CN101816913B - A micro ball manufacturing method and apparatus - Google Patents

A micro ball manufacturing method and apparatus Download PDF

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CN101816913B
CN101816913B CN 201010177862 CN201010177862A CN101816913B CN 101816913 B CN101816913 B CN 101816913B CN 201010177862 CN201010177862 CN 201010177862 CN 201010177862 A CN201010177862 A CN 201010177862A CN 101816913 B CN101816913 B CN 101816913B
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microspheres
means
apparatus
gas
droplet
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CN 201010177862
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Chinese (zh)
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CN101816913A (en )
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吴传斌
温新国
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吴传斌
广州新济药业科技有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction

Abstract

本发明提供了微球的制造方法和制造设备。 The present invention provides a method and a manufacturing apparatus for manufacturing microspheres. 该微球制造方法是通过本发明设备以简单和连续地的方式生产微球。 The method for producing microspheres by the apparatus of the present invention is a simple and continuous manner produce microspheres. 在生产微球的方法中,将液体形式的原料供给设备,经设备处理形成微滴,微滴在设备内运行,逐渐固化形成微球,通过吹扫气体或液体的方式,在设备收集器收取微球产品。 In the method of producing microspheres, the liquid form of material supply devices, the processing device is formed by a droplet, the droplet runs inside the device, and gradually solidified to form microspheres by purging a gas or liquid manner, collected at the collector device microspheres product.

Description

一种微球制造方法及制造设备 A micro ball manufacturing method and apparatus

技术领域: FIELD:

[0001 ] 本发明涉及一种微球的制造方法和制造设备。 [0001] The present invention relates to a method and apparatus for manufacturing microspheres.

背景技术: Background technique:

[0002] -种微小的实体球形颗粒,其粒径范围一般为1-250 ym,被称作微球。 [0002] - fine seed entity spherical particles having a particle size range is generally 1-250 ym, is referred to as microspheres. 随着药物科学的发展,发现可以利用微球一些优良的特性达到药物的靶向或缓释、长效输送效果。 With the development of pharmaceutical science, we found that the microspheres can be used to achieve a number of excellent features targeted or sustained-release drug delivery depot effect. 微球即可以输送化学小分子药物,又可以用来输送蛋白质和多肽等大分子药物。 I.e., microspheres may be delivered chemical small molecule drug, and can be used to deliver macromolecular drugs and other proteins and polypeptides. 这些含药的微球被称为药物微球。 These drug-containing microspheres is referred to as microballoons. 药物微球可以经口服,或肌肉、皮下注射给药。 Pharmaceutical microspheres can be administered orally, or intramuscular, subcutaneous administration.

[0003] 制备药物微球,一般要求药物微球的外形接近球形,载药率较高,药物包封率较高,粒径控制在一定的范围内,且分布集中。 [0003] Preparation of pharmaceutical microspheres, microballoons generally require nearly spherical shape, a higher drug loading, higher encapsulation efficiency, particle size controlled within a certain range, and the distribution is concentrated. 对于缓释或长效药物微球还需要防止突释,释放速度受到控制。 For long-acting or sustained release pharmaceutical microspheres also necessary to prevent a burst, the release rate is controlled.

[0004] 作为可以使用的药物制品,需要尽量减少在制备中带来的无关的残留物,例如有机溶剂残留。 [0004] The product can be used as a pharmaceutical, the need to minimize brought in the preparation unrelated residues, for example residual organic solvents. 对于有些敏感性药物,例如很多高效而又敏感的多肽和蛋白质药物,还需要在药物微球的制备过程中尽可能地使用温和条件保证药物有效的稳定性和活性。 For some sensitive drugs, efficient and sensitive, for example, many polypeptides and protein drugs, also need to use mild conditions to ensure the stability and activity of the drug effective as possible during the preparation of pharmaceutical microspheres.

[0005]目前,用于大规模生产药物微球的简单可靠的方法不多。 [0005] At present, not many simple and reliable method for large-scale production of pharmaceutical microspheres.

[0006] 常见的有以下一些制备方法(《药剂学》第6版,人民卫生出版社,崔福德主编)。 [0006] There are a number of common preparation method ( "Pharmacy" 6th edition, People's Medical Publishing House, CUI Fu-de editor).

[0007] "溶剂-非溶剂法",其制备过程一般如下:在材料溶液中加入一种对材料不溶的溶剂(非溶剂),引起相分离,而将药物包裹,制成微球。 [0007] "solvent - non-solvent method", the process is generally prepared as follows: A material is added to a solution of a material insoluble in a solvent (non-solvent), causing phase separation, and the drug package, made of microspheres. 其中需要用到很多毒性的溶剂,药物微球的工业规模生产中未见此法。 Many of which need to use toxic solvents, industrial scale production of pharmaceutical microspheres seen this method.

[0008] "液中干燥法",一般从乳液中除去分散相中的挥发溶剂,制备含药微球,亦称为"乳化-溶剂挥发法"。 [0008] "liquid drying method", a volatile solvent is generally removed from the emulsion dispersed phase was prepared containing microspheres, also known as "emulsion - solvent evaporation method." 多使用乳化和大量有机溶剂,批间操作控制较困难,药物微球的工业规模生产中少见此法。 Multi emulsifying and large amounts of organic solvents, more difficult to control between a batch operation, the industrial scale production of pharmaceutical microspheres rare this method.

[0009] "喷雾干燥法",一般是将药物分散在材料的溶液中,喷雾法将此混合液通过小的喷嘴,经过高压气体剪切后喷入高温气流中,得到含药微球。 [0009] "spray drying method", the drug is generally dispersed in the solution of material, spraying this mixture through a small nozzle, after the high-pressure gas is injected into a high temperature gas stream shear, to give drug-containing microspheres. 此法需要高温,而且颗粒的外形和粒径分布难以控制,限于少数较特别的材料制备微球。 This method requires a high temperature, and particle shape and size distribution is difficult to control, limited to a few more specific microspheres prepared material. 通过"喷雾干燥法"得到的喷干颗粒,外形大多无规则,因此,能够采用此法生产微球产品的应用极少。 Spray-dried particles by "spray drying" obtained, mostly irregular shape, it is possible to use very few applications of this method produced microspheres products.

[0010] 还有一些变通"喷雾干燥法"的用法,其制备方法是,先将载体材料、药物表面活性剂、水、有机溶剂等制成乳液,再将乳液喷雾入大量的由液氮冷冻的乙醇冰中,升温除去有机液,得到药物微球。 [0010] There are alternative uses "spray drying method" in which preparation method, first the carrier material, a pharmaceutical surface-active agent, water, an organic solvent, an emulsion, then spraying the emulsion into a large amount of liquid nitrogen ice ethanol, heated to remove the organic liquid, to give microballoons. 其制备过程较复杂,成本高昂。 The preparation process is complicated and costly.

[0011] 目前所见的上述方法,一般需要使用大量表面活性剂或者有机溶剂,或者产品的产率和包封率较低,或者生产工艺条件复杂,工业生产的可靠性和重复性差;工艺中大量使用有机溶剂使蛋白质多肽失活,以及产品的溶剂残留毒性等难题限制了药物微球的工业规模生产和广发应用。 [0011] The present method can be seen, generally requires the use of large amount of surfactants or organic solvents, or lower product yield and encapsulation efficiency, or complex production process conditions, industrial production reliability and reproducibility difference; Process extensive use of organic solvents inactivating protein polypeptide, and a solvent product problems such as residual toxicity limits the industrial-scale production of a medicament GF and microspheres. 目前,工业规模上没有适合进行药物微球生产的物理机械以及相应生产方法。 Currently, no pharmaceutical microspheres suitable for mechanical production and a corresponding method of production on an industrial scale.

发明内容: SUMMARY:

[0012] 本发明拟解决的问题 [0012] The present invention intends to solve the problem

[0013] 在这样的情形下,本发明的目的是提供生产微球的方法。 [0013] Under such circumstances, an object of the present invention to provide a method for the production of microspheres. 该方法能够通过简单的机械设备,以连续、可规模化的生产方式生微球。 The method can by a simple mechanical device, a continuous, large-scale production can be green microspheres. 该方法还可以适合于一些需要避免有机溶剂和表面活性剂先行乳化的微球制备方式,但也不排除适用与由这些溶剂来制备微球。 The method may also be suitable for the preparation of microspheres necessary to avoid some embodiments an organic solvent and a surfactant preceding emulsified, but not exclusively, applicable to the preparation of the microspheres these solvents. 也可提供相对较低的温度条件而适合对高温敏感的药物微球的制备。 Also provides a relatively low temperature conditions for the preparation of pharmaceutical microspheres sensitive to high temperatures being suitable. 本发明的另一个目的是提供生产微球的设备。 Another object of the present invention is to provide production equipment microspheres.

[0014] 解决问题的方式 [0014] problem-solving approach

[0015] 根据本发明,提供通过简单的机械设备,可以连续、规模化的生产方式生产药物微球。 [0015] According to the present invention, there is provided by a simple mechanical device, continuous, large-scale production of microsphere manufacture of a medicament.

[0016] 这种根据本发明提供的机械设备生产微球的方式可以描述为,分散成液体状的原料的混合液,通过供液装置输送到,设备的微滴发生装置,混合液经过微滴发生装置后,被以微滴的形式高度分散于主体腔内,微滴在主腔体中运行的过程中,逐渐除去溶剂或冷凝固化形成微球产物;微球产物被收集装置收集。 [0016] Such microspheres can be described according to the production apparatus of the present invention provides a mechanically is dispersed into a liquid mixture of the starting material, conveyed through the liquid supply means, a droplet generator apparatus, droplet mixture via after generating means are in a highly dispersed form of droplets in the body cavity, the droplet during the operation of the main cavity, the solvent was removed gradually solidified to form microspheres or condensation products; microsphere product was collected by collection means.

[0017] 根据本发明,提供了微球的生产设备,该设备包含: [0017] According to the present invention, there is provided a microsphere production equipment, the apparatus comprising:

[0018] 用于微球制备的主要容器装置,本发明称之为主体腔;主体腔壁优选的为含有隔热层的双层结构。 [0018] The main container means for preparing microspheres, the present invention is referred to as the body cavity; body cavity wall is preferably a bilayer structure containing a heat-insulating layer.

[0019] 用于将混合液输入到微滴发生装置的供液装置,该供液装置包含至少一个供液喷嘴,经过喷嘴可以输送混合液到微滴发生装置; [0019] The mixture for input to the liquid supply apparatus droplet generating means, the fluid supply means comprises at least one liquid supply nozzle, the mixture may be delivered through a nozzle to a droplet generating means;

[0020] 用于将混合液形成微滴的装置,该装置至少包括受到驱动可以高速旋转的碟片, 以及驱动碟片的动力装置,可以是高速马达; [0020] The apparatus for forming droplets of the liquid mixture, the apparatus comprising at least a disk drive can be rotated at high speed, and a disc drive power apparatus, the motor may be a high speed;

[0021] 用于向高速旋转的碟片平面中心向心吹气的气流环; [0021] for the high-speed rotation of the ring center plane of the disc of blowing air flow to the heart;

[0022] 用于形成切向旋风的气流装置; [0022] The apparatus for forming a tangential cyclone airflow;

[0023] 用于收集微球的装置,该装置由样品收集器和多个扇形托盘组成。 [0023] The means for collecting the microspheres, the device consists of a plurality of sectors and a sample collector trays.

[0024] 发明效果 [0024] Effect of the Invention

[0025] 如上文所述,依照本发明,将混合液供入微滴发生装置,并通过主体腔内的气流约束运行,逐渐形成固态颗粒,颗粒随气流进入收集装置形成微球产物。 [0025] As described above, according to the present invention, the mixture dropwise for nuanced generating means, and the airflow through the constraints running body cavity, gradually formed solid particles to form a microsphere product particles into the air collection means. 由此,能够以简单的方式有效生产微球。 Thus, in a simple manner can be efficiently produced microspheres.

[0026] 附图简述 [0026] BRIEF DESCRIPTION

[0027] 图1 :本发明的微球生产设备的一个实施方案的示图。 [0027] FIG 1: a diagram of one embodiment of the production apparatus of the microspheres of the present invention.

[0028] 图2 :本发明的微球生产设备的一个实施方案所用的切向旋风的气流装置包含的圆环示图。 A cut ring embodiment illustrated in FIG microsphere production apparatus used in the present invention comprises the cyclone gas flow device: [0028] FIG.

[0029] 图3 :本发明的微球生产设备的一个实施方案所用的收集微球装置所包含的一个托盘的示图。 [0029] FIG 3: a collection tray microspheres Microspheres embodiment of a device production apparatus according to the present invention is used is shown in FIG included.

[0030] 图4 :本发明实施例1生产的药物微球的显微照片图。 [0030] FIG. 4: Drug photomicrograph microspheres produced in Example 1 of the present invention.

[0031] 图5 :本发明实施例2生产的药物微球的显微照片图。 [0031] Figure 5: Example of drug production 2 photomicrograph of microspheres of the present invention.

[0032] 图6 :本发明实施例3生产的药物微球的显微照片图。 [0032] Figure 6: Example 3 Production photomicrograph pharmaceutical microspheres embodiment of the present invention.

[0033] 图7 :本发明实施例4生产的药物微球的显微照片图。 [0033] Figure 7: Example 4 Production of pharmaceutical microspheres of the present invention is a photomicrograph of FIG.

[0034] 图8 :本发明实施例5生产的药物微球的显微照片图。 [0034] Figure 8: Example 5 Production photomicrograph pharmaceutical microspheres embodiment of the present invention.

[0035] 图9 :本发明实施例6生产的药物微球的显微照片图。 [0035] Figure 9: Example 6 Production of pharmaceutical microspheres photomicrograph embodiment of the present invention.

[0036] 实施本发明的最佳方式 [0036] The best mode embodiment of the present invention.

[0037] 依照本发明的生产微球的方法,将溶液、微粒悬浮液、乳液或熔融液形式的原料混合液供入微滴发生装置。 [0037] In accordance with a method of producing the microspheres of the present invention, solution, microparticle suspension, emulsion or melt of the raw material mixture in the form of drops for nuanced generating means.

[0038] 在较佳实施例中,混合液包括溶剂,而欲微球化的物质被溶解于其中,其中溶剂为水。 [0038] In the preferred embodiment, the solvent comprises a mixture, of microspheres and wish substances are dissolved therein, wherein the solvent is water.

[0039] 在较佳实施例中,混合液包括溶剂,而欲微球化的物质被溶解于其中,其中溶剂可为有机溶剂,例如乙醇。 [0039] In the preferred embodiment, the solvent comprises a mixture, of microspheres and wish substances are dissolved therein, wherein the solvent may be an organic solvent such as ethanol.

[0040] 在较佳实施例中,混合液还可以是乳状液,欲微球化的物质分散于其中,例如,将多肽药物溶解入水中,与溶解于二氯甲烷的材料液混合形成乳状液。 [0040] In the preferred embodiment, the mixture may be an emulsion, microspheres, a substance to be dispersed therein, e.g., the polypeptide drug is dissolved into water, and the material was dissolved in methylene chloride were mixed to form an emulsion .

[0041] 在较佳实施例中,混合液还可以是微粒悬浮液,欲微球化的物质,可以被分散在其中,悬浮物颗粒粒径最好小于30微米以下。 [0041] In the preferred embodiment, the mixture may also be a suspension of microparticles, microspheres, a substance to be, which can be dispersed, suspended solids particle size is preferably less than 30 microns or less. 例如,药物分散在微粉乙基纤维素悬浮液中。 For example, the drug is dispersed in a suspension of micronized ethylcellulose.

[0042] 在较佳实施例中,欲微球化的物质,还可以是融化状的液体,例如,将药物微粉混合入融化的蜡油中,形成融化状液。 [0042] In the preferred embodiment, the microspheres to be of material may also be melted in liquid form, e.g., micronised drug is mixed into the melted wax to form a melt humor.

[0043] 依照本发明,通过供液装置将混合液输入到微滴发生装置。 [0043] In accordance with the present invention, the liquid supply means is inputted to the mixture droplet generator. 具体而言,该供液装置包含至少一个供液喷嘴,经过喷嘴可以输送混合液到微滴发生装置所属的旋碟面上,优选喷嘴的直径为2_以下;喷嘴不与旋蝶面接触,优选喷嘴与碟片近距离3_以下。 Specifically, the liquid supply means comprises at least one liquid supply nozzle, the mixture may be delivered through a nozzle to the surface of the rotating disk apparatus belongs droplets occurs, the diameter of the nozzle is preferably less 2_; nozzle surface is not in contact with the rotating disc, preferably the nozzle and the disc close 3_. 混合液经喷嘴加至旋碟面上,优选以连续液滴的形式。 Was added to the mixture through a nozzle rotating disc surface, preferably in a continuous form of droplets.

[0044] 依照本发明,混合液经微滴发生装置处理形成微滴。 [0044] According to the present invention, the droplets are formed, means for processing the mixture through a droplet occurs. 该微滴发生装置包含圆形碟片,以及驱动碟片旋转的驱动马达。 The droplet generator comprises a circular disc, and the disc drive motor to rotate. 具体而言,混合液被均匀加至旋转的碟片上,优选的是碟片的中心位置,通过旋转碟片的高速旋转离心作用,混合液在碟片上分散并运行到碟片的边缘,受到碟片边缘气流的作用,形成微滴,进入主体腔运行。 Specifically, the mixture is uniformly applied onto a rotating disc, it is preferable that the center position of the disc, by rotating the disc rotates at high speed centrifugation, the mixture was dispersed and run to the edge of the disc on the disc, stream subjected disc edge, forming droplets, into the body cavity operation. 优选碟片的运行速度为2000转/分钟以上。 Preferably the disc runs at 2000 revolutions / min or more.

[0045] 依照本发明,向心吹气的气流环装置提供向心气流,优选气流环与碟片所处的水平面相同或以上,优选距离为低于10厘米的高距;气流的温度和大小可以受到控制。 [0045] In accordance with the present invention, the air flow to the heart blowing ring means to provide air flow to the heart, preferably the same level as the gas stream in which the disc and the ring or more, preferably a distance less than 10 cm high from; the size and temperature of the airflow It can be controlled. 微滴在向心气流的作用下,微滴极少飞行到主体腔壁上,保持在主体腔内运行。 Droplets under the action of the gas flow to the heart, few droplets fly to the body cavity wall, held in the body cavity operation.

[0046] 依照本发明,形成切向旋风的气流装置,提供受到大小控制的旋风,可以提供上述微滴在主体腔持续运行的动力。 [0046] In accordance with the present invention, a tangential gas flow device is formed cyclone is provided by cyclone controlled size, the droplets may be provided above the body cavity in a power running continuously. 切向气流在主体腔壁的入口数目没有具体限制,优选为入口数目为四个。 Cut is not particularly limited in the number of inlet gas flow to the body cavity wall, preferably four in number entry. 入口位置,优选在主体腔底部位置水平面以上5cm,分别均匀布置。 Entry position, preferably 5cm, are uniformly arranged in the bottom position of the body cavity above the horizontal plane. 切线气流入口底下,还包括一个圆环,可以控制局部切线气流主要向上运行。 Under tangential air inlet, further comprising a ring, may be controlled locally tangential flow mainly upward run. 圆环的可以是多个扇形圆环片组成,其外直径应接近主体腔内径,圆环面宽度不受限制,优选为10厘米。 The ring may be composed of a plurality of fan-shaped annular plates, the inner diameter of the outer diameter of the body should be close to the chamber, the width of the torus is not limited, preferably 10 cm. 圆环9 放置位置应低于切线气流入口,优选的水平高度差应小于3厘米。 Ring 9 is placed below the position of the tangential air inlet should preferably be smaller than the level difference of 3 cm.

[0047] 依照本发明,优选由三部分收集微球产物。 [0047] In accordance with the present invention, the preferred microspheres are collected by a product of three parts.

[0048] 第一部分,包括多个扇形托盘组成,优选如图1所示位置12,和图1-2所示。 [0048] The first portion, comprising a plurality of trays composed of sectors, preferably the position shown in FIG. 12, FIGS. 1-2 and FIG. 托盘的数量没有具体限制,但需围成一个整圆。 The number of trays is not particularly limited, but must enclose a full circle. 托盘放置于主体腔底部,如图1所示位置12,各个托盘分别向心对准主体腔底部的通道口13,如图1所示位置13。 The bottom of the tray is placed in the body cavity, the position 12 shown in FIG. 1, each of the trays are aligned with the passage opening at the bottom of the body cavity 13 to the heart, as shown in FIG 13 the position 1. 各个扇形托盘均有一个对应的吹扫口,如图1所示位置11,可以平行托盘平面向心吹扫气体;或者可以描绘成本发明的特定实施方案,该吹扫口可以根据需要吹扫出液体,例如液氮,或其它处理液体。 Trays each sector has a corresponding purge port, the position 11 shown in FIG. 1, the heart may be parallel to the tray plane purge gas; or cost invention may be depicted in a particular embodiment, the purge port may be purged as required liquids, such as liquid nitrogen, or other treatment liquid.

[0049] 第二部分,由第一样品收集装置组成。 [0049] The second part consists of a first sample collection means. 优选形式如图1所示,包括由气流通道13, 回旋沉降装置14,样品收集器15,以及可被描述为本发明特定实施方案使用的液体循环通道出口22,以及回流接口23组成。 Preferably in the form shown in Figure 1, includes a gas flow passage 13, the swirling settling device 14, a sample collector 15, and can be described using a specific embodiment of the present invention, a liquid circulation passage outlet 22, the interface 23 and the return composition.

[0050]第三部分,由第二样品收集器装置组成。 [0050] The third portion, the second composition of the sample collection means. 优选形式如图1所示,包括由与14相连的通道,回旋沉降装置16,样品收集器17,以及气体循环调节器21组成的。 Preferably in the form shown in Figure 1, it includes a passage 14 connected, swirling sedimentation device 16, a sample collector 17, and the air circulation adjuster 21 thereof.

[0051] 依照本发明的方法,在一般情况下,可以生产出以粒径在1-250 ym之间的固体微球。 [0051] In accordance with the method of the present invention, in general, the particle size can be produced in solid microspheres of between 1-250 ym. 在原料混合液含有药物的情况下,会得到固态的药物微球。 In the case where the raw material mixture containing a drug, the drug will be solid microspheres. 可以描绘成本发明的特定实施方案,例如在吹扫口(图示1-1位置11)吹扫液体或液氮,会得到微球悬浮液。 Cost may depict a particular embodiment of the invention, for example in the purge port (11 illustrates the position 1-1) or a liquid nitrogen purge, will be microsphere suspension. 实施例 Example

[0052] 下面将参照图1描述本发明的微球生产设备的一个实施方案。 [0052] The embodiment will now be described with reference to one embodiment of the present invention, the microsphere production apparatus 1 of FIG.

[0053]该设备具有用于向设备主体腔1,引入原料混合液的喷嘴3,和将原料混合液变为微滴20的微滴发生装置所包含的高速旋碟4 ;用于向心吹气的气流环装置5,该装置可以向高速旋转的转碟提供气流,约束微滴运行的范围,并根据需要提供一定温度的气体,对微滴所含溶剂进行蒸发,起到初步浓缩的作用;切线气流装置8用于产生沿着主体腔内壁旋转气流,可以延长经初步浓缩的微滴在腔体内的运行距离,进一步除去微滴所含的溶剂,使微滴固化为固状的微球物体;用于辅助微球产物收集的扇形托盘装置12,和提供平行于每个托盘平面吹扫气体的吹扫口11,该装置促进部分沉降于托盘的固体微球产物向心集中; 微球产物经过通道口13,进入第一样品收集装置15。 [0053] The apparatus has a chamber to the apparatus main body 1, the raw material mixture introduced into the nozzle 3, and the raw material mixture becomes a droplet 20 droplet generating apparatus comprising a high-speed rotary disk 4; means for blowing centripetal stream gas ring device 5, the apparatus may be provided to the rotating disk rotates at high speed air flow, the droplet constraint operating range, and, if necessary to provide a certain temperature of the gas, the droplets contain solvent was evaporated, play the role of preliminary concentration ; tangential air flow along the means 8 for generating a rotational air flow body cavity wall, may be extended by the preliminary concentration of the droplets in the cavity distance running, to further remove the solvent contained in the droplets, the droplets solidified to form solid microspheres objects; fan tray for auxiliary microsphere product collection means 12, and provided in parallel to the plane of each tray purge gas purge port 11, which means promote the product portion of the solid microspheres settle to the tray radial concentration; microspheres The product through the passage opening 13, 15 into the first sample collection device.

[0054] 对喷嘴3的类型没有具体限制,只要该喷嘴可以将混合液均匀可控地加至高速旋转碟的中心,优选直径为2mm以下的雾化喷嘴。 [0054] No type nozzle 3 particularly limited, as long as a uniform mixture of the nozzle may be controllably added to the center disc rotates at high speed, preferably having a diameter of 2mm or less atomizing nozzle.

[0055]在微滴发生装置,通过高速旋转的旋碟4将原料混合液分散,形成微滴的进入主体腔内运行。 [0055] In the droplet generator, by rotating the disc 4 rotating at high speed dispersing raw material mixture is formed into the body cavity running droplets. 转碟的转速没有限制,优选转碟转速为2000转以上,一般不超过15000转,但不限制该转速上限。 Plate spinning speed is not limited, preferably rotating disk rotational speed 2000 rpm or more, usually not more than 15,000 rpm, but not limited to the upper limit rotational speed. 该装置包括,将原料混合液分散为微滴的转碟4,为转盘提供旋转动力的马达6,以及用于吸气的装置7。 The apparatus comprises the raw material mixture is dispersed into droplets rotating disk 4, to provide rotational power to the turntable motor 6, and 7 for air suction means. 吸气装置用于除去转碟4可能产生的少量漏液或不规则物质19,其口径不作限制,优选不大于旋碟直径2厘米,吸气口高度位置可调,优选其位置平面低于旋碟但不超过5厘米。 Suction means for removing a small amount of leakage substances or irregularly rotating disk 4 19 may be generated, which is not limited in diameter, preferably not more than 2 cm in diameter rotating disk, the height position of the intake port is adjustable, preferably its rotation position is below the plane dish but not more than 5 cm.

[0056]经微滴发生装置产生的微滴,进入主体腔运行,受到有向心吹气的气流环装置5产生的向心气流作用。 [0056] means for generating a droplet by droplet occurs, running into the body cavity, by blowing air with a radial ring device 5 centripetal action produced gas stream. 装置5可以向旋转碟平面向心提供气流,约束微滴运行的范围,对微滴所含溶剂进行蒸发,起到初步浓缩的作用。 5 may be provided to the rotary disc plane radial gas flow, droplets operating range constraints, the solvent contained in the droplets was evaporated, play the role of preliminary concentration. 微滴在向心气流的作用下,微滴极少飞行到主体腔壁上,保持在主体腔内运行。 Droplets under the action of the gas flow to the heart, few droplets fly to the body cavity wall, held in the body cavity operation. 该气流环装置位置,优选与旋碟所处的水平面相同或以上,优选超出高度不超过10厘米;气流环与其它外接装置连接,该外接装置提供温度和大小受控制的气流。 The gas flow ring device location, preferably the same level with which the disc rotation or more, preferably beyond the height of not more than 10 cm; gas flow ring with another external device connected to the external device providing temperature controlled air flow and size.

[0057]微滴在主体腔内逐渐向下运行,受到主体腔内切线气流发生装置8产生的旋转气流的作用,运行距离延长,微滴所含溶剂被除去,形成固体状微球。 [0057] In the droplet gradually runs down the body cavity, subjected to the action of the whirling airflow generating means 8 tangential flow generating body cavity, operation distance is extended, the solvent contained in the droplets is removed to form a solid microspheres. 用于产生沿主体腔切向旋转气流的切线气流发生装置8,该装置气流入口数量不受限制,优选四个入口均匀分布在同一水平面。 For generating a body cavity along a tangential direction tangential airflow occurs whirling airflow means 8, which means the number of inlet gas stream is not limited, preferably four inlets distributed uniformly at the same level. 四个入口的气流流向应一致,优选与转碟4的旋转方向一致。 Four inlet air flow should be identical, preferably with the rotating disk 4 in the direction of rotation. 切线气流发生装置还包括一个圆环9 (示图1-2),也可以是多个扇形圆环片组成,其外直径应接近主体腔内径,圆环面宽度不受限制,优选为10厘米。 Tangential flow generating means further comprises an annular ring 9 (shown in FIG. 1-2), may be a film composed of a plurality of annular segment, the inner diameter of the outer diameter of the body should be close to the chamber, the width of the torus is not limited, preferably 10 cm . 圆环9放置位置应低于切线气流入口,优选的水平高度差应小于3厘米。 Ring 9 is placed below the position of the tangential air inlet should preferably be smaller than the level difference of 3 cm.

[0058]形成的固体状微球逐渐向主体腔的底部运行,经通道13,进入第一样品收集装置14,大部分微球沉降于样品收集器15。 [0058] The solid microsphere gradually running towards the bottom of the body cavity, through the passage 13, into the first sample collection device 14, most of the microspheres to settle the sample collector 15.

[0059] 在本实施方案的设备中,作为第二样品收集器装置16主要是提高微球的收集效率,通过通道与14相连,收集15没有收集的部分微球可以在样品收集器17中得到。 [0059] In the apparatus of this embodiment, the second sample collection device 16 is mainly to improve the collection efficiency of the microspheres, coupled with the passage 14 through the collecting portion 15 without collecting the microspheres can be obtained in the sample collector 17 . 其中气体可以由排气调剂装置21,控制气流的分配,例如排除气量的50%通过调节装置返回到吹扫气体通道口10。 21 wherein the gas may be, controlled by the exhaust adjust air distribution means, for example to exclude 50% of the gas returned to the purge gas passage opening 10 by the adjusting device.

[0060] 在本实施方案的设备中,作为辅助收集装置的扇形托盘12,可以承接沉降在主体腔底部的部分微球。 [0060] In the apparatus of this embodiment, as an auxiliary fan tray collection apparatus 12, can undertake the microspheres settle at the bottom part of the body cavity. 当每个扇形托盘都有一个喷嘴或液体入口11,托盘最高处在圆环9的水平面下,优选应少于5毫米。 When each tray has a fan-shaped nozzle or fluid inlet 11, the tray at the highest level of the ring 9, preferably should be less than 5 mm.

[0061] 可以描述成本实施方案的特定实施方式,当采取气体吹扫方式时,通过21装置泵入气体,此时入口11为气体喷嘴,每个托盘有由通道21泵入的吹扫气体吹洗托盘,此时由22, 23, 24连接的液体通路处于关闭状态。 [0061] The specific embodiments described embodiment can cost embodiment, when the purge gas is taken embodiment, the gas pumped through the apparatus 21, when a gas inlet nozzle 11, into each tray has a pump passage 21 by the purge gas injection wash tray, this time by the liquid passage 22, 23, 24 are connected in a closed state.

[0062] 可以描述成本实施方案的另一特定实施方式,当需要采取液体冲洗或处理微球产物时,通过每个托盘的液体入口24,将液体冲洗每个托盘,而连接通道口22和循环装置23 可以将样品收集器上清液返回,循环冲洗,在输入起始液体时,可由22或23接入口输入,不作限制。 [0062] Another particular embodiment may describe costs embodiment, when the need for rinsing or treatment liquid microsphere product through the liquid inlet 24 of each tray, each tray rinsing liquid, and the connecting passage 22 and the circulation port the apparatus 23 may return the sample collector supernatant, rinse cycle, when the input starting liquid, may enter the inlet 22, or 23, is not limited. 当采用液体冲洗时,通道21的气体调节不泵入气体。 When flushing liquid, gas passage 21 into the gas pump is not adjusted.

[0063] 当第一、第二样品收集器装置16提供足够的微球收集效果时,不必提供更多的收集装置。 [0063] When the first and second means for providing a sample collector to collect a sufficient effect of the microspheres 16, necessary to provide more collection devices. 为了进一步提高微球的收集效果,可以将多个同第二收集装置连接在一起。 To further improve the collection performance of the microspheres, can be connected together with a plurality of second collecting means.

[0064] 下面将描述使用上述实施方案的设备,进行微球生产的实施例。 [0064] The apparatus will be described below using the above-described embodiment, for the microspheres produced in Example.

[0065] 实施例1 [0065] Example 1

[0066] 将150克明胶溶解于温度约60度的1000毫升水中,搅拌中加入10克盐酸多西环素,至完全溶解。 [0066] 150 grams of gelatin dissolved in 1000 ml water at a temperature of about 60 degrees, stirring 10 g of doxycycline hydrochloride, until completely dissolved. 将此含药混合液按照实施方案制备盐酸多西环素药物微球。 This drug-containing mixture of doxycycline hydrochloride was prepared microballoons embodiment. 其中在辅助收集的托盘操作中采用气体吹扫法。 Wherein the gas purge method using the tray in operation auxiliary collected. 在收集器15和17处收集微球,由此产生实施例1的药物微球。 The collector 15 and the microspheres were collected at 17, thereby producing a pharmaceutical microspheres Example 1 embodiment.

[0067] 实施例2 [0067] Example 2

[0068] 将100克乙基纤维素溶解于1000毫升82%的乙醇中,加入对乙酰氨基酚15克。 [0068] 100 g of ethyl cellulose were dissolved in 1000 ml of 82% ethanol, was added 15 g of acetaminophen. 将此含药混合液按照实施方案制备对乙酰氨基酚药物微球。 This drug-containing mixture was prepared in accordance with embodiments of the drug acetaminophen microspheres. 其中在辅助收集的托盘操作中采用气体吹扫法。 Wherein the gas purge method using the tray in operation auxiliary collected. 在收集器15和17处收集微球,由此产生实施例2的药物微球。 15 and the collector 17 to collect the microspheres, microballoons thereby generating the second embodiment.

[0069] 实施例3 [0069] Example 3

[0070] 将40克右旋糖酐溶入250毫升水中,轻微搅拌中加入胸腺五肽1克,将此水溶液在分钟400转的搅拌速度下,均匀加入至300毫升10%的聚乳酸-羟基乙酸的二氯甲烷溶液中,形成乳白状乳液。 [0070] 40 g of dextran dissolved in 250 ml of water, stirred slightly thymopentin was added 1 gram of this solution under stirring at 400 revolutions minute, evenly added to 300 ml of a 10% polylactic acid - glycolic acid di chloride solution to form a milky emulsion. 将此含药乳状液按照实施方案制备胸腺五肽药物微球。 This drug-containing emulsion thymopentin pharmaceutical microspheres prepared in accordance with the embodiment. 其中在辅助收集的托盘操作中采用气体吹扫法。 Wherein the gas purge method using the tray in operation auxiliary collected. 在收集器15和17处收集微球,由此产生实施例3 的药物微球。 The collector 15 and the microspheres were collected at 17, thereby producing a pharmaceutical microspheres according to the third embodiment.

[0071] 实施例4 [0071] Example 4

[0072] 将120克微粉乙基纤维素(粒径分布在30微米以下),均匀分散于300毫升5% 的羟丙甲基纤维素中,再将酒石酸美托洛尔药物20克溶解于其中,搅拌均匀,得到含药悬浮液。 [0072] The 120 g of ethyl cellulose powder (particle size distribution is 30 microns or less), are uniformly dispersed in 300 ml of a 5% hydroxypropylmethyl cellulose, and then the drug metoprolol tartrate dissolved therein 20 g , stir to give a drug containing suspension. 将此含药乳状液按照实施方案制备酒石酸美托洛尔药物微球。 This drug-containing emulsion was prepared in accordance with embodiments of the drug metoprolol tartrate microspheres. 其中在辅助收集的托盘操作中采用气体吹扫法。 Wherein the gas purge method using the tray in operation auxiliary collected. 在收集器15和17处收集微球,由此产生实施例4的药物微球。 The collector 15 and the microspheres were collected at 17, thereby producing a pharmaceutical microspheres of Example 4.

[0073] 实施例5 [0073] Example 5

[0074] 取100克鲸蜡醇,加热融化,向此蜡油中加入5克利培酮,搅拌均匀,得到利培酮的含药融化状液。 [0074] Take 100 grams of cetyl alcohol, heated to melt, to this was added 5 Keli Pei one wax, and mixed homogeneously to obtain the drug-containing melt humor risperidone. 将此含药融化状液按照实施方案制备利培酮药物微球。 This drug-containing melt was prepared according to embodiments humor risperidone microballoons. 其中在辅助收集的托盘操作中采用气体吹扫法。 Wherein the gas purge method using the tray in operation auxiliary collected. 在收集器15和17处收集微球,由此产生实施例5的药物微球。 The collector 15 and the microspheres were collected at 17, thereby producing a pharmaceutical microspheres of Example 5.

[0075] 实施例6 [0075] Example 6

[0076] 将12克海藻酸钠溶解入200毫升水中,再加入干扰素0. 3克,轻轻搅拌形成干扰素海藻酸钠溶液。 [0076] The 12 g of sodium alginate was dissolved into 200 ml of water and adding 0.3 g of interferon, interferon gently stirred to form a solution of sodium alginate. 另配制3%的磷酸二氢钙水溶液2000毫升,作为液体处理冲洗液。 Another formulation of 3% aqueous solution of calcium dihydrogen phosphate 2000 ml, a liquid treatment rinse. 其中在辅助收集的托盘操作中采用液体冲洗法。 Wherein the flushing method using a liquid in the operation of the auxiliary tray collected. 在收集器15处收集微球悬浮液,离心后产生实施例6的凝胶状药物微球。 After the collector 15 of the microsphere suspension was collected, centrifuged to produce a gel-like pharmaceutical microspheres of Example 6.

[0077] 测试实施例1 [0077] Test Example 1

[0078] 1.对实施例1-6的微球试样外观进行显微观测和拍照,使用仪器为徕卡显微镜(LeicaDM5000B,Germany),采用相干涉光源拍照。 [0078] 1. The appearance of microspheres of Examples 1-6 samples for microscopic observation and photographing, the instrument used Leica microscope (LeicaDM5000B, Germany), photographed using a light source interfere. 图4-9显示。 Figure 4-9 shows.

[0079] 图片显示采用本发明提供的设备和实施方法,以连续的方式制备的药物微球试样的球形度良好,分散性优良。 [0079] and image display apparatus using the embodiment of the present invention provides a method, spherical microballoons of the sample prepared in a continuous manner a good, excellent dispersibility.

[0080] 2.对实施例1-6的微球样品进行粒径分布分析,仪器为MASTERSIZER 2000(MALVERNINSTRUMENT)〇 [0080] Embodiment 2. Examples 1-6 Samples of microspheres were particle size distribution analysis, the instrument is a MASTERSIZER 2000 (MALVERNINSTRUMENT) square

[0081] 其中对实施例1-5试样,采用干法测定;对实施例6试样采用湿法测定,介质为PH 5. 0的磷酸盐缓冲液。 [0081] Example 1-5 in which a sample embodiment using dry assay; Example 6 Sample embodiment of a wet assay, the medium is phosphate buffer PH of 5.0.

[0082] 粒径检测结果见表1。 [0082] The particle size of the detection results shown in Table 1. 结果显示,采用本发明提供的设备和实施方法,以连续的方式制备的药物微球试样的粒径分布集中,一致性优良。 The results show that, using apparatus and method of the present embodiment provided herein, the particle size of microballoons prepared specimen in a continuous manner the distribution of concentration, excellent consistency.

[0083] 表1 [0083] TABLE 1

[0084] [0084]

Figure CN101816913BD00081

[0085] 3.对实施例1-6的微球试样进行药物含量测定。 [0085] 3. Determination of drug content in the microspheres of Examples 1-6 samples. 结果见表2。 The results are shown in Table 2.

[0086] 药物包封率(%)=测定微球药物含量/药物投入含量X 100% [0086] Drug encapsulation efficiency (%) = drug content measured microspheres / drug content inputs X 100%

[0087] 结果显示,采用本发明提供的设备和实施方法,以连续的方式制备的药物微球试样的包封率均在95%以上。 [0087] The results show that, using apparatus and method of embodiments of the present invention provides, microsphere encapsulation efficiency of drug samples prepared in a continuous manner at least 95%.

[0088] 对各实施例微球试样药物含量的分析方法分别描述如下: [0088] describe methods for drug content analysis of each Example a sample embodiment of the microspheres as follows:

[0089] 实施例1试样,参照《中国药典》2010版二部,盐酸多西环素片含量项下方法测定。 [0089] Example Sample 1 embodiment, with reference to two "Chinese Pharmacopoeia" 2010, Determination of the content item multi doxycycline hydrochloride tablets.

[0090] 实施例2试样,参照《中国药典》2010版二部,对乙酰氨基酚片含量项下方法测定。 [0090] Example 2 Sample, refer to "Chinese Pharmacopoeia" 2010 version two, a method of measuring the content item paracetamol tablets.

[0091] 实施例3试样,参照《国家药品标准》WSl-(X-027)-2004Z,胸腺五肽含量测定项下方法测定。 [0091] Example 3 a sample embodiment, with reference to the measurement method in the item "National Drug Standards" WSl- (X-027) -2004Z, thymopentin determination.

[0092] 实施例4试样,参照《中国药典》2010版二部,酒石酸酸美托洛尔片含量项下方法测定。 [0092] Example 4 Sample, refer to "Chinese Pharmacopoeia" 2010 two, determination of the metoprolol tartrate tablets acid content item.

[0093] 实施例5试样,参照《国家药品标准》WSl-(X-056)-2003Z,利培酮片含量测定项下测定。 [0093] Example 5 Sample, WSl- (X-056) -2003Z, measured at entry Risperidone Tablets by reference to "national drug standards."

[0094] 实施例6试样,先将凝胶微球冻干作为试样,测定时精密称取干燥的微球10毫克, 加入水10毫升震荡3次,每次3分钟,0. 2微米滤膜过滤,取续滤液,用紫外-可见分光光度计在波长280nm处测定,与原料配制的标准液测值计算含量。 [0094] Example 6 Sample embodiments, the first hydrogel microspheres freeze-dried as a sample, accurately weighed dried microspheres 10 mg of measurement, 10 ml of water was added 3 times shaking, 3 minutes each, 0.2 m membrane filter, the filtrate, UV - visible measured value calculation standards formulated content feedstock in a spectrophotometer at 280nm.

[0095]表2 [0095] TABLE 2

[0096] [0096]

Figure CN101816913BD00091

Claims (6)

  1. 1. 生产微球的方法,其特征在于该方法具体为将溶液、微粒悬浮液、乳液或熔融液形式的原料混合液供入微滴发生装置;通过微滴发生装置将原料混合液以微滴的形式分散于主体腔;通过含有高速旋转碟的微滴发生装置将原料混合液形成高度分散的微滴;微滴在主腔体内受到向心气流和切线旋转气流的约束运行;逐渐除去溶剂或冷凝固化形成微球产物;微球产物被收集装置收集。 1. A method of producing microspheres, which is characterized in that it is the particular solution, microparticle suspension, emulsion or melt of the raw material mixture in the form of droplets generating means for nuanced; the raw material mixture by the droplet generator of droplets dispersed in the body cavity; a raw material mixture is formed by the highly dispersed droplets comprising a high speed rotary disc droplet generator; droplet is constrained to run centripetal whirling airflow in the main stream and the tangential cavity; gradually removing the solvent or condensing the product solidified to form microspheres; microsphere product is collected by collection means.
  2. 2. 依照权利要求1的生产微球的方法,其特征在于,其中待微球化的原料是液体的形式。 2. The process for producing microspheres according to claim 1, wherein, wherein the microspheres of the starting material to be in liquid form.
  3. 3. 依照权利要求1的生产微球的方法,其特征在于,微球产物被收集装置收集。 3. The process for producing microspheres according to claim 1, wherein the microspheres are collected means for collecting the product.
  4. 4. 生产微球的设备,其特征在于该设备包含: 用于微球制备的主要容器装置含有隔热层和双层结构; 用于将混合液输入到微滴发生装置的供液喷嘴,经过喷嘴将原料混合液输送到微滴发生装置; 用于将原料混合液形成微滴的装置,该装置至少包括受到驱动可以高速旋转的碟片; 用于向高速旋转的碟片平面中心向心吹气的气流环; 用于形成切向旋风的气流装置; 用于收集微球的装置。 4. Production of the microspheres, characterized in that the apparatus comprises: a primary container means containing microspheres prepared and a two-layer structure insulating layer; mixture for input to the liquid nozzle for droplet generating means, through the raw material mixture supplied to the nozzle droplet generating means; means for forming droplets of the raw material mixture, the apparatus comprising at least a disk drive can be rotated at high speed; means for blowing the radial center plane of the disc rotating at high speed gas flow ring; means for forming a tangential cyclonic airflow; and means for collecting the microspheres.
  5. 5. 依照权利要求4的生产微球的设备,其特征在于,用于形成切向旋风的气流装置,包含提供切向气流的入口,以及切线气流入口底下可以控制局部切线气流主要向上运行的圆环。 The microspheres according to the manufacturer apparatus as claimed in claim 4, wherein the air flow means for forming the tangential cyclone, comprising a tangential inlet to provide a gas stream, the tangential air inlet may be controlled under the local tangent circle running upward flow mainly ring.
  6. 6. 依照权利要求5的生产微球的设备,其特征在于,其收集微球产物的装置包含, 第一部分,多个扇形托盘和每个扇形托盘对应的吹扫口,吹扫口可以平行托盘平面向心吹扫气体;或者吹扫液体; 第二部分,第一样品收集装置,该装置包含气流通道,回旋沉降装置,样品收集器;还包含可以将液体循环至回流至吹扫口的通道装置; 第三部分,第二样品收集器装置,该装置包含与第一样品相连的通道,回旋沉降装置, 样品收集器,以及可以将气体循环至吹扫口的调节器装置。 6. The apparatus in accordance with the production of microspheres as claimed in claim 5, characterized in that means for collecting the product comprises microspheres, a first portion, a plurality of sectors and each sector pallet trays corresponding purge port, the purge port may be parallel to the tray radial plane purge gas; or purge fluid; a second portion, a first sample collection device, the apparatus comprising a gas flow passage, the swirling sedimentation device, the sample collector; further comprises circulating the liquid to be returned to the purge port passage means; a third portion, the second sample collection means, the apparatus comprising a first passage connected to the sample, swirling sedimentation device, a sample collector, and the gas can be recycled to the purge port means of the regulator.
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