 - 15% (w/w),优选为0 - 10% (w/w); (9) 所述吐温80的含量为0 - 15% (w/w),优选为0 - 5% (w/w)。 [0009] According to the present invention, any one of clarithromycin fat emulsion concentrate, characterized in that any of (1) an item (9) below in one or more of: (1) The clarithromycin square in an amount of 2 - 2. 5% (w / w), preferably 0. 6 - I. 2% (w / w);. (2) the content of the medium chain fatty acid glycerides is 40% - 60 % (w / w), preferably 45% - 55% (w / w); (3) the vitamin E content of 5% - 30% (w / w), preferably 10 - 25% (w / w) (4) the 1,2-propanediol in an amount of 5% - 15% (w / w), preferably 8% - 12% (w / w); (5) the content of phospholipid is 5% - 15% (w / w), preferably from 7. 5% - 12% (w / w); (6) the oil content of the polyglycerol ester is 0 - 8% (w / w), preferably 0 - 5% (w / w); the content of (7), polyethylene glycol hydroxy stearate twelve is 0 - 15% (w / w), preferably 0 - 10% (w / w); (8) a polyoxyethylene ether (35) sesame oil bacteria content is 0 - 15% (w / w), preferably 0 - 10% (w / w); (9) for the Tween 80 content 0 - 15% (w / w), preferably 0 - 5% (w / w).

[0010] 根据本发明任一项所述的克拉霉素脂肪乳浓缩液,其特征在于如下的(1)一(7)项中的任意一项或者多项: (1) 所述克拉霉素脂肪乳浓缩液不含水或含水量低于1% ; (2) 所述克拉霉素脂肪乳浓缩液不含糖类; (3) 所述克拉霉素脂肪乳浓缩液不含糊精; (4) 所述克拉霉素脂肪乳浓缩液其制备方法不包含除去或者降低水分的步骤(例如旋转蒸发、喷雾干燥或冷冻干燥); (5) 可选地,所述克拉霉素脂肪乳浓缩液还包含抗氧化剂;具体地,所述抗氧化剂选自油酸和油酸钠的任意一种或两种; (6) 所述克拉霉素脂肪乳浓缩液为透明、单相溶液; (7) 所述克拉霉素脂肪乳浓缩液采用0. 22 μ m微孔滤膜方式除菌。 [0010] According to the present invention, any one of clarithromycin fat emulsion concentrate, characterized in that any of the following (1) - (7) in one or more of: (1) The clarithromycin fat emulsion concentrate free of water or a water content below 1%; (2) the free clarithromycin fat emulsion concentrate sugars; (3) the clarithromycin fat emulsion concentrate unambiguous fine; (4) the concentrate was clarithromycin fat emulsion preparation method does not comprise the step of reducing or removing the moisture (e.g. rotary evaporation, spray drying or freeze drying); (5) Alternatively, the concentrate was further clarithromycin fat emulsion comprising antioxidants; in particular, the antioxidant is selected from any one or both of oleic acid and sodium oleate; (6) the clarithromycin fat emulsion concentrate was a clear, single phase solution; (7) clarithromycin fat emulsion concentrates using 0. 22 μ m microporous membrane sterilization mode.

[0011] 根据本发明任一项所述的克拉霉素脂肪乳浓缩液,其组分和含量如下面1) 一2) 组中的任意一组所示: 1) 克拉霉素0. 6~1. 2克中链脂肪酸甘油酯45~55克维生素E 10-25克1,2-丙二醇8~12克大豆卵磷脂7. 5~12克聚甘油油酸酯(Γ5克聚乙二醇十二羟基硬脂酸酯7~10克吐温80 3~5克油酸(Γ〇. 3克; 2) 克拉霉素0. 6~1. 2克中链脂肪酸甘油酯45~55克维生素E 10-25克1,2-丙二醇8~12克大豆卵磷脂7. 5~12克聚甘油油酸酯(Γ5克聚氧乙烯醚(35)蓖麻油8~10克油酸(Γ0. 3克。 [0011] According to the present invention according to any one of the clarithromycin fat emulsion concentrate, such as its composition and content of below 1) a 2) any group of a group shown: 1) 0.6 ~ clarithromycin 1.2 g medium chain fatty acid glycerides 45 to 55 grams of vitamin E 10-25 g of 1,2-propanediol 8 to 12 grams of soy lecithin, 7.5 to 12 g of polyglycerol oleate (Γ5 ten grams of polyethylene glycol dihydroxy-stearate 7 to 10 grams of Tween 80 three to five grams of oleic acid (3 g Γ〇;. 2). clarithromycin 0.6 to 1 g of 2-chain fatty acid glycerides 45 to 55 g vitamin E 10-25 g of 1,2-propanediol 8 to 12 grams soy lecithin 7.5 to 12 g of polyglycerol oleate (Γ5 g of polyoxyethylene (35) castor oil, 8 to 10 grams of oleic acid (Γ0. 3 g .

[0012] 根据本发明任一项所述的克拉霉素脂肪乳浓缩液,其组分和含量如下面的(1) 一(4)组中的任意一组所示: (1) 克拉霉素〇. 6克中链脂肪酸甘油酯54克维生素E 12. 5克1,2-丙二醇8. 4克大豆卵磷脂7. 5克聚甘油油酸酯4. 2克聚乙二醇十二羟基硬脂酸酯8. 3克吐温80 4. 2克油酸0.3克; (2) 克拉霉素0. 8克中链脂肪酸甘油酯51. 4克维生素E 16克1,2-丙二醇9克大豆卵磷脂12克聚乙二醇十二羟基硬脂酸酯7. 3克吐温80 3. 5克; (3) 克拉霉素1. 2克中链脂肪酸甘油酯44克维生素E 24克1,2-丙二醇10克大豆卵磷脂7. 6克聚甘油油酸酯3. 5克聚氧乙烯醚(35)蓖麻油9. 5克油酸0.2克; (4) 克拉霉素〇. 8克中链脂肪酸甘油酯50克维生素E 17克1,2-丙二醇10. 2克大豆卵磷脂12克聚氧乙烯醚(35)蓖麻油9. 9克油酸0. 1克。 [0012] According to the present invention, any one of clarithromycin fat emulsion concentrate, such as its composition and content of the following (1) - (4) shown in any of the group group consisting of: (1) clarithromycin square. 6 g medium chain fatty acid glycerides of vitamin E 12. 5 54 g g of 1,2-propylene glycol 8.4 g soy lecithin 7.5 g polyglycerol oleate 4.2 g of polyethylene glycol twelve hydroxystearic aliphatic ester 8.3 g Tween 80 4.2 g 0.3 g oleic acid; (2) 0.8 g of clarithromycin-chain fatty acid glycerides 51.4 g vitamin E 16 g of 1,2-propanediol 9 g of soy lecithin 12 g of polyethylene glycol hydroxystearate twelve 7.3 g Tween 80 3.5 g; (3) 1.2 g of clarithromycin medium chain fatty acid glyceride 44 g vitamin E 24 g of a 1, propanediol 10 g soybean lecithin 7.6 g polyglycerol oleate 3.5 g polyoxyethylene (35) castor oil 9.5 g oleic acid 0.2 g;. (4) 8 grams of clarithromycin square chain fatty acid glyceride 50 g vitamin E 17 g of 1,2-propanediol 10.2 g soy lecithin 12 g polyoxyethylene (35) castor oil 9.9 g oleic acid 0.1 g.

[0013] 需要说明的是,上述的1) 一2)组或者(1) 一(4)组中的单位克表示各组分之间的比例,如果修改为其它的重量单位,包括但不限于,例如千克和毫克等,也均在本发明的保护范围之内。 [0013] Incidentally, the above-mentioned 1) a 2) or a group of (1) a (4) units of the group represented by the ratio g between the components, if the basis weight into other modifications, including but not limited to , e.g. kg mg and the like, are also within the scope of the present invention.

[0014] 本发明的再一方面涉及一种注射用克拉霉素脂肪乳,其由本发明中任一项所述的克拉霉素脂肪乳浓缩液加水或水溶液自乳化制得;具体地,所述注射用克拉霉素脂肪乳平均粒径为〇· 05 - 0· 7 μ m ;优选为0· 1 - 0· 4 μ m ;更优选地,为0· 17 - 0· 22 μ m。 [0014] In another aspect of the invention relates to an injection clarithromycin fat emulsion, which clarithromycin fat emulsion a concentrate according to any one of the present invention with water or an aqueous solution prepared by self-emulsifying; in particular, the injection clarithromycin fat emulsion average particle size of square · 05 - 0 · 7 μ m; preferably 0 · 1 - 0 · 4 μ m; more preferably, 0 · 17 - 0 · 22 μ m.

[0015] 本发明的克拉霉素脂肪乳浓缩液遇水稀释后,可自发乳化为符合注射要求的克拉霉素脂肪乳。 Clarithromycin fat emulsion concentrate [0015] of the present invention after dilution with water, spontaneous emulsification may be to comply with the requirements for injections clarithromycin fat emulsion.

[0016] 本发明的再一方面涉及本发明中任一项所述的克拉霉素脂肪乳浓缩液的制备方法,包括下述步骤: 1) 在20 - 45°C,将低HLB值表面活性剂加入中链脂肪酸甘油酯,在2000 - 20000rpm 条件下,搅拌至形成透明清亮溶液; 2) 在20 - 45°C条件下,将克拉霉素加入维生素E产物,并在200 - 2000rpm搅拌条件下持续搅拌,直至整个体系呈透明清亮状; 3) 在20 - 45°C条件下,将步骤2)产物、助溶剂、高HLB值表面活性剂以及可选的抗氧化剂加入步骤1)产物,并在200 - 800rpm搅拌条件下持续搅拌,直至形成单相、透明清亮的均匀制剂,经〇. 22 μ m微孔滤膜除菌后,最终获得克拉霉素脂肪乳浓缩液。 [0016] another aspect of the invention relates to a method of preparing clarithromycin fat emulsion of the present invention, the concentrate according to any preceding claim, comprising the following steps: 1) at 20 - 45 ° C, the low HLB value of a surfactant is added medium chain fatty acid glycerides, 2000 - the following conditions 20000rpm, stirred until a clear transparent solution; 2) 20 - the following conditions of 45 ° C, the clarithromycin product was added to vitamin E, and 200-- stirring under 2000rpm stirring was continued until the entire system like a clear clear; 3) 20-- 45 ° C under the conditions of step 2) the product, a co-solvent, a high HLB value surfactant, and optionally an antioxidant is added in step 1) of the product, and stirring was continued with stirring at 800rpm, until a single phase is formed, a transparent clear homogeneous formulation square after sterilization 22 μ m microporous membrane, ultimately clarithromycin fat emulsion concentrate - 200.

[0017] 关于步骤1)或步骤2)或步骤3)中所使用的油、低HLB值表面活性剂、高HLB值表面活性剂和助溶剂,其中水分含量要低于1%,或者没有游离水的存在。 [0017] For step 1) or step 2) or step 3 oil) used, the low HLB value of a surfactant, a high HLB value surfactant and co-solvent, wherein the moisture content to less than 1%, or no free the presence of water.

[0018] 步骤3)中的产品,在不经过除去或者降低水分的步骤(例如旋转蒸发、喷雾干燥或冷冻干燥),含水量低于1% (按重量百分比计)。 In [0018] Step 3) the product, without passing through the step of removing or reducing moisture (e.g. rotary evaporation, spray drying or freeze drying), water content below 1% (in weight percent).

[0019] 本发明的再一方面涉及本发明中任一项所述的克拉霉素脂肪乳浓缩液或者本发明的注射用克拉霉素脂肪乳在由敏感细菌所致的上、下呼吸道,包括扁桃体炎、咽喉炎、副窦炎、支气管炎、肺炎等、皮肤、软组织感染、脓疖、丹毒、毛囊炎、伤口感染等疾病的治疗。 [0019] In another aspect of the invention relates to concentrated liquid or clarithromycin fat emulsion of the present invention, the present invention according to any one of injectable fat emulsion on clarithromycin caused by sensitive bacteria, lower respiratory tract, including treat tonsillitis, pharyngitis, sinusitis deputy, bronchitis, pneumonia and other diseases of the skin and soft tissue infections, pus boils, erysipelas, folliculitis, wound infections.

[0020] 本发明涉及的部分术语的解释: 脂肪乳,又称脂质微球是指,乳液或脂肪乳浓缩液乳化后,形成的一种以脂肪油为软基质并被磷脂膜包封,平均粒径为〇. 2 μ m左右的微粒分散体系。 [0020] The term part of the explanation of the present invention: fat emulsion, also known as the lipid microsphere refers to a fat emulsion after the emulsion or emulsifiable concentrates, formed in the fat and oil is a soft matrix encapsulating phospholipid membrane, the average particle size of square. about 2 μ m particle dispersion.

[0021] 本发明中,对于各个组分的含量的百分比,如果没有特别说明,均指占药物组合物总重量的重量百分比(w/w)。 [0021] In the present invention, the percentage content of each component, unless otherwise specified, are by total weight of the pharmaceutical composition by weight percentage (w / w).

[0022] 发明的有益效果本发明产品流动性好,不挂壁,外观呈单相、透明、清亮状,能够接受澄明度检测,反复冻融后不会发生制剂分层现象;本发明的产品遇水形成克拉霉素脂肪乳体系过程中,无需均质处理,仅需要轻微振荡即能自发乳化,临床使用时经生理盐水或葡萄糖溶液等水溶液稀释并轻微振荡后,能够自发乳化为符合注射要求的脂肪乳体系,在优选条件下,乳化后平均粒径在0. 2 μ m左右,粒径分布狭小充分体现注射脂肪乳特性。 Advantageous Effects [0022] The product of the present invention is the invention of good fluidity, not linked to the wall, the appearance of a single-phase, transparent, clear shape capable of receiving the detection clarity, formulation delamination does not occur after repeated freezing and thawing; product of the invention water formed during clarithromycin fat emulsion system without homogenization, i.e. oscillations need only slight spontaneous emulsification, and after gentle shaking dilute aqueous saline or glucose solution clinical use over time, it is possible to comply with the requirements for injections spontaneous emulsification fat emulsion system, under the preferred conditions, the average particle size after emulsification is about 0. 2 μ m, a narrow particle size distribution characteristics fully reflect the fat emulsion injection.

[0023] 本发明制备工艺简单,仅需要普通物理搅拌过程,不需要均质工艺,不需要除水工艺,本发明制备的克拉霉素脂肪乳浓缩液,可以通过0. 22μπι微孔滤膜除菌。 [0023] The preparation process is simple and requires only ordinary physical mixing process does not require homogenization process, the process does not require addition of water, clarithromycin fat emulsion concentrate was prepared in the present invention, other microporous membrane by 0. 22μπι bacteria. 本发明具有制备工艺简单、生产成本低廉,易于运输、储存的优势,极具应用前景。 The present invention has a simple preparation process, low production cost, easy to transport, storage advantages, very promising.

[0024] [0024]

具体实施方式下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。 DETAILED DESCRIPTION The following embodiments in conjunction with embodiments of the present invention will be described in detail, those skilled in the art will appreciate that the following examples merely illustrate the invention and should not be construed as limiting the scope of the present invention. 实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。 Examples are the specific conditions are not specified embodiment, in accordance with conventional conditions or conditions recommended by the manufacturer. 所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。 The reagents or equipment not specified by the manufacturer, are the conventional products available through the city.

[0025] 实施例1 :克拉霉素脂肪乳浓缩液样品1的制备其组成成分如下: 克拉霉素〇. 6克中链脂肪酸甘油酯54克维生素E 12. 5克1,2-丙二醇8. 4克大豆卵磷脂7. 5克聚甘油油酸酯4. 2克聚乙二醇十二羟基硬脂酸酯8. 3克吐温80 4. 2克油酸0.3克该克拉霉素脂肪乳浓缩液制备方法如下: 1) 在20°C,将上述重量的大豆卵磷脂、聚甘油油酸酯加入中链脂肪酸甘油酯中,在20000rpm条件下,搅拌至形成透明清亮溶液; 2) 在20°C条件下,将上述重量的克拉霉素加入维生素E中,并在200rpm搅拌条件下持续搅拌,直至整个体系呈透明清亮状; 3) 在20°C条件下,将步骤2)产物及上述重量的1,2-丙二醇、吐温80、聚乙二醇十二羟基硬脂酸酯、油酸加入步骤1)产物,并在200rpm搅拌条件下持续搅拌,直至形成单相、透明清亮的均匀制剂,经〇. 22 μ m微孔滤膜除菌后,最终获得克拉霉素脂肪乳浓 [0025] Example 1: Preparation of clarithromycin fat emulsion a concentrate sample of the composition which is as follows: 6 g of clarithromycin billion medium chain fatty acid glyceride 54 g Vitamin E 12. 5 8 g of 1,2-propanediol. 4 g soy lecithin 7.5 g polyglycerol oleate twelve 4.2 g of polyethylene glycol hydroxy stearate 8.3 g Tween 80 4.2 g oleic acid 0.3 g the clarithromycin fat emulsion concentrate was prepared as follows: 1) 20 ° C, by weight of the above-described soybean lecithin, polyglycerol oleate added to medium-chain fatty acid glycerides, under conditions 20000rpm, stirred until a clear transparent solution; 2) at 20 ° C under conditions described above clarithromycin weight of vitamin E was added and stirring was continued with stirring at 200rpm, until the entire system like a clear clear; 3) at 20 ° C conditions, step 2) and said product by weight of 1,2-propylene glycol, Tween 80, polyethylene glycol twelve hydroxy stearate, oleic acid was added in step 1) of the product, and stirring was continued at 200rpm stirring, until a single phase is formed, a uniform transparent clear preparations, square. 22 μ m microporous membrane after sterilization, concentration of the finally obtained fat emulsion clarithromycin 液。 Liquid.

[0026] 实施例2 :克拉霉素脂肪乳浓缩液样品2的制备其组成成分如下: 克拉霉素〇. 8克中链脂肪酸甘油酯51. 4克维生素E 16克1,2-丙二醇9克大豆卵磷脂12克聚乙二醇十二羟基硬脂酸酯7. 3克吐温80 3. 5克该克拉霉素脂肪乳浓缩液制备方法如下: 1) 在45°C,将上述重量的大豆卵磷脂加入中链脂肪酸甘油酯,在2000rpm条件下,搅拌至形成透明清亮溶液; 2) 在35°C条件下,将上述重量的克拉霉素加入维生素E中,并在1000 rpm搅拌条件下持续搅拌,直至整个体系呈透明清亮状; 3) 在30°C条件下,将步骤2)产物,及上述重量的1,2-丙二醇、吐温80、聚乙二醇十二羟基硬脂酸酯,及油酸加入步骤1)产物,并在SOOrpm搅拌条件下持续搅拌,直至形成单相、 透明清亮的均匀制剂,经〇. 22 μ m微孔滤膜除菌后,最终获得克拉霉素脂肪乳浓缩液。 [0026] Example 2: Preparation of clarithromycin fat emulsion Sample 2 which concentrate composition as follows: 8 g of clarithromycin billion medium chain fatty acid glycerides 51.4 g Vitamin E 16 g of 1,2-propanediol 9 g soybean lecithin 12 g of polyethylene glycol hydroxystearate twelve 7.3 g Tween 80 3.5 g the clarithromycin fat emulsion concentrate was prepared as follows: 1) 45 ° C, by weight of the above soy lecithin clear clear solution was added medium chain fatty acid glycerides, under conditions 2000rpm stirred until formation; 2) conditions at 35 ° C, the above-mentioned weight of vitamin E added to clarithromycin and stirred at 1000 rpm under conditions stirring was continued until the entire system like a clear clear; 3) at 30 ° C conditions, step 2) the product, 1,2-propanediol and said weight, Tween 80, polyethylene glycol twelve-hydroxystearic acid ester, oleic acid was added in step 1) of the product, and stirring was continued at SOOrpm stirring, until a single phase is formed, a transparent clear homogeneous preparations, square. 22 μ m microporous membrane after sterilization, finally obtained clarithromycin fat emulsion concentrate.

[0027] 实施例3 :克拉霉素脂肪乳浓缩液样品3的制备其组成成分如下: 克拉霉素1. 2克中链脂肪酸甘油酯44克维生素E 24克1,2-丙二醇10克大豆卵磷脂7. 6克聚甘油油酸酯3. 5克聚氧乙烯醚(35)蓖麻油9. 5克油酸0.2克该克拉霉素脂肪乳浓缩液制备方法如下: 1) 在30°C,将上述重量的大豆卵磷脂、聚甘油油酸酯加入中链脂肪酸甘油酯,在1000 Orpm条件下,搅拌至形成透明清亮溶液; 2) 在45°C条件下,将上述重量的克拉霉素加入维生素E中,并在2000rpm搅拌条件下持续搅拌,直至整个体系呈透明清亮状; 3)在45°C条件下,将步骤2)产物,及上述重量的1,2-丙二醇、聚氧乙烯醚(35)蓖麻油、油酸,及维生素E加入步骤1)产物,并在500rpm搅拌条件下持续搅拌,直至形成单相、 透明清亮的均匀制剂,经〇. 22 μ m微孔滤膜除菌后,最终获得克拉霉素脂肪乳浓缩液。 [0027] Example 3: Preparation of clarithromycin in its composition a sample fat emulsion concentrates 3 as follows: 1.2 g of clarithromycin medium chain fatty acid glyceride 44 g Vitamin E 24 g of 1,2-propanediol 10 g soy lecithin phospholipids 7.6 g polyglycerol oleate 3.5 g polyoxyethylene (35) castor oil 9.5 g oleic acid 0.2 g the clarithromycin fat emulsion preparation of rapamycin concentrate was as follows: 1) at 30 ° C, by weight of the above-described soybean lecithin, polyglycerol oleate was added medium chain fatty acid glycerides, 1000 Orpm under conditions of agitation to form a clear transparent solution; 2) at 45 ° C conditions, the above addition of the weight of clarithromycin vitamin E, and stirring was continued at 2000rpm stirring, until the entire system like a clear clear; 3) at 45 ° C conditions, the 1,2-propanediol in step 2) the product, and said weight of polyoxyethylene ethers (35) castor oil, oleic acid, and vitamin E is added in step 1) of the product, and stirring was continued with stirring at 500rpm, until a single phase is formed, a transparent clear homogeneous preparations, square. 22 μ m microporous membrane sterilization after finally obtained clarithromycin fat emulsion concentrate.

[0028] 实施例4 :克拉霉素脂肪乳浓缩液样品4的制备其组成成分如下: 克拉霉素〇. 8克中链脂肪酸甘油酯50克维生素E 17克1,2-丙二醇10. 2克大豆卵磷脂12克聚氧乙烯醚(35)蓖麻油9. 9克油酸〇. 1克该克拉霉素脂肪乳浓缩液制备方法如下: 1) 在25°C,将上述重量的大豆卵磷脂加入中链脂肪酸甘油酯,在SOOOrpm条件下,搅拌至形成透明清亮溶液; 2) 在25°C条件下,将上述重量的克拉霉素加入维生素E中,并在1000 rpm搅拌条件下持续搅拌,直至整个体系呈透明清亮状; 3) 在25°C条件下,将步骤2)产物,及上述重量的1,2-丙二醇、聚氧乙烯醚(35)蓖麻油加入步骤1)产物,并在500rpm搅拌条件下持续搅拌,直至形成单相、透明清亮的均匀制剂,经0. 22 μ m微孔滤膜除菌后,最终获得克拉霉素脂肪乳浓缩液。 [0028] Example 4: Preparation of clarithromycin fat emulsion Sample 4 which concentrate composition as follows: 8 g of clarithromycin billion medium chain fatty acid glyceride 50 g Vitamin E 17 g of 1,2-propanediol 10.2 g soybean lecithin 12 g polyoxyethylene (35) castor oil, 9.9 g of oleic acid 1 gram of this square clarithromycin fat emulsion preparation of rapamycin concentrate was as follows: 1) at 25 ° C, by weight of the above-described soybean lecithin added to medium-chain fatty acid glycerides, under conditions SOOOrpm, stirred until a clear transparent solution; 2) at 25 ° C, the above-mentioned weight of clarithromycin in vitamin E was added and stirring continued at 1000 rpm stirring, until the entire system like a clear clear; 3) at 25 ° C, and the step 2) of the product, and said weight of 1,2-propanediol, polyoxyethylene (35) castor oil was added in step 1) of the product, and 500rpm stirring was continued under stirring, until a single phase is formed, a uniform transparent clear formulation after 0. 22 μ m microporous membrane sterilization, the finally obtained clarithromycin fat emulsion concentrate.

[0029] 实施例5 :光密度测定试骑用日立U-2001紫外可见分光光度计,在室温条件下,600nm处测定光密度。 [0029] Example 5: Determination of the optical density using a Hitachi test ride visible spectrophotometer U-2001, measured optical density at 600nm at room temperature. 其中克拉霉素脂肪乳浓缩液为按照实施例1 一4制备步骤所得的样品1 一4,结果如表1所示。 Wherein clarithromycin fat emulsion a concentrate according to Example 1 as a sample preparation obtained in step 4 1 a 4, the results shown in Table 1.

[0030] 表1 :不同样品溶液的光密度倌 [0030] Table 1: Different optical density of the sample solution groom

Figure CN104706590AD00101

光密度表示光的透过性,数值越低,表明样品越澄清均一,由结果可知,本发明产品外观均一、清亮、透明。 The optical density represents the light permeability, the lower the value, the more clear and homogeneous samples show, seen from the results, the product according to the present invention appeared uniform, clear, transparent.

[0031] 实施例6 :稳定件试骑实施例1 一4制备的样品1 一4。 [0031] Example 6: stability test ride member 4 a sample of Example 1 prepared in Example 1 a 4.

[0032] 实验方法:将不同样品在_20°C冷冻过夜后,放置于20°C自然解冻,如此反复冻融6次,环境条件下观察样品外观,试验结果见表2。 [0032] Experimental method: The different samples after _20 ° C freezer overnight and allowed to stand at 20 ° C natural thawing, freezing and thawing is repeated six times so, the appearance of the sample, the test results are shown in Table 2 were observed under ambient conditions.

[0033] 表2 :不同样品经冻融后,样品外观变化 [0033] Table 2: Different samples after freeze-thaw, changes in appearance of the sample

Figure CN104706590AD00102

由表2可见,样品1 一4均具有极好的稳定性,经过反复冻融,外观仍能保持透明均一相,不挂壁、不分层,具有良好的流动性。 Seen from Table 2, Sample 4 has a 1 excellent stability, after repeated freezing and thawing, it can maintain the appearance of a transparent homogeneous phase, not linked to the wall, not hierarchical, having good flowability.

[0034] 实施例7 :粒径测定本发明实施例1 一4制备的样品1 一4,采用Mastersizer 2000粒度分析仪检测粒径, 样品加入10倍体积的生理盐水,经轻微振荡自发乳化后测定。 Particle size measurement sample prepared in Example 1 a 1 a 4 Embodiment 4 of the present invention using a particle size analyzer Mastersizer 2000 particle size, sample is added to 10 volumes of physiological saline, gently shaken measured after spontaneous emulsification: 7 [0034] Example .

[0035] 表3 :不同样品乳化后粒径分布注:d (0. 1)表示样品的累计粒度分布数为 [0035] Table 3: The emulsion particle size distribution of the different samples Note: d (0. 1) represents a cumulative particle size distribution of the sample was

Figure CN104706590AD00111

10%对应的粒径,d (0. 5)、d (0.9)、d (1) 依此类推。 For a 10% particle diameter, d (0. 5), d (0.9), d (1) and so on.

[0036] 其粒径分布如表3所示,四个实施例的粒径分布在0. 1-0. 8μπι之间,平均粒径0. 2 μ m,充分体现脂肪乳特征,四个实施例产品的d (0. 9)均小于0. 6 μ m,满足注射脂肪乳粒径要求。 [0036] The particle size distribution shown in Table 3, four embodiments of a particle size distribution of between 0. 1-0. 8μπι, an average particle diameter of 0. 2 μ m, fully reflect the fat emulsion features, four embodiments d (0. 9) Example products are less than 0. 6 μ m, to meet the requirements of injectable fat emulsion particle.

[0037] 尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。 [0037] While specific embodiments of the present invention have been described in detail, those skilled in the art will appreciate. 根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。 According to the teachings disclosed herein, various modifications and alternatives to those details are within the scope of the invention these changes. 本发明的全部范围由所附权利要求及其任何等同物给出。 The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims (8)

1. 一种克拉霉素脂肪乳浓缩液,其包含: 主药:克拉霉素, 油:中链脂肪酸甘油酯和维生素E, 助溶剂:1,2-丙二醇, 低HLB值表面活性剂(4 < HLB < 9):磷脂,和高HLB值表面活性剂(HLB > 12):聚乙二醇十二羟基硬脂酸酯和/或聚氧乙烯醚(35) 蓖麻油; 可选地,所述低HLB值表面活性剂还包含聚甘油油酸酯; 可选地,所述高HLB值表面活性剂还包含吐温80。 An clarithromycin fat emulsion concentrates, comprising: a main agent: clarithromycin, oil: medium chain fatty acid glycerides and vitamin E, co-solvent: 1,2-propylene glycol, low HLB value surfactant (4 <HLB <9): phospholipids, and a high HLB value surfactant (HLB> 12): twelve polyethylene glycol hydroxy stearate and / or polyoxyethylene (35) castor oil; alternatively, the It said low HLB value of a surfactant further comprises a polyglycerol oleate; alternatively, the high HLB value surfactant further comprises Tween 80.
2. 根据权利要求1所述的克拉霉素脂肪乳浓缩液,其特征在于如下的(1) 一(5)项中的任意一项或者多项: (1) 所述克拉霉素的含量为〇. 1 - 5% (w/w),优选为0. 2 - 2. 5% (w/w); (2) 所述油的含量为45 - 85% (w/w),优选为50 - 70% (w/w); (3) 所述助溶剂的含量为5 - 30% (w/w),优选为5 - 15% (w/w); (4) 所述低HLB值表面活性剂的含量为5% - 15% (w/w); (5) 所述高HLB值表面活性剂的含量为5% - 20% (w/w)。 The clarithromycin fat emulsion concentrate according to claim 1, wherein any one of the following (1) - (5) or more items: (1) the content of clarithromycin square 1 - 5% (w / w), preferably 0. 2 - 2. 5% (w / w);. (2) content of the oil is 45 - 85% (w / w), preferably 50 - 70% (w / w); (3) the content of the co-solvent is 5 - 30% (w / w), preferably 5 - 15% (w / w); (4) a low HLB value of a surfactant content of the active agent is 5% - 15% (w / w); content (5) of the high HLB value of the surfactant is 5% - 20% (w / w).
3. 根据权利要求1、2所述的克拉霉素脂肪乳浓缩液,其特征在于如下的(1) 一(9)项中的任意一项或者多项: (1) 所述克拉霉素的含量为〇. 2 - 2. 5% (w/w),优选为0. 6 - I. 2% (w/w); (2) 所述中链脂肪酸甘油酯的含量为40% - 60% (w/w),优选为45% - 55% (w/w); (3) 所述维生素E的含量为5% - 30% (w/w),优选为10 - 25% (w/w) (4) 所述1,2-丙二醇的含量为5% - 15% (w/w),优选为8% - 12% (w/w); (5) 所述磷脂的含量为5% - 15% (w/w),优选为7. 5% - 12% (w/w); (6) 所述聚甘油油酸酯的含量为0 - 8% (w/w),优选为0 - 5% (w/w); (7) 所述聚乙二醇十二羟基硬脂酸酯的含量为0 - 15% (w/w),优选为0 - 10% (w/ w); (8) 所述聚氧乙烯醚(35)菌麻油的含量为0 - 15% (w/w),优选为0 - 10% (w/w); (9) 所述吐温80的含量为0 - 15% (w/w),优选为0 - 5% (w/w)。 The clarithromycin fat emulsion concentrate according to claim 1, characterized in that any (1) a (9) of the following one or more of: (1) The clarithromycin content of square 2 - 2. 5% (w / w), preferably 0. 6 - I. 2% (w / w);. (2) the content of the medium chain fatty acid ester is 40% - 60% (w / w), preferably 45% - 55% (w / w); (3) the vitamin E content of 5% - 30% (w / w), preferably 10 - 25% (w / w ) (4) the 1,2-propanediol in an amount of 5% - 15% (w / w), preferably 8% - 12% (w / w); (5) the content of phospholipid is 5% - 15% (w / w), preferably from 7. 5% - 12% (w / w); the content of said polyglycerol oleate (6) 0 - 8% (w / w), preferably 0 - 5% (w / w); the content of the polyethylene glycol hydroxy stearate twelve (7) is 0 - 15% (w / w), preferably 0 - 10% (w / w); ( 8) polyoxyethylene ethers (35) sesame oil bacteria content is 0 - 15% (w / w), preferably 0 - 10% (w / w); (9) the Tween 80 content is 0 - 15% (w / w), preferably 0 - 5% (w / w).
4. 根据权利要求1至3所述的克拉霉素脂肪乳浓缩液,其特征在于如下的(1) 一(7) 项中的任意一项或者多项: (1) 所述克拉霉素脂肪乳浓缩液不含水或含水量低于1% ; (2) 所述克拉霉素脂肪乳浓缩液不含糖类; (3) 所述克拉霉素脂肪乳浓缩液不含糊精; (4) 所述克拉霉素脂肪乳浓缩液其制备方法不包含除去或者降低水分的步骤(例如旋转蒸发、喷雾干燥或冷冻干燥); (5) 可选地,所述克拉霉素脂肪乳浓缩液还包含抗氧化剂;具体地,所述抗氧化剂选自油酸和油酸钠的任意一种或两种; (6) 所述克拉霉素脂肪乳浓缩液为透明、单相溶液; (7) 所述克拉霉素脂肪乳浓缩液采用0. 22 μ m微孔滤膜方式除菌。 The clarithromycin fat emulsion concentrate according to claim 13, wherein any one of the following (1) - (7) or more items: (1) The clarithromycin fat non-aqueous liquid milk concentrate or a water content below 1%; (2) the free clarithromycin fat emulsion concentrate sugars; (3) the clarithromycin fat emulsion concentrate unambiguous fine; (4) said concentrate clarithromycin fat emulsion preparation method does not comprise the step of reducing or removing the moisture (e.g. rotary evaporation, spray drying or freeze drying); (5) Alternatively, the concentrate was further clarithromycin fat emulsion comprising an anti- oxidants; in particular, the antioxidant is selected from any one or both of oleic acid and sodium oleate; (6) the clarithromycin fat emulsion concentrate was a clear, single phase solution; (7) the carat ADM fat emulsion concentrates using 0. 22 μ m microporous membrane sterilization mode.
5. -种克拉霉素脂肪乳浓缩液,其组分和含量如下面1) 一2)组中的任意一组所示: 1) 克拉霉素0. 6~1. 2克中链脂肪酸甘油酯45~55克维生素E 10-25克1,2-丙二醇8~12克大豆卵磷脂7. 5~12克聚甘油油酸酯(Γ5克聚乙二醇十二羟基硬脂酸酯7~10克吐温80 3~5克油酸(Γ〇. 3克; 2) 克拉霉素0. 6~1. 2克中链脂肪酸甘油酯45~55克维生素E 10-25克1,2-丙二醇8~12克大豆卵磷脂7. 5~12克聚甘油油酸酯(Γ5克聚氧乙烯醚(35)蓖麻油8~10克油酸(Γ0. 3克。 5. - Species clarithromycin fat emulsion concentrate, such as its composition and content of below 1) a 2) any group of a group shown: 1) clarithromycin 0.6 to 1 g of 2-chain fatty acid monoglycerides 45 to 55 g of an ester of vitamin E 10-25 g of 1,2-propanediol 8 to 12 grams of soy lecithin, 7.5 to 12 g of polyglycerol oleate (Γ5 g of polyethylene glycol having 7 to twelve hydroxy stearate 10 g 3-5 Tween 80 grams of oleic acid (3 g Γ〇;. 2). clarithromycin 0.6 ~ 12 g of medium-chain fatty acid glycerides 45 to 55 g of 1,2 g of vitamin E 10-25 propylene glycol 8 to 12 grams of soy lecithin, 7.5 to 12 g of polyglycerol oleate (Γ5 g of polyoxyethylene (35) castor oil, 8 to 10 grams of oleic acid (Γ0. 3 grams.
6. -种注射用克拉霉素脂肪乳,其由权利要求1至5中所述的克拉霉素脂肪乳浓缩液加水或水溶液自乳化制得;具体地,所述注射用克拉霉素脂肪乳平均粒径为〇. 05 - 〇· 7 μ m ;优选为0· 1 - 0· 4 μ m ;更优选地,为0· 17 - 0· 22 μ m。 6 - Injection in clarithromycin fat emulsion consisting of the claim 15 to claim clarithromycin fat emulsion concentrate emulsifying with water or an aqueous solution from the system; in particular, the injection clarithromycin fat emulsion square average particle diameter 05 - billion · 7 μ m;. preferably 0 · 1 - 0 · 4 μ m; more preferably, 0 · 17 - 0 · 22 μ m.
7. 权利要求1至5种任一项所述的克拉霉素脂肪乳浓缩液的制备方法,包括下述步骤: 1) 在20 - 45°C,将低HLB值表面活性剂加入中链脂肪酸甘油酯,在2000 - 20000rpm 条件下,搅拌至形成透明清亮溶液; 2) 在20 - 45°C条件下,将克拉霉素加入维生素E产物,并在200 - 2000rpm搅拌条件下持续搅拌,直至整个体系呈透明清亮状; 3) 在20 - 45°C条件下,将步骤2)产物、助溶剂、高HLB值表面活性剂以及可选的抗氧化剂加入步骤1)产物,并在200 - 800rpm搅拌条件下持续搅拌,直至形成单相、透明清亮的均匀制剂,经〇. 22 μ m微孔滤膜除菌后,最终获得克拉霉素脂肪乳浓缩液。 15 The method according to any one of clarithromycin fat emulsion concentrate preparation, comprising the steps of claim 7: 1) at 20 - 45 ° C, the lower HLB value surfactant is added to medium-chain fatty acid glycerides, 2000 - the following conditions 20000rpm, stirred until a clear transparent solution; 2) 20 - the following conditions of 45 ° C, the clarithromycin product was added to vitamin E, and 200 - continuous stirred at 2000rpm with stirring, until the entire system was transparent and clear like; 3) 20-- 45 ° C under the conditions of step 2) the product, a co-solvent, a high HLB value surfactant, and optionally an antioxidant is added in step 1) of the product, and 200-- stirring 800rpm under constant stirring conditions until a single phase is formed, a uniform transparent clear formulation after square. 22 μ m microporous membrane sterilization, the finally obtained clarithromycin fat emulsion concentrate.
8. 权利要求1至5中任一项所述的克拉霉素脂肪乳浓缩液或者权利要求6所述的注射用克拉霉素脂肪乳在由敏感细菌所致的上、下呼吸道,包括扁桃体炎、咽喉炎、副窦炎、支气管炎、肺炎等、皮肤、软组织感染、脓疖、丹毒、毛囊炎、伤口感染等疾病的治疗。 Clarithromycin fat emulsion for injection 1 to claim 6 or clarithromycin fat emulsion concentrate as claimed in any one of claims 5 on caused by sensitive bacteria, lower respiratory tract, including claim tonsillitis treatment of diseases of the throat, deputy sinusitis, bronchitis, pneumonia, skin and soft tissue infections, pus boils, erysipelas, folliculitis, wound infections.
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