CN103588846B - A method for preparing fluticasone propionate particle and its use - Google Patents

A method for preparing fluticasone propionate particle and its use Download PDF

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CN103588846B
CN103588846B CN201210290478.3A CN201210290478A CN103588846B CN 103588846 B CN103588846 B CN 103588846B CN 201210290478 A CN201210290478 A CN 201210290478A CN 103588846 B CN103588846 B CN 103588846B
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fluticasone propionate
solvent
method
solution
particle size
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CN103588846A (en
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兰洁
陈李平
张凌远
管璐晗
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重庆华邦制药有限公司
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Abstract

一种制备粒度D98小于5μm的丙酸氟替卡松微粒的方法,采用重结晶方法,将丙酸氟替卡松原料溶于溶剂中制成溶液,再将该溶液加入含表面活性剂的水中,析出所需粒度的丙酸氟替卡松微粒。 A process for preparing a particle size D98 of less than 5μm fluticasone propionate microparticles method, recrystallization method, fluticasone propionate starting material dissolved in a solvent to prepare a solution, and the solution was added to water containing a surfactant, the desired particle size of the precipitated fluticasone propionate particles. 与传统方法相比,本方法收率更高,生产成本低,无需依赖于使用特殊设备,且能耗小。 Compared with traditional methods, the present method a higher yield, low production cost, without relying on the use of special equipment, and less power consumption. 本方法不产生粉尘,所用试剂无毒害,环保;产物粒度小、粒度分布窄,圆整度高、流动性好,非常适合用于作为药物制剂原料。 This method does not produce dust, the reagents non-toxic, environmentally friendly; product of small particle size, narrow particle size distribution, and high round, good fluidity, is very suitable for a raw material as a pharmaceutical formulation.

Description

-种丙酸氣替卡松微粒的制备方法及其用途 - kind of gas for preparing fluticasone propionate particle and its use

技术领域 FIELD

[0001] 本发明属于制药领域,具体设及一种制备粒度D98在扣mW下的丙酸氣替卡松微粒的方法,W及该丙酸氣替卡松微粒在制备鼻喷雾剂、吸入气雾剂和吸入粉雾剂方面的用途。 [0001] The present invention belongs to the pharmaceutical field, and a method of preparing a D98 particle size of the acid gas in the particulate fluticasone buckle mW specific set, W, and the gas fluticasone propionate nasal spray preparation of fine particles, the suction gas and the use of inhalation aerosol inhalation aspects.

[0002] 发明背景 [0002] Background of the Invention

[0003] 丙酸氣替卡松是一种肾上腺激素类药物,用于预防和治疗鼻炎或哮喘等疾病。 [0003] fluticasone propionate gas is an adrenal hormone drugs for preventing and treating diseases such as rhinitis or asthma.

[0004] 丙酸氣替卡松的常用剂型是鼻喷雾剂、吸入气雾剂和吸入粉雾剂等。 [0004] Common forms of fluticasone propionate gas are nasal sprays, inhalation, and powder for inhalation aerosols and the like. 在运些制剂中,丙酸氣替卡松通过呼吸道进入人体内,为了使其到达病灶并被有效吸收利用,对丙酸氣替卡松的粒度有较严格的要求。 In operation these formulations, fluticasone propionate gas into the body through the respiratory tract, in order to make effective and reach the lesion absorption, fluticasone propionate particle size of the gas for more stringent requirements. 如美国药典中丙酸氣替卡松鼻喷雾剂的标准为:丙酸氣替卡松的粒度要求D98在扣mW下。 The USP standard for acid gas as nasal sprays propionate: fluticasone propionate gas requirements for the D98 particle size of at buckle mW. 而通过一般合成方法或重结晶方法得到的丙酸氣替卡松, 粒度往往高达SOwiiW上。 Obtained by the general synthetic methods or recrystallization gas fluticasone propionate, often as high as the particle size SOwiiW. 因此,为了得到粒度较小的丙酸氣替卡松微粒,需要采取特殊的方法来减小其粒度(即对其进行微粒化)。 Accordingly, in order to obtain smaller particle size particulate fluticasone propionate, gas, and require special methods to reduce the particle size (i.e. be atomized). 现有技术中主要使用的是机械微粉化的方法。 The prior art mainly use a mechanical micronization.

[0005] 如CN1098680C制备丙酸氣替卡松混悬制剂,所用的原料丙酸氣替卡松通过微粉化法制备。 [0005] The acid gas feed gas CN1098680C fluticasone propionate prepared suspension formulation, the use of fluticasone propionate prepared by micronization process.

[0006] CN101106975A公开了几种具体的丙酸氣替卡松微粉化方法:强剪切混合、球墨、气流粉碎、高压均质机研磨等。 [0006] CN101106975A discloses several specific gas fluticasone propionate micronization process: high shear mixing, ductile, jet milling, grinding, high-pressure homogenizer.

[0007] 然而,机械粉碎手段对于药物的工业生产存在很大的问题,一是要依赖于昂贵的粉碎设备,如球磨机、高压均质机等,成本较高;另外,丙酸氣替卡松属于制剂剂量较小的药物,原料药的批量一般不大,因此机械粉碎过程中会有较大的损失,收率低;而且,粉碎过程不可避免地产生大量粉尘,污染环境。 [0007] However, the mechanical pulverizing means there is a big problem for the industrial production of drugs, it is necessary to rely on expensive grinding equipment, such as a ball mill, a high pressure homogenizer and the like, high cost; Further, fluticasone propionate gas belonging to a smaller dose of drug formulation, generally small quantities of the drug, and therefore have a greater mechanical pulverization process losses, low yield; Further, the comminution process inevitably produces a lot of dust, pollution of the environment.

[000引因此,需要一种更为经济、简便、环保的制备丙酸氣替卡松微粒的方法。 [000 cited Accordingly, a need for a more economical, simple and environmentally friendly method for preparing fluticasone propionate gas particles.

发明内容: SUMMARY:

[0009] 本发明的目的是提供一种简便、经济、环保的制备D98小于扣m丙酸氣替卡松微粒的方法,避免采用机械微粉化的方法。 [0009] The object of the present invention is to provide a simple, environmentally-friendly economic preparation, method of deduction m D98 fluticasone propionate particle is less than the gas, to avoid the use of mechanical methods micronized.

[0010] D98小于5]im是指制得的丙酸氣替卡松微粒成品中,粒径小于5]im的颗粒量占颗粒总量的98%。 [0010] D98 of less than 5] im refers gas obtained fluticasone propionate finished microparticles, particle size less than 5] 98% of the total amount of particles of particles im.

[0011] 采用结晶法,将丙酸氣替卡松制成溶液后再析出结晶的方法,虽然可W避免机械粉碎带来的诸多问题。 [0011] The crystallization method, the gas fluticasone propionate solution was formed after crystal precipitation method, although W to avoid problems caused by mechanical pulverization. 然而,常规的结晶方法得到的丙酸氣替卡松结晶粒度较大,只能得到几十微米左右的微粒,而丙酸氣替卡松喷雾、吸入等制剂要求丙酸氣替卡松的粒度在扣mW 下。 However, the conventional method of crystallization gas fluticasone propionate obtained crystal grain size is large, only about several tens of micrometers to obtain fine particles, and fluticasone propionate, air spray, inhalation formulations in claim fluticasone propionate particle size of the gas in the buckle mW.

[0012] 要使用结晶法得到低粒度的丙酸氣替卡松,就需要找出影响结晶粒度的主要因素,通过实验对比,对结晶的条件进行选择和优化。 [0012] To obtain a low acid gas crystalline size fluticasone method, it is necessary to identify the main factors affecting the crystal grain size of, for crystallization conditions are selected and optimized by experimental comparison.

[0013] 发明人发现:关键是寻找到适当的丙酸氣替卡松溶剂,并选择出一种适当的反溶剂。 [0013] The inventors have found that: the key is to find an appropriate solvent fluticasone propionate, gas, and selecting an appropriate anti-solvent. 所述反溶剂是不溶解丙酸氣替卡松的液体物质。 The anti-solvent is a liquid substance that does not dissolve fluticasone propionate of gas. 发明人通过反复试验,找到了关键的溶剂一一二甲亚讽、N,N-二甲基甲酯胺或聚乙二醇,W及反溶剂一一表面活性剂和水的混合物,可W很好的将丙酸氣替卡松微粒化,得到适于制剂的D98小于如m的丙酸氣替卡松微粒。 The inventors by trial and error to find the key dimethylsulfoxide solvent eleven Bitterness, N, N- dimethyl amine or a polyethylene glycol ester, W, and eleven anti-solvent mixture of surfactants and water W may be the good atomization of fluticasone propionate gas, adapted to obtain a formulation such as acid gas is less than the D98 particle fluticasone m.

[0014] 具体的技术方案是: [0014] The specific technical solution is:

[0015] -种制备丙酸氣替卡松微粒的方法,采用重结晶方法,将丙酸氣替卡松原料溶于溶剂中制成溶液,再将该溶液与反溶剂混合,析出所需粒度的丙酸氣替卡松微粒;其特征是: [0015] - A method for the preparation of gas species fluticasone propionate particles, recrystallization method, the solution of fluticasone propionate prepared feed gas dissolved in a solvent, then the solution is mixed with anti-solvent, precipitation of the desired particle size gas particulate fluticasone propionate; wherein:

[0016] 1)所述溶剂选自二甲亚讽、N,N-甲基甲酯胺或聚乙二醇中的一种或多种。 [0016] 1) the solvent is selected from one or more ridicule dimethylsulfoxide, N, N- methyl methyl amine or polyethylene glycol.

[0017] 所述聚乙二醇可W是液态,如聚乙二醇200、聚乙二醇400,也可W是固态,如聚乙二醇4000、聚乙二醇6000,优选聚乙二醇400。 [0017] W is the polyethylene glycol may be a liquid such as polyethylene glycol 200, polyethylene glycol 400, W may be a solid, such as polyethylene glycol 4000, polyethylene glycol 6000, preferably polyethylene alcohol 400. 当使用的溶剂为固态时,可W采用加热的方法将溶剂烙融后再将丙酸氣替卡松原料溶解。 When the solvent used is a solid, W can be employed a method of heating the solvent and then branded into the gas fluticasone propionate starting material dissolved.

[0018] 2)所述反溶剂是表面活性剂和水的混合溶剂,所述表面活性剂可W选用药物制剂中适用的阴离子表面活性剂(如十二烷基横酸钢)、阳离子表面活性剂(如十八烷基=甲基漠化锭、苯扎氯锭)、两性离子表面活性剂(如卵憐脂)或者非离子表面活性剂(如平平加0、 吐溫)。 [0018] 2) The anti-solvent is a mixed solvent of water and a surfactant, the surfactant may be selected W pharmaceutical formulation suitable anionic surfactants (e.g., lauryl acid cross-steel), cationic surfactants agents (e.g., methyl octadecyl = desertification ingot, the ingot benzalkonium chloride), zwitterionic surfactants (e.g., egg fat pity) or a non-ionic surfactant (e.g. peregal 0, Tween). 表面活性剂与水的质量比为0.01~1:500。 Mass ratio of surfactant to water is 0.01 to 1: 500.

[0019] 3)丙酸氣替卡松溶液与反溶剂混合时的加入方向必须是溶液加入到反溶剂中。 [0019] 3) fluticasone propionate solution with added gas direction must be anti-solvent mixture was added to the reaction solvent.

[0020] 本方法得到的丙酸氣替卡松微粒的粒度为D98小于如m。 [0020] The particle size obtained by the method of the present gas fluticasone propionate particles was smaller than D98 as m.

[0021] W下对本方法中各物料的作用、用量等进行说明: [0021] W of the role of the various materials of the present method, the dosage will be described:

[0022] 溶剂的用量:溶剂的目的是将原料丙酸氣替卡松制成均一的溶液,因此,本领域技术人员可W根据实际的需要,选择适当的用量,只要能形成均一的溶液即可。 The amount of [0022] Solvent: The purpose is to feed the solvent gas fluticasone propionate homogeneous solution was formed, therefore, those skilled in the art may be W according to actual needs, select the appropriate dosage, as long as a uniform solution that is capable of forming can. 当溶剂为固态时,可W采用加热的方法将溶剂烙融后再将原料溶解;当溶剂为液态时,为了使溶解速度更快,也可W加热。 When the solvent is solid, W can be employed a method of heating the solvent and then dissolve the starting materials into branded; when the solvent is a liquid, in order to dissolve faster, W may be heated. 为了使成品微粒析出更快,可W对丙酸氣替卡松溶液的浓度进行一定的限定,因此,优选的溶剂用量是Ig丙酸氣替卡松使用30~600g溶剂。 In order to precipitate particles of product faster, W can be certain of the acid gas concentration is defined for fluticasone solution, therefore, the amount of the solvent is preferably Ig gas fluticasone propionate using 30 ~ 600g solvent.

[0023] 反溶剂的用量:反溶剂的作用是降低原料在体系中的溶解度,使得丙酸氣替卡松微粒析出。 [0023] The amount of anti-solvent: antisolvent effect is to decrease the solubility of the raw material in the system, such that gas fluticasone propionate particles precipitated. 为了使丙酸氣替卡松微粒更好的析出,可W通过试验确定溶剂与反溶剂的比例。 In order to better particulate fluticasone propionate gas precipitation, W may determine the ratio of solvent to anti-solvent by experiment. 优选的质量比为1:2~60。 The preferred mass ratio of 1: 2 ~ 60.

[0024] 反溶剂中加入表面活性剂是本发明的一个创新。 [0024] The anti-solvent is added to a surfactant of the present invention is innovative. 传统的反溶剂结晶方法中往往采用水、己烧等惰性溶剂作为反溶剂,本发明独辟暧径,在水中加入了表面活性剂作为反溶剂。 Conventional antisolvent crystallization process are often employed water, an inert solvent such as hexyl burning antisolvent, the present invention is the provision of separate heating diameter, it added to the water surfactant as an anti-solvent. 试验证明,反溶剂中不含表面活性剂时,成品的粒度达不到要求(见对比例1);而加入微量的表面活性剂后就能使成品粒度D98达到如mW下。 Tests show that when an anti-solvent without surfactant, mainly the particle size of the finished product (see Comparative Example 1); and after addition of a trace amount of surfactant can achieve product size D98 as follows mW.

[0025] 溶液与反溶剂的混合方式是本发明的另一个创新。 [0025] The solution was mixed with anti-solvent is another embodiment of the present invention is innovative. 只有采用将溶液加入到反溶剂中的方式才能达到本发明的目的和效果,经实验证明,采用将反溶剂加入到溶液中的方式会使成品微粒的粒度偏大(见对比例2)。 The solution was added to only the use of anti-solvent in a manner to achieve the purpose and effect of the present invention, the experiment proved that, by way of the anti-solvent is added to the solution to make the size of the larger particles of product (see Comparative Example 2).

[0026] W下是本发明一种制备方式: [0026] W is a preparation of the present invention:

[0027] 1)将5~30重量份的丙酸氣替卡松加入到500~7000重量份的聚乙二醇中,加热揽拌使完全溶解,得到溶液A; [0027] 1) 5 to 30 parts by weight of fluticasone propionate gas is added to 500 to 7000 parts by weight of polyethylene glycol and heated embrace mix completely dissolved to obtain a solution A;

[00%] 2)取0.2~20重量份的十二烷基横酸钢、吐溫、卵憐脂、苯扎氯锭、平平加0或/和十八烷基=甲基漠化锭,溶解于水中,再加水至17000~70000重量份,得到反溶剂B; [00%] 2) takes 0.2 to 20 parts by weight of sodium lauryl steel cross acid, Tween, egg fat pity, benzalkonium chloride, lozenges, or peregal 0 / = methyl and stearyl desertification ingot, dissolved in water, add water to 17,000 to 70,000 parts by weight, the resulting anti-solvent B;

[0029] 3)在揽拌下,将溶液A加入反溶剂B中,持续揽拌5~30min,得到含有丙酸氣替卡松微粒的混悬液。 [0029] 3) In embrace stirred solution was added to the reaction solvent B in A, embrace continuous stirred 5 ~ 30min, to obtain a suspension containing particles of fluticasone propionate gas.

[0030] 本方法得到的丙酸氣替卡松微粒,可W用于制备鼻喷雾剂、气雾剂或粉雾剂等不同剂型的制剂。 [0030] obtained by the method of the present gas fluticasone propionate particles, W may be a different formulation of the dosage form prepared nasal sprays, aerosols or dry powder inhalation for.

[0031] 制备鼻喷雾剂:在溶剂和反溶剂体系中析出丙酸氣替卡松微粒形成混悬液后,不经处理,直接将此混悬液作为原料投料,与鼻喷雾剂常用的辅料混合,按鼻喷雾剂的常规生产工艺制备丙酸氣替卡松鼻喷雾剂。 [0031] Nasal spray: after precipitation in antisolvent and solvent system to form a suspension of fluticasone propionate gas particles, without any treatment, this suspension is directly used as a raw material feeding, nasal spray with common excipients mixing, propionic acid gas conventionally produced fluticasone nasal spray process nasal spray.

[0032] 制备气雾剂:将上述得到的含丙酸氣替卡松微粒的混悬液过滤、水洗后投料,用于制备气雾剂。 Preparation of [0032] aerosol: The above-obtained suspension containing the particulate fluticasone propionate gas filtration, washed with water feed, for preparing an aerosol.

[0033] 制备粉雾剂:将上述得到的含丙酸氣替卡松微粒的混悬液过滤、水洗、干燥后投料,用于制备粉雾剂。 Preparation [0033] The inhalation powder: The above-obtained suspension containing gas fluticasone propionate particles was filtered, washed with water, dried feed, for the preparation of inhalation.

[0034] 本发明的技术效果是: [0034] Technical effects of the invention are:

[0035] 1.生产成本低。 Low [0035] 1. Production costs. 本发明方法无需依赖于使用球磨机、均质机等特殊设备,且能耗小,生产成本低。 The method of the present invention need not rely on special equipment using a ball mill, a homogenizer, etc., and low energy consumption and low production cost.

[0036] 2.环保。 [0036] 2. Environmental protection. 本发明生产过程中不产生粉尘,所用试剂无毒害,是一种环境友好的方法。 No dust in the production process of the present invention, the reagents with non-toxic, is an environmentally friendly method.

[0037] 3.产物圆整度高、流动性好,适于制剂。 [0037] 3. The high rounded product, good fluidity, suitable for formulation. 与一般的结晶方法不同,本发明所得产物为楠圆形,具有圆整度高、流动性好等优点,非常适合用于制剂。 General crystallization methods, the resulting product of the present invention Nan circular round having a high brightness, and good flowability, is very suitable for the formulation.

[0038] 4.产物粒度小、粒度分布窄。 [0038] 4. The product of small particle size, narrow particle size distribution. 本发明可W得到D98小于如m的丙酸氣替卡松微粒。 The present invention may be less than W D98 obtained as acid gas particulate fluticasone m.

附图说明 BRIEF DESCRIPTION

[0039] 图1为实施例1所得产物丙酸氣替卡松微粒在1000倍光学显微镜下的图像。 [0039] FIG acid gas product at 1000 magnification optical microscopy image of the fluticasone particles obtained in Example 1. (图中量尺的最小刻度为1皿)。 (FIG dipstick minimum scale is 1 dish).

具体实施方式 Detailed ways

[0040] 下面通过实施例的方法对本发明的技术方案进行具体说明,但实施例所用各种物料的种类和用量并不构成对发明技术方案的限制。 [0040] Next will be specifically described aspect of the invention by the method of the embodiment, but the embodiment is used in a variety of types and amounts of materials are not intended to limit the technical solution of the invention.

[0041] W下各实施例成品粒度的检测中:所用方法为《中国药典》2010版二部附录IX E粒度和粒度分布测定法中的第=法(光散射法),所用仪器为马尔文激光粒度分析仪。 [0041] W follows the respective detecting of an embodiment finished size of: the method used is the "Chinese Pharmacopoeia" 2010 Appendix IX E size and particle size distribution measurement Method = method (light scattering method), the instruments of Malvern laser particle size analyzer.

[0042] 实施例1丙酸氣替卡松微粒制备 [0042] Example 1 Preparation of fluticasone propionate gas microparticles

[0043] 方法; [0043] Method;

[0044] 1)制备丙酸氣替卡松溶液A:将IOg丙酸氣替卡松加入到550g聚乙二醇400中,加热揽拌使完全溶解,得到溶液A; [0044] 1) Preparation of fluticasone propionate gas Solution A: IOg gas fluticasone propionate was added to 550g of polyethylene glycol 400, mixed with heating embrace completely dissolved to obtain a solution A;

[0045] 2)制备反溶剂B:取2.05g吐溫80和1.91g苯扎氯锭,溶解于水中,再加水至17050g, 得到反溶剂B; Preparation of [0045] 2) Anti-Solvent B: Take 2.05g Tween 80 and 1.91g benzalkonium chloride ingot, dissolved in water, add water to 17050g, to give an anti-solvent B;

[0046] 3)溶液A与反溶剂B混合方式:在揽拌下,将溶液A加入反溶剂B中,持续揽拌lOmin, 得混悬液。 [0046] 3) A solution of the anti-solvent B are mixed manner: In embrace stirred, solution A was added in an anti-solvent B for lOmin embrace mix, to give a suspension.

[0047] 结果: [0047] Results:

[004引用激光粒度仪检测,混悬液中丙酸氣替卡松微粒的D98为3.47曲1,见图1。 [004 detected reference laser particle size analyzer, gas fluticasone propionate suspension of fine particles was 3.47 D98 1, shown in Figure 1.

[0049] 实施例2~6 [0049] Examples 2 to 6

[0050] 按照实施例1的操作方法和表1中各物料的种类和用量,制备丙酸氣替卡松微粒。 [0050] The materials according to various embodiments of the method of operation of Example 1 and Table 1. The kind and amount of gas microparticles fluticasone propionate prepared. [0051 ]所得产物丙酸氣替卡松微粒的粒度见表1。 [0051] The resulting product fluticasone propionate particle size for air in Table 1.

[0052]表1制备丙酸氣替卡松微粒使用的各物料种类、用量、产物粒度 [0052] Preparation of Table 1 for each type of material gas fluticasone propionate particles used, amount, particle size of the product

[0化3] [0 of 3]

Figure CN103588846BD00061

[0054]对比例I反溶剂中不加表面活性剂制备丙酸氣替卡松微粒[0化5] 方法; [0054] propanoic acid Example I Preparation of an anti-solvent without surfactant particulate fluticasone gas [0 of 5] method;

[0056] 1)制备丙酸氣替卡松溶液A,同实施例1; [0056] 1) Preparation of a solution of fluticasone propionate gas A, the same as in Example 1;

[0057] 2)反溶剂B: 17050g水(不含表面活性剂); [0057] 2) Anti-Solvent B: 17050g water (no surfactant);

[005引3)溶液A与反溶剂B混合方式,同实施例1。 [005 primer 3) A solution of anti-solvent B are mixed with the embodiment, same as in Example 1.

[0059] 结果:用马尔文激光粒度仪检测,混悬液中丙酸氣替卡松微粒的D98为19.45WI1。 [0059] Results: Malvern Zetasizer detection, suspension of fluticasone propionate gas particles D98 is 19.45WI1.

[0060] 结论:制备所需粒度丙酸氣替卡松微粒时,表面活性剂在反溶剂中起到关键作用。 [0060] Conclusion: the preparation of the desired particle size particulate fluticasone propionate, gas, surface active agents play a key role in the anti-solvent.

[0061 ]对比例2采用反溶剂加入溶液的方法制备丙酸氣替卡松微粒 [0061] propionic acid gas method of Comparative Example 2 using an anti-solvent solution of fluticasone particles

[0062] 方法; [0062] Method;

[0063] 1)制备丙酸氣替卡松溶液A,同实施例1; [0063] 1) Preparation of a solution of fluticasone propionate gas A, the same as in Example 1;

[0064] 2)制备反溶剂B,同实施例1; Preparation of [0064] 2) anti-solvent B, a same as in Example 1;

[0065] 3)溶液A与反溶剂B混合方式:在揽拌下,将反溶剂B加入溶液A中,持续揽拌lOmin, 得混悬液。 [0065] 3) A solution of the anti-solvent B are mixed manner: In embrace mixed, B is added to the anti-solvent solution A for lOmin embrace mix, to give a suspension.

[0066] 结果:用马尔文激光粒度仪检测,混悬液中丙酸氣替卡松微粒的D98为13.23WI1。 [0066] Results: Malvern Zetasizer detection, suspension of fluticasone propionate gas particles D98 is 13.23WI1.

[0067] 结论:逆向加入方式得不到所需粒度的丙酸氣替卡松微粒。 [0067] Conclusion: reverse manner not added acid gas fluticasone particles of the desired size. 实施例7用本发明的丙酸氣替卡松微粒制备丙酸氣替卡松鼻喷雾剂 Example 7 of the present invention with the acid gas particulate fluticasone propionate prepared fluticasone propionate nasal spray gas

[0068] 取880g实施例1中得到的含有丙酸氣替卡松微粒的混悬液、0.5g吐溫80、2.5g苯乙醇、5g葡萄糖、1.地微晶纤维素、2.5g簇甲基纤维素钢、0.2g BHT,加水至1000 g,揽拌,混合均匀,混合好的药液用栋色玻璃瓶灌装,每瓶装量16g,安装喷雾累头,得丙酸氣替卡松鼻喷雾剂。 [0068] Example 1 Take 880g resulting suspension containing particles of fluticasone propionate gas, 0.5g Tween 80,2.5g phenylethyl alcohol, 5g of glucose, 1 to microcrystalline cellulose, 2.5 g of cluster A cellulose steel, 0.2g BHT, add water to 1000 g, embrace mixed, uniformly mixed, the mixed liquid filling bottles with a ridge color, Mei Pingzhuang amount of 16g, tired mounting spray heads to obtain fluticasone propionate gas nasal spray.

[0069] 实施例8用本发明的丙酸氣替卡松微粒制备丙酸氣替卡松粉雾剂 [0069] Example 8 of the present invention with the acid gas particulate fluticasone propionate prepared gas fluticasone inhalation powder

[0070] 取实施例1中得到的含有丙酸氣替卡松微粒的混悬液,用0.45皿的有机滤膜过滤, 用水洗涂滤饼6~8次,收集药物滤饼,于80°C减压干燥化,得丙酸氣替卡松微粒。 [0070] Example 1 was taken in a suspension containing gas fluticasone propionate particles embodiment, the organic membrane filter 0.45 dish, coated with a filter cake was washed 6-8 times, of drug collected cake was 80 ° C under reduced pressure of the dried, to obtain fluticasone propionate gas particles.

[0071] 取IOOmg丙酸氣替卡松微粒、乳糖lOOg,采用等量递增法混和均匀,装3号胶囊,得丙酸氣替卡松胶囊型粉雾剂300粒。 [0071] The air taken IOOmg fluticasone propionate particles, lactose lOOg, using the same amount gradually increasing uniformly mixed, loaded capsules No. 3 to give the gas fluticasone propionate inhalation powder capsule 300.

[0072] 实施例9用本发明的丙酸氣替卡松微粒制备丙酸氣替卡松气雾剂 [0072] Example 9 of the present invention with the acid gas particulate fluticasone propionate prepared fluticasone aerosol gas

[0073] 取实施例1中得到的含有丙酸氣替卡松微粒的混悬液,用0.45皿的有机滤膜过滤, 用水洗涂滤饼6~8次,收集药物滤饼作为原料,用CNl 168630的方法制备,得到丙酸氣替卡松气雾剂。 [0073] Example 1 was taken in a suspension containing gas fluticasone propionate particles embodiment, the organic dish 0.45 membrane filter, the filter cake was washed with water 6-8 times Tu, the filter cake was collected as a pharmaceutical raw material, preparation CNl 168630 obtain fluticasone propionate aerosols gas.

Claims (8)

1. 一种制备粒度D98小于5μπι的丙酸氟替卡松微粒的方法,先将丙酸氟替卡松原料溶于溶剂中制成溶液,再将该溶液与反溶剂混合,析出所需粒度的丙酸氟替卡松微粒;其特征是: 1) 反溶剂:含表面活性剂的水,表面活性剂与水用量的质量比为0.01~1:500; 2) 丙酸氟替卡松溶液与反溶剂混合时的加入方向:必须是将丙酸氟替卡松溶液加入到反溶剂中,而不能逆向加入; 3) 溶剂:选自二甲亚砜、Ν,Ν-二甲基甲酰胺或聚乙二醇中的一种或多种; 所述表面活性剂选自药物制剂可接受的阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂或者非离子表面活性剂。 D98 particle size of less than 1. A process for preparing fluticasone propionate 5μπι propionate microparticles alternative method, the first solvent to form a solution of fluticasone propionate and fluticasone propionate starting material was dissolved, then the solution is mixed with anti-solvent, precipitation of the desired particle size fluticasone propionate particles fluoro; characterized in that: 1) the anti-solvent: surfactant-containing water, the mass ratio of surfactant to water an amount of 0.01 to 1: 500; 2) fluticasone propionate solution and added direction anti-solvent mixture: must be fluticasone propionate was added to the reaction solvent, but the reverse is not added; 3) solvent: dimethylsulfoxide selected, Ν, Ν- dimethylformamide or polyethylene glycol, one or more; the surfactant selected from a pharmaceutically acceptable formulation of an anionic surfactant, a cationic surfactant, zwitterionic surfactant or a nonionic surfactant.
2. 权利要求1所述的方法,所述溶液与反溶剂混合,是在搅拌下将丙酸氟替卡松溶液加入到反溶剂中,并继续搅拌5min~30min,形成含所需粒度的丙酸氟替卡松微粒的混悬液。 2. The method as claimed in claim 1, said solution is mixed with anti-solvent, stirring is fluticasone propionate was added to the reaction solvent, and stirring was continued for 5min ~ 30min, fluticasone propionate is formed containing the desired fine particle size fluticasone suspension.
3. 权利要求1所述的方法,所述聚乙二醇选自聚乙二醇200、聚乙二醇400、聚乙二醇4000或聚乙二醇6000。 3. The method of claim 1, wherein the polyethylene glycol selected from polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 4000 or polyethylene glycol 6000.
4. 权利要求1所述的方法,所述表面活性剂选自十二烷基磺酸钠、十八烷基三甲基溴化铵、苯扎氯铵、卵磷脂、平平加〇或者吐温。 4. The method of claim 1, wherein the surfactant is selected from sodium dodecyl sulfate, stearyl trimethyl ammonium bromide, benzalkonium chloride, lecithin, Tween or square peregal .
5. 权利要求1所述的方法,所述溶剂用量是lg丙酸氟替卡松使用30g~600g溶剂。 The method according to claim 1, wherein the solvent is used in an amount of fluticasone propionate using lg 30g ~ 600g solvent.
6. 权利要求1所述的方法,溶剂与反溶剂的质量比为1:2~60。 6. The method of claim 1, solvent anti-solvent weight ratio of 1: 2 ~ 60.
7. -种制备粒度D98小于5μπι的丙酸氟替卡松微粒的方法,步骤如下: 1) 将5~30重量份的丙酸氟替卡松加入到500~7000重量份的聚乙二醇中,加热搅拌使完全溶解,得到溶液Α; 2) 取0.2~20重量份的十二烷基磺酸钠、吐温、卵磷脂、苯扎氯铵、平平加0或/和十八烷基三甲基溴化铵,溶解于水中,再加水至17000~70000重量份,得到反溶剂Β; 3) 在搅拌下,将溶液Α加入反溶剂Β中,持续搅拌5min~30min,得到含有丙酸氟替卡松微粒的混悬液。 7. - Preparation of seed particle size D98 less than fluticasone propionate 5μπι propionate microparticles alternative method, the following steps: 1) 5 to 30 parts by weight of fluticasone propionate was added to 500 to 7000 parts by weight of polyethylene glycol and heated with stirring to complete was dissolved to obtain a solution Α; 2) 0.2 to 20 parts by weight taking sodium dodecyl sulfate, Tween, lecithin, benzalkonium chloride, peregal 0 and / or stearyl trimethyl ammonium bromide , dissolved in water, adding water to 17,000 to 70,000 parts by weight, the resulting anti-solvent Β; 3) under stirring, and the solution was added to the reaction solvent Α Beta, the stirring was continued for 5min ~ 30min, to obtain a suspension containing fine particles of fluticasone propionate .
8. 权利要求1~6中任一所述方法制备的丙酸氟替卡松微粒在制备鼻喷雾剂、气雾剂或粉雾剂中的应用。 1-6 the fluticasone propionate prepared according to any method of application of a particulate fluticasone propionate in the manufacture of a nasal spray, aerosol or dry powder inhalation of the claim.
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CN1819818A (en) * 2003-07-07 2006-08-16 阿斯利康(瑞典)有限公司 Process for the preparation of micron-size crystalline particles using a solvent, a non-solvent and ultrasonic energy
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