CN101987081A - Controlled release preparation - Google Patents

Controlled release preparation Download PDF

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CN101987081A
CN101987081A CN 201010227254 CN201010227254A CN101987081A CN 101987081 A CN101987081 A CN 101987081A CN 201010227254 CN201010227254 CN 201010227254 CN 201010227254 A CN201010227254 A CN 201010227254A CN 101987081 A CN101987081 A CN 101987081A
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soluble
water
insoluble
polymer
controlled release
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CN 201010227254
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Chinese (zh)
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CN101987081B (en )
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钟术光
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钟术光
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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
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846Poly(meth)acrylates

Abstract

The invention discloses a controlled release preparation with improved performance. The controlled release preparation comprises a core containing medicament and a controlled release film covering the outside of the core and being almost insoluble in water as well as stomach and intestines digestive juice. The controlled release film comprises particulate matters of a water soluble medicinal additive, the water-soluble medicinal additive is covered by a polymer film which can be soluble in the stomach and/or intestines digestive juice but almost insoluble in water, the polymer and the medicinal additive can not produce chemical reaction or can produce chemical reaction but do not produce water-insoluble non-gaseous products and the pharmaceutically unacceptable products, and the amount of the polymer is no more 700% of that of the medicinal additive. The invention also discloses a preparation method of the controlled release preparation. The controlled release preparation has the advantages of improved medicament release reproducibility, reduced medicament release lag time, accelerated medicament release and improved bioavailability, can realize located controlled release, delayed controlled release and interval type or pulse type controlled release of the medicament in the gastrointestinal tract, and the like.

Description

一种控释制剂 A controlled release formulation

技术领域 FIELD

[0001] 本发明涉及一种控释制剂。 [0001] The present invention relates to a controlled release formulation. 更具体地说,本发明涉及一种性能改善的控释制剂特别是零级释放的控释制剂。 More particularly, the present invention relates to such an improved controlled release formulation of controlled-release formulations particularly zero order release. 本发明还涉及该控释制剂的制备方法。 The present invention also relates to a method for preparing the controlled-release formulations.

背景技术 Background technique

[0002] 一些水不溶性聚合物在控释制剂,特别是零级释放的控释制剂中通过包衣控制药物释放。 [0002] Some water-insoluble polymer in a controlled release formulation, controlled release formulation in particular zero-order release of drug release control by coating. 由于聚合物的水不溶性,常常需要在衣膜中形成微孔来改善控释衣膜的通透性(permeability)以利于水分的渗透及药物的释放,特别是药物的溶解性偏低及制剂总表面积较小时。 Since the water-insoluble polymer, it is often necessary to form micropores in the coating film to improve the permeability of the controlled release film coat (permeability) to facilitate the release of water permeation and drug, particularly low solubility drugs and total formulation surface area is small.

[0003] 至今,相关包衣膜控释制剂技术有三个典型代表: [0003] So far, the relevant film-coating technology has three controlled-release formulations typical:

[0004] 一是以US4629619为代表的:此类技术把可溶于水的致孔剂分散并混悬于含有水不溶性聚合物的有机溶剂中,通过包衣使水溶性物质存在于水不溶性聚合物的衣膜中,此衣膜中的可溶于水的致孔剂在消化道中被消化液溶解形成较大的微孔。 [0004] First, US4629619 represented by: Such techniques are the water soluble porogen dispersed and suspended in an organic solvent containing a water-insoluble polymer by a water-soluble substance is present in the coating water-insoluble polymeric coating film composition, a water soluble porogen this coating film in the digestive fluids in the digestive tract are dissolved to form larger pores. 此技术的缺陷之一在于制剂最终成型时使用了有机溶剂。 One drawback of this technique is the use of an organic solvent forming the final formulation.

[0005] 二是以US5472712及US5639476为代表的:此类技术把可溶于水的致孔剂溶解于含有水不溶性聚合物的水分散液(体)(Aqueous polymeric dispersion)中,通过包衣使水溶性物质存在于水不溶性聚合物的衣膜中,此衣膜中的水溶性物质在消化道中被消化液溶解形成很小的微孔。 [0005] Second, US5472712 and US5639476 represented by: Such techniques are the water soluble porogen dissolved in an aqueous dispersion containing water-insoluble polymer (bulk) (Aqueous polymeric dispersion) by making the coating water-soluble substances present in the water-insoluble polymer coating film, the coating film of this water-soluble material is dissolved to form a small micropores digestive juices in the gastrointestinal tract. 此技术的优点在于避免了使用有机溶剂。 The advantage of this technique is to avoid the use of organic solvents. 但也有诸多缺陷:水溶性致孔剂以单分子状态存在衣膜中,微孔的孔径大小受制于水溶性致孔剂的分子大小,孔径较以混悬态制备(如US4629619)的小很多,不利于分子半径较大的药物的穿透;因此,当包衣膜的通渗性可以满足实际应用要求时,特别是药物的溶解性偏低及制剂总表面积较小时,其机械强度非常弱;实际可用的孔道不好控制,生产重现性较差。 But there are many defects: a water soluble porogen is present in a monomolecular state in the coating film, the pore size of micropores is subject to the molecular size of the water soluble porogen, the pore size than the suspended state preparation (e.g. US4629619) to much smaller, large molecular radius is not conducive to the penetration of drugs; therefore, when the through-permeable coating membrane can meet practical requirements, particularly low solubility drugs and formulations of the total surface area is small, its mechanical strength is very weak; not actually available control channels, producing poor reproducibility.

[0006] 三是US6974591为代表的:此类技术一股地把不溶于水但可溶于酸性或碱性的消化液的致孔剂分散并混悬于含有水不溶性聚合物的水分散液(体)(AqUeoUS polymeric dispersion)中,通过包衣使致孔剂存在于水不溶性聚合物的衣膜中,此衣膜中的致孔剂在消化道中被消化液溶解形成较大的微孔。 [0006] Third, US6974591 represented by: Such techniques are generically the water-insoluble and soluble in an acidic or alkaline digestive juices porogen dispersed and suspended in an aqueous dispersion containing water-insoluble polymer ( body) (aqUeoUS polymeric dispersion) by making coated porogen present in the water-insoluble polymer coating film, the coating film in this porogens are dissolved in the digestive tract digestive form larger pores. 此技术一定程度地结合了前两类技术的优点,也一定程度地克服了前两类技术的缺点。 This technique combines the advantages of two technologies before a certain extent, also to some extent overcome the disadvantages of the prior art two. 但此技术的缺陷也不少:如微孔的形成或致孔剂的溶解受消化液的酸性或碱性的强弱或PH值的高低及消化液量的多少等体内因素影响程度较大;微孔的形成或致孔剂溶解(特别是非聚合物类的致孔剂如酒石酸氢钾)需要相对较长的时间,药物的释放表现出较高的时滞性(特别是非聚合物类的致孔剂如酒石酸氢钾)。 The drawback of this technique but also a lot of: forming micropores such as dissolving or porogen affected by the level and amount of the digestive juice or the strength of the like number of acidic or basic PH value of the factor a greater degree in vivo digestive juice; forming micropores or porogen was dissolved (such as in particular porogen polymers are non-potassium hydrogen tartrate) require a relatively long time, it exhibits a high drug release time lag (particularly non-induced polymers pore formers such as potassium hydrogen tartrate). 这些因素将使药物的释放行为变得不稳定,出现体内因素药物释放稳定性或重现性变差。 These factors will enable drug release behavior becomes unstable factors occur in vivo drug release stability or poor reproducibility.

[0007] 需要特别指出的是,以US46296 19、US6974591为代表的技术,其中以消化液可溶性的极性的小分子物质作为一股致孔剂,以消化液不溶性的非极性聚合物为一股衣膜材料,故二者共混时会出现两相间界面能甚高,相互间的相容性及粘合力甚差的问题,结果造成分散不均,粒状的致孔剂也将成为衣膜中的应力集中点,成为衣膜中的薄弱环节,使衣膜机械强度大幅降低,进而可能使控释制剂突释(dose-dumping)。 [0007] Of particular note is that, to US46296 19, US6974591 represented technology, which digestive soluble polar small molecules as an porogen, non-polar polymer is insoluble in a digestive Unit coating film material, so the two will appear when blended interfacial energy between the two phases is very high, and the compatibility problem of very poor adhesion with one another, resulting in non-uniform dispersion, particulate porogen will also become coated stress concentration points in the film, the coating film becomes weak link, so that the mechanical strength of the coating film significantly decreases, which may cause burst release formulation (dose-dumping). 这些弊端不但限制了致孔剂在衣膜中的添加量,而且还严重影响制剂产品性能,特别是用药完全性。 These drawbacks not only limit the amount of added porogens in the coating film, but also seriously affect the performance of the product formulation, in particular drugs complete. (参见:《高分子化学及物理》,王梓杰主编,中国轻工业出版社出版,1992年04月第1版,第345页;《高聚物的表面与界面》,吴人洁主编,科学出版社(北京),第104〜10页;无机填料的改性,江西化工,2001年,第4期,第17〜18页)。 (See: "Polymer Chemistry and Physics", edited by Wang Zi Jie, China Light Industry Press, April 1992 1st edition, p. 345; "polymer surface and interface," Wu Renjie editor, Science Press (Beijing ), the 104~10 page; inorganic fillers modified, Jiangxi Chemical, 2001, No. 4, pp. 17~18).

[0008] 此外,由于相容性甚差,特别是在湿气作用下,这些水溶性物质容易从聚合物膜中析出,出现所谓的“泛霜”现象;水溶性物质容易从聚合物膜中析出后留下微孔,微孔在表面张力及其他因素如水汽等作用下缩小甚至完全愈合,从而使药物的释放行为变得不稳定, 出现体外因素药物释放稳定性或重现性变差。 [0008] Further, since the compatibility is very poor, particularly under the action of moisture, these water-soluble substances likely to be precipitated from the polymer film, so-called "efflorescence" phenomenon; readily water-soluble substance from the polymer film after precipitation leaving micropores in the microporous reduced surface tension and other factors such as the role of water vapor or even completely healed and the like, so that the drug release behavior becomes unstable factors in vitro release of drug occurs stability or reproducibility is deteriorated.

[0009] 另外,US6974591为代表的技术还使用一些消化液可溶但水不溶的聚合物作为致孔剂。 [0009] Further, US6974591 technical representatives also use some digestive juice-soluble but water-insoluble polymer as a porogen. 这些聚合物致孔剂与消化液不溶性的聚合物衣膜材料通常表现为部分相容和完全相容。 These polymeric coating polymeric film material and porogen usually presents digestive insoluble biocompatible and fully compatible portion. 当两种聚合物相互接触时,首先在界面处相互湿润,然后两相大分子链段通过热运动而相互扩散,扩散的结果,使得两种聚合物在界面两边产生明显的浓度梯度。 When the two polymers are contacted with each other, each first wetting at the interface, and then the two phases macromolecular chain segments to each other by thermal diffusion movement, the result of diffusion, such that the two polymers have a significant concentration gradient on both sides of the interface. 这种具有明显浓度梯度的区域构成了两相间的界面层。 This region constitutes a significant concentration gradient of the interface layer between the two phases. 界面层的厚度主要决定于两种聚合物的相容性。 The thickness of the interface layer is mainly determined on the compatibility of the two polymers. 随着相容性的增加,扩散程度提高,相界面越来越模糊,界面层厚度越来越大,以致最终相界面完全消失,成为均相共混物,达到完全相容(参见:聚合物合金的相容性与增容,青岛大学学报,1995年5月,第10卷,第1期,第91页)。 With increase the compatibility and improve the degree of diffusion, interfacial increasingly blurred, increasing the thickness of the interface layer, and eventually the phase boundary disappears completely, the blend was homogeneous, fully compatible reached (see: Polymer compatibility with extenders alloy, Qingdao University, May 1995, Vol. 10, No. 1, p. 91). 正是由于聚合物间的这种相互扩散渗透, 结果大分子的致孔剂与控释衣膜间的界面随时间的延长变得越来越模糊,可形成的微孔也随时间的延长变得越来越模糊,孔径大小也变得不恒定,从而使药物的释放行为变得不稳定,出现体外因素药物释放稳定性或重现性变差。 It is this mutual diffusion between the polymer penetration between the macromolecules result screen porogen controlled release coating film becoming increasingly blurred with time, pores can be formed also increases with time more and more blurred, the pore size also becomes constant, so that the drug release behavior becomes unstable factors in vitro drug release occurs stability or reproducibility is deteriorated.

[0010] 因此,现实中还需要一种控释制剂特别是零级释放的控释制剂制备技术,此技术既能继承或进一步发扬上述已有技术的优势,又能克服上述已有技术的诸多缺陷。 [0010] Thus, in reality, is also a need for a controlled release formulation is especially zero-order controlled-release formulations release preparation technology, this technology not only inherited or further develop the advantages of the above prior art, but also overcome many of the above-mentioned prior art defect.

[0011] 发明目的 [0011] Object of the Invention

[0012] 本发明目的之一就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该技术制得的制剂药物释放稳定性或重现性被改善。 [0012] One object of the present invention to provide an improved controlled release formulation of the above properties in particular zero-order release of the controlled release formulation and preparation techniques, the pharmaceutical formulation art prepared discharging stability or reproducibility is improved.

[0013] 具体地说,就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该控释制剂的释药微孔孔径大小在贮藏和/或生产过程中更稳定,受体外因素的影响更小,如在贮藏和/或生产过程中,该控释制剂控释膜中的水溶性致孔剂不易从聚合物膜中析出,该控释制剂中的大分子的致孔剂与控释衣膜间的界面互相扩散变得模糊而引起的释药不稳定被限制在一定可接受的范围内。 [0013] Specifically, to provide an improved controlled release formulation of the above properties in particular zero-order release of the controlled release formulation and preparation techniques, controlled-release formulations release the pore size in the size storage and / or production more stable, the influence of external factors receptors less, such as in the storage and / or production process, the controlled release formulations release film easily soluble porogen precipitated from the polymer film, the controlled release formulation the macromolecules induced interface between coating film porogen diffusion controlled release blurred due to release each other is limited within a certain instability in the acceptable range.

[0014] 本发明目的之一就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该控释制剂的释药微孔的形成受体内因素影响程度更小,具有更佳的药物体内释药性行为。 [0014] One object of the present invention is to provide a controlled release formulation of the above improved properties particularly zero order release controlled release formulation and preparation techniques, the formation of micropores release of the controlled release formulation extent influenced by factors in vivo smaller, have better drugs in vivo drug release behavior.

[0015] 本发明目的之一就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该控释制剂的释药微孔的形成所需要时间缩短,药物的溶出表现出的时滞性更小。 [0015] One object of the present invention is to provide a controlled release formulation of the above improved properties in particular zero-order controlled release formulation and preparation technology release, shortening the time required form micropores release of the controlled release formulation of the drug exhibit dissolution time lag smaller.

[0016] 本发明目的之一就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该控释制剂的控释衣膜机械强度被提高,不易发生突释(dose-dumping),用药完全性被提高。 [0016] One object of the present invention is to provide a controlled release formulation of the above improved properties in particular zero-order controlled release formulation and preparation technology release, controlled release coating film mechanical strength of the controlled release formulation is increased, less prone to projecting release (dose-dumping), complete treatment is improved.

[0017] 本发明目的之一就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该控释制剂可以实现药物在胃肠道中定位控释释放,如胃、肠、结肠控释释放,特别是肠、结肠控释释放; [0017] One object of the present invention is to provide a controlled release formulation of the above improved properties particularly zero order release controlled release formulation and preparation technology, which can achieve controlled-release pharmaceutical formulations positioned controlled release in the gastrointestinal tract, such as stomach, intestines, colon controlled release, especially the intestines, colon controlled release;

[0018] 本发明目的之一就是提供一种上述性能改善的控释制剂特别是零级释放的控释制剂及其制备技术,该控释制剂可以实现药物在胃肠道中延时控释释放、间隙式或脉冲式控释释放; [0018] One object of the present invention to provide an improved controlled release formulation of the above properties in particular zero-order release of the controlled release formulation and preparation techniques, the controlled release formulation can be achieved delayed controlled release of the drug in the gastrointestinal tract, gaps or pulsed controlled release;

[0019] 本发明的其他目的参见下列说明书。 [0019] Other objects of the present invention is found in the following description.

发明内容 SUMMARY

[0020] 本发明涉及一种性能改善的控释制剂特别是零级释放的控释制剂,该控释制剂包括: [0020] The present invention relates to an improved performance particularly zero order release formulations release a controlled release formulation, the controlled release formulation comprising:

[0021] a)、含有一种药物的核芯; [0021] a), a drug containing core;

[0022] b)、外覆于上述核芯的控释衣膜,其中,该控释衣膜包含药学上可接受的增塑剂、 药学上可接受的不溶于或几乎不溶于水及胃和肠消化液的聚合物及包埋于其中的作为致孔剂的被含有药学上可接受的增塑剂或不含有增塑剂的药学上可接受的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物,上述可溶于水的药用添加剂与上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物在体内消化液中不能发生化学反应或者能发生化学反应但不生成不溶于水且常温(25°C)下为固体或液体的产物及药学上不可接受的产物,且上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量不超过上述可溶于水的药用添加剂的用量的700% (重量/重量)。 [0022] b), the outer cover to the core of the controlled release coating film, wherein the controlled release film coating comprising a pharmaceutically acceptable plasticizer, a pharmaceutically acceptable insoluble or almost insoluble in water and gastric and soluble in the stomach and / or intestines and intestinal digestive juices polymer entrapped therein is as a porogen comprising a pharmaceutically acceptable plasticizer or without a pharmaceutically acceptable plasticizer digestive juices but insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble pharmaceutically acceptable additive particles, the above-described water-soluble pharmaceutical additives may be dissolved in the above-mentioned gastric and / or intestinal digestive juices but insoluble or hardly water-soluble polymer does not chemically react in vivo digestive fluids, but does not produce or insoluble in water and at room temperature (25 ° C) the product is a solid or liquid pharmaceutically acceptable and unacceptable chemical reaction can occur product and said soluble in the stomach and / or intestinal digestive juices but the amount is insoluble or hardly water-insoluble polymer coating film is not more than (wt / 700% the amount of water-soluble pharmaceutically acceptable additives weight).

[0023] 本发明还涉及一种性能改善的被控释衣膜包覆的控释制剂特别是零级释放的控释制剂的制备方法,该方法包含下列几个基本步骤:1)、制备含有一种药物的芯料;2)、对可溶于水的药用添加剂的颗粒物用含有药学上可接受的增塑剂或不含有增塑剂的药学上可接受的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的溶液或分散液包覆衣膜,上述可溶于水的药用添加剂与上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物在体内消化液中不能发生化学反应或者能发生化学反应但不生成不溶于水的非气态(即常温(25°C)下为固体或液体的)的产物及药学上不可接受的产物,且上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量不超过上述可溶于水的药用添加剂的用量的700% (重量/重量);3)、对上述 [0023] The present invention further relates to a method for preparing a controlled release formulation is especially zero order controlled-release formulations coated with a release coating film improved properties, the method comprising the following basic steps: 1) was prepared containing a pharmaceutical core material; 2), of water-soluble pharmaceutically acceptable additives containing particulate matter with a pharmaceutically acceptable plasticizer containing no plasticizer or a pharmaceutically acceptable soluble in the stomach and / or intestinal digestive juices but coated with a solution or dispersion coating film is insoluble or hardly water-soluble polymer, said water-soluble pharmaceutical additives may be dissolved in the above-mentioned gastric and / or intestinal digestive juices but insoluble almost insoluble in water or in the polymer does not chemically react in vivo digestive fluids, but does not generate a chemical reaction or water-insoluble non-gaseous occur (i.e., room temperature (25 ° C) is solid or liquid) products and pharmaceutically unacceptable product, and the above-described soluble in the stomach and / or intestinal digestive juices but the amount is insoluble or hardly water-insoluble polymer coating film does not exceed the amount of the water-soluble pharmaceutically acceptable additive 700% (wt / wt); 3), above 有一种药物的芯料用含有药学上可接受的增塑剂的药学上可接受的不溶于或几乎不溶于水及胃和肠消化液的聚合物的溶液或分散液包覆控释衣膜,其中,该聚合物的溶液或分散液中分散有作为致孔剂的被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的上述的可溶于水的药用添加剂的颗粒物,该聚合物的溶液或分散液不溶解或不降解或几乎不溶解或几乎不降解所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物;4)、必要时,对上述衣膜进行愈合(老化)处理。 There is a drug containing core material is insoluble or hardly water-soluble polymers and gastric and intestinal digestive juices of the solution or dispersion of a film-coated controlled release coating pharmaceutically acceptable pharmaceutically acceptable plasticizers, wherein the solution or dispersion of the above-mentioned polymer dispersed porogen may be soluble in the above-described gastric and / or intestinal digestive juice but insoluble or hardly water-insoluble polymer coating as a film-coated the pharmaceutically acceptable water-soluble particulate additive solution or dispersion of the polymer does not dissolve or degrade or hardly soluble or hardly soluble degradation of the stomach and / or intestinal or digestive fluids, but almost insoluble water-insoluble polymer; 4), if necessary, the above-described coating film healing (aging) treatment.

[0024] 本发明使用的术语“活性成分”、“生物活性成分”、“药用活性组分”、“活性物”、“活性剂”及“生物活性物质”、“药物”等是指任何物质当其施予活体时具有可检测的生物效应包括任何生理学的、诊断的、预防性的或药理学效应。 [0024] the present invention the term "active ingredient", "bioactive ingredient", "pharmaceutically active ingredient", "active", "active agent" and "biologically active substance", "drugs" and the like refers to any a detectable substance having a biological effect when administered to a living body which includes any physiologically, diagnostic, prophylactic or pharmacological effect. 此术语旨在包括但不限于任何药学的、治疗学的、预防性的、营养学的物质。 This term is intended to include, but not limited to any pharmaceutically acceptable, therapeutic, and preventive, nutritional substance. [0025] 本发明使用的术语“控释衣膜”是指包覆于控释制剂的核芯外表面上的含有足够量的疏水性(聚合物)材料的并具有足够机械强度维持控释制剂在置于水溶液释药过程中的不破裂的包衣膜,该包衣膜能延缓释放上述控释制剂被置于水溶液时其所含的药物或洽疗活性剂。 [0025] The term used herein "controlled release coating film" refers to a controlled release formulation coated on the outer surface of a core containing a sufficient amount of hydrophobic (polymer) material and having sufficient mechanical strength to maintain a controlled release formulation placed in an aqueous release coating membrane is not broken during the film coating to delay the drug release Huoqia therapeutically active agent is placed in the above-described controlled release formulation which contains an aqueous solution.

[0026] 本发明使用的术语“包含”及“含有”是指包括但不限于或除了此物还可以包含其他成分等类似的含义。 [0026] the present invention, the term "comprising" and "comprising" is meant to include, but is not limited to this or in addition may also contain other components such similar meaning.

[0027] 本发明使用的术语“一种”是指至少为一种,可以为只有一种,也可以为二种或多种。 The term as used herein [0027] The present "an" means at least one kind, may be only one, or may be two or more.

[0028] 本发明涉及的“药学上可接受的,,是指在制剂中能彼此混合且相互无有害作用而不会降低制剂稳定性和/或效力且适用于局部或全身给药的意思。 [0028] The present invention relates to a "pharmaceutically acceptable ,, refers to the formulation can be mixed with each other and without reducing formulation stability and / or efficacy and suitable for topical or systemic administration means no adverse effect on each other.

[0029] 本发明使用的术语“约”是指量的变化幅度为士30% (例如某量为p,则P的可取值范围为0. 7p〜1.3p),较佳地为士20%,最佳地为士10%。 [0029] used herein, the term "about" refers to the amount of amplitude variation of ± 30% (e.g., an amount of p, then P may be in the range of 0. 7p~1.3p), preferably of ± 20 %, most preferably of ± 10%.

[0030] 本发明使用的术语“致孔剂”是指有助于在本发明的控释衣膜中形成孔或者提高控释衣膜的通渗性或水渗透性的物质,致孔剂在应用环境中可从控释衣膜中被溶解(dissolved)、浸出(extracted)、降解(leached)和/或化学反应(生成可溶于水的产物和/或气体)掉而形成孔。 [0030] The term used in the present invention, "porogen" refers to a hole formed in a controlled release coating helps film of the present invention or a substance improving water permeability through permeable or controlled release coating film, the porogen application environment may be dissolved (dissolved) from the controlled release film coating, leaching (Extracted), degradation (leached), and / or chemical reaction to form a hole (the product can be dissolved in water and / or gas) out.

具体实施方式 detailed description

[0031] 本发明的一个目的就是提供一种控释制剂特别是零级释放的控释制剂,该控释制剂通过外层包覆的分散或包埋于其中的作为致孔剂的已被含有药学上可接受的增塑剂或不含有增塑剂的药学上可接受的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物的控释衣膜来控制药物释放。 [0031] An object of the present invention is to provide a zero-order controlled release formulation is especially controlled-release release formulations, controlled release formulations which are dispersed through the outer covering or embedded therein as a porogen has been comprising pharmaceutically acceptable acceptable acceptable not contain a plasticizer or a plasticizer soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film may be coated with soluble the controlled release pharmaceutical additives coating film of the water particles to control drug release. 该致孔剂在消化液中形成释药孔道。 The porogen release channels formed in the digestive fluids.

[0032] 希望不完全受此原理或理论的限制,由于作为致孔剂的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的大分子聚合物颗粒中一部分空间被可溶于水的药用添加剂取代,聚合物间(即致孔剂衣膜与控释衣膜间)的相互扩散渗透被限制在一定范围内(因致孔剂聚合物与可溶于水的药用添加剂相容性差、几乎不相互扩散渗透),致孔剂聚合物颗粒中间至少有一定量的不改变的空间来形成大小相对稳定的微孔,从而使药物的释放行为在一定范围内变得相对稳定;同时,因可溶于水的药用添加剂的在水中的溶解相对较快、受体内因素影响通常相对较小,其取代致孔剂聚合物颗粒内部部分空间后,需溶解的致孔剂聚合物的量减少,药物的溶出表现出的时滞性将会相对变小,药物释放受体内因素影响也将相对变小。 [0032] Incomplete desired or theoretical principles so limited, since as the porogen soluble in the stomach and / or but insoluble or hardly water-soluble macromolecular polymer particles in the space portion of the intestinal digestive juices substituted water-soluble pharmaceutical additives, permeation interdiffusion between the polymer (i.e., between the actuator and the controlled release film coating agent pore coating film) is limited within a certain range (due to porogen polymer water-soluble drug poor compatibility additive hardly permeable interdiffusion), the intermediate polymer porogen particles having at least a certain amount of space is not changed to form a relatively stable size of micropores, so that the drug release behavior becomes relatively within a predetermined range stable; the same time, due to the dissolution of water-soluble pharmaceutical additives relatively fast in water, affected by factors often relatively small body, which after substitution actuator inner space porogen polymer particle fraction, dissolved need porogen dose reduction of the polymer, dissolution of the drug will exhibit a relatively small time lag, drug release will be affected by factors in vivo is relatively small. 此外,致孔剂聚合物包覆可溶于水的药用添加剂后,也能防止可溶于水的药用添加剂在潮湿环境下从控释聚合物衣膜中析出(“泛霜”)。 In addition, the porogen polymer coated water-soluble pharmaceutically acceptable additives, can be prevented from water-soluble pharmaceutical additives release polymer precipitated from the coating film in a wet environment ( "scumming"). 因从,药物释放的稳定性或重现性被改善。 Drug release due to the stability or reproducibility is improved from.

[0033] 可溶于水的药用添加剂通常具有非常高的极性,而控释衣膜的聚合物通常为疏水性的,故二者间相容性甚差;可溶于水的药用添加剂某些机械性能较差,如较大的脆性,而可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的致孔剂聚合物通常(相对于疏水性的控释衣膜材料聚合物)有一定量的酸性和/或碱性等极性基团,故二者有相对较好的相容性;另外,可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的致孔剂聚合物与疏水性的控释衣膜材料聚合物的亲合性通常大于可溶于水的药用添加剂与疏水性的控释衣膜材料聚合物的亲合性,因可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的致孔剂聚合物常含有较多的疏水性基因。 A pharmaceutically acceptable water-soluble; [0033] water-soluble pharmaceutical additives typically have a very high polarity, and a controlled release polymeric coating film is generally hydrophobic, so that very poor compatibility between the two some additives poor mechanical properties, such as high brittleness, while the stomach can be dissolved and / or intestinal digestive juice but insoluble or hardly water-soluble polymer is generally porogen (hydrophobic controlled release coating with respect to polymer film material) with a certain amount of acidic and / or basic polar group, so the two relatively good compatibility; Further, soluble in the stomach and / or intestinal or digestive fluids, but almost insoluble the affinity of water-insoluble polymer porogen affinity with the hydrophobic controlled release coating material of the polymer film is generally greater than the water-soluble additive with a pharmaceutically acceptable controlled release coating material of the polymer film is hydrophobic, soluble because the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer porogens typically contain more hydrophobic gene. 因此,可溶于水的药用添加剂被可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物包覆后能改善控释衣膜的机械性能。 Thus, water-soluble pharmaceutical additive is soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating can improve the mechanical properties of the controlled release film coat.

[0034] 特别需要进一步指出的是,作为致孔剂的大分子聚合物颗粒中一部分空间被可溶于水的药用添加剂取代后,作为致孔剂的大分子聚合物颗粒需被溶解或降解径距(其含义由下列“ Ar”所定义)大大减少,胃肠液只需溶蚀薄层中的一小部分衣膜聚合物就可以快速溶蚀衣膜里面的可溶于水的药用添加剂,可溶于水的药用添加剂快速溶蚀完后,更大量聚合物衣膜的表面暴露于胃肠液中,从而聚合物衣膜溶蚀速度大大加快,药物溶出表现出的时滞性也随之大大变小,药物溶出速度大大加快,聚合物衣膜溶蚀受体内因素影响也随之大大减少,药物释放的重现性或稳定性大大改善。 [0034] It is further noted that in particular, as the macromolecular polymer substituted porogen particles in the space portion of the water-soluble pharmaceutical additives, as the macromolecular polymer porogen particles need to be dissolved or degraded span (which is defined by the following meanings as "Ar") is greatly reduced, only a small portion of the gastrointestinal fluids polymer coating film erosion in a thin layer of fast dissolution can be water-soluble pharmaceutical additives inside the coating film, water-soluble pharmaceutical additives after rapid dissolution, a larger amount of polymer surface coating film is exposed to the gastrointestinal fluids, such that the polymer coating film erosion greatly accelerate the speed, the drug dissolution time lag exhibit also will greatly becomes smaller, much faster drug dissolution, the polymer coating film erosion also will be affected by factors in vivo significantly reduced, reproducibility, or stability of the drug release is greatly improved. 以下以一数学模型作说明,假设可溶于水的药用添加剂与可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物二者的密度分别为ρ1、ρ2,二者粒径(半径)分别为r1、r2,二者重量分别为Wp W2,则二者重量与粒径间存在如下关系: In the following a mathematical model for the description, it is assumed pharmaceutically acceptable water-soluble additive is soluble in both the stomach and the coating film, but polymer is insoluble or almost insoluble in water density / or intestinal digestive rho] 1, respectively, ρ2, both the particle diameter (radius) r1, r2, respectively, both the weight Wp W2, the following relationship exists between them and the weight of the particle sizes of:

[0035] [0035]

Figure CN101987081AD00141

[0036] 由上式可得可溶于水的药用添加剂包衣增重W2/W1与颗粒物的粒径增加Δr/r1的关系为: [0036] can be obtained by the above formula a pharmaceutically acceptable water-soluble additive coating weight W2 / W1 increases relationship Δr / r1 particle diameter of the particulate matter is:

[0037] [0037]

Figure CN101987081AD00142

[0038] 当上述的可溶于水的药用添加剂与可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物二者的密度比P i/p 2近似为1时,通过上式可以求得不同可溶于水的药用添加剂包衣增重W2/W1下颗粒物的粒径增加Δr/r1值,详见下表: [0038] When the above-described water-soluble pharmaceutically acceptable additive which is soluble in the stomach and / or intestinal digestive juices but both the polymeric coating film is insoluble or almost insoluble in water density than P i / p 2 Approximate is 1, the formula can be obtained by different water-soluble pharmaceutical additives coating weight W2 / W1 of the particle diameter increase Δr / r1 value, the table below:

[0039] [0039]

Figure CN101987081AD00143

[0040] [0040]

Figure CN101987081AD00151

[0041] 从表中数据可得,可溶于水的药用添加剂被可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物包覆增重较多时,而粒径增幅非常小,通常不到聚合物包覆增重幅度的三分之一。 [0041] The available data in the table, a pharmaceutically acceptable water-soluble additive is soluble in the stomach and / or but insoluble or hardly water-soluble film coating polymer coating weight gain when large bowel digestive juice, the increase in particle size is very small, usually less than one-third of the weight of polymer coated gain amplitude.

[0042] 另外特别指出的是,药物释放时间的提前,药物溶出表现出的时滞性减小,对定位控释释药的控释制剂特别有利。 [0042] otherwise specifically indicated, the drug release time in advance, exhibited drug dissolution time lag is reduced, particularly advantageous for positioning a controlled release drug delivery of a controlled release formulation. 定位控释释药的控释制剂在特定的部位滞留的时间有限, 如小肠定位控释释药,尤其是胃定位控释释药较短,特别是结肠定位控释释药特别短,而且控释制剂释药的时间相对常规制剂要长,因而,药物释放时间的提前,相当于有效释药的时间的延长,从而有利于药物疗效的发挥,有利于提药物高生物利用度。 Positioning a limited release controlled-release formulations release the retention time at a specific site, such as a controlled release drug delivery targeting intestine, especially gastric controlled release drug delivery targeting shorter, particularly controlled release drug delivery colon - particularly short, and control release time release formulations relative to conventional formulations length, thus early drug release time, corresponding to the prolonged release of the active, thereby facilitating exert drug efficacy, beneficial increase bioavailability of the drug.

[0043] 根据上表列出的数据,用于本发明的上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜在致孔剂中的用量通常不超过上述可溶于水的药用添加剂包衣前的用量的(或者说“可溶于水的药用添加剂包衣增重至”)700% (重量/重量),较佳不超过上述的可溶于水的药用添加剂包衣前的用量的300% (重量/重量),更佳地约2〜约200 % (重量/重量),更佳地约2〜约100 % (重量/重量),更佳地约3〜约50 % (重量/重量),最佳地约3〜约30% (重量/重量)(此外术语“约”是指量的变化幅度为士30% (例如某量为P,则P的可取值范围为0. 7ρ〜1. 3ρ),较佳地为士20%,最佳地为士10%,未特别标明其他处含义均同此)。 [0043] The data listed in the table, the present invention is soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film in the amount of porogen is generally not the amount of the former than the water-soluble pharmaceutical additives of the above-described coating (or "water-soluble pharmaceutical additives to the coating weight") 700% (wt / wt), preferably not more than the above may be 300% of the amount of water-soluble coating front pharmaceutical additives (wt / wt), more preferably from about 2 ~ to about 200% (wt / wt), more preferably from about 2 ~ to about 100% (wt / wt) , more preferably from about 3 ~ to about 50% (wt / wt), most preferably from about 3 ~ to about 30% (wt / wt) (in addition to the term "about" it refers to the amount of amplitude variation of ± 30% (e.g., a quantity is P, then P may be in the range of 0. 7ρ~1. 3ρ), preferably of ± 20%, most preferably of ± 10%, are not particularly indicated are the same meaning as elsewhere herein). 通常较少的包衣增重不利于形成完整的衣膜,较多的增重将降低预期效果。 Typically less coating weight is not conducive to the formation of a complete coating film, more weight gain will reduce the desired effect.

[0044] 本发明所用的术语“可溶于水的药用添加剂”是指在水中的溶解度(温度25V )不小于33mg/ml,较佳地不小于50mg/ml,更佳地不小于100mg/ml,更佳地不小于500mg/ml, 最佳地不小于1000mg/ml的、平均粒径通常为1〜500 μ m,较佳地为5〜250 μ m,更佳地为10〜150 μ m,最佳地为25〜100 μ m的且与可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物(及含有此聚合物的衣膜中其他成分)在体内消化液中不能发生化学反应或者能发生化学反应但不生成不溶于水的非气态的产物及药学上不可接受的产物的可作药用助剂的无机物或有机物,未特别标明其他处含义均同此。 [0044] As used herein, the term "pharmaceutically acceptable water-soluble additive" refers to a solubility (25V temperature) water of not less than 33mg / ml, preferably not less than 50mg / ml, more preferably not less than 100mg / ml, more preferably not less than 500mg / ml, most preferably not less than 1000mg / ml, the average particle diameter is generally 1~500 μ m, preferably of 5~250 μ m, more preferably of 10~150 μ m, most preferably of 25~100 μ m and which is soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer (and the coating film comprising the polymer of other components) in pharmaceutically acceptable additives may be inorganic or organic chemical reactions can not occur in vivo or digestive fluids, but does not generate unacceptable water-insoluble non-gaseous products and pharmaceutical products of a chemical reaction can occur, particularly not at the other indicated meanings with all this. 过小的溶解度不利于形成孔。 The solubility is too small is not conducive to the formation of holes. 过大或过小的粒径可能在生产引起生产重现性、物释放的重现性或稳定性较差等难以预测的问题。 Too large or too small particle size may lead to the production of reproducible production, reproducibility or stability problems such as poor release of unpredictable.

[0045] 可用于本发明的可溶于水的药用添加剂实例包括但不限于可溶于水的氨基酸、寡肽(2-10肽),可溶于水的单糖及其药学上可接受的衍生物、寡聚糖(2-6糖)及其药学上可接受的衍生物,可溶于水的钠、钾或铵离子的无机盐,可溶于水的碳原子数不超过6的有机酸及其可溶于水的钠、钾或铵离子盐,可溶于水的碳原子数不超过6的有机碱及其可溶于水的盐,可溶于水的非离子型表面活性剂,可溶于水的药学上可接受的非离子型聚合物(较佳地为可溶于水的、低粘度的(此处术语“低粘度”是指2%的水溶液的粘度不高于300 厘泊(mPa · s),未特别标明含义均同此),以及它们的混合物。 [0045] Examples of pharmaceutically acceptable additives may be used in the present invention may be water-soluble include, but are not limited to acceptable water-soluble amino acid, an oligopeptide (2-10 peptide), water-soluble and pharmaceutically acceptable monosaccharide derivatives, oligosaccharides (sugar 2-6) and pharmaceutically acceptable derivatives thereof, water-soluble sodium, potassium or ammonium ion of an inorganic salt, water-soluble carbon atoms does not exceed 6 organic acids and their water soluble sodium, potassium or ammonium salt, the number of water-soluble carbon atoms does not exceed its water-soluble organic base salt 6, water-soluble nonionic surfactants agent, a pharmaceutically acceptable water-soluble nonionic polymer (preferably a water-soluble, low viscosity (the term "low viscosity" means a viscosity of 2% aqueous solution of not more than 300 centipoise (mPa · s), it is not particularly indicated are the same meaning as here), and mixtures thereof.

[0046] 可用于本发明的可溶于水的氨基酸或寡肽的实例如,但不限于此:丙氨酸、甘氨酸、丝氨酸、缬氨酸、天冬酰胺、赖氨酸、谷氨酰胺、甲硫氨酸、精氨酸、羟脯氨酸、脯氨酸、力肽(L-丙氨酰-L-谷胺酰胺)、谷胱甘肽。 [0046] Examples of amino acid or oligopeptide may be used in the present invention are soluble in water, such as, but not limited to: alanine, glycine, serine, valine, asparagine, lysine, glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L- alanyl -L- glutamine), glutathione.

[0047] 可用的可溶于水的单糖及其药学上可接受的衍生物包括,但不限于左旋和/或右旋的单糖及其糖醇,其实例如,但不限于此:丙糖(如D-甘油醛和二羟基丙酮)、丁糖(如D-赤藓糖、D-赤藓酮糖、赤藻糖醇)、戊糖(如D-核糖、D-2-脱氧核糖、D-木糖、L-阿拉伯糖)、戊酮糖(如D-核酮糖、D-木酮糖、木糖醇)、己糖(如葡萄糖、半乳糖、甘露醇、甘露糖)、己酮糖(如果糖、山梨糖))、庚糖(如D-甘露庚酮糖、D-景天庚酮糖)。 [0047] Pharmaceutically usable water-soluble monosaccharides and their pharmaceutically acceptable derivatives include, but are not limited to left and / or dextrose and sugar alcohols of monosaccharides, in fact, such as, but not limited to: triose (e.g., D- glyceraldehyde and dihydroxyacetone), tetroses (e.g., D- erythrose, D- erythrulose, erythritol), pentoses (e.g., D- ribose, D-2- deoxyribose, D- xylose, L- arabinose), ketopentoses (e.g. ribulose D-, D- xylulose, xylitol), hexoses (e.g., glucose, galactose, mannitol, mannose), hexyl ketoses (fructose, sorbitol)), heptose (e.g. D- mannoheptulose, sedoheptulose D-).

[0048] 可用的可溶于水的寡聚糖及其药学上可接受的衍生物的实例如,但不限于此:双糖(如麦芽糖、乳糖、蔗糖、纤维二糖、龙胆二糖、蜜二糖、海藻二糖、异麦芽糖醇、麦芽糖醇、 拉克替醇、海藻糖、壳聚二糖),三糖(如棉子糖、壳聚三糖)、四糖(如水苏糖、脱乙酰壳聚四糖)、五糖(如毛蕊花糖、麦芽五糖)、六糖(如麦芽六糖)。 [0048] Examples of pharmaceutically usable water-soluble oligosaccharide and its pharmaceutically acceptable derivatives, such as, but not limited to: disaccharides (e.g. maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose, alginic disaccharides, isomalt, maltitol, lactitol, trehalose, chitosan disaccharide), trisaccharides (e.g. raffinose, chitosan trisaccharide), tetrasaccharides (such as stachyose, off acetylated chitosan tetrasaccharides), pentasaccharide (e.g., verbascose, maltopentaose), hexose (e.g., maltohexaose).

[0049] 可用的可溶于水的钠、钾或铵离子的无机盐的实例如,但不限于此:卤素平衡离子如溴、氟、碘和氯化物的可溶于水的钠、钾或铵离子的盐,磷酸根、磷酸氢根、硫酸根、硫酸氢根、亚硫酸根、亚硫酸氢根、焦亚硫酸根、硝酸根、碳酸根、碳酸氢根及过碳酸根的可溶于水的钠、钾或铵离子的盐。 [0049] The usable water-soluble sodium, potassium or ammonium ions, examples of inorganic salts such as, but not limited to: a halogen counter ion such as bromine, fluorine, iodine chloride and water-soluble sodium, potassium or salt, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, bisulfite, metabisulfite sulfate, nitrate, ammonium carbonate ion, bicarbonate and carbonate may be dissolved through sodium and water, a salt of potassium or ammonium ions.

[0050] 可用的可溶于水的碳原子数不超过6的有机酸及其可溶于水的钠、钾或铵离子盐的实例如,但不限于此:己二酸、反/顺丁烯二酸、苹果酸、枸橼酸、洒石酸、植酸、琥珀酸、甘醇酸以及其钠盐、钾盐、铵盐。 [0050] The number of available water soluble carbon atoms and no more than 6, sodium, potassium examples of organic acids or water-soluble salts, such as ammonium ion, but not limited to: adipic acid, trans / cis-butoxy alkenyl acid, malic acid, citric acid, tartaric acid, phytic acid, succinic acid, glycolic acid and its sodium, potassium, ammonium.

[0051] 可用的可溶于水的碳原子数不超过6的有机碱的实例如,但不限于此:水溶性碱性氨基酸、葡甲胺以及及其可溶于水的盐。 [0051] The number of usable water-soluble organic base of carbon atoms does not exceed 6 as examples, but not limited to: water-soluble basic amino acid, meglumine, and its water-soluble salts.

[0052] 可用的可溶于水的非离子型表面活性剂的实例如,但不限于此:可溶于水的聚氧乙烯烷基醚类表面活性剂(如Brij 35,Brij 98,Cremophor A6, Cremophor A25, Ethylan 2560, Ritox 35, Ritox 721, Texofor AlP, Texofor AlO, Texofor A14, Texofor A30,Texofor A45, Texofor A60,Volpo S10, Volpo S20, Volpo S20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23),可溶于水的聚氧化乙烯蓖麻油类表面活性剂(如Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-IOO, Jeechem CAH-200, Lipocol HC0-60), Polysorbate 61,P0lyS0rbate65,可溶于水的聚氧乙烯硬脂酸酯类表面活性剂(如Polyoxyl 150 distearate, Polyoxyl 32distearate, Polyoxyl IOOstearate, Polyoxyl 50stearate)。 [0052] Examples of useful water-soluble nonionic surfactants such as, but not limited to: a water-soluble polyoxyethylene alkyl ether surfactants (e.g., Brij 35, Brij 98, Cremophor A6 , Cremophor A25, Ethylan 2560, Ritox 35, Ritox 721, Texofor AlP, Texofor AlO, Texofor A14, Texofor A30, Texofor A45, Texofor A60, Volpo S10, Volpo S20, Volpo S20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23), water-soluble polyoxyethylene castor oil surfactant (e.g. Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-IOO, Jeechem CAH-200, Lipocol HC0-60), Polysorbate 61, P0lyS0rbate65, water-soluble polyoxyethylene stearate ester surfactant (e.g., Polyoxyl 150 distearate, Polyoxyl 32distearate, Polyoxyl IOOstearate, Polyoxyl 50stearate).

[0053] 可用的药学上可接受的可溶于水的、非离子型聚合物的实例如,但不限于此:可溶于水的环糊精及环糊精衍生物(如α-环糊精、Y-环糊精、2,6 二甲基-β-环糊精、羟丙/乙基-β -环糊精、支链_ β _环糊精、糖基_环糊精、磺丁基醚_ β _环糊精、可溶于水的低分子量环糊精聚合物(如分子量3000-6000)),葡聚糖结合剂(Dextrates),可溶于水的药学上可接受的低聚糖(聚合度7-20)(如低聚果糖(聚合度7-20)、低聚异麦芽糖(聚合度7-20))、可溶于水的葡聚糖(如分子量为1200-2000的葡聚糖),羟乙基纤维素(如商品名如下的低粘度的产品:WP 02、WP and QP 09、WP and QP 3、WP and QP 40、WP and QP300),羟乙基甲基纤维素,羟丙基纤维素(如商品名如下的低粘度的产品:Klucel JF、 Klucel LF, Klucel EF),羟丙甲基纤维素(如商品名如下的低粘度的产品=Methocel KlOO Premium LVEP> Methocel F50 [0053] The water-soluble, examples of usable pharmaceutically acceptable nonionic polymers such as, but not limited to: water-soluble cyclodextrin and a cyclodextrin derivative (such as α- cyclodextrin fine, Y- cyclodextrin, 2,6-dimethyl -β- cyclodextrin, hydroxypropyl / ethyl -β - cyclodextrin, branched cyclodextrin _ beta] _, _ cyclodextrin glycosyl, sulfo _ _ beta] -cyclodextrin-butyl ether, water-soluble pharmaceutically cyclodextrins low molecular weight polymer (e.g., molecular weight 3000-6000)), dextrates (of dextrates), water-soluble pharmaceutically oligosaccharides (7-20 polymerization degree) (e.g., fructooligosaccharides (7-20 polymerization degree), isomalto (7-20 polymerization degree)), water-soluble dextran (e.g., molecular weight 1200 2000 dextran), hydroxyethyl cellulose (e.g., trade name product as a low viscosity: WP 02, WP and QP 09, WP and QP 3, WP and QP 40, WP and QP300), hydroxyethyl methyl cellulose, hydroxypropyl cellulose (e.g., trade name product as a low viscosity: Klucel JF, Klucel LF, Klucel EF), hydroxypropylmethyl cellulose (e.g., trade name product as a low viscosity = Methocel KlOO Premium LVEP> Methocel F50 Premium、Methocel E3Premium LV> Methocel E5 Premium LV、MethocelE6 Premium LV、Methocel E15Premium LV、Methocel E50 Premium LV、低粘度级Metolose60SH、低粘度级Metolose 65SH、低粘度级Metolose 90SH),低粘度甲基纤维素(如商品名如下的产品:A15-LV),聚乙烯醇,聚维酮(如商品名如下的低粘度的产品: Κ-11/14、Κ-16/18、Κ-24/27、Κ-28/32、Κ-85/95),分子量为2000-20000 的PEG (聚乙二醇)。 Premium, Methocel E3Premium LV> Methocel E5 Premium LV, MethocelE6 Premium LV, Methocel E15Premium LV, Methocel E50 Premium LV, a low viscosity grade Metolose60SH, low viscosity grade Metolose 65SH, low viscosity grade Metolose 90SH), low viscosity methyl cellulose (e.g. tradename following products: A15-LV), polyvinyl alcohol, povidone (e.g., trade name product as a low viscosity: Κ-11/14, Κ-16/18, Κ-24/27, Κ-28 / 32, Κ-85/95), the molecular weight of PEG 2000-20000 (polyethylene glycol).

[0054] 可用于本发明的可溶于水的药用添加剂较佳地选自溶解基本不受消化液中的酸、 碱影响而变慢的,更佳地还基本不受消化液中的酶和微生物的影响而变慢的可溶于水的药用添加剂,从而使药物释放受体内酸、碱、酶和微生物等体内因素影响大大减小。 It slowed [0054] may be water-soluble pharmaceutical additives used in the present invention are preferably selected from acid substantially dissolve, the digestive juice after alkali, more preferably also substantially free digestive enzymes Effect of the microorganism and slow water-soluble pharmaceutical additives, so that the drug release in vivo effects is greatly reduced by acid, base, enzymes and microorganisms in vivo factors. 合适的溶解基本不胃肠受消化液中的酸、碱影响而变慢的可溶于水的药用添加剂实例包括但不限于:可溶于水的单糖、双糖、糖醇及由它们组成的可溶于水的寡聚糖(2-6糖)或低聚糖(聚合度7-20),可溶于水的中性无机盐,可溶于水的非离子型表面活性剂,药学上可接受的可溶于水的、非离子化型聚合物(较佳地为可溶于水的、低粘度的(此处术语“低粘度”是指2%的水溶液的粘度不高于300厘泊(mPa · s),未特别标明其他处含义均同此)、药学上可接受的聚合物),以及它们的混合物。 Suitable substantially dissolved parenteral Examples of pharmaceutically acceptable additives may be water-soluble in the digestive juice slowed by acids, bases affected include but are not limited to: water-soluble monosaccharides, disaccharides, and sugar alcohols thereof by a water-soluble oligosaccharide (sugar 2-6), or composed of oligosaccharides (7-20 polymerization degree), the water-soluble neutral inorganic salt, water-soluble nonionic surfactant, pharmaceutically acceptable water-soluble, non-ionizable polymer (preferably a water-soluble, low viscosity (the term "low viscosity" means a viscosity of 2% aqueous solution of not more than 300 centipoise (mPa · s), are not particularly indicated are the same meaning as elsewhere here), a pharmaceutically acceptable polymers), and mixtures thereof.

[0055] 上述可用的溶解基本不受消化液中的酸、碱、酶和微生物的影响而变慢的可溶于水的单糖、双糖、糖醇及由它们组成的可溶于水的寡糖(3-6糖)实例如,但不限于此:丙糖(如D-甘油醛和二羟基丙酮),丁糖(如D-赤藓糖、D-赤藓酮糖、赤藻糖醇),戊糖(如D-核糖、D-2-脱氧核糖、D-木糖、L-阿拉伯糖、戊酮糖(如D-核酮糖、D-木酮糖、木糖醇), 己糖(葡萄糖、半乳糖、甘露醇、甘露糖、己酮糖(如果糖、山梨糖)),庚糖(如D-甘露庚酮糖、D-景天庚酮糖),双糖(如麦芽糖、乳糖、蔗糖、纤维二糖、龙胆二糖、蜜二糖、海藻二糖、 异麦芽糖醇、麦芽糖醇、拉克替醇、海藻糖),三糖(如棉子糖)、四糖(如水苏糖)、五糖(如毛蕊花糖、麦芽五糖)、六糖(如麦芽六糖)。 [0055] The usable dissolved substantially unaffected, alkali, acids affect the digestive enzymes and microorganisms of the slow water-soluble monosaccharides, disaccharides, sugar alcohols, and composed of these water-soluble oligosaccharides (sugar 3-6) as examples, but not limited to: triose (e.g., D- glyceraldehyde and dihydroxyacetone), tetroses (e.g., D- erythrose, D- erythrulose, erythritol alcohol), pentoses (e.g., D- ribose, D-2- deoxyribose, D- xylose, L- arabinose, ketopentoses (e.g. ribulose D-, D- xylulose, xylitol), hexoses (glucose, galactose, mannitol, mannose, ketohexoses (fructose, sorbitol)), heptose (e.g. D- mannoheptulose, sedoheptulose D-), disaccharides (e.g. maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose, alginic disaccharides, isomalt, maltitol, lactitol, trehalose), trisaccharides (e.g., raffinose), tetrasaccharides ( such as stachyose), five sugar (such as mullein sugar, maltopentaose), six sugar (such as maltohexaose).

[0056] 上述可用的溶解基本不受消化液中的酸、碱、酶和微生物的影响而变慢的可溶于水的中性无机盐实例如,但不限于此:中性可溶于水的卤素平衡离子的盐如氯化物的钠、钾盐;中性可溶于水的阴离子物质,如硝酸根的钠、钾盐。 [0056] Examples of water-soluble neutral inorganic salt is not substantially dissolving said available, alkali, acids influence digestive juices and enzymes and microbes such as slow, but not limited to: water-soluble neutral halogen counter ion salts such as sodium chloride, potassium; neutral water soluble anionic species, such as sodium nitrate, potassium salt. [0057] 上述可用的溶解基本不受消化液中的酸、碱、酶和微生物的影响而变慢的可溶于水的非离子型表面活性剂的实例如,但不限于此:可溶于水的聚氧乙烯烷基醚(如Brij 35,Brij 98,Cremophor A6,Cremophor A25,Ethylan 2560, Ritox 35, Ritox 721, Texofor AlP,TexoforAlO,Texofor A14,Texofor A30,Texofor A45,Texofor A60,Volpo S10,Volpo S20, VolpoS20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23),可溶于水的聚氧化乙烯蓖麻油类表面活性剂(如Jeechem CA-200,Jeechem CAH-60,Jeechem CAH-100, Jeechem CAH-200, Lipocol HC0-60),Polysorbate 61,Polysorbate 65,可溶于水的聚氧乙烯硬月旨酸酉旨(如Polyoxyl 150distearate, Polyoxyl 32distearate, Polyoxyl IOOstearate, Polyoxyl 50 stearate)。 [0057] Examples of the dissolving said available nonionic surfactants may be substantially free from water-soluble, alkaline, Enzyme acid and digestive fluids of the microorganism, such as slow, but not limited to: soluble water, polyoxyethylene alkyl ether (e.g. Brij 35, Brij 98, Cremophor A6, Cremophor A25, Ethylan 2560, Ritox 35, Ritox 721, Texofor AlP, TexoforAlO, Texofor A14, Texofor A30, Texofor A45, Texofor A60, Volpo S10 , Volpo S20, VolpoS20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23), water-soluble polyoxyethylene castor oil surfactant (e.g. Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-100, Jeechem CAH-200, Lipocol HC0-60), Polysorbate 61, Polysorbate 65, water-soluble polyoxyethylene purpose hard months acid unitary purpose (e.g. Polyoxyl 150distearate, Polyoxyl 32distearate, Polyoxyl IOOstearate, Polyoxyl 50 stearate).

[0058] 上述可用的溶解基本不受消化液中的酸、碱、酶和微生物的影响而变慢的药学上可接受的可溶于水的非离子型聚合物的实例如,但不限于此:可溶于水的环糊精及非离子型环糊精衍生物(如α-环糊精、Y-环糊精、2,6 二甲基-β-环糊精、羟丙/乙基-β-环糊精、支链_ β _环糊精、糖基_环糊精、可溶于水的非离子型低分子量环糊精聚合物(如分子量3000-6000)),葡聚糖结合剂(Dextrates),可溶于水的药学上可接受的低聚糖(聚合度7-20)(如低聚果糖(聚合度7-20)、低聚异麦芽糖(聚合度7-20))、可溶于水的葡聚糖(如分子量为1200-2000的葡聚糖),羟乙基纤维素(如商品名如下的低粘度的产品: WP 02、WP andQP 09、WP and QP 3、WP and QP 40、WP and QP 300),羟丙基纤维素(如商品名如下的低粘度的产品:Klucel JF.Klucel LF.Klucel EF),羟乙基甲基纤维素,羟丙甲基纤维素(如商 [0058] said available on the slower dissolving substantially unaffected, alkali, acids Enzyme digestive fluids and microorganisms Examples of pharmaceutically acceptable water-soluble nonionic polymers such as, but not limited to : water soluble cyclodextrin and cyclodextrin derivative nonionic (e.g. α- cyclodextrin, Y- cyclodextrin, 2,6-dimethyl -β- cyclodextrin, hydroxypropyl / ethyl -β- cyclodextrin, branched cyclodextrin _ beta] _, _ cyclodextrin glycosyl, water-soluble non-ionic low molecular weight polymer of cyclodextrin (e.g., molecular weight 3000-6000)), dextran binding agent (of Dextrates), a pharmaceutically acceptable water-soluble oligosaccharides (7-20 polymerization degree) (e.g., fructooligosaccharides (7-20 polymerization degree), isomalto (7-20 polymerization degree) ), water-soluble dextran (e.g., dextran having molecular weight of 1200-2000), hydroxyethyl cellulose (e.g., low-viscosity product tradename follows: WP 02, WP andQP 09, WP and QP 3 , WP and QP 40, WP and QP 300), hydroxypropyl cellulose (e.g., trade name product as a low viscosity: Klucel JF.Klucel LF.Klucel EF), hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose (such as business 名如下的低粘度的产品:Methocel KlOO Premium LVEP、Methocel F50 Premium、Methocel E3 Premium LV、Methocel E5 Premium LV、Methocel E6 Premium LV> Methocel E15Premium LV、Methocel E50 Premium LV、低粘度级Metolose 60SH、低粘度级Metolose 65SH、低粘度级Metolose 90SH),低粘度甲基纤维素(如商品名如下的产品: A15-LV),聚乙烯醇,聚维酮(如商品名如下的低粘度的产品:K-11/14、Κ-16/18、Κ-24/27、 Κ-28/32、Κ-85/95),分子量为2000-20000 的PEG (聚乙二醇)。 Name as low viscosity products: Methocel KlOO Premium LVEP, Methocel F50 Premium, Methocel E3 Premium LV, Methocel E5 Premium LV, Methocel E6 Premium LV> Methocel E15Premium LV, Methocel E50 Premium LV, a low viscosity grade Metolose 60SH, low viscosity grade Metolose 65SH, low viscosity grade Metolose 90SH), low viscosity methyl cellulose (tradename, such as the following products: A15-LV), polyvinyl alcohol, povidone (e.g., trade name product as a low viscosity: K-11 / 14, Κ-16/18, Κ-24/27, Κ-28/32, Κ-85/95), the molecular weight of PEG 2000-20000 (polyethylene glycol).

[0059] 较佳地,可溶于水的药用添加剂含有或加有崩解剂,以利于可溶于水的药用添加剂的分散与溶解,更充分发挥其作用。 [0059] Preferably, the water-soluble additive contains or a pharmaceutically acceptable disintegrating agents added to facilitate water-soluble pharmaceutical additives may be dispersed and dissolved more fully play its role. 可用于本发明的崩解剂是本领域技术人员熟知的,并更具体地描述于Journal of Pharmaceutical Sciences (85 卷,No. 11,1996 年11 月)。 Disintegrating agents can be used in the present invention are well known to the skilled person, and more particularly described in the Journal of Pharmaceutical Sciences (85 volumes, No. 11,1996 November). 优选用于本发明的崩解剂包括但不限于,低取代的羟丙基纤维素、羧甲基纤维素钠、交联聚维酮、交联羧甲基纤维素钠或钙、纤维素纤维、交联聚丙烯酸、交联琥石树脂、藻酸盐、羧甲基淀粉或微晶淀粉、微晶纤维素及其混合物。 Disintegrant preferably used in the present invention include, but are not limited to, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cross-linked povidone, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber , crosslinked polyacrylic acids, crosslinked resin amber stone, alginates, carboxymethyl starch, or microcrystalline starch, microcrystalline cellulose, and mixtures thereof. 以微晶纤维素为优选。 Microcrystalline cellulose is preferred. 一个可用的可溶于水的药用添加剂实例为含有结晶纤维素和乳糖的球形颗粒产物,例如Freund Industrial Co., Ltd.(日本)制造的商品名为Nonpareil系列产品,100〜200 μ m且含有结晶纤维素(3份) 和乳糖(7份)的球形颗粒产物Nonpareil 105 (70-140)、100〜200 μ m且含有结晶纤维素(4. 5份)和乳糖(5. 5份)的球形颗粒产物Nonpareil 105T (70-140) ; 150〜250 μ m且含有结晶纤维素(3份)和乳糖(7份)的球形颗粒产物Nonpareil NP-7 : 3、150〜250 μ m 且含有结晶纤维素((5份)和乳糖(5份)的球形颗粒产物Nonpareil NP-5 : 5,等等。 Examples of pharmaceutically acceptable additives may be water-soluble spherical particles having a usable product comprising crystalline cellulose and lactose, for example, Freund Industrial Co., Ltd. (Japan) under the trade name Nonpareil products, 100~200 μ m and comprising crystalline cellulose (3 parts) and lactose (7 parts) of the spherical particles of the product Nonpareil 105 (70-140), 100~200 μ m and comprising crystalline cellulose (4.5 parts) and lactose (5.5 parts) spherical particulate product Nonpareil 105T (70-140); 150~250 μ m and comprising crystalline cellulose (3 parts) and lactose (7 parts) of the spherical particle product Nonpareil NP-7: 3,150~250 μ m and containing crystalline cellulose ((5 parts) and lactose (5 parts) spherical particulate product Nonpareil NP-5: 5, and the like.

[0060] 崩解剂的用量为可溶于水的药用添加剂的用量的5〜50% (重量/重量),较佳的10〜40%。 [0060] The amount of 5~50% disintegrant is water-soluble pharmaceutically acceptable additive amount (wt / wt), preferably 10 ~ 40%. 崩解剂在可溶于水的药用添加剂中的用量不适过高,尤其是高效能的超级崩解剂。 The amount of disintegrant in the pharmaceutical additives may be water-soluble in excessive discomfort, especially high-performance super disintegrant. 因其膨胀幅度过大可能损害控释衣膜。 Because the expansion rate is too large may damage the controlled-release coating film. [0061] 在本发明所用的术语“可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物”是指主要由在水中的溶解度(温度25°C )不大于30mg/ml,较佳地不大于10mg/ml, 更佳地不大于lmg/ml,最佳地不大于0. lmg/ml的但能被胃和/或肠消化液中的酸、碱、酶和/或微生物等溶解或降解的药学上可接受的聚合物,未特别标明其他处含义均同此。 [0061] The terms used in the present invention, "soluble in the stomach and / or but insoluble or hardly water-insoluble polymer intestinal digestive juices" refers primarily by the solubility (temperature 25 ° C) in water of not greater than 30mg / ml, preferably not more than 10mg / ml, more preferably not more than LMG / ml, most preferably not greater than 0. lmg / ml, but can be the stomach and / or intestine in the digestive acids, bases, enzymes and pharmaceutically / or microorganisms and other pharmaceutically acceptable polymer dissolved or degraded, are not particularly indicated are the same meaning as elsewhere herein. 可用于本发明的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜材料包括但不限于胃溶性聚合物、肠溶性聚合物、既可肠溶又可胃溶的聚合物、酶和/或微生物可降解的聚合物、生物可降解的聚合物及它们的混合物。 Can be used in the present invention are soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble film coating material include, but are not limited to, the stomach-soluble polymer, an enteric polymer, an enteric but also both a gastric polymers, enzymes and / or microorganisms degradable polymers, biodegradable polymers, and mixtures thereof.

[0062] 胃溶性和/或肠溶性的聚合物通常为含有酸性和/或碱性基团的聚合物。 [0062] soluble in the stomach and / or enteric polymer is generally a polymer containing acidic and / or basic groups.

[0063] 适用于本发明的胃溶性聚合物,通常为在pH6或更低值的水中可溶解的及具有成膜性的高分子物质,包括包括但不限于(a)具有单或二取代氨基的纤维素衍生物,(b)具有单或二取代氨基的聚乙烯衍生物,(c)具有单取代的氨基的丙烯酸聚合物,(d)其他类聚氨基葡糖(Chitosan)及它们的混合物。 [0063] stomach-soluble polymers suitable for the present invention is usually in water or a lower value of pH6 soluble polymer material and having film-forming property, including but not limited to (a) a mono or disubstituted amino cellulose derivatives, (b) having mono or disubstituted amino derivatives of polyethylene, (c) an acrylic polymer having mono-substituted amino group, (d) other types of chitosan (chitosan), and mixtures thereof . (a)的特别例子包括但不限于,苄基氨基甲基纤维素,二乙基氨基甲基纤维素,哌啶基乙基羟乙基纤维素,醋酸纤维素二乙基氨基醋酸酯及它们的混合物;(b)的特别例子包括但不限于乙烯基二乙基胺-醋酸乙烯酯共聚物,乙烯苄基胺-醋酸乙烯酯共聚物,聚乙缩醛醋酸二乙基氨基乙烯酯,乙烯哌啶基-乙酰乙缩醛乙烯共聚物,聚二乙基氨基甲基苯乙烯及它们的混合物;(c)的特别例子包括但不限于Eudragit E (Rohm-Pharma的商品名,即甲基丙烯酸甲酯-甲基丙烯酸丁酯-甲基丙烯酸二甲基氨基乙酯共聚物),聚甲基丙烯酸二甲基氨基乙酯及它们的混合物;(d)其他类特别例子包括但不限于聚氨基葡糖(Chitosan)。 (A) Specific examples of include but are not limited to, aminomethyl benzyl cellulose, diethylaminomethyl cellulose, piperidyl ethyl hydroxyethyl cellulose, cellulose acetate diethylamino acetate, and their mixture; (b) the particular examples include, but are not limited to vinyl diethylamine - vinyl acetate copolymer, vinyl benzylamine - vinyl acetate copolymer, polyvinyl acetal diethylamino acetate, vinyl acetate, vinyl piperidinyl - acetyl acetal copolymer, polydiethyl aminomethyl styrene and mixtures thereof; (c) special examples include but are not limited Eudragit E (Rohm-Pharma's trade name, methacrylic acid, i.e. methacrylate - butyl methacrylate - dimethylaminoethyl methacrylate methacrylate copolymer), polymethyl methacrylate, dimethylaminoethyl methacrylate, and mixtures thereof; (d) other types Specific examples include but are not limited to polyamino glucose (Chitosan). 其中,较优选的胃溶性聚合物为聚乙缩醛二乙基氨基醋酸乙烯酯或EudragitE。 Among them, more preferable gastric soluble polymer is a polyvinyl acetal diethylamino acetate or EudragitE.

[0064] 适用于本发明的肠溶聚合物,通常为具有成膜性和可在pH5或更高些的水中溶解的聚合物,包括但不限于(1)羧烷基纤维素,(2)具有二元酸的单酯键的纤维素衍生物,(3) 具有二元酸单酯键的聚乙烯基衍生物,(4)马来酸_乙烯其聚物,(5)丙烯酸类聚合物,(6) 其他类及它们的混合物。 [0064] The enteric polymers suitable for the present invention, typically having a film-forming properties and can be dissolved in water pH5 or more of these polymers, including but not limited to, (1) carboxyalkyl cellulose, (2) a cellulose derivative having monoester bond of dibasic acid, (3) having a monoester bond of dibasic acid polyvinyl derivatives, (4) _ ethylene maleic acid copolymer thereof, (5) an acrylic polymer , (6) other types and mixtures thereof. (1)的特别例子包括但不限于羧甲基纤维素,羧甲基乙基纤维素(CMEC)及它们的混合物,(2)的特别例子包括但不限于邻苯二甲酸酯酸纤维素,琥珀酸醋酸纤维素酯,邻苯二甲酸甲基纤维素酯,邻苯二甲酸羟甲基乙基纤维素酯,邻苯二酸羟丙基甲基纤维素酯,琥珀酸羟丙基甲基纤维素酯及类似物及它们的混合物;(3)的特别例子包括但不限于乙烯基聚合物的二元酸单酯,例如邻苯二甲酸聚乙烯醇酯,邻苯二甲酸聚乙烯丁酯,乙酰基乙缩醛邻苯二甲酸聚乙烯酯及类似物及它们的混合物;(4)的特别例子包括但不限于醋酸乙烯酯_马来酸酐共聚物,丁基乙烯醚_马来酸酐共聚物,苯乙烯_马来酸单酯共聚物及它们的混合物;(5)的特别例子包括但不限于丙烯酸甲酯-甲基丙烯酸共聚物, 苯乙烯-丙烯酸共聚物,丙烯酸甲酯-甲基丙烯酸-丙烯酸辛酯共聚物,Eudragit L和S (1) Specific examples include, but are not limited to the particular example carboxymethyl cellulose, carboxymethyl ethyl cellulose (CMEC), and mixtures thereof, (2) include, but are not limited to cellulose acetate phthalate succinate, cellulose acetate phthalate, methylcellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropylmethyl cellulose acid succinate, hydroxypropyl methylcellulose cellulose esters, and the like, and mixtures thereof; (3) Specific examples of the vinyl polymer include but are not limited to dibasic acid monoester, such as phthalic acid polyvinyl alcohol phthalate, polyvinyl butyrate esters, acetyl esters of polyvinyl acetal phthalate, and the like, and mixtures thereof; (4) Specific examples include, but are not limited to _ vinyl acetate-maleic anhydride copolymer, vinyl butyl ether, maleic anhydride _ copolymers, styrene-maleic acid monoester copolymer _ and mixtures thereof; (5) Specific examples include, but are not limited to, methyl acrylate - methacrylic acid copolymer, styrene - acrylic acid copolymer, methyl acrylate - methyl yl methacrylate - octyl acrylate copolymer, Eudragit L and S Eudragit FS(结肠定位用)及它们的混合物;(6)其他类特别例子包括但不限于虫胶。 Eudragit FS (colon positioning) and mixtures thereof; (6) Others Specific examples include but are not limited to shellac. 其中较优选的肠溶性聚合物为羧甲基纤维素,羧甲基乙基纤维素,邻苯二酸羟丙基甲基纤维素酯,琥珀酸羟丙基甲基醋酸纤维素酯,Eudragit L, Eudragit S, Eudragit FS或虫胶。 More preferably wherein the enteric polymer is carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate succinate, hydroxypropyl methyl cellulose acetate, Eudragit L , Eudragit S, Eudragit FS or shellac.

[0065] 适用于本发明的既可肠溶又可胃溶的聚合物,通常为具有成膜性和在pH4. 5或更低些的水以及PH6或更高些的水中能溶解的聚合物,包括但不限于乙烯基吡啶_丙烯酸类共聚物,具有单或二取代的氨基的羧甲基多糖或聚乙烯氨基酸类衍生物及它们的混合物。 Either an enteric [0065] useful in the present invention but also gastroresistant polymer, typically having a film-forming properties and at pH4. 5 or lower and water PH6 or higher polymer can be dissolved in water , including but not limited to vinyl pyridine _ acrylic copolymer, carboxymethyl having mono- or di-substituted amino group or polyvinyl amino acid type polysaccharide derivatives and mixtures thereof. 乙烯基吡啶-丙烯酸共聚物特别的例子包括但不限于2-甲基-5-乙烯基吡啶/甲基丙烯酸甲基/甲基丙烯酸共聚物,2-甲基-5-乙烯基吡啶/丙烯酸甲酯/甲基丙烯酸共聚物,2-乙烯基-5-乙烯基吡啶/甲基丙烯酸/苯乙烯共聚物,2-乙烯基-5-乙烯基吡啶/甲基丙烯酸/甲基丙烯酸甲酸共聚物,2-乙烯基吡啶/甲基丙烯酸/甲基丙烯酸共聚物,2-乙烯基吡啶/甲基丙烯酸/丙烯腈共聚物及它们的混合物。 Vinylpyridine - Specific examples include, but are not limited to acrylic copolymers of 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid copolymer, 2-methyl-5-vinylpyridine / methyl acrylate methacrylate / methacrylic acid copolymer, 2-vinyl-5-vinylpyridine / methacrylic acid / styrene copolymer, 2-vinyl-5-vinylpyridine / methacrylic acid / methacrylic acid copolymer, 2-vinylpyridine / methacrylic acid / methacrylic acid copolymer, 2-vinylpyridine / methacrylic acid / acrylonitrile copolymers, and mixtures thereof. 具有单或二取代的氨基的羧甲基多糖的特别例子包括但不限于羧甲基哌啶基淀粉,羧甲基苄基氨基纤维素及它们的混合物。 Specific examples of carboxymethyl polysaccharides having mono- or di-substituted amino group include, but are not limited to carboxymethyl piperidyl starch, carboxymethyl cellulose, benzyl group and mixtures thereof. 聚乙烯基氨基酸类衍生物的特别例子包括但不限于聚_2-(乙烯基苯基)甘氨酸,N-乙烯基甘氨酸_苯乙烯共聚物及它们的混合物。 Specific examples of polyvinyl amino acid derivatives include, but are not limited glycine, N- vinylglycine-styrene copolymer, and mixtures _ _2- poly (vinylphenyl) thereof. [0066] 合适的生物可降解的聚合物的实例包括但不限于天然的生物降解聚合物(如纤维蛋白及胶原)、脂肪族聚酯类(如聚丙交酯、聚乙交酯、聚丙交酯-聚乙交酯、聚己内酯、聚丙交酯-己内酯)、聚氨及其共聚物、聚氨基酸、聚原酸酯、聚氰基丙烯酸酯、聚丙;ϋ酸类、poly (3-hydroxybutyrate)及其共聚物、polyanhydri es、poly (methyl vinyl ether-maleic acid)、聚氨基甲酸酯类、生物溶蚀型水凝胶(如以N-乙烯基吡咯酮或丙烯酰胺与N,N'-亚甲基对丙烯酰胺共聚形成的水凝胶聚合物,以不饱和二酸与低分子量二元醇缩合得到含有乙烯基的不饱和预聚物后,用乙烯吡咯烷酮(VP)使之交联即得到主链水解的溶蚀型水凝胶)及它们的混合物。 [0066] Examples of suitable polymers include biodegradable but are not limited to, natural biodegradable polymers (such as fibrin and collagen), aliphatic polyesters (e.g., polylactide, polyglycolide, polylactide - polyglycolide, polycaprolactone, polylactide - caprolactone), polyurethanes and copolymers thereof, polyaminoacids, polyorthoesters, polycyanoacrylates, polypropylene; ϋ acid, poly (3 -hydroxybutyrate) and copolymers thereof, polyanhydri es, poly (methyl vinyl ether-maleic acid), polyurethanes, bioerodible hydrogels (e.g., to N- vinylpyrrolidone or acrylamide with N, N ' - a methylene group of the hydrogel polymer formed by copolymerizing acrylamide, an unsaturated low molecular weight diol and diacid condensation gives the unsaturated vinyl group-containing prepolymer with vinyl pyrrolidone (VP) by crosslinking i.e., obtain the hydrolysis of the backbone dissolution hydrogels), and mixtures thereof.

[0067] 合适的酶和/或微生物可降解的聚合物的实例包括但不限于含偶氮键或二硫键的聚合物(如由丙烯酸树脂和偶氮芳香交联基团组成的聚合物,由不同包衣材料(或乙烯类单体)通过与含偶氮芳香基团的聚合单体(如由丙烯酸树脂和能被偶氮还原配降解的偶氮芳香交联基团组取代的或未取代的二乙烯基偶氮芳香基苯乙烯)交联或共聚制得的聚合物)、能被肠细菌产生的特殊多糖酶(如糖苷酶)分解但不溶水的或不能被小肠消化酶消化的且不溶水的多糖(如果胶、右旋糖酐、半乳甘露聚糖、9-右旋葡萄糖苷酸等)及它们的混合物。 [0067] Suitable enzymes and / or microorganism degradable Examples of polymers include but are not limited to azo bond or disulfide containing polymers (polymer such as an acrylic resin and an aromatic azo group consisting of crosslinking, different coating material (or vinyl monomers) by polymerization of monomers containing an aromatic azo group (e.g., an acrylic resin and a reduction of the azo ligand degradation can be crosslinked aromatic azo group a substituted or unsubstituted missions substituted aromatic azo group divinyl styrene) or a cross-linked polymer obtained by copolymerizing), special polysaccharidase (e.g., glycosidase) can be produced by enteric bacteria or decomposition of water-insoluble but intestinal digestive enzymes can not be digested and water-insoluble polysaccharides (pectin, dextran, galactomannan, 9-glucuronide, dextrose, etc.), and mixtures thereof.

[0068] 可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜材料的(种类)选择除了考虑与控释衣膜聚合物的相容性外,通常根据药物的性质及药物释放要求、临床应用等决定。 [0068] soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble film coating material (type) in addition to considering the compatibility with selected controlled release film coating polymer, the drug is generally in accordance with the nature and decided to request the release of the drug and clinical applications. 如对于适合在胃中或近胃端吸收的(如在对碱不稳定的、酸易溶的、胃或胃近端如十二指肠有吸收窗的或对胃或近胃端局部起治疗作用的)药物适选择胃溶性聚合物;对于适合在肠中吸收的(如对酸不稳定的、碱易溶的、对胃较强毒副作用的如对胃有较强刺激作用的、在肠局部直接起治疗作用的、在肠段基本吸收良好的、以肠段为基本吸收部位的或需延时释放的)药物适选择肠溶性聚合物;对于适合在结肠中吸收的(如对消化酶敏感的(如肽、蛋白质类)、用于(局部、直接)治疗结肠部位疾病的、对消化道上部(如胃、小肠) 有较强毒副作用的如有较强刺激作用的或需延时释放的)药物适选Eudragit S.Eudragit FS、结肠中酶和/或微生物可降解的等聚合物。 The absorption window of the stomach or absorbed in the stomach or adapted for the near end of the stomach (as for base-labile, acid-soluble, such as the stomach or the duodenum or proximal topical treatment from near the end of stomach effect) polymer soluble in the stomach selected medicament adapted; suitable for absorption in the intestine (e.g., acid-labile, base soluble, such as stomach strong side effects on the stomach of a strong stimulation of intestinal directly from the treatment of partial, well absorbed in the intestine basic to basic intestine site of absorption or delayed release required) to select a drug suitable enteric polymer; suitable for absorption in the colon (such as digestive enzymes if strong sensitive (e.g., peptides, proteins), for the (local, direct) treatment of colonic disease site, there is a strong toxicity to the upper gastrointestinal tract (e.g., stomach, small intestine) or stimulation of the need to delay release) pharmaceutical aptamer selected from Eudragit S.Eudragit FS, colon enzymes and / or microorganisms and other degradable polymers. 再如药物需要服用后过一定时间再被吸收发挥作用(即药物释放需时滞性,即延时释放)的制剂可选择衣膜溶解或降解缓慢的聚合物如生物可降解的聚合物(如脂肪族聚酯类聚合物)、消化酶和/或消化道微生物降解缓慢的聚合物(如多糖类,果胶,桃胶)。 Formulation certain time after another example, the drug is absorbed and then need to take the role (i.e., drug release time lag required, i.e., time-release) coating film selectively dissolve or degrade slowly polymers such as biodegradable polymers (e.g. aliphatic polyester-based polymer), polymer slow degradation enzyme digestion and / or gastrointestinal microorganisms (such as polysaccharides, pectin, peach gum). 其中,对于适合在肠中吸收的(如对酸不稳定的、碱易溶的、对胃较强毒副作用的如对胃有较强刺激作用的、在肠局部直接起治疗作用的、在肠段基本吸收良好的、以肠段为基本吸收部位的或需延时释放的)药物适选择肠溶性聚合物在本发明为最优选。 Wherein, adapted for absorption in the intestine (e.g., acid-labile, base soluble, strong side effects on the stomach, such as a strong stimulating effect on the stomach directly from the treatment of locally in the intestine, in the intestine segments substantially well absorbed, absorption site in intestine is substantially delayed release or needs) to select a drug suitable enteric polymers of the present invention is preferably at most.

[0069] 通常,上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物与上述可溶于水的药用添加剂在体内消化液中不能发生化学反应或者能发生化学反应但不生成不溶于水的非气态(即常温(25°C)下为固体或液体的)的产物及药学上不可接受的产物, 这是因为若有不溶于水且常温(25°C )下为固体或液体的产物生成,它们将附着或沉积于已生成的释药小孔中,从而使释药受阻,速度变慢。 [0069] Generally, the above-described soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer and the above-described water-soluble pharmaceutically acceptable additives do not chemically react or in vivo digestive fluids can occur but does not generate a chemical reaction of the water-insoluble non-gaseous (i.e., room temperature (25 ° C) is solid or liquid) on a product, and a pharmaceutically unacceptable product, which is insoluble in water and because if a normal temperature (25 ° C generating) the product as a solid or a liquid, which is deposited or adhered release orifice generated, so that the release is blocked, slowed down.

[0070] 此外,利用可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜的不同厚度(如衣膜厚度的递增)及衣膜材料的种类、药物释放速率调节物质的种类及其不同用量(药物释放速率调节物质用量的递增或的递减,详见下文)等可获得间隔不同时间释放药物的丸或片,它们组合在一起(如装胶囊或粘接在一起)可获得脉冲式或间隙式药物释放体系。 [0070] In addition, the use of soluble in the stomach and / or intestinal digestive juices but insoluble or hardly the type of water-soluble films of different thickness of the coating (e.g., incremental coating film thickness) and the material of the coating film, the drug release rate modifier different types and amounts of the substance (a drug substance release rate increment or decrement amount, see below) and the like can be obtained at different time intervals release of drug pellets or tablets, they are combined together (e.g., bonded together or encapsulating ) obtained pulse or gap type drug delivery systems.

[0071] 本发明一个优选的致孔剂即被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物实例为,可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自含有酸性和/或碱性基团的能溶于消化液的水不溶的聚合物材料即肠溶性和/或胃溶性的聚合物,被其包覆的可溶于水的药用添加剂选自与聚合物的酸碱性正好相反的且在体内消化液中与之发生中和反应但不生成不溶于水的非气态(即常温(25°C )下为固体或液体)的产物及药学上不可接受的产物的可溶于水的常温(25°C )下固态的药学上可接受的碱性物质或酸性物质,上述可用的碱性物质选自,但不限于:可溶于水的钠、钾的或铵离子的无机碱性盐、可溶于水的碳原子数不超过6的常温(25°C )下固态的有机碱(如己二胺、萄甲胺)及其呈碱 [0071] The present invention is a preferred porogen is soluble in the stomach i.e. above and / or but insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble pharmaceutically acceptable additives intestinal digestive juices examples are particles, soluble in the stomach and / or digestive juices soluble in water but insoluble or hardly water-soluble polymer selected from the group comprising acidic and / or basic groups of the intestinal digestive juices insoluble polymeric material i.e. enteric and / or gastro-soluble polymers, and the opposite of its acid-base coated with a water-soluble pharmaceutical additives selected from polymers in vivo and in digestive fluids, but the reaction acceptable water-soluble at room temperature (i.e., room temperature of (25 ° C) in the solid or liquid) does not generate water-insoluble non-gaseous products and unacceptable products pharmaceutically acceptable solid at (25 ° C) the alkaline substance or an acidic substance, the basic substance is selected from said available, but are not limited to: water-soluble sodium, potassium or inorganic alkaline salts of ammonium ion, carbon atoms, soluble in water no more than 6 room temperature solid organic base at (25 ° C) (such as hexamethylene diamine, grape methylamine) as a base, and 的盐、可溶于水的碳原子数不超过6的有机多元酸的呈碱性的钠、钾的或铵离子的盐及它们的混合物,上述可用的酸性物质选自,但不限于:可溶于水的碳原子数不超过6的常温(25°C )下固态的有机酸(如己二酸、反/顺丁烯二酸、苹果酸、枸橼酸、洒石酸、植酸、琥珀酸)及其呈酸性的钠、 钾的或铵离子的酸式盐。 Salts, water-soluble carbon atoms does not exceed 6, the organic polyacid alkaline sodium, potassium or ammonium salts and mixtures thereof, said acidic substance is selected from the available, but are not limited to: a solid water-soluble organic acid having a carbon number of not more than 6 at room temperature (25 ° C) lower (e.g., adipic acid, trans / maleic acid, malic acid, citric acid, tartaric acid, phytic acid, succinic acid) and acid salts of the acidic form of sodium, potassium or ammonium ions. 因酸性或碱性的可溶于水的药用添加剂与酸碱性与之相反的聚合物在衣膜中有较强的结合力,有利于提高衣膜机械性能,而且对此聚合物的溶解或降解有良好的促进作用,药物释放时间被更早地提前,药物溶出表现出的时滞性更大的减小。 Due to water-soluble pharmaceutical additives and acidic or basic pH contrary polymers are stronger binding force of the coating film, help to improve the mechanical properties of the coating film, and dissolving this polymer or degradation has a good role in promoting drug release time is earlier advance, the greater the decrease drug dissolution show time lag.

[0072] 本发明一个更优选的致孔剂即被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物实例为,可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自含有酸性基团的能溶于消化液的水不溶的聚合物材料即肠溶性的聚合物,被其包覆的可溶于水的药用添加剂为能在体内消化液中与之反应产生气体(包括但不限于C02、S02、02、C12)但不生成不溶于水且常温(25°C )下为固体或液体的产物及药学上不可接的产物的可溶于水的药用添加剂,这类可溶于水的药用添加剂可选用的实例如碳酸氢根的钠、钾或铵盐,碳酸根的钠、钾或铵盐,甘氨酸碳酸盐, L-赖氨酸的碳酸盐,精氨酸的碳酸盐,氨基酸的钠、钾或铵碳酸盐,含钠、钾或铵糖基的碳酸盐,亚硫酸根的钠、钾或铵盐,亚硫酸氢根的钠、钾 [0072] The present invention is a more preferred porogens described above are soluble i.e. stomach and / or intestinal digestive juice but insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble pharmaceutical additives examples of particulate matter, soluble in the stomach and / or intestinal digestive juices but the polymeric material is insoluble or hardly water-soluble polymer is selected from water-soluble digestive juice containing an acidic group, i.e., insoluble enteric polymer, which is coated with water-soluble pharmaceutically acceptable additives thereto capable of generating gas (including but not limited to C02, S02,02, C12) in vivo digestive fluids, but does not generate the reaction and insoluble in water at room temperature ( at 25 ° C) of unacceptable product, and the product is a solid or liquid pharmaceutically acceptable water-soluble pharmaceutical additives, such water-soluble pharmaceutically acceptable additive examples of such optional bicarbonate sodium, potassium or ammonium salts, sodium carbonate, potassium or ammonium salts, glycine carbonate, L- lysine carbonate, arginine carbonate, amino acids, sodium, potassium or ammonium carbonate, sodium , potassium or ammonium carbonate glycosyl groups, of sodium sulfite, potassium or ammonium salts, sodium bisulfite, potassium 或铵盐,焦亚硫酸根的钠、钾或铵,钠、钾或铵的过碳酸盐,及它们的混合物。 Or ammonium sulfate, sodium metabisulfite, and potassium or ammonium, sodium, potassium or ammonium percarbonates, and mixtures thereof. 它们不仅与酸性的聚合物在衣膜中有较强的结合力,有利于提高衣膜机械性能,而且对此聚合物的溶解或降解有更强的促进作用,这是因为,二者相互作用的主要产物为可溶于水的聚合物盐及特别有用的气体如二氧化碳、二氧化硫等, 而其他产物为水或水溶性小分子盐,故特别有利于可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的溶解,因而特别有利于释药微孔的快速形成,药物释放时间被更大幅地提前,更大幅地减少溶出时滞,促使药物快速溶出,提高药物生物利用度。 They have not only an acidic polymer coating film in stronger binding force, help to improve the mechanical properties of the coating film, and this dissolution or degradation of the polymer has a role in promoting a stronger, this is because the interaction between the two the main product is water-soluble polymers and salts are particularly useful gases such as carbon dioxide, sulfur dioxide, and other products as a small molecule or water-soluble salts, it is particularly advantageous soluble in the stomach and / or intestinal digestive juices but is insoluble or hardly water-soluble polymer is dissolved, it is particularly conducive to the rapid formation of micropores release, drug release time is significantly more advanced and more greatly reduced elution time delay, causes rapid dissolution of the drug, the drug improved bioavailability. [0073] 在上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜(干) 中,可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物有用量较佳地为35%〜 100%重量比,更佳地50%〜100%重量比,最佳地65%〜100%重量比,这是基于上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的干总重量。 [0073] In the above-soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble film coating polymer (dry) may be dissolved in the stomach and / or intestinal or digestive fluids, but almost insoluble water-insoluble polymers are preferably used in an amount ratio of 35% to 100% by weight, more preferably 50% ~ 100% by weight, most preferably 65% ​​~ 100% by weight, which is soluble in the stomach based on the and / or intestinal digestive juices but total dry weight of the insoluble or hardly water-insoluble polymer coating film. 必要时,该衣膜中可加入增塑剂及其他可加入的通用添加剂,详见下文。 If necessary, the coating film may be added a plasticizer, and other common additives may be added, as detailed below.

[0074] 被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物(即致孔剂,胃和/或肠溶包衣+水溶芯料)在分散液(体)混悬包衣液中的用量由此技术领域中技能熟练的技术人员依据药物的性质及所期望的释药速率决定。 [0074] The above is soluble in the stomach and / or intestinal digestive juices but pharmaceutically acceptable additive is insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble particles (i.e., porogen, and stomach / + soluble or enteric coated core material) thereby art skilled in the art the amount of the coating suspension dispersion liquid (bulk) properties of the drug and determined according to the desired release rate. 致孔剂的用量通常依其粒径、控释衣膜聚合物的种类及其用量、药物的性质、所希望的释药速率等决定,通常为5%〜95% (重量比或体积比),较佳地为25%〜 90%,更佳地为40%〜85%,这是基于控释衣膜组分的干总重量或体积。 Properties of porogen usually used in an amount according to their diameter, the controlled release coating film type and amount of polymer, drug, desired release rate and the like, and is usually 5 ~ 95% (weight or volume) , preferably from 25% to 90%, more preferably 40% ~ 85%, based on the total weight or volume of the dry coating film release component. 通常相对较高含量的致孔剂有利于提高控释衣膜的机械性能。 Typically relatively high levels of porogen help to improve the mechanical properties of the controlled release film coat.

[0075] 由于致孔剂的用量是影响或决定控释衣膜的孔隙率的主要因素,因此,控释衣膜的孔隙率通常位于5 %〜95 %,较佳地位于25 %〜90 %,更佳地位于40 %〜85 %。 [0075] Since the amount of porogen is the main factor or porosity determined release coating film, therefore, the porosity of the controlled release film coat usually located 5 ~ 95%, preferably located ~ 90% 25% , more preferably between 40% ~ 85%. 此处所用的术语“孔隙率”是指控释衣膜中的致孔剂溶解或降解后所留下的空间占原完整控释衣膜的体积的比例,未特别标明其他处含义均同此。 As used herein, the term "porosity" release coating is accused of the film after porogen dissolve or degrade the space left by the proportion of the original volume of complete release of the coating film is not specifically indicated have the same meaning as elsewhere herein. 为了简便计算,且因致孔剂的溶解或降解并不影响原控释衣膜内在或外在的尺寸大小,“孔隙率”也可以用控释衣膜中的致孔剂的重量占整个原控释衣膜的重量的比例近似地表示。 For easy calculation, and degradation by lytic or porogen does not affect the original film in the controlled release coating or external size, "porosity" can be the total original weight of the porogen with a controlled release film coating the weight ratio of the controlled release film coat represents approximately. 故“孔隙率”在本发明可用下列两种计算公式计算: Therefore, "porosity" can be used in the present invention, two kinds of the following formula is calculated:

[0076]公式 1 : [0076] Equation 1:

[0077] [0077]

Figure CN101987081AD00221

[0079]公式 2 : [0079] Equation 2:

[0080] [0080]

Figure CN101987081AD00222

[0081] 为了延缓上述可溶于消化液但不溶于水的衣膜的溶解或降解,调控药物释放速率,可在衣膜加入酸或碱性药用添加剂等药物释放速率调节物质,如一实施例可在衣膜加入与可溶于消化液但不溶于水的聚合物的碱性或酸性正好相反的酸或碱等物质来延缓药物释放速率。 [0081] In order to retard the above-described soluble in digestive fluids, but dissolve or degrade the water-insoluble coating film, the rate of drug release regulation, rate of drug release can be added to a pharmaceutically acceptable acid or basic additives in the coating film adjusting substance as one embodiment may be acid or alkaline substance is added to the coating film is soluble in digestive fluids, but water-insoluble polymer basic or acidic opposite to retard drug release rate. 又如一实施例,在胃溶性聚合物衣膜中加入有机酸如枸橼酸促进衣膜溶解,或加入有机碱如碱性氨基酸、葡甲胺等延缓衣膜溶解。 Another example is an embodiment, adding an organic acid such as citric acid in the stomach-soluble polymer coating film promoting coating film dissolves, or an organic base such as a basic amino acid, meglumine delaying coating film dissolved. 再如一实施例,在肠溶性聚合物衣膜中加入有机酸如枸橼酸延缓衣膜溶解。 Another example of an embodiment, addition of an organic acid such as citric acid is dissolved in an enteric film coat delaying polymer coating film. 如又一实施例,在生物可降解的聚合物衣膜中,如脂肪族聚酯类(如聚丙交酯、聚乙交酯、聚丙交酯-聚乙交酯、聚己内酯、聚丙交酯-己内酯)、聚氨基酸、聚原酸酯、聚氰基丙烯酸酯,加入有机碱如碱性氨基酸、葡甲胺等或有机酸如枸橼酸等促进衣膜溶解。 As still another embodiment, the biodegradable polymer coating film, such as aliphatic polyesters (e.g., polylactide, polyglycolide, polylactide - polyglycolide, polycaprolactone, polylactides ester - caprolactone), polyamino acids, polyorthoesters, polycyanoacrylates, addition of organic bases such as basic amino acids, organic acids meglumine or the like such as citric acid coating film to promote dissolution. 可用于此的酸、碱为不会与可溶于消化液但不溶于水的衣膜聚合物反应生成水不溶性的产物的常温(25°C )下固态的碱性物质或酸性物质,合适可用于本发明的碱性物质选自,但不限于:可溶于水的钠、钾或铵离子的无机碱性盐、可溶于水的碳原子数不超过6的常温(25°C )下固态的有机碱及其呈碱性的盐、可溶于水的碳原子数不超过6 的有机多元酸的呈碱性的钠、钾或铵离子的盐及它们的混合物,上述可用的碱性物质选自, 但不限于:酸性物质选自可溶于水的碳原子数不超过6的常温(25°C )下固态的有机酸及其呈酸性的钠、钾或铵离子的酸式盐。 The acid used for this, but the base is not normal water-insoluble polymer coating film reacted with the water-soluble digestive products insoluble basic substance or an acidic substance solid at (25 ° C), can be used suitably basic substance in the present invention are selected from, but not limited to: water-soluble sodium, potassium or ammonium salts of inorganic alkaline ions, water-soluble carbon atoms does not exceed 6 at room temperature (25 ° C) solid organic base and its alkaline salts, the number of carbon atoms does not exceed the water-soluble organic polyacids 6 alkaline sodium, potassium or ammonium salts and mixtures thereof, said available alkaline substance is selected from, but not limited to: an acidic substance is selected from water-soluble carbon atoms, no more than 6 at room temperature (25 ° C) as a solid organic acid and acidic acid salts of sodium, potassium or ammonium ions . 这些物质在可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜中的用量及种类由此技术领域中技能熟练的技术人员依据衣膜材料的性质及所期望的释药速率等决定,通常为1 %〜50 % (重量比),较佳地为3 %〜30 %,更佳地为5%〜20%,这是基于控释衣膜组分的干重量。 These substances are soluble in the stomach and / or intestinal digestive juices but coating film properties is insoluble or almost insoluble in water and in an amount whereby art type skilled in the art based coating film material and the desired release rate and the like, and is usually 1% ~ 50% (weight ratio), preferably from 3% ~ 30%, more preferably from 5% ~20%, based on the dry weight of the controlled release component coating film . 为了防止上述在制备过程中被水溶解,可衣膜外再包一薄层可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣,或者采用非水包衣技术。 To prevent the above is dissolved in water during preparation, coating film may be a thin layer of the outer package can be re-dissolved in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble coating, or a non-aqueous coating techniques. 衣层厚度通常为内层衣的厚度的〜100%,较佳地为2%〜50%, 更佳地为3%〜30%。 An inner coating layer thickness is typically ~ 100% of the thickness of the coat, preferably 2% ~ 50%, more preferably from 3% ~ 30%.

[0082] 为了获得控释衣膜更高的机能性能,较佳地,可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物选用与控释衣膜聚合物完全相溶或部分相容即非完全不相容的聚合物,特别是完全相溶的聚合物。 [0082] In order to obtain higher performance properties of the controlled release coating film, preferably, soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble film coating polymer selected controlled release polymeric coating film It was completely miscible or partially miscible non i.e. completely incompatible polymers, in particular polymers completely miscible. 更佳地,为了进一步获得控释衣膜较好的药物释放稳定性,可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物与控释衣膜聚合物相溶性愈高,上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量较可溶于水的药用添加剂包衣前的用量愈低;例如,当可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物选用与控释衣膜聚合物完全相溶的聚合物时,上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量为上述可溶于水的药用添加剂包衣前的用量为3〜50% (重量),较佳地5〜30% (重量);当可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜聚合物选用与控释衣膜聚合物部分相溶的聚合物时,上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量与上述可溶于 More preferably, in order to further achieve a controlled release drug releasing coating film good stability, soluble in the stomach and / or but insoluble or hardly water-soluble film coating polymer and the enteric polymer coating film release digestive juice the amount of the compatibility before the higher the amount used is soluble in the stomach and is insoluble or hardly water-soluble film coating polymer and / or intestinal digestive juices more water-soluble pharmaceutical additives lower the coating; e.g. when soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble film coating polymer film with polymer coating of controlled release polymer is completely miscible with the gastric-soluble and / or intestinal digestive juices but the amount is insoluble or almost insoluble in water is a polymer coating film before the amount of water-soluble pharmaceutically acceptable coating additive to the above-described 3~50% (wt), preferably 5~30% (by weight); soluble when the stomach and / or intestinal digestive juice but insoluble or hardly water-soluble film coating polymer compatible with polymer controlled release polymer coating film portion, a gastric soluble but the amount is insoluble or hardly water-soluble film coating polymer and / or intestinal digestive juices and soluble in the above-described 的药用添加剂包衣前的用量相比可以相对较多,如为可溶于水的药用添加剂包衣前的用量的5〜80% (重量),较佳地10〜50% (重量),更佳地15〜30% (重量)。 The amount of pharmaceutically acceptable additives before coating may be relatively large compared to, such an amount of 5~80% before the water soluble pharmaceutically acceptable coating additives (wt), preferably 10~50% (by weight) , more preferably 15~30% (by weight).

[0083] 下面介绍聚合物间相容性的判断方法。 [0083] The compatibility between the polymer judging method described below. 聚合物间相容性也存在“相似相容”原贝丨J,因而可以用来评价聚合物共混物的相容性。 There are "like dissolves" raw shellfish Shu J compatibility between the polymer and thus can be used to evaluate the compatibility of the polymer blend. 如Eudragit E、Eudragit L、Eudragit S、 EudragitFS 与Eudragit RL, Eudragit RS 有良好的相容性。 Such as Eudragit E, Eudragit L, Eudragit S, EudragitFS and Eudragit RL, Eudragit RS has a good compatibility.

[0084] 由于溶解度参数能表征聚合物分子间内聚力的大小,因而可以用来评价聚合物共混物的相容性。 [0084] Since the size of the solubility parameter between the polymer molecules can be characterized cohesion, and thus can be used to evaluate the compatibility of the polymer blend. 通常情况下,尤其对于非极性无定形聚合物共混物,当两聚合物的溶度参数之差小于0. 5或聚合物与有机溶剂的溶度参数之差小于1. 5时,二者便能以任意比例混容,体系就有很好的相容性。 Normally, when, in particular, for non-polar amorphous polymer blend, when the difference in solubility parameter of less than 0.5 two or difference in solubility parameter polymer and the organic solvent is less than 1.5, two are able miscible at any ratio, the system has a good compatibility. 对于含有结晶聚合物的共混体系或者聚合物分子具有很强的极性及能形成氢键时,可以采用二维或三维溶解度参数来判断体系的相容性(参见=Shaw Μ. T.,J Appl Polym Sci,1974,18 :449)。 For blends containing a crystalline polymer or polymer molecule has a strong polarity and hydrogen bond forming, two or three dimensions may be employed to determine the solubility parameters of the compatibility of the system (see = Shaw Μ. T., J Appl Polym Sci, 1974,18: 449).

[0085] 本发明推荐应用下列较简便的方法来证明或预测聚合物与聚合物间的相容性: 1)、共同溶剂法,把两种高分子分别溶解到同一种溶剂中,然后相混合,根据两溶液混合情况来判断高分子相容性大小。 [0085] The present invention proposes the following relatively simple method applied to predict or demonstrate the compatibility between the polymer and the polymer: 1), co-solvent method, the two kinds of polymer are dissolved in the same solvent and then mixed The two solutions were mixed case to determine the compatibility of the polymer size. 2)、显微镜法,用相差显微镜法特别是电子显微镜法可直接观察其混相容程度。 2), microscopy, electron microscopy in particular the degree of mixing can be directly observed by phase contrast microscopy compatible. 3)、溶液粘度法,溶液的粘度可以揭示共混聚合物溶液的相容程度,在不同聚合物浓度下,以粘度对聚合物的百分组成作图,如其关系成线性,表明聚合物间达到分子水平的完全相容;如其关系成非线性,则是部分相容;当是完全不相容共混体系,则其关系呈S型曲线。 3), the solution viscosity method, the viscosity of the solution can reveal the degree of compatibility of the blend of the polymer solution, at different polymer concentrations, viscosity is plotted as percent of the polymer composition, as is a linear relationship, between the polymer showed achieve molecular level fully compatible; and, if a non-linear relationship, it is partially miscible; when the blend is totally incompatible, then the relationship S-shaped curve. 4)、热方法及动态力学分析方法(测玻璃化温度Tg),本发明特别推荐此方法,聚合物合金体系会出现三种Tg变化趋势,假设二元合金体系中两种聚合物的Tg分别为Tg1和Tg2(Tg1 < Tg2),(1)、完全相容体系:只出现一个Tg, Tg1 < Tg < Tg2 ; (2)、完全不相容体系:出现二个Tg,分别为Tgl&T&;(3)、部分相容体系:出现二个Tg1' ,Tg2',Tg1 < Tg1' < Tg2' <Tg2。 4), and dynamic mechanical thermal analysis method (measured glass transition temperature Tg), the present invention is especially recommend this method, a polymer alloy system will Tg three kinds of trends, assuming the binary alloy system of two polymers Tg's of Tg1 and Tg2 (Tg1 <Tg2), (1), fully compatible system: There is only one Tg, Tg1 <Tg <Tg2; (2), totally incompatible systems: two appear Tg, respectively Tgl & T &; ( 3), partially miscible systems: two appear Tg1 ', Tg2', Tg1 <Tg1 '<Tg2' <Tg2.

[0086] 更多或更为详细的聚合物与衣膜聚合物间的相容性的评价或预测方法可参考相关文献,如,聚合物合金相容性的预测和表征,叶佳佳等,工程塑料应用,2007年,第35卷, 第12期,第81〜83页;改善聚合物共混材料界面相容性的研究进展,董萌等,涂料涂装与电镀,2006年10月,第4卷第5期,第24〜29页;高分子合金膜的聚合物间相容性预测及表征,谷晓昱等,高分子材料科学与工程,2004年1月,第20卷第1期,第5〜8页;聚合物共混:II.聚合物的相容性,姜胶东,高分子通报,1993年9月,第3期,第178〜184页;聚合物共混的相容性及其理论计算,吕飞杰等,热带农业科学,1985年02期,第15〜19页。 [0086] More or more detailed evaluation of the compatibility between the polymer or prediction methods and the polymer coating film may refer to the relevant literature, e.g., prediction and characterization of a polymer alloy compatibility, Yejia Jia like, engineering plastics applications, 2007, Vol. 35, No. 12, pp. 81~83; Research progress on compatibility of polymer blends to improve the interface, such as Dong Meng, paint coating and plating, October 2006, No. 4 Vol. 5, pp. 24~29; compatibility between forecast and characterization of polymer alloy film of polymer, such as Gu Xiao Yu, polymer materials Science and Engineering, January 2004, Vol. 20, No. 1, No. 5 ~ 8 pages; polymer blend:. II compatible polymers, ginger Shandong, polymer Bulletin, September 1993, No. 3, pp. 178~184 pages; compatible polymer blends and theoretical calculations, Lvfei Jie, etc., tropical agriculture, 1985, 02, pp. 15~19.

[0087] 适合用于本发明的控释衣膜的聚合物可以为药学上可接受的不溶于或几乎不溶于水及胃和肠消化液的嵌段聚合物或共聚物,通常为疏水性聚合物。 [0087] Suitable polymers for controlled release coating film of the present invention may be a pharmaceutically acceptable polymer or a block copolymer is insoluble or almost insoluble in water and digestive juices of the stomach and intestine, generally hydrophobic polymeric thereof. 合适的不溶于或几乎不溶于水及胃和肠消化液的聚合物可选自但不限于不溶于或几乎不溶于水及胃和肠消化液的纤维素酯类、丙烯酸(酯)类聚合物、聚醋酸乙烯酯类、聚氯乙烯类及其组合物。 Suitable insoluble or almost insoluble in water and digestive juices of the stomach and intestines selected from, but not limited to, a polymer is insoluble or almost insoluble in water and digestive juices of the stomach and intestines cellulose esters, acrylic (ester) polymer , polyvinyl acetates, polyvinyl chloride, and combinations thereof. 优选的示例的合适的聚合物实例包括但不限于乙基纤维素、醋酸纤维素、丙酸纤维素、醋酸丁酸纤维素、醋酸丙酸纤维素(cellulose acetate propionate)、硝酸纤维素、三戊酸纤维素、 三十二酸纤维素、三棕榈酸纤维素、二琥珀酸纤维素、二棕榈酸纤维素、聚乙烯乙酸酯、甲基丙烯酸(酯)聚合物、氯乙烯_乙烯醇_醋酸乙烯酯的三元共聚物、氯乙烯_乙烯乙酸酯共聚物、聚碳酸酯、聚甲基丙烯酸甲酯、丙烯酸乙酯-间丙烯酸甲酯聚合物、聚氯乙烯、聚乙炼、聚异丁炼、poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacryl atchloride)及其组合物。 Preferred examples of suitable polymers include but are not limited to the example ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cellulose acetate propionate), cellulose nitrate, triamyl cellulose acetate, cellulose thirty acid, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, polyvinyl acetate, methacrylic acid (ester) polymer, a vinyl chloride-vinyl alcohol _ _ terpolymers of vinyl acetate, vinyl chloride-vinyl acetate copolymer _, polycarbonate, polymethyl methacrylate, ethyl acrylate - methacrylate polymer between, polyvinyl chloride, refining, poly Lian isobutoxy, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacryl atchloride) and combinations thereof.

[0088] 可采用上述聚合物商业上可供应的胶乳、伪胶乳及乳状液包控释衣膜,如乙基纤维素(EC)有:Aquacoat®禾口Surelease®,丙炼酸积ί月旨有:Eudragit® RS30D、Eudragit® RE30D 及Eudragit®RL30D,醋酸纤维索(CA)有:CA398_10胶乳,聚醋酸乙烯酯有:Kollicoat SR 30D 及K0LLID0N SR。 [0088] The polymer latex above may be used on commercially available supply, and pseudo latex emulsion release coating film packages, such as ethyl cellulose (EC) has: Aquacoat® Wo mouth Surelease®, propionic acid refining months aimed product ί there are: Eudragit® RS30D, Eudragit® RE30D and Eudragit®RL30D, acetate fiber cable (CA) has: CA398_10 latex, polyvinyl acetate has: Kollicoat SR 30D and K0LLID0N SR.

[0089] 另一个可采用的不溶于或几乎不溶于水及胃和肠消化液的聚合物实例为US4557925所提供的含80〜95%的聚氯乙烯、0. 5〜19%的聚乙烯乙酸酯及0. 5〜10%聚乙烯醇的三元共聚物的水分散液(体)包衣液。 [0089] Another example of a polymer is insoluble or almost insoluble in water and digestive juices of the stomach and intestine can be offered to US4557925 containing 80~95% of polyvinyl chloride, 0. 5~19% of polyvinyl acetate esters of polyvinyl alcohol and 0. 5 to 10% aqueous dispersion of terpolymer (body) coating liquid.

[0090] 另一个可用的不溶于或几乎不溶于水及胃和肠消化液的聚合物实例为含50〜 100%的聚氯乙烯及0〜50%的聚乙烯乙酸酯共聚物的水分散液(体)包衣液。 [0090] Another example of a polymer is insoluble or almost insoluble in water and digestive juices of the stomach and intestines is available aqueous dispersion of 50~ 100% 0~50% of PVC and polyvinyl acetate copolymer liquid (body) coating liquid.

[0091] 控释衣膜聚合物在干衣中的比例依所选择的聚合物的种类、致孔剂的种类及其用量、药物的性质、所选择的剂型及其所希望的释药模式等决定,通常为5%〜95%重量比, 较佳地10 %〜75 %,更佳地15 %〜60 %,这是基于控释衣膜组分的干重量。 [0091] The proportion of polymer in the controlled release coating film drying is selected depending upon the kind of polymer, the nature of the porogen type and amount of drug, the dosage form chosen and the desired mode of release , and is usually 5 ~ 95% by weight, preferably 10% ~ 75%, more preferably 15% ~ 60%, which is a controlled release coating on a dry weight components of the film. 该衣膜中可加入的其他通用添加剂见下文。 The coating film other common additives may be added below.

[0092] 为了提高或增强控释衣膜的机械性能及药物释放稳定性,尤其是提高温度低于其玻璃化转变温度(Tg)时聚合物出现的玻璃态的韧性及抗冲击能力和/或提高温度高于其玻璃化转变温度(Tg)时聚合物出现的高弹态的尺寸稳定性及强度,本发明可在控释衣膜加入聚合物的增强剂和/或增韧剂等机械性能改善剂。 [0092] In order to improve or enhance the mechanical properties and drug release release coating film stability, especially to improve the toughness and impact resistance appeared glassy polymers at temperatures below their glass transition temperature (Tg) and / or dimensional stability and strength of the rubbery state occurs when raising the temperature of the polymer above its glass transition temperature (Tg), the polymer of the present invention may be incorporated in a controlled release coating film enhancer and / or other mechanical properties of the toughener improving agent.

[0093] 机械性能改善剂通常用量0.5%〜40% (重量比),较佳地〜25%,更佳地2%〜15%,这是基于衣膜组分的干重量。 [0093] Mechanical properties of modifiers are conventionally used in an amount of 0.5% ~ 40% (weight ratio), preferably ~ 25%, more preferably 2% ~ 15%, based on the dry weight of the coating film component.

[0094] 为了获得优异性能的衣膜,本发明可以添加二种或二种以上水不溶性聚合物作为混合膜形成剂。 [0094] In order to obtain an excellent coating film properties, the present invention can be added to two kinds of two or more water-insoluble polymer as a mixed film-forming agent. 为了使这些成膜聚合物有较好的相容性,使之聚合物间粘接力增大,形成稳定的结构,使分散相和连续相均勻,不易发生相分离,本发明可以在包衣液中添加通过嵌段或接枝等作用相容的相容剂。 For these film-forming polymers have good compatibility, the adhesive force is increased between the polymer to form a stable structure, so uniformly dispersed and continuous phases, phase separation hardly occurs in the coating of the present invention can be compatibilizing agent solution was added by the action of other compatible block or graft. 相容剂的通常用量是成膜聚合物的重量的0. 〜40%,较佳地0. 5%〜25%,更佳地〜10%。 The amount of compatibilizer is usually 0.05 ~ 40% by weight of the film-forming polymer, preferably 0.5% ~ 25%, more preferably ~ 10%.

[0095] 在本发明涉及的包衣液中可以添加通用添加剂材料。 [0095] The additive material may be added in a coating liquid general the present invention relates to the. 通用添加剂材料在药物包衣层中的加入量和应用是专业人员熟悉的。 Universal application amount and additive materials in the drug coating layer are familiar to professionals. 通用的添加剂包括但不限于抗粘着剂(分离剂)、 稳定剂、颜料、消泡剂、抗氧化剂、促渗透剂、光泽剂、香料或调味剂。 Common additives include, but are not limited to, anti-sticking agents (separating agent), stabilizers, pigments, defoamers, antioxidants, penetration promoters, gloss agents, flavoring agents, or perfumes. 它们用作加工助剂,并应该保证安全和可重现的制备方法以及长时间贮存稳定性或赋予药物剂型附加的有利特性。 They are used as processing aids, and should ensure safe and reproducible preparation process as well as prolonged storage stability or additional pharmaceutical dosage form to impart advantageous properties. 它们在加工前加入配制的聚合物中,能影响衣层的渗透性,这同样可以用作附加的调节参数。 They are added prior to processing of the polymer formulation, the coating layer can affect the permeability, which can also be used as additional adjustment parameter.

[0096] 可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜及控释衣膜中常用的添加剂的介绍如下。 [0096] soluble in the stomach and / or intestinal digestive juices but describes a controlled release film coat coating film is insoluble or hardly water-soluble additives conventional follows.

[0097] ·增塑剂 [0097] · plasticizer

[0098] 为改进衣膜的质量,常在包衣处方中添加增塑剂以降低聚合物的玻璃化转变温度(Tg)至合适的范围内,并提高包衣材料的成膜能力,增强衣膜的柔韧性和强度,改善衣膜对底物的粘附状态。 [0098] In order to improve the quality of the coating film, the coating formulation often add a plasticizer to lower the glass transition temperature of the polymer (Tg) to within a suitable range, and to improve the film forming ability of the coating material, Enhances flexibility and strength of the film, to improve the state of adhesion of coating film to the substrate. 合适的玻璃化转变温度(Tg)范围通常为0〜70°C,较佳地为10〜50°C, 最佳地为佳地为15〜40°C。 Suitable glass transition temperature (Tg) usually in the range of 0~70 ° C, preferably for 10~50 ° C, preferably for best 15~40 ° C.

[0099] 必要时可利用不同性质的增塑剂例如可溶于水的、水中难溶或水中不溶的增塑剂来调节控释衣膜的释药速率。 [0099] may be, for example, insoluble water-soluble, water soluble or water to adjust the release rate of a plasticizer release coating film using different properties of a plasticizer, if necessary.

[0100] 增塑剂一股地为高沸点、低挥发性并能与聚合物混溶的小分子(Mr约为150〜 800,较佳地为300〜500)的液体物质或低熔点的固体物质。 [0100] plasticizer for an high boiling point, low volatility and can be miscible with the polymer a small molecule (Mr about 150~ 800, preferably a 300~500) a liquid substance or a low melting point solid substance. 可用增塑剂的实例如生理学 Examples of plasticizers such as physiologically available

相容的由C6〜C4tl (优选C6〜C3tl、特别优选Cltl〜C16)脂肪族或芳香族一至三元羧酸与C1〜 C8(优选C2〜C6、特别优选C2〜C5)脂肪族醇形成的亲脂性的酯。 Compatible by C6~C4tl (preferably C6~C3tl, particularly preferably Cltl~C16) an aliphatic or aromatic carboxylic acid with one to three yuan C1~ C8 (preferably C2~C6, particularly preferably C2~C5) aliphatic alcohols of lipophilic esters. 这种增塑剂的实例如邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、癸二酸二丁酯、癸二酸二乙酯、枸橼酸三乙基酯、乙酰柠檬酸三乙酯、甘油三乙酸酯、三丁基葵二酸酯、脱水山梨醇酯、蔗糖酯。 Examples of such a plasticizer such as dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, triethyl citrate ester, acetyl tributyl citrate ethyl ester, triacetin, tributyl sebacic acid esters, sorbitan esters, sucrose esters. 其他可用增塑剂的实例如甘油、丙二醇、聚乙二醇、蓖麻油。 Examples of other useful plasticizers such as glycerol, propylene glycol, polyethylene glycol, castor oil.

[0101] 增塑剂的用量依据所期望衣膜的性质,如玻璃化转变温度、机械性能等,增塑剂的种类,成膜剂(即水不溶性成膜聚合物)的种类、用量等而定,通常用量为5〜50% (重量比),优选10〜40% (重量比),特别优选10〜30% (重量比),这是基于衣膜组分的干重量。 [0101] The amount of plasticizer based on the desired properties of the coating film, such as glass transition temperature, mechanical properties, etc., the type of the type plasticizer, film-forming agent (i.e., water insoluble film forming polymer), and the dosage set, typically in an amount of 5~50% (weight ratio), preferably 10 ~ 40% (weight ratio), particularly preferably 10~30% (by weight), based on the dry weight of the coating film component.

[0102] •抗粘着剂(分离剂) [0102] • antiadherent (separating agent)

[0103] 抗粘着剂(分离剂)通常为有益的疏水材料,一股加入喷射悬浮液中。 [0103] antiadherent (separating agent) is generally beneficial to hydrophobic material, an injection was added to the suspension. 它们阻止成膜期间核的聚集。 They prevent the aggregation of nuclei during the film. 优选使用滑石,硬脂酸镁或硬脂酸钙,研细的硅酸,高岭土或HLB值为3〜8的非离子型乳化剂。 Preferably talc, magnesium stearate or calcium stearate, finely divided silicic acid, kaolin or nonionic emulsifiers having an HLB value of 3~8. 在本发明的衣层中的通常用量为聚合物的0.5〜100% (重量比)。 The amount of the coating layer generally present invention is 0.5~100% of the polymer (weight ratio). 在特别有利的实施方案中,分离剂以浓缩形式作为最终涂层加入。 In a particularly advantageous embodiment, the separating agent in a concentrated form is added as a final coating. 涂覆以粉末形式或由5〜30%固含量的悬浮液通过喷涂而进行。 Applied in powder form or of 5~30% solids suspension by spraying is carried out. 需要量比加工入聚合物层中时的用量少,占药物剂型重量的0.1〜2%。 With less than the required processing into the polymer layer, accounted 0.1~2% by weight of the pharmaceutical dosage form.

[0104] ·稳定剂 [0104] Stabilizer

[0105] 稳定剂优选为乳化剂或表面活性剂,即有一定界面活性物质,对分散液(体)起稳定作用。 [0105] The stabilizer is preferably a surfactant or emulsifier, i.e. a certain interface-active substances, the dispersion liquid (bulk) a stabilizing effect. 合适的稳定剂实例如有二乙醇胺、单乙醇胺、三乙醇胺、脂肪酸类、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、壬苯醇醚、辛苯昔醇、油酸、泊洛沙姆、聚氧乙烯50硬脂酸酯、聚乙二醇脂肪酸类(Polyoxyl fatty acid)、聚乙二醇烷基醚(Polyoxyl hydrocarbon ether)、聚山梨醇酯(Tween)、脱水山梨糖醇酯(Span)、脂肪酸盐类、聚维酮、月桂基硫酸钠、十六烷基硬脂基硫酸钠、蔗糖硬脂酸脂、多乙氧基醚及其混合物。 Examples of suitable stabilizers if diethanolamine, monoethanolamine, triethanolamine, fatty acids, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), nonoxynol, octoxynol, oleyl acid, poloxamer, polyoxyethylene 50 stearate, polyethylene glycol fatty acids (polyoxyl fatty acid), polyethylene glycol alkyl ethers (polyoxyl hydrocarbon ether), polysorbate (Tween), dehydration sorbitan esters (of Span), fatty acid salts, povidone, sodium lauryl sulfate, sodium cetyl stearyl sulfate, sucrose stearates, polysorbates, and mixtures thereof. 稳定剂的含量为1〜 15% (重量比),优选5〜10% (重量比),这是基于分散液(体)包衣液组分的湿重量。 Content of the stabilizer is 1 ~ 15% (weight ratio), preferably 5 to 10% (by weight), based on the dispersion (volume) of the wet weight of the coating component liquid.

[0106] ·颜料 [0106] Pigment

[0107] 通常用于控释衣膜中。 [0107] commonly used for a controlled release film coating. 很少以可溶性颜料形式加入。 Few joined to form a soluble pigment. 一股将氧化铝或氧化铁颜料分散加入。 An alumina or iron oxide pigment dispersion added. 二氧化钛用作白色颜料。 Titanium dioxide as a white pigment. 在本发明的衣层中颜料的加入量为聚合物混合物的20〜60% (重量比)。 Added amount of the pigment in the coating layer of the present invention is a polymer mixture of 20~60% (weight ratio). 然而由于颜料结合能力高,加入量也可以高至100% (重量比)。 However, due to the high pigment binding capacity, may be added in an amount up to 100% (by weight).

[0108] ·消泡剂 [0108] · defoamers

[0109] 消泡剂一股地为二甲基硅油。 [0109] an antifoaming agent for simethicone.

[0110] 衣膜中所有使用的添加剂原则上必须是药学上可接受的,是无毒的,在药物中对病人没有危险。 [0110] All the additives used in the coating film principle must be pharmaceutically acceptable, nontoxic, medicament in no danger to the patient.

[0111] 下面就芯料作说明。 [0111] Here will be described core material.

[0112] 可用于本发明的包衣的芯料包括但不限于规则或不规则形式的片、颗粒、丸、晶体、载药树脂。 [0112] The present invention can be used for coating the core material include but are not limited to a regular or irregular form of tablets, granules, pellets, crystals, drug resin. 颗粒、丸或晶体的尺寸通常为0. 01〜2. 5mm,片的尺寸通常在2. 5〜30mm。 Granules, pellets or size of the crystals is typically 0. 01~2. 5mm, the size of the sheet is usually 2. 5~30mm. 它们通常含有最高达95%的生物活性物质(或活性物质)以及最高达99.9% (重量比) 的其它制药助剂。 They generally contain up to 95% of the biologically active substance (or active material) and other pharmaceutical adjuvants up to 99.9% (by weight ratio).

[0113] 用于本发明的活性成分(或药物或生物活性物质)通常没有特别的限制。 [0113] an active ingredient of the present invention (or biologically active substance or medicament) normally is not particularly limited. 作为本发明所用的活性成分,可以是上述的任何药学上的或营养学上的具有治疗作用的或预防作用的物质。 As an active ingredient used in the present invention, or may be a substance having a therapeutic effect or prophylactic effect on any of the aforementioned pharmaceutically nutrition. 可用于本发明的活性成分如下:中枢兴奋药、镇痛药、解热镇痛药、抗炎镇痛药、 抗痛风药、抗震颤麻痹药、抗精神病药、抗焦虑药、抗抑郁症药、抗癫痫药、镇静药、催眠药、 抗惊厥药、植物神经系统药物、钙拈抗药、治疗慢性心功能不全的药物、抗心律失常药、防治心绞痛药、周围血管扩张药、降血压药、调节血脂药及抗动脉粥样硬化药、呼吸系统药物、抗酸药及治疗消化性溃疡病药、胃肠解痉药、助消化药、止吐药、催吐药及肠胃推动药、肝胆疾病辅助用药、泌尿系统药物、影响血液及造血系统的药物、抗组胺药、过敏反应介质阻释剂、 肾上腺皮质激素及促肾上腺皮质激素、性激素及促性激素、胰岛激素及其它影响血糖的药物、甲状腺激素类药物及抗甲状腺药物、青霉素类、头孢菌素类、内酰胺酶抑制剂、氨基糖苷类、四环素类、大环内 The active ingredient used in the present invention are as follows: central stimulant drugs, analgesics, antipyretic analgesics, antiinflammatory analgesics, anti-gout agents, antiparkinsonian drugs, antipsychotics, anxiolytics, antidepressants , antiepileptics, sedatives, hypnotics, anticonvulsants, autonomic nervous system drugs, calcium twist resistant, chronic heart failure treating drugs, antiarrhythmics, control angina drugs, peripheral vasodilators, antihypertensive drugs , lipid regulating agents and anti-atherosclerotic drugs, respiratory system drugs, antacid drugs, and treatment of peptic ulcer disease, gastrointestinal antispasmodics, Zhuxiaohuayao, antiemetics, gastrointestinal emetic and push drug, hepatobiliary diseases adjuvant, urinary tract drugs, affecting blood and hematopoietic system drugs, antihistamines, hyper-media retarded release agents, adrenocortical hormone, adrenocorticotropic hormone, gonadotropin and sex hormones, insulinotropin and other drugs affect blood sugar, thyroid hormone drugs, and anti-thyroid drugs, penicillins, cephalosporins, lactamase inhibitors, aminoglycosides, tetracyclines, large ring 类、抗结核病药、抗真菌药、抗病毒药、抗肿瘤药物、影响机体免疫功能的药物、维生素及营养类药、减肥药或中草药提取物。 Class, anti-TB drugs, antifungal, antiviral, anticancer drugs affect immune function of drugs, vitamins and nutritional medicines, diet pills or herbal extracts.

[0114] 由于,渗透泵型制剂能同步地把中草药提取物中的各种成分推出制剂,不存在因成分性质不一样而出现的活性成分释放不同步的问题,因此,本发明特别适用于需要控释中草药提取物的控释制剂,特别是渗透泵型制剂制剂。 [0114] Since, the osmotic pump formulation ingredients can herbal extract synchronization Release formulation, due to the absence of the active ingredient is not the same nature ingredient release occurs sync problems, therefore, the present invention is particularly useful for release controlled release formulation herbal extracts thereof, in particular an osmotic pump type preparation formulation. [0115] 在本发明特别适合制成胃溶性膜控控释制剂的药物实例包括但不限于环丙沙星、 卡托普利、速尿、熊去氧胆酸、复方消化酶、中药妇科千金、厄贝沙坦、格列美脲、来氟米特、 麦迪霉素、伊贝沙坦、阿莫西林、头孢氨呋肟、头孢三嗪、头孢泊肟、克拉霉素、氯碳头孢、阿奇霉素、头孢克肟、头孢羟氨苄、阿昔洛韦、地尔硫D、卡托普利、辛伐他汀、洛伐他汀、依托度酸、酮咯酸、雷尼替丁、法莫替丁、非索非那定、伪麻黄碱、苯丙醇胺、右美沙芬、右扑尔敏、 溴隐亭、环孢素、巴氧芬、别嘌醇、(+)_α-氨甲基-2-甲氧基磺酸胺基苯甲醇(专利申请ΕΡ842148实施例3. 6公开的)或3,-(2-氨基-1-羟乙基-4,-氟甲磺酸苯胺(NS49)。其他实例如苯甲酰胺类,具体例子如灭吐灵、维拉必利、阿立必利、氯波必利,更特别地是氨磺必利、硫必利、舒必利及其盐; [0115] Examples of drugs useful in the present invention is particularly suitable formed film of a gastric controlled release formulations include, but are not limited to ciprofloxacin, captopril, furosemide, ursodeoxycholic acid, compound of digestive enzymes, medicine Qianjinpian , irbesartan, glimepiride, leflunomide, midecamycin, irbesartan, amoxicillin, cefuroxime, ceftriaxone, cefpodoxime, clarithromycin, loracarbef, azithromycin, cefixime, cefadroxil, acyclovir, diltiazem D, captopril, simvastatin, lovastatin, etodolac, ketorolac, ranitidine, famotidine , fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine and right, bromocriptine, cyclosporine, Finland bar oxygen, allopurinol, (+) _ α- amino-2- (ΕΡ842148 Patent application embodiments disclosed embodiment 3.6) methoxy benzyl alcohol or amino acid 3 - (2-amino-1-hydroxyethyl -4 - aniline trifluoromethanesulfonate (NS49) other examples The benzamides, such as a specific example metoclopramide, cisapride Vera, aripiprazole cisapride, clebopride, more particularly amisulpride, tiapride, sulpiride and salts thereof; 外,还有α 1-拈抗剂,具体例子如特拉唑嗪和阿夫唑嗪以及它们的盐,尤其是盐酸阿夫唑嗪。 In addition, there α 1- antagonists, such as terazosin Specific examples and alfuzosin and their salts, in particular alfuzosin hydrochloride.

[0116] 在本发明特别适合制成肠溶性膜控控释制剂的药物实例包括但不限于:5_氨基水杨酸及其盐如锌盐,阿坎酸钙,阿雷地平,阿仑膦酸钠,阿奇霉素,阿嗪米特及其复方制齐U,阿司匹林,埃索美拉唑及其盐如镁盐、钠盐、锶盐,艾普拉唑,桉柠菔,氨糖美辛,奥美拉唑及其盐如镁盐、钠盐,奥沙普秦,吡美拉唑,苯酰甲硝唑,比沙可啶,吡罗昔康,丙硫氧嘧啶,菠萝蛋白酶及其复方制剂,促肝细胞生长素,醋氯芬酸,头孢氨苄甲氧苄啶,大蒜素,弹性酶,胞磷胆碱钠,地红霉素,丁二磺酸腺苷蛋氨酸,丁二磺酸硫代腺苷蛋氨酸,托西腺苷蛋氨酸,腺苷蛋氨酸,对氨基水杨酸钠,法罗培南钠,非诺洛芬钙,呋喃妥因,辅酶Q10,,牛胎肝提取及其复方制剂,谷氨酰胺及其复方制剂,双炔失碳酯及其复方制剂,复合磷酸酯酶,格列吡嗪二甲双胍复方制 [0116] Examples of drugs useful in the present invention is particularly suitable for a film made of an enteric controlled release formulations include, but are not limited to: amino acid 5_ its salts such as zinc salts, calcium acamprosate, aranidipine, alendronate sodium, azithromycin, and the compound prepared azintamide homogeneous U, aspirin, esomeprazole and salts thereof such as magnesium, sodium, strontium, ilaprazole, lemon eucalyptus turnip, Glucosamine indomethacin, omeprazole and its salts such as magnesium, sodium, oxaprozin, pyrazole esomeprazole, benzoyl metronidazole, bisacodyl, piroxicam, propylthiouracil, bromelain and its compound preparation, pro hepatocyte growth factor, aceclofenac, cephalexin trimethoprim, allicin, elastase, citicoline sodium, erythromycin, ademetionine succinic, succinic acid thio adenosine methionine, Tosi adenosyl methionine, adenosylmethionine, p-aminosalicylic acid, sodium faropenem, fenoprofen calcium, nitrofurantoin, coenzyme Q10 ,, fetal bovine liver extract and compound preparation, and its compound glutamine formulation, bis Anordrin its compound preparation, compound phosphatase, glipizide compound metformin Ltd. 剂,谷胱甘肽,还原型谷胱甘肽,骨肽,甘草酸二铵,桂美辛,环磷酰胺及其复方制剂,红霉素,己酮可可碱,甲砜霉素,吉他霉素,甲巯咪唑,甲芬那酸,精氨酸酮洛芬,克拉霉素,苦参碱,重组B亚单位/菌体霍乱菌苗复方制剂,枯草杆菌二联活菌复方制齐U,双歧三联活菌,赖氨匹林,雷贝拉唑钠,雷尼替丁,硫普罗宁,硫酸庆大霉素,硫酸亚铁甘氨酸复合物,诺氟沙星,芦氟沙星,洛美沙星,氯克罗孟,柳氮磺吡啶,六甲蜜胺,罗红霉素, 麦考酚钠,磷霉素及其盐如钙盐,美帕曲星,美洛昔康,美他卡韦,美他环素,盐酸门冬氨酸镁,帕罗西汀,米非司酮,米索前列醇,木瓜酶,萘普生,脑蛋白水解物,尼美舒利,尿嘧啶替加氟复方制剂,帕普拉唑,泮托拉唑及其盐如钠盐,七叶皂苷钠,曲克芦丁脑蛋白水解物复方制剂,去羟肌苷,溶菌酶, Agent, glutathione, reduced glutathione, bone peptide, diammonium glycyrrhizinate, Gui indomethacin, cyclophosphamide and compound preparation, erythromycin, pentoxifylline, thiamphenicol, guitar mildew Su, methimazole, mefenamic acid, ketoprofen arginine, clarithromycin, matrine, recombinant B subunit / cell cholera vaccine compound preparation, bacillus subtilis subtilisin made homogeneous compound U, probiotics, aspisol, rabeprazole sodium, ranitidine, tiopronin, gentamicin sulfate, ferrous glycine sulfate complex, norfloxacin, rufloxacin, Los Lomefloxaxin, chlorine Ke Luomeng, sulfasalazine, altretamine, roxithromycin, mycophenolate sodium, fosfomycin and its salts such as calcium, mepartricin, meloxicam, the beauty of his card Wei, metacycline, aspartic acid hydrochloride magnesium, paroxetine, mifepristone, misoprostol, papain, naproxen, brain protein hydrolyzate, nimesulide, tegafur uracil compound formulation, Pa Pula oxazole, pantoprazole and its salts such as sodium, sodium aescinate troxerutin brain protein hydrolyzate compound, didanosine, lysozyme, 三磷酸腺苷,三苯双脒,舍雷肽酶,司帕沙星,替米沙坦,双氯芬酸钠,酮基布洛芬,硫酸钠,细胞色素C,胸腺肽,度洛西汀,多西环素,二甲双胍,氟西汀,青藤碱,乙酰左卡尼汀,乙酰螺旋霉素,左旋咪唑,胰激肽原酶,胰酶,胰岛素,乙酰水杨酸,己酮可可碱,辛伐他汀,银耳孢糖,胶体果胶铋,牛磺酸,小牛血去蛋白提取物,吲哚拉辛,蚓激酶,右旋酮洛芬,扎托布洛芬,中性蛋白酶,左炔诺孕酮,左炔诺孕酮炔雌醚,叶绿素铜钠,依立拉唑,依托度酸,异甘草酸镁,维生素E烟酸酯。 ATP tribendimidine, serrapeptase, sparfloxacin, telmisartan, diclofenac sodium, ketoprofen, sodium, cytochrome C, thymosin, duloxetine, doxycycline, metformin, fluoxetine, sinomenine, acetyl L-carnitine, acetyl spiramycin, levamisole, pancreatic kallikrein, trypsin, insulin, acetylsalicylic acid, pentoxifylline, simvastatin, Tremella spore sugar, colloidal bismuth pectin, taurine, calf blood extract protein, indole Racine, lumbrokinase, ketoprofen, zaltoprofen, neutral protease, levonorgestrel, levonorgestrel quinestrol, sodium copper chlorophyll, irinotecan omeprazole, etodolac, isoglycyrrhizinate magnesium, vitamin E nicotinate.

[0117] 在本发明特别适合制成肠溶性膜控控释制剂的中药制剂实例包括但不限于:大蒜提取物、刺五加提取物、熊胆、虫草菌丝体、龙血竭、米曲菌胰酶(慷彼申)、至灵菌丝、桃金娘油、华蟾素或商品名为鼻渊舒、消炎利胆、妇痛宁、龙芪溶栓、慈丹、芙朴感冒、复方杜仲、 复方黄连素、感冒康、惠血生、降酶灵、降糖甲、雷丸、浙水调脂、龙香平喘、脑脉泰、平喘抗炎、七生静、七生力、心脑康、脉血康、帕朱丸、启脾、前列平、芩暴红止咳、叶下珠、益阴消渴、 薏参、脂脉康、吉如心、芪龙、三七通舒、男宝、春血安、治感佳、苓桂咳喘宁、百宝丹、丹黄祛瘀、复方杜仲健骨、更年安、抗痨、六味地黄、六味木香、溶栓脑通、神安、血塞通、止咳、复方红豆杉、消栓、感冒清热、芩连、克痹骨泰、脑立清或云芝肝泰的中成药。 [0117] In the formulation examples of the present invention is particularly suitable for Chinese film made of an enteric controlled release formulations include, but are not limited to: garlic extract, Acanthopanax extract, bear bile, Cordyceps, Dragon's Blood, koji bacteria trypsin (generous He Shen), to the spirit of the mycelium, myrtle oil, cinobufotalin or trade name Biyuanshu, Xiaoyanlidan, FuTongNing, Longqi thrombolysis, Cidan, Fu Park colds, compound Eucommia, compound berberine, cold Kang Hui blood born, JiangMei spirit, hypoglycemic armor, Lei Wan, Zhejiang water lipid, dragon incense and asthma, Naomaitai, asthma and inflammatory, seven students quiet, seven San Miguel, Xinnaokang, vein blood Kang, Zhu Wan Pa Kai spleen, prostate level, skullcap violent red cough, Phyllanthus, Yin diabetes, Yi Senate Zhimaikang, Kyrgyzstan such as heart, Qilong, March Tongshu , men and treasure, spring blood safety, Zhiganjia, Linggui Kechuanning, Babolat Dan, Dan Huang stasis, compound duzhong bone, Gengnian'an, anti-tuberculosis, Liu Wei Di Huang, Liu Wei wood, thrombolytic brain pass, ShenAn, XUESAITONG, cough, compound yew, Xiaoshuan, cold heat, Qinlian, g Bi Autograft, or Naoliqing versicolor Glucurolactone of medicine.

[0118] 在本发明特别适合制成结肠溶性膜控控释制剂的药物有代表性的例子包括但不限于:巴柳氮,柳氮磺吡啶,偶氮水杨酸,5-氨基水杨酸及其盐如锌盐,布洛芬,氢化波尼松,地塞米松,布地缩松,倍氯米松,氟替卡松,替可的松(tioxocortal),氢化可的松,甲硝唑,替硝唑,甲硝哒唑,环饱菌素,甲氨蝶呤,哌双咪酮,5-氟尿嘧啶,双乙酰氧苯基甲基吡啶,番泻(senna),胸腺肽,胰岛素,后叶加压素,生长激素,菌落刺激因子,降血钙素,免疫球蛋白,格列本脲,硫氮酮,异搏定,硝苯地平,硫甲丙脯氨酸,贝那普利,依那普利,茶碱,萘普生,环氟拉嗪,阿昔洛韦,奥美拉唑,洛伐它丁,阿仑特罗,去氨加压素,二甲双胍,甲氧乙心安,西沙必利,四氢氨基吖啶,它们的混合物和微生态调节剂(probiotics)。 [0118] In the present invention, particularly suitable for controlling insoluble membrane made of colonic drug controlled-release formulations Representative examples include, but are not limited to: balsalazide, sulfasalazine, olsalazine, 5-aminosalicylic acid and salts thereof such as zinc salts, ibuprofen, prednisolone, dexamethasone, budesonide, beclomethasone, fluticasone, tixocortol (tioxocortal), hydrocortisone, metronidazole, tinidazole , metronidazole, cephalosporins saturated ring, methotrexate, piperazine bis-one microphone, 5-fluorouracil, phenylmethyl bis acetoxymethyl pyridine, senna (Senna), thymosin, insulin, vasopressin, growth hormone, colony stimulating factors, calcitonin, immunoglobulin, glyburide, diltiazem, verapamil, nifedipine, sulfur methylpropyl proline, benazepril, enalapril, theophylline, naproxen, ring-fluoro fluphenazine, acyclovir, omeprazole, lovastatin, alendronate, desmopressin, metformin, metoprolol, cisapride, tetrakis hydrogen aminoacridine, and mixtures thereof microorganism modulator (probiotics).

[0119] 在本发明特别适合制成延时释放的控控释制剂的药物实例包括但不限于吉哌隆(G印irone)、利塞膦酸盐、帕罗西汀及其盐、莫索尼定、a-硫辛酸及其衍生物、双胍类(如二甲双胍及其盐)药物、加巴喷丁、1R,2S_甲氧胺、克拉霉素、质子泵抑制剂及其盐(如兰索拉唑、奥美拉唑、泮托拉唑、雷贝拉唑、埃索美拉唑、泰妥拉唑)。 [0119] Examples of controlled release drug formulations of the present invention is particularly suited made delayed release include but are not limited to gepirone (G printing irone), risedronate, paroxetine and salts thereof, moxonidine, a- lipoic acid and derivatives thereof, biguanides (such as metformin and salts thereof) drugs, gabapentin, 1R, 2S_ methoxyamine, clarithromycin, and salts of proton pump inhibitors (e.g. lansoprazole, olmesartan omeprazole, pantoprazole, rabeprazole, esomeprazole, tenatoprazole).

[0120] 用于本发明活性物包括以下活性成分其药学上可选用的盐形式、游离酸形式、游离碱形式、水合物、光学异构体及各种晶型。 [0120] The present invention comprises an active substance in the form of a pharmaceutically acceptable salt of the active ingredient can be selected which, in free acid form, free base forms, hydrates, various optical isomers and polymorphs.

[0121] 芯料除了活性物质还可以含有其它制药助剂,如缓控释材料、致孔剂、填充剂、粘合剂、崩解剂、促崩解剂、润滑剂(包括助流剂、抗粘着剂)、渗透压活性物质(即渗透压促进剂)、促渗透聚合物(助渗剂)等基本成分。 [0121] In addition to active materials the core material may also contain other pharmaceutical auxiliaries, such as slow-release material, porogen, fillers, binders, disintegrants, promoting disintegrants, lubricants (glidants including, antiadherent), osmotic active substance (i.e., osmolality promoting agent), the penetration of the polymer (penetration aids) and other basic ingredients. 此外,还可以包含增溶剂、助悬剂、甜味剂、芳香齐U、色素、吸收剂及表面活性剂(如起润湿、分散、增溶、乳化等作用)。 In addition, may also contain solubilizers, suspending agents, sweetening agents, aromatic Qi U, dye, absorbent and a surfactant (e.g. from wetting, dispersion, solubilization, emulsification and so on). 制药助剂及其用量由此领域技术熟练的技术人员根据实际情况如药物的性质、所希望的释药速率等选择。 The amount of pharmaceutical adjuvants and thereby skilled skilled in the art according to actual conditions such as nature of the drug, the release rate desired and other options.

[0122] 控释制剂的制备方法 [0122] The method of preparing a controlled release formulation

[0123] 本发明的另一目的就是涉及一种性能改善的控释制剂的制备方法,下面就控释制剂的制备方法中的各个基本步骤作详细说明。 [0123] Another object of the present invention is directed to a method for preparing a controlled release formulation of the improved performance, the following detailed description on the various steps of the basic method of preparation of controlled-release formulations.

[0124] 1)、制备含有一种药物的芯料 [0124] 1) Preparation of core material containing a drug

[0125] 制备含有一种药物的芯料的方法没有特别的限制。 Method [0125] A pharmaceutical preparation comprising a core material is not particularly limited. 通常制备方法是将药用活性物质、制药助剂等成分通过直接挤压方法,干、湿或烧结颗粒的挤压方法,挤出和随后倒圆,湿或干态造粒或直接造丸(例如在圆盘上)或将粉末(粉末层)粘结到无活性物质的球(粒子)或含活性物质的颗粒上,或者进一步对上述颗粒以一定方式如压制制成片。 Preparation method is usually a pharmaceutically active substances, pharmaceutical adjuvants and other components by a direct extrusion method, dry, wet or sintered granules extrusion process, the extrusion and subsequent rounding, moist or dry granulation or direct pelleting ( e.g. on the disk) or the powder (powder layer) is bonded to the ball inactive substance (particle) containing the active substance or granules, or further the above-described particles in a manner such as press formed sheet.

[0126] 2)、制备致孔剂_即对可溶于水的药用添加剂的颗粒物包覆含有药学上可接受的增塑剂或不含有增塑剂的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜 [0126] 2) Preparation of porogen _ i.e., water-soluble pharmaceutical additives coated particles comprising a pharmaceutically acceptable plasticizer or a plasticizer soluble in the stomach and / or intestinal digestion liquid but is insoluble or hardly water-insoluble polymer coating film

[0127] 在一实施例中,将可溶于水的药用添加剂分散并混悬于含有药学上可接受的增塑剂或不含有增塑剂的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的(有机或水)溶液或(有机或水)分散液(其中,所述聚合物在有机分散液中的粒度通常应与聚合物在水分散液的粒度相当或更细)中(必要时,可加入衣膜其他添加剂,如增塑剂),混合均勻。 [0127] In one embodiment, the water-soluble pharmaceutical additives containing dispersed and suspended in a pharmaceutically acceptable plasticizer or a plasticizer soluble in the stomach and / or intestinal digestive juices but it is insoluble or hardly water-soluble polymer (organic or aqueous) solution or (aqueous or organic) dispersion (wherein said organic polymer particle size in the dispersion should generally be in the aqueous polymer dispersion particle size equal to or finer) are (if necessary, other additives may be added to film coating, such as a plasticizer) mixed evenly. 利用上述所得的溶液或混悬液通过浇铸、浸醮、涂刷或喷涂等涂层方法对芯料制备衣层。 Using the resulting solution or suspension by casting coating method, dip dipped, spray painting or the like on the coating layer prepared core material. 较佳地采用喷涂方式进行。 Preferably by spraying manner.

[0128] 在另一实施例中,使可溶于水的药用添加剂悬浮于空中,对该悬浮的颗粒物喷含有药学上可接受的增塑剂或不含有增塑剂的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的(有机或水)溶液或(有机或水)分散液(必要时,可加入衣膜其他添加剂,如增塑剂),采用喷涂方式进行包衣。 [0128] In another embodiment, the water-soluble pharmaceutical additives may be suspended in the air, the suspension containing particles is sprayed or a pharmaceutically acceptable plasticizer not containing a plasticizer soluble in the stomach and / or intestinal digestive juices but dispersed insoluble or hardly water-soluble polymer (organic or aqueous) solution or (aqueous or organic) liquid (if necessary, other additives, can be added to film coating, such as a plasticizer), using spraying coated.

[0129] 在一特别的实施例中,可溶于水的药用添加剂与包覆其的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物能在水或体内消化液发生化学反应,此等情况下, 采用非水(不含水)的有机溶剂作为该聚合物的溶剂或分散剂,再进行上述的操作,否则, 二者提前反应于水性介质中。 [0129] In a particular embodiment, the pharmaceutical additives may be water-soluble and the coating which is soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymers can be water or vivo digestive chemical reaction, such cases, non-aqueous (non-aqueous) solvent as an organic solvent or dispersant of the polymer, then the above-described operation, or both before the reaction in an aqueous medium.

[0130] 聚合物在(有机或水)溶液中的含量通常为1〜15%,较佳地2〜10%,更佳地3〜8 %。 [0130] In the content of the polymer (organic or aqueous) solution is usually 1~15%, preferably 2~10%, more preferably 3~8%. 聚合物在(有机或水)分散液(体)中的含量通常为2〜30 %,较佳地5〜20 %, 更佳地8〜15%。 The content of the polymer (organic or aqueous) dispersion (volume) is usually 2~30%, preferably 5~20%, more preferably 8~15%. 水分散液(体)还可含有一定量的有机溶剂,其含量常为1〜20%,较佳地1〜10%,更佳地2〜5%。 Aqueous dispersion (bodies) may also contain a certain amount of organic solvent, the content thereof is usually 1~20%, preferably 1~10%, more preferably 2 ~ 5%. 聚合物在分散液特别是在有机分散液中的粒度通常应不大于50 μ m, 一股地不大于10 μ m,较佳地不大于1 μ m,更佳地不大于300nm,更佳地不大于lOOnm,更佳地不大于30nm,最佳地不大于10nm。 In particular, the polymer dispersion in an organic dispersion particle size should generally be no greater than 50 μ m, an not more than 10 μ m, preferably not more than 1 μ m, more preferably not more than 300nm, more preferably not more than lOOnm, more preferably not greater than 30nm, most preferably no greater than 10nm.

[0131] 对可溶于水的药用添加剂的颗粒物包覆上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜是否完整包覆取决于二者能否在水或体内消化液发生化学反应及下面的控释衣膜包覆过程中是否用到水性介质,即如果二者能在水或体内消化液发生化学反应及所述控释衣膜包覆过程采用水作为控释衣膜聚合物的分散剂或含水的有机溶剂作控释衣膜聚合物的溶剂或分散剂,则通常要求对可溶于水的药用添加剂的颗粒物包覆的上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜必须完整,该衣膜对水的通透性必须为0,如通过下面所述的愈合处理,否则,二者提前反应于水性介质中;如果所述控释衣膜包覆过程采用非水的有机溶剂作为控释衣膜聚合物的溶剂或分散剂,通常不要求对可溶于水的药用添加剂的颗粒物包覆上述 [0131] The particulate water-soluble pharmaceutical additives may be dissolved in the above-described coating the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film depends on both the cladding is complete the controlled release coating film and the coating process the following chemical reaction can occur in water or digestive fluids if used in vivo aqueous medium, i.e., if water or both can occur in vivo digestive fluids of the chemical reaction and release coating film package solvent or dispersant for the organic solvent release film coating polymer dispersing or aqueous coating process using water as a controlled release polymer coating film, it is generally required for the water-soluble particles coated with the pharmaceutically acceptable additive soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film must be complete, the coating film of the water permeability must be 0, by the healing process as described below, otherwise , both ahead of the reaction in an aqueous medium; if the film-coated controlled release coating process using a non-aqueous organic solvent as a solvent or a dispersant polymer release coating film, is not usually required for acceptable water soluble additive particles coated with the above-described 的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜必须完整。 Soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film must be complete.

[0132] 成膜过程不依赖于涂层方法而通过能量输入来进行,可以通过对流(热)、辐射(红外或微波)或传导来完成。 [0132] the deposition process does not depend on the coating method is carried out by energy input via convection (heat), radiation (infrared or microwaves) or conduction to complete. 由此将为涂覆而作为溶剂或悬浮剂使用的溶剂蒸发掉,必要的话也可能应用真空加速蒸发。 Whereby as a solvent for coating the solvent or suspending agent to evaporate, if necessary, may also be applied to accelerate the evaporation in vacuo. 此过程需要较高干燥效率,因此本发明常采用高效率包衣设备(如流化床)。 This process requires high drying efficiency, thus the present invention is a coating apparatus is often used with high efficiency (e.g., fluidized bed).

[0133] 可溶于水的药用添加剂用上述含有药学上可接受的增塑剂或不含有增塑剂的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的溶液或分散液包覆后,该聚合物衣膜的用量通常不超过可溶于水的药用添加剂包衣前的用量的700% (重量/重量), 较佳地不超过可溶于水的药用添加剂包衣前的用量的300% (重量/重量),更佳地约2〜 约200 % (重量/重量),更佳地约2〜约100 % (重量/重量),更佳地约3〜约50 % (重量/重量),最佳地约3〜约30% (重量/重量)。 [0133] The water-soluble pharmaceutical additives containing the above pharmaceutically acceptable plasticizer or a plasticizer soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymeric after the solution or dispersion of the coating composition, the amount of the polymer coating film is usually not more than 700% (w / w) amount of water-soluble before coating pharmaceutical additives, preferably no more than soluble 300% of the amount of coating pharmaceutical additives before water (wt / wt), more preferably from about 2 ~ to about 200% (wt / wt), more preferably from about 2 ~ to about 100% (wt / wt), more best from about 3 ~ to about 50% (wt / wt), most preferably from about 3 ~ to about 30% (wt / wt).

[0134] 包衣用的温度应高于聚合物的最低成膜温度(MFT)(最低成膜温度是指聚合物形成连续性衣膜的最低温度,在最低成膜温度以下,聚合物粒子不能变形融合而成膜)。 [0134] coated with a temperature above the minimum film-forming temperature of the polymer (the MFT) (minimum film-forming temperature is the lowest temperature at continuous polymer coating film is formed in minimum film-forming temperature, polymer particles can not modification and fusion deposition). 包衣用的温度通常高出最低成膜温度10〜20°C。 Coated with temperatures generally higher than the minimum film forming temperature 10~20 ° C. 若温度过低,可能使衣膜出现裂缝;温度过高则过分软化聚合物,导致衣膜粘连。 If the temperature is too low, the coating film may cause cracks; excessively soften the polymer temperature is too high, resulting in coating film adhesion.

[0135] 包衣时,通常预热至20〜90°C,较佳地30〜70°C,更佳地30〜50°C,先以较低喷液速率包衣,至芯料表面已包覆一薄层衣膜后,再提高喷液速率至包衣结束。 When the [0135] coating, typically preheated to 20~90 ° C, preferably 30~70 ° C, more preferably 30~50 ° C, the first coating liquid at a lower discharge rate, to the surface of the core material has after coating a thin coating film, to further increase the rate of liquid discharge to the end of the coating. [0136] 最合适或较合适的工艺参数由此领域技术熟练的技术人员根据包衣材料和芯料性质及实验结果等确定。 [0136] The most suitable or more appropriate process parameters whereby art skilled in the art according to the determined nature of the coating material and the core material and the results of experiments. 例如流化床包衣,其包衣温度、流化风量、雾化压力和喷液速率等工艺条件均可根据实际情况优化定量控制。 Such as fluidized bed coating, which coating temperature, the fluidizing air flow, atomization pressure and spray solution rate and other process conditions can be optimized quantitative control of the actual situation.

[0137] 3)、包覆控释衣膜 [0137] 3), coated with a controlled release coating film

[0138] 在一优选实施例中,将致孔剂即被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的上述可溶于水的药用添加剂的颗粒物分散并混悬于上述含有药学上可接受的增塑剂或不含有增塑剂的不溶于或几乎不溶于水及胃和肠消化液的聚合物的(有机或水)分散液(体),特别是水分散液(体)中,必要时还可以把其它控释衣膜添加剂基至部分药物加入该分散液(体)中,混合均勻。 [0138] In a preferred embodiment, i.e. the porogen is soluble in the above-described gastric and / or intestinal digestive juice but insoluble or hardly water-insoluble polymer coating film coated with the water-soluble pharmaceutically acceptable additive particles dispersed and suspended in the above (organic or aqueous) containing a plasticizer or a pharmaceutically acceptable polymer is insoluble or almost insoluble in water and digestive juices of the stomach and intestines do not contain a plasticizer dispersion the liquid (volume), in particular an aqueous dispersion (bodies), the can where necessary, other additives, controlled release coating film to the base portion of the drug was added to the dispersion liquid (volume) and mix well. 上述水分散液(体)的PH值应在该致孔剂包衣膜不溶解或降解或几乎不溶解或降解的PH值范围内,故该水分散液(体) 的PH值通常应在致孔剂加入前调节至致孔剂包衣膜不溶解或降解的pH值范围内。 The aqueous dispersion liquid (body) PH value should be in the range of PH value of the porogen or degrade the coating film does not dissolve or hardly dissolve or degrade, so that the aqueous dispersion (body) should normally be activated PH value the pore former is added to adjust the porogen does not dissolve or degrade the coating film pH range. 上述不溶于或几乎不溶于水及胃和肠消化液的聚合物在分散液(体)中的含量通常为2〜30%, 较佳地5〜20%,更佳地8〜15%。 Above is insoluble or almost insoluble in water and gastric and intestinal contents of digestive juices in the polymer dispersion (volume) it is usually 2~30%, preferably 5~20%, more preferably 8~15%. 分散液(体)还可含有一定量的不能溶解可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的衣膜的其他溶剂,其含量常为1〜20%,较佳地1〜10%,更佳地2〜5%。 Dispersion (body) may not dissolve a certain amount of gastric-soluble and / or insoluble but hardly soluble in water or other solvents enteric coating film of the digestive juice in an amount of usually 1~20%, preferably to 1~10%, more preferably 2 ~ 5%. 上述有机分散液(体)应不溶解或不降解或几乎不溶解或几乎不降解上述的致孔剂包衣膜即上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜。 The organic dispersion (body) should be insoluble or hardly soluble or does not degrade or hardly degrade the aforementioned porogen i.e. film coating the above-described soluble stomach and / or intestinal digestive juice but insoluble or almost insoluble polymer coating film of water.

[0139] 利用上述所得的分散液(体)的混悬液通过浇铸、浸蘸、涂刷或喷涂等涂层方法对芯料制备衣层。 [0139] The suspension obtained as described above using the dispersion liquid (body) by casting, dipping, brushing or spraying coating processes like coating layer prepared core material pair. 较佳地采用喷涂方式进行。 Preferably by spraying manner. 成膜过程不依赖于涂层方法而通过能量输入来进行。 Film formation does not depend on the coating method carried out by the energy input. 这可以通过对流(热)、辐射(红外或微波)或传导来完成。 This may, radiation (infrared or microwaves) or conduction accomplished by convection (heat). 由此将为涂覆而作为悬浮剂使用的水蒸发掉,必要的话也可能应用真空加速蒸发。 Whereby the coating will be used as a suspending agent to evaporate the water, if necessary, may also be applied to accelerate the evaporation in vacuo. 此过程需要较高干燥效率,因此本发明常采用高效率包衣设备(如流化床、高效包衣锅)。 This process requires high drying efficiency, thus the present invention is often used in high-efficiency coating equipment (such as fluidized bed, efficient coating pan).

[0140] 在另一实施例中,控释衣膜聚合物可溶解于适当的有机溶剂中,并加入增塑剂(必要时,可加入衣膜其他添加剂),依上述方法制备控释衣膜,需要特别指出的是,该溶剂应不溶解或不降解或几乎不溶解或几乎不降解上述的致孔剂包衣膜即上述的可溶于胃和/ 或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜。 [0140] In another embodiment, the controlled release film coating polymer is soluble in an appropriate organic solvent, and adding a plasticizer (if necessary, other additives may be added to coating film), according to the above method of preparing a controlled release coating film , necessary to point out that the solvent should not dissolve or does not degrade or hardly soluble or hardly degrade the aforementioned porogen i.e. film coating the above-described soluble stomach and / or intestinal or digestive fluids, but almost insoluble water-insoluble polymer coating film.

[0141] 在一特别的实施例中,对于上述芯料物质可以与包覆其的聚合物在水液中发生化学反应的致孔剂,较佳地分散其于上述控释衣膜聚合物的不含水的有机溶剂或分散剂中, 且该不含水的有机溶剂或分散剂不溶解或不降解或几乎不溶解或几乎不降解上述的致孔剂包衣膜即上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜。 [0141], a chemical reaction may take place in a special aqueous solution of the above-described embodiment, the core material and the cladding material of the polymeric porogen thereof, which is preferably dispersed in the above-described controlled release polymer coating film an organic non-aqueous solvent or dispersant, the dispersant and the organic solvent or water-free does not dissolve or degrade or hardly soluble or hardly degrade the aforementioned porogen i.e. above film-coating are soluble in the stomach and / intestinal or digestive juice but insoluble or hardly water-insoluble polymer coating film.

[0142] 控释衣膜材料的用量通常为芯料包衣前的用量的0.5〜50% (重量),较佳为5〜 30% (重量),最佳地10〜20% (重量);包衣层厚度通常为5〜500 μ m,较佳为50〜 300 μ m,更佳地100 〜200 μ m。 [0142] The amount of the controlled release film coating material is typically used in an amount of 0.5~50% before coating the core material (by weight), preferably from -5 to 30% (by weight), most preferably 10-20% (wt); the thickness of the coating layer is generally 5~500 μ m, preferably 50~ 300 μ m, more preferably 100 ~200 μ m.

[0143] 包衣时芯料表面温度应高于分散液(体)最低成膜温度(MFT)(最低成膜温度是指分散液(体)形成连续性衣膜的最低温度, 在最低成膜温度以下,聚合物粒子不能变形融合而成膜)。 [0143] When coating the core material should be higher than the surface temperature of the dispersion liquid (volume) minimum film-forming temperature (the MFT) (minimum film-forming temperature refers to the lowest temperature of the dispersion liquid (body) is formed of continuous coating film, the minimum film-forming temperature of the polymer particles can not be deformed and fused deposition). 芯料表面温度在本发明通常高出最低成膜温度10〜20°C。 Comparing the surface temperature of the core material is generally minimum film forming temperature 10~20 ° C in the present invention. 若芯料表面温度过低,可能使衣膜出现裂缝,影响制剂释药特性;芯料表面温度过高则过分软化聚合物,导致衣膜粘连。 If the core material surface temperature is too low, cracks may cause coating film, the influence release characteristics formulation; surface of the core material is excessively soften the polymer temperature is too high, resulting in coating film adhesion.

[0144] 水分散液(体)包衣时,芯料通常预热至20〜90°C,较佳地30〜70°C,更佳地30〜50°C,先以较低喷液速率包衣,至芯料表面已包覆一薄层衣膜后,再提高喷液速率至包衣结束,此操作可避免水分渗入芯料内部,造成储存过程芯料性质发生变化。 [0144] When the aqueous dispersion (volume) coated core material is typically preheated to 20~90 ° C, preferably 30~70 ° C, more preferably 30~50 ° C, to a lower spray solution rate coating, to the surface of the core material has been coated with a thin layer of the coating film, to further increase the rate of liquid discharge to the end of the coating, this operation may prevent water from penetrating inside the core material, the core material during storage resulting in changes in the nature.

[0145] 水分散液(体)包衣前,根据实际还可对芯料进行隔离层包衣,这有助于:①避免水敏感性药物在包衣过程中水解;②避免水溶性药物随水分蒸发而迁移至衣膜;③提高芯料的表面平整性,减小孔隙率,保证衣膜连续性;④改善芯料表面疏水性,以利于水性包衣液的铺展;⑤改善芯料脆碎度,避免包衣过程中的破碎现象。 [0145] before the aqueous dispersion (volume) coating, also in accordance with the actual isolation of the core material coated layer, which helps to: ① avoid hydrolysis of water sensitive drugs during the coating process; ② avoid water-soluble drug with migrate to the water evaporation coating film; ③ improved surface flatness of the core material, reduced porosity, guarantee the continuity of the film coating; ④ the core material to improve the surface hydrophobicity, in order to facilitate spreading the aqueous coating liquid; ⑤ improve brittle core material friability, to avoid the phenomenon of fragmentation of the coating process. 根据实际情况,可选择水溶性材料(如如羟丙基甲基纤维素溶液和羟丙基纤溶液)或聚合物有机溶液进行隔离层包衣。 According to the actual situation, selectively water soluble material (e.g., a solution such as hydroxypropylmethylcellulose and hydroxypropylcellulose solution) or a polymer organic release layer coating solution. 然而,此任一包衣都应充分薄,以免妨制剂的释药性能。 However, any of this coating should be sufficiently thin so as not to hinder the release properties of the formulation.

[0146] 最合适或较合适的工艺参数由此领域技术熟练的技术人员根据包衣材料和芯料性质及实验结果等确定。 [0146] The most suitable or more appropriate process parameters whereby art skilled in the art according to the determined nature of the coating material and the core material and the results of experiments. 以流化床包衣为倒,包衣温度、流化风量、雾化压力和喷液速率等工艺条件均可根据实际情况优化定量控制。 In an inverted fluidised bed coating, a coating temperature, the fluidizing air flow, atomization pressure and spray solution rate and other process conditions can be optimized quantitative control of the actual situation.

[0147] 4)、愈合(老化)处理控释衣膜 [0147] 4), healing (aging) for a controlled release film coating

[0148] 在上述两次包衣结束后,衣膜中聚合物粒子往往未完全融合,还具有一定的通透性。 [0148] After the completion of the two coatings, the coating film of the polymer particles tend to not fully integrated, but also have a certain permeability. 这特别对于上述芯料物质可以与包覆其的聚合物在水液中发生化学反应的致孔剂在下一步用水分散液(体)包控释衣膜时不利,因水分可能渗于其中,使它们在制备过程反应, 失去其应有作用。 This is particularly the porogen a chemical reaction can occur in aqueous solution to said core polymer material and the cladding thereof (bulk) release the package when the coating film is disadvantageous in aqueous dispersion for the next step, because of the moisture therein may bleed, so that During the preparation of their reaction, it should lose its role.

[0149] 控释衣膜存放过程中发生进一步融合现象。 [0149] further enhance the fusion controlled-release coating film storage. 据信,在聚合物_空气间的界面张力产生的微孔附加压(ΔΡ)作用下,这些极小的微孔自动缓缓缩小,存放过程中发生融合现象,使衣膜的通透性发生不断的改变,从而使制剂的药物释放行为变得不稳定。 It is believed that the additional porous pressure (Ap) at the air interface between the polymer _ tension generating effect, these tiny pores gradually reduced automatically, fusion phenomenon occurs during storage, so that the permeability of the coating film occurred constantly changing, so that the drug release behavior of the preparation becomes unstable.

[0150] 因此,在本发明中,在包衣完成后进行愈合处理。 [0150] Accordingly, in the present invention, a healing process after completion of coating.

[0151] 在本发明中,对于控释衣膜的愈合处理(curing treating)包括下列过程:上述控释衣膜中溶剂或分散剂基本蒸发后,在封闭环境中,将上述已包覆控释聚合物衣膜的芯料置于高于上述衣膜的玻璃化转变温度的温度下足够长时间直至终点,使上述制剂控释衣膜中的聚合物粒子融合完全或基本完全,消除或基本消除包衣过程中形成的极小微孔并形成完整致密或基本完整致密的衣膜,上述控释衣膜的渗透性能或者说释药性能达到稳定的状态或者说基本不变的状态。 [0151] In the present invention, the release treatment coating film of healing (curing treating) comprises the following procedure: the above-described controlled release coating film after the solvent or dispersant substantially evaporated in a closed environment, the controlled release coating has the above-described polymer film coating core material for a sufficient time until the end point is placed at a temperature above the glass transition temperature of the coating film, so that the polymer particles of controlled release formulations in fused coating film completely or substantially completely, eliminated or substantially eliminated coating process extremely small micropores and formed a complete or substantially complete densification of the dense coating film, the permeability of the above-described controlled release coating or the release properties of the film reach a steady state or a substantially constant state. 更具体地说,就是在高于上述控释衣膜的玻璃化点的温度下愈合处理上述控释包衣制剂直至制剂在例如约40 士2°C的温度及70%至80%的相对湿度下的加速贮存条件下放置3个月和/或6个月或更长其溶出特性基本上不受影响为止。 More specifically, it is at a temperature above the glass transition point of the controlled release film coat e.g. healing process temperature of about 40 [deg.] C of persons, and 70 2% relative humidity to 80% above the controlled release coating formulation until the formulation is for 3 months, and / or 6 months, or longer until the dissolution properties substantially unaffected under the accelerated storage conditions. 或者换言之,将刚愈合处理后的生物活性物质的体外溶出与在约40 士2°C的温度及70%至80%的相对湿度下的加速贮存条件下被放置3个月和/或6个月的生物活性物质的体外溶出相比,愈合处理的包衣制剂具有稳定的溶出特性。 Or in other words, the newly healed in vitro dissolution of the biologically active substance after the treatment with the left for 3 months and / or 6 under accelerated storage conditions at a temperature of about 40 persons to 2 ° C and 70-80% relative humidity vitro dissolution as compared to the months of the biologically active substance, coating formulations healing process has a stable dissolution profile. 此外术语“稳定的”的意思是与刚固化结束的、固化包衣制剂的溶出特性比较,其体外溶出处于可接受的限度内,可接受的限度由管理机构,如中国药品食品管理监督局、美国食品和药品管理局等确定。 Furthermore the term "stability" means the end of the freshly cured, the cured coating formulation dissolution profile comparison, in vitro dissolution falls within acceptable limits, acceptable limits by a regulatory agency, such as the Chinese Food and Drug Administration regulatory oversight, The US food and Drug Administration and other OK. 基本不受加速贮存条件影响的稳定的溶出特性。 Stabilized dissolution profile substantially unaffected by impact of accelerated storage conditions.

[0152] 在本发明一个特别的实施例中,对于上述芯料物质可以与包覆其的聚合物在水液中发生化学反应的致孔剂,在下一步用含有该致孔剂的控释衣膜的聚合物的水分散液(体)包控释衣膜前,该致孔剂的衣膜应愈合处理(curing treating)至上述致孔剂的衣膜对水的渗透性能为0的状态终点,该愈合处理包括下列过程:上述致孔剂的衣膜的中溶剂或分散剂基本蒸发后,在封闭环境中,将上述致孔剂(即被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂)置于高于上述衣膜的玻璃化转变温度的温度下足够长时间直至上述致孔剂衣膜对水的渗透性能为O的状态终点,使上述致孔剂衣膜中的聚合物粒子融合完全,消除包衣过程中形成的极小微孔并形成完整致密的衣膜,在上述状态终点下,上述致孔剂在上述的不溶 [0152] In a particular release coating embodiment of the present invention, the porogen for said core material can chemically react with the coating polymer aqueous solution thereof, containing porogen in the next step of the actuator aqueous dispersion of a polymer film (bulk) release packets before coating film, the coating film should porogen healing process (curing treating) to the above-described coating film permeability to water porogen to the end state 0 the healing process comprises the following procedures: after the solvent or dispersant of the above-described coating film porogen is substantially evaporated in a closed environment, the above-mentioned porogen (i.e., the above-described soluble stomach and / or intestinal digestive juices but insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble pharmaceutical additives) was placed until such a time sufficient porogen coating film at a temperature above the glass transition temperature of the above-described coating film of permeability to water of the state of the end point O, the polymer porogen particles of the coating film fusion completely eliminate the formation of very small pores in the coating process and form a complete compact coating film, in the state at the end of the porogen in the above-insoluble 或几乎不溶于水及胃和肠消化液的聚合物的水分散液(体)中不发生化学反应,至少要在接下来的整个用水分散液(体)包覆控释衣膜的过程中不发生化学反应。 Or hardly water-soluble polymers and aqueous dispersion of gastric and intestinal digestive juices which does not react chemically (body), at least not to be coated with a controlled release coating film during the entire next water dispersion liquid (the body) of A chemical reaction occurred.

[0153] 在本发明,愈合处理所需的时间通常为数十小时甚至更长。 [0153] In the present invention, the time required for the healing process is generally several tens of hours or more. 愈合处理所选择的温度应高于衣膜玻璃化转变温度,较佳地高于衣膜玻璃化转变温度10°C以上,更佳地高于衣膜玻璃化转变温度20〜30°C,愈合处理所选择的温度且应以不使包衣物料中的成分完全软化或熔化或不发生衣膜粘连为度。 Healing the selected process temperature should be above the glass transition temperature of the coating film, coating film is preferably higher than the glass transition temperature of at least 10 ° C, more preferably higher than the glass transition temperature of the coating film 20~30 ° C, healing and process temperature should be chosen so as not to the coating composition or material is completely melted or softened coating film does not occur to the degree of blocking. 愈合处理时较佳地使用一定的湿度,因控释衣膜在水分或湿气的作用下,其玻璃化转变温度会显著下降,从而有利于加速愈合处理。 Healing process is preferably used when a certain humidity, due to a controlled release coating film under the action of water or moisture, the glass transition temperature decreases significantly, thus contributing to accelerate the healing process.

[0154] 愈合处理可以以烘箱和流化床等热处理方式进行。 [0154] healing process may be performed in a fluidized bed and the heat treatment oven. 流化床热处理具有高效、省时等特点,可在同一设备中完成包衣和热处理操作,产业化适用性较高。 Having a fluidized bed heat efficient, time-saving features, the coating and heat treatment operation to be completed in the same device, high industrial applicability. 包衣结束后升高系统温度,物料在同一流化床设备中继续流化干燥,短时间内可促进膜愈合平衡。 After raising the temperature of the coating system, the material in the same fluidized bed equipment continues to fluidized drying, the membrane may promote healing of equilibrium within a short time. 但与烘箱方式相比,流化床方式对丧膜机械性能的要求较高,且热处理后膜愈合程度相对较低。 However, compared with the way the oven, a fluidized bed mode funeral film require a higher mechanical properties, and the film after heat treatment is relatively low degree of healing. 故本发明较佳地采用烘箱热处理方式。 Therefore, the present invention is preferred to employ an oven heat treatment.

[0155] 在较高热处理温度下,为了防止低熔点药物(如布洛芬)可能迁移进入衣膜中,造成制剂释药加快现象、衣膜机械性能下降等问题,可对载药芯料进行隔离层包衣,或者降低热处理温度。 [0155] In the heat treatment at higher temperatures, in order to prevent a low melting point drugs (such as ibuprofen) can migrate into the coating film, resulting in the phenomenon of accelerated release formulation, coating film mechanical performance deterioration may be made of drug-loaded core material spacer layer coatings, or to reduce the heat treatment temperature.

[0156] 最合适或较合适的工艺参数,如愈合温度、湿度、时间由此领域技术熟练的技术人员根据实验结果等确定。 [0156] The most suitable or more appropriate process parameters, such as the healing of temperature, humidity, time, whereby the field determination skilled in the art according to the results of experiments.

[0157] 如果在包衣过程中衣膜已愈合完全,可不进行愈合(老化)处理,如用Surelease(EC)水分散液(体)包衣的制剂。 [0157] If the coating process coating film was completely healed, without performing healing (aging) treatment, such as with Surelease (EC) aqueous dispersion (body) coating formulations.

[0158] 用上述任一方法制备的制剂都可以包上一薄层包衣材料以改善制剂的表面整体性或防止在贮存过程中制剂相互粘结。 [0158] The formulation prepared by any of the above methods may be coated on a thin layer of coating material to improve the surface integrity of the formulation or to prevent mutual adhesion of the formulation during storage. 合适的包衣材料包括但不限于二糖如蔗糖、多糖如麦芽糖糊精和果胶、和纤维素衍生物如羟丙基甲基纤维素和羟丙基纤维素,然而,任一包衣都应充分薄并且是可溶于水的,以免妨碍制剂的释药性能。 Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrins and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, have any of a coating It should be sufficiently thin and water soluble, so as not to interfere with the release properties of the formulation.

[0159] 用上述任一方法制备的药物剂型基本上可直接使用,如直接口服。 [0159] The pharmaceutical dosage form prepared by either method can be substantially used directly, such as directly administered orally. 用上述方法制备的小片、丸或颗粒等也可用计量设备装入如胶囊、袋(小药囊)或合适的多计量容器中。 Platelets prepared by the above methods, pellets or particles may also be charged with a metering device such as capsules, bags (sachets) or multiple dosing suitable container. 可能的话,用上述方法制备的丸或颗粒等在与其它助剂混合后通过适宜方法如压制得到新的制剂如片剂,该制剂在服用后分解,大部分或全部包覆的小单元释放出来。 If possible, pellets or particles prepared by the above method after mixing with other additives by a suitable method such as pressing the obtained new preparations such as tablets, after taking the formulation decomposed, most or all of cell-coated release . 同样可以考虑将由上述方法制备的控释制剂包埋入聚乙二醇或脂质或其他基质中以制备栓剂或阴道用药物剂型。 The same package may be considered a controlled release formulation prepared by the method of embedding a polyethylene glycol or a lipid, or other substrates to prepare a pharmaceutical dosage form of suppositories or vaginal. 包覆的片剂用半球形容器或多剂量容器包装,病人服用前直接取出。 Coated tablets, directly taken by the patient before taking a hemispherical multi-dose containers packaging.

[0160] 由此已详细地描述了本发明,对本领域技术人员而言在本发明的范围内显然还可有各种改变,本发明并不受说明书所述的限制。 [0160] Having thus described in detail the present invention, to those skilled in the art various changes may be apparent within the scope of the present invention, the present invention is not limited specification.

[0161] 本发明相对以往技术具有下列技术优势: [0161] The present invention is a conventional technique has the following technical advantages relative:

[0162] 1)、药物释放重现性或稳定性提高; [0162] 1), the drug release or stability improved reproducibility;

[0163] 2)、体内因素对药物释放影响减轻; [0163] 2), the factors in vivo release of the drug to alleviate;

[0164] 3)、体外因素对药物释放影响减轻,如可防止水溶性物质容易从聚合物膜中析出,克服“泛霜”现象; [0164] 3), in vitro release of factors mitigate drugs, such as water-soluble substance can be prevented easily precipitated from the polymer film, to overcome the "efflorescence" phenomenon;

[0165] 4)、药物释放的时滞性降低,药物释放提前,药物释放加快,生物利用度提高; [0165] 4), the time delay of drug release decreases, early drug release, the drug release rate, increased bioavailability;

[0166] 5)、控释衣膜机械性能增强; [0166] 5), a controlled release coating film enhanced mechanical properties;

[0167] 6)、可以实现药物在胃肠道中定位控释释放,如胃、肠、结肠控释释放; [0167] 6) can be positioned to achieve controlled release of the drug in the gastrointestinal tract, such as stomach, intestines, colon controlled release;

[0168] 7)、可以实现药物在胃肠道中延时控释释放、间隙式或脉冲式控释释放。 [0168] 7), the drug can be achieved in the gastrointestinal tract delayed controlled release of the gap release or pulsed release.

附图说明 BRIEF DESCRIPTION

[0169] 图1实施例1及对照品1辛伐他汀体外释放测试结果 [0169] FIG. 1 and Example 1 in vitro release of simvastatin Reference Sample 1 Test Results

[0170] 图2实施例2及对照品3盐酸地尔硫卓体外释放测试结果 2 and Reference Sample vitro diltiazem hydrochloride 3 [0170] Example 2 FIG release test results

[0171] 图3实施例3及对照品5盐酸二甲双胍体外释放测试结果 [0171] FIG 3 Example 3 and Reference Sample 5 in vitro release test results of metformin hydrochloride

[0172] 图4实施例4及对照品7布地奈德体外释放测试结果 [0172] Figure 4 Example 7 Example 4 and Reference Sample budesonide in vitro release test results

[0173] 图5实施例5及对照品8双氯芬酸钠体外释放测试结果 [0173] Figure 5 Examples 5 and 8 embodiment the reference diclofenac sodium in vitro release test results

[0174] 图6实施例6及对照品9曲匹地尔外释放测试结果 [0174] FIG 6 Example 9 Example 6 and Reference Sample trapidil outer release test results

实施例 Example

[0175] 以下非选择性实施例进一步描述了本发明范围内的优选实施例。 [0175] The following examples further describe the non-selective within the scope of the preferred embodiment of the invention. 在本发明的范围内这些实施例还可有许多变化。 Within the scope of the present invention to these embodiments it may have many variations.

[0176] 实施例1及对照例1-2 [0176] Example 1 and Comparative Example 1-2

[0177] 1、制备样品及照用样品 [0177] 1, according to the sample preparation and sample

[0178] 1)、按下列处方及工艺制备片芯: [0178] 1), according to the following formulation and process for preparing the core:

[0179] [0179]

Figure CN101987081AD00331

[0180] 将辛伐他汀、CABB0P0L 974P、磨碎的二水枸橼酸钠、乳糖和聚乙烯吡咯烷酮混合均勻,用含水10% (按重量计)的乙醇溶液(含所需的BHA)进行造粒;将湿的粒状物料强制过18目筛并干燥24小时;整粒后,加入硬脂酸镁混勻,用一个1/4英寸的标准的凹形圆形冲模压制片,所用的压制力为800〜1000磅。 [0180] Simvastatin, CABB0P0L 974P, milled sodium citrate dihydrate, lactose and polyvinylpyrrolidone uniformly mixed with 10% aqueous be made (by weight) in ethanol (containing the required BHA) tablets; wet mass was forced through the 18 mesh sieve and dried for 24 hours; after sieved and magnesium stearate and mix with a concave circular standard 1/4 inch punch tableting press, with the pressing force is 800~1000 pounds. 压制后片剂的厚度为3. 89mm,硬度为8〜 IOkg0[0181] 2)、制备肠溶衣膜包衣颗粒 The thickness of the tablet after pressing 3. 89mm, hardness 8~ IOkg0 [0181] 2), an enteric film coating granules prepared

[0182] 包衣液处方 [0182] Coating liquid formulation

组分 % Component%

Figure CN101987081AD00341

[0184] 说明,# :经测试羧甲基乙基纤维素与下列控释衣膜聚合物醋酸纤维素相容。 [0184] Description #: Compatibility tested carboxymethyl ethylcellulose polymer with the following release coating cellulose acetate film.

[0185] 按上述包衣液处方配制羧甲基乙基纤维素的包衣液。 [0185] Coating liquid formulation prepared according to the above coating solution of carboxymethyl ethyl cellulose. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入碳酸氢钠颗粒(粒径300〜400目,38〜48 μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added sodium hydrogen carbonate (particle diameter 300~400 mesh, 38~48 μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂碳酸氢钠粉,碳酸氢钠颗粒增重约100%。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, sprayed with a spray liquor prepared above sodium bicarbonate powder, sodium bicarbonate particles to about 100% weight gain. 干燥并愈合(温度为55°C,愈合时间不低于72 小时,直至其中的钠离子不渗出,不渗水发生中和化学反应为至)后所得颗粒经240目圆形筛(61 μ m)和300目圆形筛(48 μ m)筛分,得到含有碳酸氢钠核芯的肠溶衣膜包衣颗粒(粒径48 〜61ym)0 Healing and dried (temperature of 55 ° C, the healing time is not less than 72 hours until the sodium ions which are not bleeding, occurrence and impermeable to a chemical reaction) The resulting particles are 240 mesh circular sieve (61 μ m an enteric film coating granules) and 300 mesh circular sieve (48 μ m) sieve to give a core containing sodium bicarbonate (particle size 48 ~61ym) 0

[0186] 3)、制备控释衣膜包衣液: [0186] 3) Preparation of film-coated controlled-release coating solution:

[0187] 将醋酸纤维素加入乙酸乙醋-乙醇(95 : 5)中制得5%的溶液作为油相,以3mg/ ml的十二烷基硫酸钠水溶液为水相;用高速乳勻机,在搅拌速度不小于3000转/分钟的条件下把水相缓缓滴加入油相中形成W/0型乳剂,继续滴加直至形成0/W型的初乳。 [0187] Cellulose acetate was added acetic acid ethyl ester - ethanol (95: 5) was prepared as a 5% solution of oil phase to 3mg / ml of sodium dodecyl sulfate aqueous solution into an aqueous phase; high-speed homogenizer , under stirring speed of not less than 3000 rev / min the aqueous phase was slowly dropwise added to the oil phase to form a W / 0 type emulsion, continued until the solution of colostrum type 0 W / formed. 将初乳通过高压勻质机,反复6次。 The colostrum by a high pressure homogenizer, repeated six times. 使用旋转蒸发仪在40°C,减压条件下将有机溶剂从所得乳剂中除去。 Using a rotary evaporator and the organic solvent was removed from the resulting emulsion at 40 ° C, under reduced pressure conditions.

[0188] 4)、包控释衣膜: [0188] 4), including a controlled release film coating:

[0189] 片芯包控释衣膜前、后包隔湿保护涂层。 [0189] before the core pack release coating film, the moisture barrier bag protective coating. 隔湿保护涂层用的包衣料为含4. 5%羟丙基甲基纤维素(Pharmacoat,603/ShinEtsu)、0. 52%的PEG 400及1. 5%微粉化的滑石的混悬液。 The moisture barrier coating material with a protective coating containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603 / ShinEtsu), 400, and 1.5% micronized talc 0.52% PEG suspension of . 包衣条件参数:喷洒时间约20秒,鼓风时间约30〜40秒,鼓风温度50〜55°C,片芯温度30〜40°C。 Parameters coating conditions: Spraying time is about 20 seconds, the blowing time of about 30 to 40 seconds, blast temperature 50~55 ° C, die temperature 30~40 ° C. 隔湿保护涂层包衣增重约为1 %。 The moisture barrier coat protective coating weight gain of about 1%.

[0190] 在上述制得的醋酸纤维素加水分散液(体)中加入肠溶衣膜包衣颗粒及作增塑剂用的二乙酸甘油酯,其中醋酸纤维素:肠溶衣膜包衣颗粒:二乙酸甘油酯为1 : 2 : 1(重量比),用水稀释至含3%的醋酸纤维素混悬液制得包衣液,必要时,预先调节醋酸纤维素混悬液的PH值至3. 5〜4.0。 [0190] Add an enteric film coating granules and glycerol diacetate as a plasticizer is added with an aqueous dispersion of (body) prepared in the above-described cellulose acetate, cellulose acetate wherein: an enteric film coating granules : glyceryl diacetate is 1: 2: 1 (weight ratio), diluted with water containing 3% cellulose acetate suspensions prepared coating solution, if necessary, adjusting the PH value of the advance to a suspension of a cellulose acetate 3. 5~4.0. 用制得的包衣液对片芯包控释衣膜。 The controlled release coating film with a coating solution prepared for packet core. 控释衣膜包衣增重为16%。 The controlled release coating film coat weight gain was 16%.

[0191] 用定时自动薄膜包衣机包衣,包衣条件参数为:喷洒时间约20秒,鼓风时间约30〜40秒,鼓风温度50〜70°C,片芯温度40〜50°C。 [0191] with the timing of automatic film coater coating, coating conditions parameters: spray time of about 20 seconds, the blowing time of about 30 to 40 seconds, blast temperature 50~70 ° C, die temperature 40~50 ° C.

[0192] 5)、愈合控释衣膜 [0192] 5), a controlled release coating film healing

[0193] 愈合处理在密闭烘箱中进行。 [0193] healing process in a closed oven. 愈合温度为65°C,愈合时间为30小时。 Healing temperature of 65 ° C, the healing time is 30 hours.

[0194] 6)、制备对照例[0195] 在上述制得的醋酸纤维素加水分散液(体)中加入羧甲基乙基纤维素的颗粒(粒径48〜61μπι)及作增塑剂用的二乙酸甘油酯,其中,醋酸纤维素:羧甲基乙基纤维素颗粒:二乙酸甘油酯为1 : 2 : 1(重量比),用水稀释至含3%的醋酸纤维素混悬液制得包衣液。 [0194] 6) Preparation of Comparative Example [0195] Add carboxymethyl ethylcellulose dispersion with water (body) prepared in the above-described cellulose acetate particles (particle diameter 48~61μπι) as a plasticizer and acid diglycerides, wherein the cellulose acetate: carboxymethyl ethyl cellulose particles: glyceryl diacetate is 1: 2: 1 (weight ratio), diluted with water containing 3% cellulose acetate suspensions prepared to obtain a coating solution. 然后,按上述的方法制备控释衣膜含有羧甲基乙基纤维素颗粒的对照例1。 Then, according to the methods described above a controlled release film coating comprising carboxymethyl ethyl cellulose particles of Comparative Example 1.

[0196] 在醋酸纤维素的丙酮溶液中加分别加入碳酸氢钠颗粒(粒径48〜61 μ m)及作增塑剂用的二乙酸甘油酯,其中,醋酸纤维素:碳酸氢钠:二乙酸甘油酯为1 : 2 : 1(重量比),用丙酮稀释至含3%的醋酸纤维素混悬液制得包衣液。 [0196] in an acetone solution of cellulose acetate were added sodium bicarbonate (particle diameter 48~61 μ m) and as plasticizer glycerol diacetate, wherein the cellulose acetate: sodium bicarbonate: two triacetin is 1: 2: 1 (weight ratio), diluted to a 3% suspension of a cellulose acetate coating solution was prepared with acetone. 然后,按上述的方法制备控释衣膜含有碳酸氢钠颗粒的对照例2。 Then, according to the above method of preparing a controlled release coating of a film containing sodium bicarbonate particles of Comparative Example 2.

[0197] 2、体外释放度试验[0198] 采用中国药典2005年版桨法测定。 [0197] 2, in vitro release test [0198] The determination of Chinese Pharmacopoeia 2005 paddle method. 转速为50r/min,温度为(37士1)°C,递质分别用人工胃液(PH1.2盐酸液)及含0.4%十二烷基硫酸钠的人工肠液(pH6.0磷酸盐缓冲液)、含0. 4%十二烷基硫酸钠的人工肠液(pH7. 4磷酸盐缓冲液)各900mL。 Speed ​​is 50r / min, a temperature of (37 persons 1) ° C, respectively neurotransmitter artificial gastric juice (pH 1.2 HCl buffer solution) and artificial intestinal juice containing 0.4% sodium dodecyl sulfate (pH 6.0 phosphate buffer ), artificial intestinal juice containing 0.4% sodium dodecyl sulphate (pH7. 4 phosphate buffer) each 900mL. 用流过型(flow-through)紫外分光光度计监视药物的释放情况。 With a flow-through (flow-through) spectrophotometer drug released was monitored. 图1显示出了药物从控释包衣片剂及对照例1释放的情况。 1 shows a case where the drug release from coated tablets and release of Comparative Example 1.

[0199] 结果显示,实施例样品中药物在人工肠液中释放较快,受酸碱度的影响较小,时滞性也较小,而对照例中药物在人工肠液中释放相对较慢,受酸碱度的影响相对较大,时滞性也相对较大;二者中药物均在人工胃液中基本不释放。 [0199] The results show that the sample of Example faster drug release in an artificial intestinal juice, less affected by the pH, the time lag is small, and the release of the drug in Comparative Example simulated intestinal fluid is relatively slow, the pH by Effect of relatively large, relatively large time lag; both of the drugs were substantially not released in artificial gastric juice.

[0200] 实施例2及对照例3-4 [0200] Example 2 and Comparative Example 3-4

[0201] 1)、按下列处方及工艺制备片芯: [0201] 1), according to the following formulation and process for preparing the core:

组分 mg/片 Component mg ​​/ tablet

盐酸地尔硫卓 300 Diltiazem hydrochloride 300

柠檬酸二氢钠 218 Sodium dihydrogen citrate 218

[0202] [0202]

聚维酮(K25) 42. 4 Povidone (K25) 42. 4

硬脂酸镁 12. 6 12.6 Magnesium stearate

总计 573 Total 573

[0203] 将盐酸地尔硫卓、柠檬酸二氢钠和聚维酮混合均勻,用无水乙醇溶液进行造粒;将湿的粒状物料强制穿过一个18目的筛子并干燥24小时;整粒后,加入硬脂酸镁混勻,用一个12mm的标准的凹形圆形冲模压制片,所用的压制力为1200〜2000kg,压制时间1〜2s。 [0203] The diltiazem hydrochloride, sodium dihydrogen citrate, and povidone uniformly mixed, granulated with absolute ethanol; wet granular mass forced through a 18 mesh sieve and dried for 24 hours; after sieved, added magnesium stearate are blended, using a 12mm standard concave round punches of the tableting press, the compression force used is 1200~2000kg, pressing time 1~2s. 硬度为6〜IOkgo Hardness 6~IOkgo

[0204] 2)、制备胃溶衣膜包衣颗粒 [0204] 2) Preparation of gastric coating film of coated granules

[0205] 包衣液处方 [0205] Coating liquid formulation

组分 Constituent

Γ Ί EUDRAGIT E100* 25g Γ Ί EUDRAGIT E100 * 25g

[0206] [0206]

柠檬酸二氢钠颗粒(粒径45〜53 μ m) 50g 无水乙醇 633g[0207] Sodium dihydrogen citrate (particle diameter 45~53 μ m) 50g of anhydrous ethanol 633g [0207]

Figure CN101987081AD00361

[0208] 说明,* :经测试EUDRAGIT ElOO与下列控释衣膜聚合物EUDRAGIT® RS 30 D、 EUDRAGIT®. RL 30 D部分相容,相容程度较高。 [0208] Note, *: EUDRAGIT ElOO and tested following a controlled release film coating polymer EUDRAGIT® RS 30 D, EUDRAGIT® RL 30 D partial compatibility, a high degree of compatibility.

[0209] 按上述包衣液处方配制EUDRAGIT ElOO的溶液。 [0209] EUDRAGIT ElOO was prepared according to the above coating solution formulation. 用喷雾干燥机(TCSD :日本车辆), 以入口温度80°C、热风流量34〜38mmH20、喷雾速度2g/min,喷雾干燥该液,蒸馏除去溶剂, 颗粒增重约50%,干燥并愈合(温度为45°C,愈合时间不低于60小时,直至其中的钠离子不渗出,不渗水发生中和化学反应为至)后的颗粒过230及270目的筛,得到胃溶衣膜包覆的柠檬酸二氢钠核芯的胃溶衣膜包衣颗粒(粒径53〜62 μ m)。 Using a spray dryer (TCSD: Japan vehicle), at an inlet temperature of 80 ° C, hot air flow rate 34~38mmH20, spraying speed of 2g / min, spray-drying the solution, the solvent was distilled off, about 50% weight gain of the particles, dried and healing ( temperature of 45 ° C, the healing time is not less than 60 hours until the sodium ions which are not bleeding, impervious and 230 mesh and 270 mesh to a particle through a chemical reaction) after the occurrence, to give film-coated gastric coating the core of the sodium dihydrogen citrate gastric coating film coated granules (particle diameter 53~62 μ m).

[0210] 3)、对片芯按下列处方及工艺包衣: [0210] 3) of the following core formulation and coating process:

[0211] 包衣液处方(1000片用量): [0211] Coating liquid formulation (dosage 1000):

[0212] [0212]

Figure CN101987081AD00362

[0213] 水分散液(体)的固体含量为16(重量)%。 [0213] The solids content aqueous dispersion (body) 16 (wt)%.

[0214] 将片芯在Hicoater/Fruend包衣机上包衣。 [0214] The tablet cores are coated on a Hicoater / Fruend coater. 包衣条件参数:入口温度,50〜60°C; 出口温度,30〜35°C ;片芯温度31〜36°C ;片芯增重12. 63%。 The coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 30~35 ° C; die temperature 31~36 ° C; core weight gain of 12.63%.

[0215] 4)、愈合控释衣膜 [0215] 4), a controlled release coating film healing

[0216] 愈合处理在密闭烘箱中进行。 [0216] healing process in a closed oven. 愈合温度为45°C,愈合时间为24小时。 Healing temperature of 45 ° C, the healing time of 24 hours.

[0217] 5)、制备对照用品。 [0217] 5), supplies a control was prepared.

[0218] 把包衣液处方中的胃溶衣膜包覆的柠檬酸二氢钠丸换成包衣的EUDRAGIT ElOO的颗粒(粒径53〜62 μ m)或未包衣的柠檬酸二氢钠颗粒(粒径53〜62 μ m),按上述方法及条件制备对照用品3或4。 [0218] The gastric coating film of the coating solution formulation of sodium dihydrogen citrate coated pellets into EUDRAGIT ElOO coated particles (particle diameter 53~62 μ m) or uncoated dihydrogen citrate sodium (particle diameter 53~62 μ m), prepared as described above and supplies a control condition 3 or 4.

[0219] 2、体外释放度试验 [0219] 2, in vitro release test

[0220] 采用中国药典2005年版桨法测定。 [0220] Chinese Pharmacopoeia 2005 edition paddle by. 转速为lOOr/min,温度为(37士1)°C,递质用人工胃液I (PH2. 0的盐酸液)、人工胃液II (pH4. 0的盐酸液)及人工肠液(pH7. 5磷酸盐缓冲液)各1000mL。 Speed ​​of lOOr / min, a temperature of (37 persons 1) ° C, neurotransmitters artificial gastric juice I (PH2. 0 solution of hydrochloric acid), artificial gastric juice II (pH4. 0 solution of HCl) and artificial intestinal juice (pH7. 5-phosphate salt buffer) each 1000mL. 将实施例2及对照用3样品分别直接投入溶出杯中,每隔一定时间取样5mL,并补充同体积溶出递质。 Control Example 2 and 3 samples were used directly into the dissolution vessel at regular intervals sampled 5mL, adding the same volume of dissolution neurotransmitters. 用0.8μπι微孔滤膜过滤,取续滤液,用水稀释制成每Iml 中约含8 μ g的溶液。 With 0.8μπι filter membrane, the filtrate diluted with water containing about each made Iml 8 μ g solution. 另精密称取经105°C干燥2小时的盐酸地尔硫卓对照品适量,加水溶解并定量稀释制成每Iml中约含Syg的溶液。 Another precision learn drying 105 ° C 2 hours diltiazem hydrochloride reference substance, dissolved in water and made every Iml of a solution containing about Syg quantitative dilution. 取上述两种溶液,照分光光度法(中国药典2005年版附录IV A),在240nm的波长处分别测定吸收度,计算出每片在不同时间的溶出量。 Take the two solutions, according to spectrophotometry (Chinese Pharmacopoeia 2005 Appendix IV A), absorbance was measured at 240nm wavelength were calculated at different times of the elution amount per tablet. 结果见附图2。 Results See Fig.

[0221] 结果显示,实施例样品中药物在人工胃液中释放较快,受酸碱度的影响较小,时滞性也较小,而对照例中药物在人工胃液中释放较慢,受酸碱度的影响较大,时滞性也较大; 二者中药物在人工肠液中基本释放。 [0221] The results show the impact of pH less affected, time lag is small, while in Comparative Example slower drug release in artificial gastric juice, pH by the sample of Example faster drug release in artificial gastric juice, large time lag is large; substantially release the drug in both an artificial intestinal fluid.

[0222] 实施例3及对照例5-6 [0222] Example 3 and Comparative Example 5-6

[0223] 1、制备样品及照用样品 [0223] 1, according to the sample preparation and sample

[0224] 1)、按下列处方及工艺制备片芯: [0224] 1), according to the following formulation and process for preparing the core:

Figure CN101987081AD00371

[0225] [0225]

Figure CN101987081AD00372

[0226]聚维酮 *,分子量为1,000,000 ;动力粘度(10% w/v,20°C )为300 〜700mPas. [0226] * povidone, molecular weight of 1,000,000; kinematic viscosity (10% w / v, 20 ° C) to 300 ~700mPas.

[0227] 将盐酸二甲双胍和十二烷基硫酸钠反复过40目筛,混勻;将聚维酮K-90-F溶解于纯水中;把盐酸二甲双胍和十二烷基硫酸钠的混合粉置入流化床中;喷入聚维酮的溶液造粒;入口温度50〜70°C,气压1〜3bars,喷速10〜lOOml/min。 [0227] The metformin HCl and sodium lauryl sulfate repeatedly through a 40 mesh sieve, mix; povidone K-90-F dissolved in pure water; metformin HCl and sodium lauryl sulfate mixed powder into the fluidized bed; the solution sprayed granulated polyethylene of povidone; inlet temperature of 50~70 ° C, pressure 1~3bars, spraying rate of 10~lOOml / min. 颗粒干燥后过18目筛, 加入硬脂酸镁混勻,用一个12mm的标准的凹形圆形冲模压制片,所用的压制力为1200〜 2000kg,压制时间1〜2s。 After the dried granules through 18 mesh screen, magnesium stearate was added mixed with a standard concave round punches of 12mm tableting press, compression force used is 1200~ 2000kg, pressing time 1~2s. 硬度为6〜IOkgo Hardness 6~IOkgo

[0228] 2)、制备胃肠两溶衣膜包衣颗粒 [0228] 2), two parenteral solution prepared coating film of coated granules

[0229] 包衣液处方: [0229] Coating liquid formulation:

组分 % Component%

2 —甲基一5—乙烯基吡啶/甲基丙烯酸2 2 - methyl-5-vinyl pyridine / methacrylic acid 2

[0230] 甲基/甲基丙烯酸共聚物※ [0230] methyl / methacrylic acid copolymer ※

甘露醇(粒径15〜25 μ m) 2.5 Mannitol (particle diameter 15~25 μ m) 2.5

三乙酸甘油酯 0. 2 Triacetin 0.2

丙酮 47. 7 Acetone 47.7

[0231] 二氯甲烷 47.6 [0231] dichloromethane 47.6

总计 100 Total 100

[0232] 说明,※:经测试2-甲基-5-乙烯基吡啶/甲基丙烯酸甲基/甲基丙烯酸共聚物与下列控释衣膜聚合物聚乙烯乙酸几乎完全相容。 [0232] Description, ※: Tested 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid copolymer with the following release coating film is almost completely compatible polymer polyvinylacetate.

[0233] 按上述包衣液处方配制胃肠两溶衣膜包覆颗粒包衣混悬液。 [0233] the above-described coating solution formulation of two parenteral solution formulation coated particle coating film coating suspension. 将得到的包衣混悬液用喷雾干燥机(TCSD:日本车辆)喷雾干燥,颗粒增重约80%,得到胃肠两溶衣膜包覆的甘露醇颗粒(粒径18〜30 μ m)。 The resulting coating suspension using a spray dryer (TCSD: Nippon Sharyo) spray dried particles about 80% weight gain, gastrointestinal obtain two coating film dissolving mannitol coated granules (particle diameter 18~30 μ m) .

[0234] 3)、包控释衣膜: [0234] 3), including a controlled release film coating:

[0235] 片芯包衣液处方(1000片用量): [0235] tablet core coating solution formulation (dosage 1000):

Figure CN101987081AD00381

[0237] 按上述处方配制包衣液,必要时,调节pH值至5左右。 [0237] formulated with the above coating liquid, if necessary, adjust the pH to about 5. 将片芯在Hicoater/Fruend 包衣机上包衣。 The tablet cores are coated on a Hicoater / Fruend coater. 包衣条件参数:入口温度,50〜60°C;出口温度,35〜37°C;片芯温度36〜 380C ;片芯增重13. 96%。 The coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 35~37 ° C; die temperature 36~ 380C; core weight gain of 13.96%.

[0238] 3)、愈合控释衣膜 [0238] 3), a controlled release coating film healing

[0239] 愈合处理在密闭烘箱中进行。 [0239] healing process in a closed oven. 愈合温度为45°C,愈合时间为24小时。 Healing temperature of 45 ° C, the healing time of 24 hours.

[0240] 4)、制备对照用品。 [0240] 4), supplies a control was prepared.

[0241] 把包衣液处方中的胃肠两溶衣膜包覆的颗粒换成2-甲基-5-乙烯基吡啶/甲基丙烯酸甲基/甲基丙烯酸共聚物颗粒(粒径18〜30 μ m),按上述方法及条件制备含共聚物的对照用品5。 [0241] The coating solution formulation of two parenteral solution coating film coated particles into 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid copolymer (particle diameter 18~ 30 μ m), 5 supplies control containing copolymers prepared by the above method and conditions.

[0242] 用下列包衣液对上述片芯按上述方法及条件制备含甘露醇的对照用品6。 [0242] supplies a control containing mannitol was prepared with the following coating solution 6 on the sheet core and conditions as described above. 包衣液处方:1000片用量:聚乙烯乙酸酯30g,甘露醇颗粒(粒径18〜30ym)45g,三乙酸甘油酯1. 8g,二氧化钛(粒径20nm) 2g,乙醇1000ml。 Coating solution formulation: the amount of 1000: polyvinyl acetate 30g, mannitol (particle diameter 18~30ym) glycerol 45g, triacetate 1. 8g, titanium dioxide (particle diameter 20nm) 2g, ethanol 1000ml.

[0243] 2、体外释放度试验 [0243] 2, in vitro release test

[0244] 采用中国药典2005年版桨法测定。 [0244] was determined by Chinese Pharmacopoeia 2005 edition paddle method. 转速为75r/min,温度为(37士1)°C,递质用pH3. 0盐酸液及pH7. 4磷酸盐缓冲液各1000mL。 Speed ​​is 75r / min, a temperature of (37 persons 1) ° C, a neurotransmitter pH3. 0 hydrochloric acid solution and pH7. 4 phosphate buffer each 1000mL. 将实施例及对照例分别直接投入溶出杯中,每隔一定时间取样5mL,并补充同体积溶出递质。 Examples and Comparative Examples, respectively, directly into the dissolution vessel at regular intervals sampled 5mL, adding the same volume of dissolution neurotransmitters. 用分光光度法在235nm的波长处测定吸收度,并计算出释放度。 Determination of absorbance at a wavelength of 235nm spectrophotometrically, and calculate the release rate. 结果见附图3。 The results are shown in Figure 3.

[0245] 结果显示,实施例样品中药物的释放较快,时滞性也较小;对照例中药物的释放相对较慢,时滞性也相对较大。 [0245] The results show that the sample embodiment the drug is released rapidly embodiment, time lag is small; the release of the drug in Comparative Example relatively slow, relatively large time lag.

[0246] 实施例4及对照例7 [0246] Example 4 and Comparative Example 7

[0247] 1)、按下列处方及工艺制备片芯: [0247] 1), according to the following formulation and process for preparing the core:

Figure CN101987081AD00391

[0249] 将布地奈德(微粉化)分散于含有乙酰基柠檬酸三丁酯及聚山梨酯80的Aquacoat E⑶30水分散液(体)中,混勻,制得包衣液;把糖丸置入流化床中;喷入上述的包衣液造粒。 Aquacoat E⑶30 aqueous dispersion (body) [0249] Budesonide (micronized) dispersion containing acetyl tributyl citrate and polysorbate 80, mixing to prepare a coating solution; the sugar spheres set into the fluidized bed; the above-described coating liquid sprayed into the granulation. 颗粒干燥后,加入乳糖、聚氧化乙烯、硬脂酸镁及微粉硅胶混勻,用一个12mm 的标准的凹形圆形冲模压制片,所用的压制力为1200〜2000kg,压制时间1〜2s。 After the granules were dried, lactose, polyethylene oxide, magnesium stearate and silica gel powder mixed with a standard concave round punches of 12mm tableting press, compression force used is 1200~2000kg, pressing time 1~2s. 硬度为6 〜IOkg0 Hardness of 6 ~IOkg0

[0250] 2)、制备结肠溶衣膜包覆的水溶性的细颗粒 [0250] 2), coated with an enteric coating film prepared junction of fine particles of a water-soluble

[0251] 结肠溶衣膜包衣液处方: [0251] an enteric film coating liquid junction formulation:

Figure CN101987081AD00392

[0254] 按上述包衣液处方配制果胶-瓜耳胶的溶液,用Na2CO3调节pH值至8。 [0254] formulated with the above-described coating liquid pectin - guar gum solution was adjusted to 8 with Na2CO3 pH value. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入蔗糖丸(粒径8O〜11;3 4 111,含20% 微晶纤维素)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added sucrose spheres (diameter 8O~11; 3 4 111, containing 20% ​​microcrystalline cellulose). 用上述制备的喷雾液喷涂蔗糖粉,蔗糖丸增约10%。 Sucrose was sprayed with a spray powder prepared above pellet by about 10% sucrose. 随后干燥,所得颗粒经175目圆形筛(孔径86 μ m)和120目(孔径120 μ m)圆形筛筛分,得到120〜175目的具有结肠溶衣膜包衣的糖芯的颗粒。 Then dried, the resulting particles are 175 mesh circular sieve (pore size 86 μ m) and 120 mesh (pore size 120 μ m) circular sieves to obtain sugar particles having a core object 120~175 junction enteric coating film coating.

[0255] 3)、对片芯按下列处方及工艺包控释衣膜: [0255] 3), the following formulation of tablet core and film coating of controlled release technology package:

[0256] 包衣液处方:[0257] [0256] Coating liquid formulation: [0257]

Figure CN101987081AD00401

[0258] 用制得的包衣液对片芯包控释衣膜。 [0258] The core pack release coating film prepared coating liquid. 采用一个Freund型HCT微型高性能涂覆机((8英寸盘),用所的包衣液给片剂涂上一个厚度为250微米的涂层。 Using a Freund Model HCT-mini-performance coater ((8 inches disk), with the coating solution to the tablets coated with a coating thickness of 250 microns.

[0259] 5)、制备对照用品 [0259] 5), supplies a control preparation

[0260] 用上述配制的果胶-瓜耳胶的溶液在聚四氟乙烯板上浇铸制成厚度250〜500 μ m 的薄膜,干燥后在温度-40〜-30°C下粉碎,所得颗粒经175目圆形筛和120目圆形筛筛分, 得到120〜175目的果胶-瓜耳胶的颗粒。 [0260] prepared by the above pectins -, dried at a temperature of pulverized -40~-30 ° C solution of guar gum in the film cast on a Teflon plate having a thickness of 250~500 μ m, the resulting particles through 175 mesh and 120 mesh round sieve round sieves, to give 120~175 object pectin - guar gum particles.

[0261] 用所得的果胶-瓜耳胶的颗粒按上述方法及条件制备含果胶-瓜耳胶的颗粒对照用品7。 [0261] The resulting pectin - Pectin was prepared containing particles of guar gum and conditions as described above - the guar gum particles 7 supplies a control.

[0262] 2、体外释放度试验 [0262] 2, in vitro release test

[0263] 采用中国药典2005年版桨法测定。 [0263] Chinese Pharmacopoeia 2005 edition paddle by. 转速为75r/min,温度为(37士1) °C,递质分别用人工胃液(SGF) *、人工肠液(SIF) **及人工结肠液(SCF) *** IOOOmL0将实施例及对照例分别直接投入溶出杯中,样品在SGF中保持2小时后换成SIF,在SIF中保持4小时换成SCF,然后在SCF中进行释放度测试,每隔一定时间取样5mL,并补充同体积溶出递质。 Speed ​​is 75r / min, a temperature of (37 persons 1) ° C, respectively neurotransmitter simulated gastric fluid (SGF) *, simulated intestinal fluid (SIF) ** colon and intraocular fluid (SCF) *** IOOOmL0 and Control Example Example were eluted directly into the cup, the sample was held for 2 hours in SGF SIF replaced, held for 4 hours in SIF SCF replaced, and then release tests in the SCF, sampled at regular intervals 5mL, adding the same volume dissolution neurotransmitters. 应用HPLC(HP-1100, Hewlett-Packard,柱:μ Bondapak C-18)测定布地缩松的释放。 Application of HPLC (HP-1100, Hewlett-Packard, Column: μ Bondapak C-18) was measured release of budesonide. 结果如图4所示。 The results shown in FIG.

[0264] 结果显示,实施例样品中药物的释放较快,时滞性也较小;对照例中药物的释放较慢,时滞性也较大。 [0264] The results show that the sample embodiment the drug is released rapidly embodiment, time lag is small; the release of the drug in Comparative Example slower time lag is also large.

[0265] 附注:人工胃液(SGF) * :此处指一种pHl. 2的溶液,每IOOOml此溶液含2gNaCl、 3. 2g胃蛋白酶溶解及适量(约7ml)HCl。 [0265] Note: artificial gastric fluid (SGF) *: pHl herein refers to a solution of 2, each solution containing IOOOml 2gNaCl, 3. 2g and the amount of pepsin were dissolved (about 7ml) HCl..

[0266] 人工肠液(SIF) ** :此处指一种pH7. 5的含0. 1 %的胰液素的磷酸钾缓冲液,此溶液制备过程如下,将6. 8g单价碱的磷酸钾溶解在250ml水中,然后加入190ml 0. 2N NaOH, 400ml水和IOg胰液素,最后加入0. 2N NaOH,将pH调节至7. 5,然后用水稀释至1000ml。 [0266] simulated intestinal fluid (SIF) **: referred to herein potassium phosphate buffer containing 0.1% of one kind pH7 5 secretin, solution prepared as follows, the monovalent base 6. 8g of potassium phosphate were dissolved. in 250ml of water, then adding 190ml 0. 2N NaOH, 400ml of water and IOg pancreatin, and finally adding 0. 2N NaOH, the pH was adjusted to 7.5, then diluted with water to 1000ml.

[0267] 人工结肠液(SCF) *** :此处指一种含有50mM磷酸盐、26pg/ml Pectinex Ultra SPL(NovoNordisk)和20unit/ml 半乳甘露聚糖酶(Novo Nordisk)的缓冲液。 [0267] Artificial colonic fluid (SCF) ***: referred to herein containing 50mM phosphate, 26pg / ml Pectinex Ultra SPL (NovoNordisk) and 20unit / ml galactomannan enzyme (Novo Nordisk) buffer.

[0268] 实施例5及对照例8 [0268] Example 5 and Comparative Example 8

[0269] 1)、按下列处方及工艺制备片芯: [0269] 1), according to the following formulation and process for preparing the core:

Figure CN101987081AD00411

[0271] 将双氯芬酸钠、羟丙基甲基纤维素、甘露醇和聚维酮混合均勻,用无水乙醇溶液进行造粒;将湿的粒状物料强制穿过一个18目的筛子并干燥24小时;整粒后,加入硬脂酸镁及胶体二氧化硅,混勻,用一个9mm的标准的凹形圆形冲模压制片,所用的压制力为200〜 2000kg,压制时间1〜2s。 [0271] The diclofenac sodium, hydroxypropyl methylcellulose, mannitol and povidone uniformly mixed, granulated with absolute ethanol; wet granular mass forced through a 18 mesh sieve and dried for 24 hours; whole after granulation, magnesium stearate and colloidal silicon dioxide, mixing with a 9mm round concave stamping are standard producers, the compression force used is 200~ 2000kg, pressing time 1~2s. 硬度为5〜IOkgo Hardness 5~IOkgo

[0272] 2)、制备结肠溶衣膜包覆的水溶性的细颗粒 [0272] 2), coated with an enteric coating film prepared junction of fine particles of a water-soluble

[0273] 结肠溶衣膜包覆颗粒包衣液处方: [0273] an enteric film coating particles junction coating solution formulation:

[0274] [0274]

[0275] [0275]

Figure CN101987081AD00412

[0276] 按上述包衣液处方配制结肠溶衣膜包覆颗粒包衣混悬液。 [0276] formulated with the above-described coating liquid junction enteric coating suspension of particles coated with a film coating. 向离心流化包衣制粒机(PowrexCorp.(日本)制造,MP-10)加入蔗糖粉(粒径48〜58 μ m)。 In the centrifugal fluidized coating granulator (PowrexCorp. (Japan), MP-10) was added powdered sucrose (particle diameter 48~58 μ m). 用上述制备的包衣液喷涂蔗糖粉,蔗糖粉增重约20%。 Sucrose powder sprayed with a coating solution prepared above, powdered sucrose to about 20% weight gain. 干燥后所得颗粒经270目圆形筛(53 μ m)和230目圆形筛(62 μ m)筛分,得到230-270目的含有糖粉核芯的粉末(粒径53〜62 μ m)。 After drying the resulting particles are 270 mesh circular sieve (53 μ m) and 230 mesh circular sieve (62 μ m) sieve to give a powder (particle diameter 53~62 μ m) 230-270 powdered sugar-containing cores of the object .

[0277] 3)、对片芯按下列处方及工艺包衣: [0277] 3) of the following core formulation and coating process:

[0278] 包衣液处方: [0278] Coating liquid formulation:

Figure CN101987081AD00421

[0280] 按上述处方配制包衣液,必要时调节pH值至5〜5. 5。 [0280] formulated with the above coating solution, adjust the pH to 5~5. 5 necessary. 水分散液(体)的固体含量为16(重量)%。 The solid content of the aqueous dispersion (body) 16 (wt)%.

[0281] 将片芯在Hicoater/Fruend包衣机上包衣。 [0281] The tablet cores are coated on a Hicoater / Fruend coater. 包衣条件参数:入口温度,50〜60°C; 出口温度,40〜42°C ;片芯温度40°C ;片芯增重12%。 The coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 40~42 ° C; die temperature 40 ° C; core weight gain of 12%. 片芯包衣后不热愈合处理。 Not heat treated after the core coating healing.

[0282] 在包上述控释衣膜前包一水溶性薄膜衣。 [0282] In the above-described controlled release coating film package before the package a water-soluble film coating. 包水溶性薄膜衣用的包衣料为含4. 5% 羟丙基甲基纤维素(Pharmacoat,603/ShinEtsu)、0. 52%的PEG 400及1. 5%微粉化的滑石的水溶液。 An aqueous solution of water-soluble film coating material package for containing laundry 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603 / ShinEtsu), 0. 52% of PEG 400 and 1.5% micronized talc. 包衣条件参数入口温度,55°C ;出口温度,30°C。 The coating conditions were inlet temperature parameters, 55 ° C; outlet temperature, 30 ° C. 水溶性薄膜衣包衣增重约为1%。 Water-soluble film coat weight gain was about 1%.

[0283] 6)、制备对照用品 [0283] 6), supplies a control preparation

[0284] 用上述配制的虫胶包衣液在聚四氟乙烯板上浇铸制成厚度250〜500 μ m的薄膜,干燥后在温度-40〜-30°C下粉碎,所得颗粒经270目圆形筛(53 μ m)和230目圆形筛(62 μ m)筛分,得到53〜62 μ m的颗粒。 [0284] with shellac prepared above, and dried at a temperature of pulverized -40~-30 ° C in a film cast on a Teflon plate having a thickness of 250~500 μ m, the resulting particles are 270 mesh circular sieve (53 μ m) and 230 mesh circular sieve (62 μ m) and sieved to obtain particles 53~62 μ m.

[0285] 用所得的颗粒按上述方法及条件制备含虫胶的颗粒对照用品8。 [0285] The particles containing shellac 8 supplies a control prepared as described above and the condition for the resulting granules.

[0286] 2、体外释放度试验 [0286] 2, in vitro release test

[0287] 采用中国药典2005年版桨法测定。 [0287] was determined by Chinese Pharmacopoeia 2005 edition paddle method. 转速为lOOr/min,温度为(37士1)°C,递质分别用人工胃液(PHI. 2的盐酸溶液,无酶)、人工肠液(pH6. 8的磷酸钾缓冲液,无酶)及磷酸盐缓冲液(PH7. 8) 1000mL。 Speed ​​of lOOr / min, a temperature of (37 persons 1) ° C, respectively neurotransmitter artificial gastric juice (PHI. Hydrochloric acid solution 2, and no enzymes), artificial intestinal fluid (potassium phosphate pH6. 8 buffer, no enzyme) and phosphate buffer solution (PH7. 8) 1000mL. 将实施例及对照例分别直接投入溶出杯中,样品在人工胃液中保持2小时后换成人工肠液,在人工肠液中保持4小时后换成磷酸盐缓冲液(pH7. 8),然后在磷酸盐缓冲液(PH7. 8)中进行释放度测试。 Examples and Comparative Examples were eluted directly into the cup, the sample holder into artificial intestinal juice after 2 hours in artificial gastric juice, artificial intestinal fluid was maintained for 4 hours into a phosphate buffer (pH7. 8), then in phosphate for release testing salt buffer (PH7. 8) in. 用分光光度法,在287nm的波长处分别测定吸收度,计算出每片在不同时间的溶出量。 By spectrophotometry, absorption were measured at a wavelength of 287nm, and the elution amount is calculated at a different time each. 结果如图5所示。 The results shown in Figure 5.

[0288] 结果显示,实施例样品中药物的释放较快,时滞性也较小;对照例中药物的释放较慢,时滞性也较大。 [0288] The results show that the sample embodiment the drug is released rapidly embodiment, time lag is small; the release of the drug in Comparative Example slower time lag is also large.

[0289] 实施例6及对照例9 [0289] Example 6 and Comparative Example 9

[0290] 1)、按下列处方及工艺制备片芯: [0290] 1), according to the following formulation and process for preparing the core:

Figure CN101987081AD00431

[0292] 将曲匹地尔、羟丙基甲基纤维素和甘露醇混合均勻,用聚维酮的乙醇溶液进行造粒;将湿的粒状物料强制穿过一个25目的筛子并干燥24小时;整粒后,加入硬脂酸镁及胶体二氧化硅,混勻,用一个9mm的标准的凹形圆形冲模压制片,所用的压制力为1200〜 2000kg,压制时间1〜2s。 [0292] The trapidil, mannitol and hydroxypropyl methylcellulose uniformly mixed, granulated with an ethanol solution of Povidone; The wet granular material forced through a 25 mesh sieve and dried for 24 hours; after sieved, and magnesium stearate colloidal silicon dioxide, mixing with a 9mm round concave stamping are standard producers, the compression force used is 1200~ 2000kg, pressing time 1~2s. 硬度为6〜IOkgo Hardness 6~IOkgo

[0293] 2)、制备延时释放衣膜包覆的水溶性的细颗粒 [0293] 2) Preparation of delayed release of a water-soluble coating film coated with fine particles

[0294] 延时释放衣膜包衣液处方(内层衣): [0294] Delay release coating solution formulation of coating film (inner coat):

Figure CN101987081AD00432

[0296] 肠溶衣膜包衣液处方(外层衣): [0296] an enteric film coating liquid formulation (outer clothing):

Figure CN101987081AD00433

[0298] 按上述包衣液处方配制聚合物poly ( ε -caprolactone)及HP-50的溶液。 [0298] Coating liquid formulation prepared according to the above polymer poly (ε -caprolactone) and a solution of HP-50. 将蔗糖粉(粒径:53〜61μπι)放进离心流化成粒器中翻滚,在吹热空气的同时,对其先喷洒上述的poly ( ε -caprolactone)的溶液的溶液,衣层厚度为27〜29 μ m (颗粒增重约700% ); 再喷洒上述的HP-50的溶液的溶液,衣层厚度约为1 μ m(颗粒增重约5% )。 Sucrose powder (particle diameter: 53~61μπι) put into a centrifugal fluidized granulator tumbling, while blowing hot air, sprayed with a solution prior to its above-described poly (ε -caprolactone) solution, coating layer having a thickness of 27 ~29 μ m (particles of about 700% weight gain); the solution is a solution of HP-50 and then sprayed coating layer thickness of about 1 μ m (particle weight gain of about 5%). 在干燥之后,得到包延时释放衣膜的糖丸。 After drying, to obtain pellets packet delay release film coating.

[0299] 3)、包控释衣膜: [0299] 3), including a controlled release film coating:

[0300] 控释衣膜包衣前、后均包隔湿保护涂层。 [0300] The controlled release coating prior to film coating, the protective coating have a moisture barrier package. 隔湿保护涂层用的包衣料为含4. 5%羟丙基甲基纤维素(Pharmacoat,603/ShinEtsu)、0. 52%的PEG 400及1. 5%微粉化的滑石的混悬液。 The moisture barrier coating material with a protective coating containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603 / ShinEtsu), 400, and 1.5% micronized talc 0.52% PEG suspension of . 包衣条件参数:喷洒时间约20秒,鼓风时间约30〜40秒,鼓风温度50〜55°C,片芯温度30〜40°C。 Parameters coating conditions: Spraying time is about 20 seconds, the blowing time of about 30 to 40 seconds, blast temperature 50~55 ° C, die temperature 30~40 ° C. 包衣前隔湿保护涂层包衣增重约为1 %,包衣后隔湿保护涂层包衣增重约为2%。 The moisture barrier coating the protective coating before coating weight of about 1%, the moisture barrier coating the protective coating coat weight gain of about 2%.

[0301] 在按实施例1的方法制得的醋酸纤维素加水分散液(体)中加入包延时释放衣膜的糖丸及作增塑剂用的二乙酸甘油酯,其中醋酸纤维素:包延时释放衣膜的糖丸:二乙酸甘油酯为1 : 2 : 1(重量比),用水稀释至含3%的醋酸纤维素混悬液制得包衣液,必要时调节醋酸纤维素混悬液的PH值至4. 0〜4. 5。 [0301] In the cellulose acetate according to the method of Example 1 was added to the aqueous dispersion was added embodiment (form) the packet delay release pellets of coating film as glycerol diacetate and the plasticizer, the cellulose acetate, wherein: packet delay release film coating pellets: glycerol diacetate is 1: 2: 1 (weight ratio), diluted with water containing 3% cellulose acetate suspensions prepared coating solution, if necessary, adjusting the cellulose acetate PH value of the suspension to 4. 0~4. 5. 用制得的包衣液对片芯包控释衣膜。 The controlled release coating film with a coating solution prepared for packet core. 控释衣膜包衣增重为16%。 The controlled release coating film coat weight gain was 16%.

[0302] 用定时自动薄膜包衣机包衣,包衣条件参数为:喷洒时间约20秒,鼓风时间约30〜40秒,鼓风温度50〜70°C,片芯温度40〜50°C。 [0302] with the timing of automatic film coater coating, coating conditions parameters: spray time of about 20 seconds, the blowing time of about 30 to 40 seconds, blast temperature 50~70 ° C, die temperature 40~50 ° C.

[0303] 5)、愈合控释衣膜 [0303] 5), a controlled release coating film healing

[0304] 愈合处理在密闭烘箱中进行。 [0304] healing process in a closed oven. 愈合温度为65°C,愈合时间为30小时。 Healing temperature of 65 ° C, the healing time is 30 hours.

[0305] 6)、制备对照用品 [0305] 6), supplies a control preparation

[0306] 用上述配制的poly( ε -caprolactone)包衣液在聚四氟乙烯板上浇铸制成厚度250〜500 μ m的薄膜,干燥后在温度_40〜_30°C下粉碎,所得颗粒经180目圆形筛(80 μ m) 和170目圆形筛(90 μ m)筛分,制备80〜90 μ m的颗粒,再用上述工艺喷洒上述的HP-50 的溶液的溶液,衣层厚度约为1 μ m(颗粒增重约5% )。 [0306] In the coating liquid film cast on a Teflon plate having a thickness of 250~500 μ m, dried at a temperature of pulverized _40~_30 ° C above prepared poly (ε -caprolactone), the resulting particles by 180 mesh circular sieve (80 μ m) and 170 mesh circular sieve (90 μ m) sieve, the granules prepared 80~90 μ m, then the process described above the spray solution of the above-described HP-50 solution, clothing a layer thickness of about 1 μ m (about 5% by weight of the particles). 用所得的颗粒按上述方法及条件制备含poly ( ε -caprolactone)的颗粒对照用品9。 The resulting particles are particles produced by the above method and conditions containing poly (ε -caprolactone) 9 supplies a control.

[0307] 2、体外释放度试验 [0307] 2, in vitro release test

[0308] 采用中国药典2005年版桨法测定。 [0308] Chinese Pharmacopoeia 2005 edition paddle by. 转速为lOOr/min,温度为(37士1)°C,递质用人工肠液(PH6.8的磷酸钾缓冲液,无酶)1000mL。 Speed ​​of lOOr / min, a temperature of (37 persons 1) ° C, neurotransmitters artificial intestinal fluid (potassium phosphate buffer, PH6.8, and no enzyme) 1000mL. 将实施例及对照例分别直接投入溶出杯中。 Examples and Comparative Examples were eluted directly into the cup. 用分光光度法(中国药典2005年版附录IV A),在300nm的波长处测定吸收度,计算出每片在不同时间的溶出量。 Spectrophotometrically (Chinese Pharmacopoeia 2005 Appendix IV A), the absorbance was measured at a wavelength of 300nm, and the elution amount is calculated at a different time each. 结果如图6所示。 The results shown in Figure 6.

[0309] 结果显示,实施例样品释药较快,时滞适当,可实现5〜6小时的延时释放,可以满足临床的需要;而对照品释药极慢,时滞过长,需30-32才始释药,以不能临床应用。 [0309] The results show that the samples of Example fast release, a suitable time delay, time-release 5 to 6 hours can be achieved, to meet clinical needs; the reference slow release, long time delay, needs 30 -32 before the beginning of the release, so as not to clinical application.

[0310] 实施例7 [0310] Example 7

[0311] 实施例1中的碳酸氢钠颗粒(粒径300〜400目,38〜48 μ m)增重约300%,同法干燥并愈合后所得颗粒经200目圆形筛(75μπι)和240目圆形筛(61μπι)筛分,得到含有碳酸氢钠核芯的颗粒(粒径61〜75 μ m)。 [0311] Example 1 sodium bicarbonate particles (particle diameter 300~400 mesh, 38~48 μ m) to about 300% weight gain, the same method the resulting granules dried and healing circular 200 mesh sieve (75μπι) and 240 mesh circular sieve (61μπι) sieved to give particles (particle diameter 61~75 μ m) of sodium bicarbonate core. 用上述得到的颗粒(粒径61〜75 μ m)按实施例1所述的处方及工艺制备实施7。 The particles (particle diameter 61~75 μ m) obtained by the above formulation and preparation of the Example 1. Example 7.

[0312] 实施例8 [0312] Example 8

[0313] 实施例1中的碳酸氢钠颗粒(粒径300〜400目,38〜48 μ m)增重约700%,同法干燥并愈合后所得颗粒经160目圆形筛(96μπι)和200目圆形筛(75 μ m)筛分,得到含有碳酸氢钠核芯的颗粒(粒径75〜96 μ m)。 [0313] Example 1 sodium bicarbonate particles (particle diameter 300~400 mesh, 38~48 μ m) to about 700% weight gain, the same method and dried after healing the resulting particles are 160 mesh circular sieve (96μπι) and 200 mesh circular sieve (75 μ m) sieve to give granules (particle diameter 75~96 μ m) of sodium bicarbonate core. 用上述得到的颗粒(粒径75〜96 μ m)按实施例1所述的处方及工艺制备实施8。 The particles (particle diameter 75~96 μ m) obtained by the above formulation and preparation of the Example 1. Example 8. [0314] 实施例9 [0314] Example 9

[0315] 实施例3中的甘露醇颗粒(粒径15〜25 μ m)增重约200%,制得到胃肠两溶衣膜包覆的颗粒(粒径23〜38 μ m)。 Mannitol (particle diameter 15~25 μ m) [0315] in Example 3 about 200% weight gain, gastrointestinal system to give granules coated with the two coating film solution (particle diameter 23~38 μ m). 用上述得到的颗粒(粒径23〜38 μ m)按实施例3所述的处方及工艺制备实施9。 The particles (particle diameter 23~38 μ m) obtained by the above formulation and preparation according to Example 3. Example 9.

[0316] 实施例10 [0316] Example 10

[0317] 实施例4中的蔗糖丸增重约2%。 [0317] Sucrose pellets Example 4 by about 2% by weight. 其他不变,用上述得到的颗粒按实施例4所述的处方及工艺制备实施10。 Other unchanged, the particles obtained according to the formulation and preparation according to Example 4 10 embodiment.

[0318] 实施例11及对照例10 [0318] Example 11 and Comparative Example 10

[0319] 按下列处方及工艺制备肠溶衣膜包覆的水溶性的细颗粒 [0319] water-soluble enteric coating film prepared in the following formulation and preparation of coated fine particles

[0320] 包衣液处方 [0320] Coating liquid formulation

Figure CN101987081AD00451

[0322] 说明,# :经测试Eudragit L与控释衣膜聚合物醋酸纤维素部分相容。 [0322] Description #: Compatibility tested with a controlled release coating Eudragit L polymer cellulose acetate membrane portion.

[0323] 按上述包衣液处方配制Eudragit L的包衣液。 [0323] prepared according to the above coating solution formulation Eudragit L coating solution. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入碳酸钠颗粒(粒径240〜150目,61〜106 μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added sodium carbonate (particle diameter 240~150 mesh, 61~106 μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂碳酸钠粉,碳酸钠颗粒增重约100%。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, sprayed with the sodium carbonate powder spray liquor prepared above, sodium percarbonate particles to about 100% weight gain. 干燥并愈合(温度为45°C,愈合时间不低于60小时,直至其中的钠离子不渗出,不渗水发生中和化学反应为至)后所得颗粒经200目圆形筛(75 μ m) 和115目圆形筛(125 μ m)筛分,得到含有碳酸钠核芯的肠溶衣膜包衣颗粒(粒径75〜 125 μ m)。 Healing and dried (temperature of 45 ° C, the healing time is not less than 60 hours until the sodium ions which are not bleeding, occurrence and impermeable to a chemical reaction) The resulting particles are 200 mesh circular sieve (75 μ m ) and 115 mesh circular sieve (125 μ m) sieve to give enteric-coated film-coated granules (particle diameter of 75~ 125 μ m) comprising a core of sodium carbonate.

[0324] 其余按实施例1及对照例1的处方及工艺制备实施例11及对照例10,其中,实施例11包控释衣膜中醋酸纤维素:肠溶衣膜包衣颗粒:二乙酸甘油酯为1 : 1.5 : 1(重量比),对照例10包控释衣膜中醋酸纤维素:Eudragit L颗粒(粒径75〜125 μ m) :二乙酸甘油酯为1 : 1.5 : 1(重量比) [0324] as in Example 1, and the remaining formulation and preparation of Comparative Example 1 and Example 11 Comparative Example 10, wherein the controlled release coating packet Example 11 cellulose acetate film: an enteric film coating granules: diacetate ester 1: 1.5: 1 (weight ratio), a controlled release coating of Comparative Example 10 packets cellulose acetate film: Eudragit L (particle diameter 75~125 μ m): glycerol diacetate was 1: 1.5: 1 ( weight ratio)

[0325] 实施例12及对照例11 [0325] Example 12 and Comparative Example 11

[0326] 按下列处方及工艺制备肠溶衣膜包覆的水溶性的细颗粒 [0326] water-soluble enteric coating film prepared in the following formulation and preparation of coated fine particles

[0327] 包衣液处方 [0327] Coating liquid formulation

Figure CN101987081AD00461

[0329] 按上述包衣液处方配制醋酸乙烯酯_马来酸酐共聚物的包衣液。 [0329] the above-described coating solution formulation prepared coating liquid _ vinyl acetate-maleic anhydride copolymer. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入葡萄糖颗粒(粒径300〜400目,38〜 48 μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added glucose (particle diameter 300~400 mesh, 38~ 48 μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂葡萄糖颗粒,葡萄糖颗粒增重约100%,所得颗粒经240目圆形筛(61μπι)和300目圆形筛(48 μ m)筛分,得到含葡萄糖核芯的肠溶衣膜包衣颗粒(粒径48〜61 μ m)。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, sprayed with a spray liquor prepared above particles glucose, glucose and about 100% by weight of the particles, the resulting particles are circular 240 mesh sieve ( 61μπι) and 300 mesh circular sieve (48 μ m) and sieved to obtain an enteric film coating core granules containing glucose (particle diameter 48~61 μ m).

[0330] 其他按实施例1的处方及工艺制备实施例12 ;把对照例1中的羧甲基乙基纤维素颗粒(粒径48〜61 μ m)换成醋酸乙烯酯-马来酸酐共聚物颗粒(粒径48〜61 μ m),其他不变,按对照例1的处方及工艺制备其中对照例11。 [0330] Other formulation and preparation according to Example 1. Example 12; in Comparative Example 1 of the carboxymethyl ethyl cellulose (particle diameter 48~61 μ m) into vinyl acetate - maleic anhydride copolymer particles (particle diameter 48~61 μ m), the other unchanged, according to the formulation and preparation of Comparative Example 1 wherein Comparative Example 11.

[0331] 实施例13及对照例12 [0331] Example 13 and Comparative Example 12

[0332] 按下列处方及工艺制备肠溶衣膜包覆的水溶性的细颗粒 [0332] water-soluble enteric coating film prepared in the following formulation and preparation of coated fine particles

[0333] 包衣液处方 [0333] Coating liquid formulation

Figure CN101987081AD00462

[0335] 按上述包衣液处方配制邻苯二甲酸聚乙烯醇酯的包衣液。 [0335] formulated with the above-described coating liquid was coated polyvinyl alcohol phthalate esters. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入柠檬酸三钠颗粒(粒径150〜100目,106〜 150 μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) trisodium citrate (particle diameter 150~100 mesh, 106~ 150 μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂柠檬酸三钠颗粒,柠檬酸三钠颗粒增重约80%。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, the above prepared spray solution sprayed particles trisodium citrate, trisodium citrate particles having a weight gain of about 80%. 干燥并愈合(温度为55°C, 愈合时间不低于72小时,直至其中的钠离子不渗出,不渗水发生中和化学反应为至)后所得颗粒经115目圆形筛(125μπι)和80目圆形筛(180 μ m)筛分,得到含有柠檬酸三钠核芯的肠溶衣膜包衣颗粒(粒径125〜180 μ m)。 Healing and dried (temperature of 55 ° C, the healing time is not less than 72 hours until the sodium ions which are not bleeding, and occurrence impermeable to chemical reaction) the resulting particles are 115 mesh circular sieve (125μπι) and 80 mesh round sieve (180 μ m) sieve to give enteric-coated film-coated core particles containing trisodium citrate (particle diameter 125~180 μ m).

[0336] 其余按实施例3及对照例5的处方及工艺制备实施例13及对照例12,其中对照例5包控释衣膜中的2-甲基-5-乙烯基吡啶/甲基丙烯酸甲基/甲基丙烯酸共聚物颗粒(粒径18〜30 μ m)换成邻苯二甲酸聚乙烯醇酯(粒径125〜180 μ m),其他不变。 [0336] Example 3 and the rest according to the formulation and preparation of Comparative Example 5 Example 13 and Comparative Example 12, Comparative Example 5 in which the controlled release coating film pack 2-methyl-5-vinylpyridine / methacrylic acid methacrylate / methacrylic acid copolymer (particle diameter 18~30 μ m) into the polyvinyl acetate phthalate (particle diameter 125~180 μ m), the other unchanged.

[0337] 实施例14及对照例13[0338] 1)、按实施例2片芯的处方及工艺制备片芯 [0337] Example 14 and Comparative Example 13 [0338] 1), prepared as described in formulation and process of Example 2 the core of the core

[0339] 2)、按下列处方及工艺制备胃溶衣膜包覆的水溶性的细颗粒 [0339] 2), gastric coating film according to the following formulation and preparation of fine particles coated with a water-soluble

[0340] 包衣液处方 [0340] Coating liquid formulation

[0341] [0341]

Figure CN101987081AD00471

[0342] 按上述包衣液处方配制醋酸纤维素二乙基氨基醋酸酯的包衣液。 [0342] the above-described coating solution formulation prepared coating liquid cellulose acetate diethylamino acetate amino. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入枸橼酸颗粒(粒径300〜400目,38〜 48 μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added citric acid (particle diameter 300~400 mesh, 38~ 48 μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂枸橼酸颗粒,枸橼酸颗粒增重约100%。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, sprayed with a spray liquor prepared above particles citrate, citric acid particles about 100% weight gain. 干燥并愈合(温度为55°C,愈合时间不低于72小时,直至不渗水发生中和化学反应为至)后所得颗粒经240目圆形筛(61 μ m)和300目圆形筛(48 μ m)筛分,得到含有枸橼酸核芯的颗粒(粒径48〜61 μ m)。 Healing and dried (temperature of 55 ° C, the healing time is not less than 72 hours until the occurrence and impermeable to a chemical reaction) The resulting particles are 240 mesh circular sieve (61 μ m) and 300 mesh circular sieve ( 48 μ m) sieve to give granules (particle diameter 48~61 μ m) comprising citrate core.

[0343] 3)、在按实施例1的方法制得的醋酸纤维素加水分散液(体)中加入上述胃溶衣膜包覆的枸橼酸颗粒及作增塑剂用的二乙酸甘油酯,其中醋酸纤维素:胃溶衣膜包覆的枸橼酸颗粒:二乙酸甘油酯为1 : 2 : 1(重量比),用水稀释至含3%的醋酸纤维素混悬液制得包衣液,必要时调节醋酸纤维素混悬液的PH值至6. 5-7. 8。 [0343] 3), in the cellulose acetate prepared according to Example 1 of the above-described embodiment have gastric film coating dispersion was added with water (body) of the coated particles and citrate as a plasticizer with glycerol diacetate wherein the cellulose acetate: gastric coating film coated particle citrate: glyceryl diacetate is 1: 2: 1 (weight ratio), diluted with water containing 3% cellulose acetate coating suspension was prepared solution, adjusting, if necessary, cellulose acetate suspension 6. PH value to 5-7. 8. 用制得的包衣液对上述片芯包控释衣膜。 The controlled release coating film with a coating solution prepared in the above-described core pack. 控释衣膜包衣增重为16%。 The controlled release coating film coat weight gain was 16%.

[0344] 用定时自动薄膜包衣机包衣,包衣条件参数为:喷洒时间约20秒,鼓风时间约30〜40秒,鼓风温度50〜70°C,片芯温度40〜50°C。 [0344] with the timing of automatic film coater coating, coating conditions parameters: spray time of about 20 seconds, the blowing time of about 30 to 40 seconds, blast temperature 50~70 ° C, die temperature 40~50 ° C.

[0345] 5)、愈合控释衣膜 [0345] 5), a controlled release coating film healing

[0346] 愈合处理在密闭烘箱中进行。 [0346] healing process in a closed oven. 愈合温度为65°C,愈合时间为36小时。 Healing temperature of 65 ° C, healing time was 36 hours.

[0347] 6)、按上述方法制备对照例13,其中胃溶衣膜包覆的枸橼酸颗粒换成醋酸纤维素二乙基氨基醋酸酯(粒径48〜61 μ m),其他不变。 [0347] 6), prepared as described above for Comparative Example 13, wherein the coating film coated gastric citrate particles into cellulose acetate diethylamino acetate (particle diameter 48~61 μ m), the other unchanged .

[0348] 实施例15及对照例14 [0348] Example 15 and Comparative Example 14

[0349] 1)、按实施例2片芯的处方及工艺制备片芯 [0349] 1), according to formulation and process of Example 2 was prepared core tablet core

[0350] 2)、按下列处方及工艺制备胃溶衣膜包覆的水溶性的细颗粒 [0350] 2), gastric coating film according to the following formulation and preparation of fine particles coated with a water-soluble

[0351] 包衣液处方 [0351] Coating liquid formulation

Figure CN101987081AD00481

[0353] 按上述包衣液处方配制乙烯哌啶基_乙酰乙缩醛乙烯共聚物的包衣液。 [0353] Coating liquid formulation prepared according to the above-piperidinyl _ acetyl ethylene acetal coating liquid ethylene copolymer. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入蔗糖颗粒(粒径150〜100目, 106〜150μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added sucrose (particle diameter 150~100 mesh, 106~150μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂蔗糖颗粒,蔗糖颗粒增重约80%,所得颗粒经115目圆形筛(125μπι) 和80目圆形筛(180 μ m)筛分,得到含有蔗糖核芯的乙烯哌啶基-乙酰乙缩醛乙烯共聚物包衣颗粒(粒径125〜180 μ m)。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, sprayed with a spray liquor prepared above particles sucrose, sucrose particles are about 80% by weight, the resulting particles are circular 115 mesh sieve ( 125μπι) and a 80 mesh round sieve (180 μ m) sieve, to obtain an ethylene-piperidinyl a core containing sucrose - acetyl acetal copolymer coated particles (particle diameter 125~180 μ m).

[0354] 3)、包控释衣膜: [0354] 3), including a controlled release film coating:

[0355] 片芯包衣液处方(1000片用量): [0355] tablet core coating solution formulation (dosage 1000):

Figure CN101987081AD00482

[0357] 按上述处方配制包衣液,必要时,调节pH值至5左右。 [0357] formulated with the above coating liquid, if necessary, adjust the pH to about 5. 将片芯在Hicoater/Fruend 包衣机上包衣。 The tablet cores are coated on a Hicoater / Fruend coater. 包衣条件参数:入口温度,50〜60°C;出口温度,35〜37°C;片芯温度36〜 380C ;片芯增重13. 96%。 The coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 35~37 ° C; die temperature 36~ 380C; core weight gain of 13.96%.

[0358] 3)、愈合控释衣膜 [0358] 3), a controlled release coating film healing

[0359] 愈合处理在密闭烘箱中进行。 [0359] healing process in a closed oven. 愈合温度为45°C,愈合时间为36小时。 Healing temperature of 45 ° C, healing time was 36 hours.

[0360] 6)、按上述方法制备对照例14,其中胃溶衣膜包覆的蔗糖颗粒换成乙烯哌啶基-乙酰乙缩醛乙烯共聚物(粒径48〜61 μ m),其他不变。 [0360] 6), prepared as described above for Comparative Example 14, wherein the coating gastric film-coated sucrose particles into ethylene-piperidinyl - acetyl acetal copolymer (particle diameter 48~61 μ m), the other is not change.

[0361] 实施例16及对照例15 [0361] Example 16 and Comparative Example 15

[0362] 按下列处方及工艺制备胃肠两溶衣膜包覆的水溶性的细颗粒 [0362] fine particles of a water-soluble formulation and preparation of the following two parenteral solution coating film coated

[0363] 包衣液处方 [0363] Coating liquid formulation

Figure CN101987081AD00491

[0365] 按上述包衣液处方配制羧甲基苄基氨基纤维素的包衣液。 [0365] Coating liquid formulation prepared according to the above coating solution benzylamino carboxymethyl cellulose. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入山梨糖颗粒(粒径300〜400目,38〜48 μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added sorbitol (particle diameter 300~400 mesh, 38~48 μ m). 分别将入口气体温度和出口气温度控制在60〜80°C和30〜40°C,用上述制备的喷雾液喷涂山梨糖颗粒,山梨糖颗粒增重约100%,所得颗粒经240目圆形筛(61μπι)和300目圆形筛(48μπι)筛分,得到含有山梨糖核芯的颗粒(粒径48〜61μπι)。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 60~80 ° C, and 30~40 ° C, sprayed with a spray liquor sorbitol particles prepared above, sorbose to about 100% by weight of the particles, the resulting particles are 240 mesh circular sieve (61μπι) and 300 mesh circular sieve (48μπι) sieved to give particles (particle diameter 48~61μπι) sorbitol containing core.

[0366] 其他按实施例3的处方及工艺制备实施例16 ;把对照例5中的羧甲基乙基纤维素颗粒(粒径48〜61 μ m)换成羧甲基苄基氨基纤维素颗粒(粒径48〜61 μ m),其他不变, 按对照例1的处方及工艺制备其中对照例15。 [0366] Other formulation and preparation according to Example 3. Example 16; Comparative Example 5 of the carboxymethyl ethyl cellulose (particle diameter 48~61 μ m) into benzylamino carboxymethyl cellulose (particle diameter 48~61 μ m), the other unchanged, according to the formulation and preparation of Comparative Example 1 wherein Comparative Example 15.

[0367] 实施例17及对照例13 [0367] Example 17 and Comparative Example 13

[0368] 1)、按实施例2片芯的处方及工艺制备片芯 [0368] 1), according to formulation and process of Example 2 was prepared core tablet core

[0369] 2)、按下列处方及工艺制备胃溶衣膜包覆的水溶性的细颗粒 [0369] 2), gastric coating film according to the following formulation and preparation of fine particles coated with a water-soluble

[0370] 包衣液处方 [0370] Coating liquid formulation

Figure CN101987081AD00492

[0372] 按上述包衣液处方配制聚氨基葡糖(Chitosan)的混悬包衣液。 [0372] Coating liquid formulation prepared according to the above coating liquid was suspended chitosan (Chitosan) of. 向离心流化包衣制粒机(Powrex Corp.(日本)制造,MP-10)加入枸橼酸颗粒(粒径300〜400目,38〜 48μ m)。 In the centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) was added citric acid (particle diameter 300~400 mesh, 38~ 48μ m). 分别将入口气体温度和出口气温度控制在70〜80°C和40〜50°C,用上述制备的喷雾液喷涂枸橼酸颗粒,枸橼酸颗粒增重约100%。 Respectively, and the outlet temperature of the inlet gas temperature is controlled at 70~80 ° C, and 40~50 ° C, sprayed with a spray liquor prepared above particles citrate, citric acid particles about 100% weight gain. 所得颗粒经240目圆形筛(61 μ m)和300目圆形筛(48 μ m)筛分,得到含有枸橼酸核芯的颗粒(粒径48〜61 μ m)。 The resulting particles are 240 mesh circular sieve (61 μ m) and 300 mesh circular sieve (48 μ m) sieve to give granules (particle diameter 48~61 μ m) comprising citrate core.

[0373] 3)、对片芯按下列处方及工艺包控释衣膜: [0373] 3), the following formulation of tablet core and film coating of controlled release technology package:

[0374] 包衣液处方:[0375] [0374] Coating liquid formulation: [0375]

Figure CN101987081AD00501

[0376] 用制得的包衣液对片芯包控释衣膜。 [0376] The core pack release coating film prepared coating liquid. 采用一个Freund型HCT微型高性能涂覆机((8英寸盘),用所的包衣液给片剂涂上一个厚度为250微米的涂层。 Using a Freund Model HCT-mini-performance coater ((8 inches disk), with the coating solution to the tablets coated with a coating thickness of 250 microns.

[0377] 测试例1药物释放稳定性测试 [0377] Test Example 1 Stability Test drug release

[0378] 下面就实施例1〜6中的样品及对照品进行稳定性考查。 [0378] Here in Example 1~6 and reference samples for stability test. 体外释放度试验按各实施例中的方法进行。 In vitro release test was carried out according to various embodiments of the method. 结果见表1〜6。 The results are shown in Table 1~6.

[0379] 表1实施例1样品及对照用品pH值6. 8时的药物释放量 [0379] Table 1 amount of drug released at 6.8 Example 1 supplies a control sample and the pH

Figure CN101987081AD00502

[0381] 12h 97.8 81. 3 90.8 66.6 87.4 [0381] 12h 97.8 81. 3 90.8 66.6 87.4

[0382] ^表示温度25 °C,相对湿度90 %的环境(以下相同); [0382] ^ represents a temperature of 25 ° C, 90% relative humidity environment (hereinafter the same);

[0383] #表示温度40°C,相对湿度50%的环境(以下相同)。 [0383] # denotes a temperature 40 ° C, relative humidity of 50% (hereinafter the same).

[0384] 表2实施例2样品及对照用品pH值2. 5时的药物释放量 [0384] Table 2 amount of drug released at 2.5 Example 2 pH of the sample and control articles

Figure CN101987081AD00511

[0386] 表3实施例3样品及对照用品(pH6. 8)的药物释放量 Example 3 Sample and control articles (pH6. 8) the amount of drug released [0386] Table 3

Figure CN101987081AD00512

[0389] 表4实施例4样品及对照用品的药物释放量[0390] [0389] Table 4 Drug embodiment supplies a control sample and release Example 4 [0390]

Figure CN101987081AD00521

[0391] [0391]

[0392] [0392]

Figure CN101987081AD00522

[0393] 试验结果显示,含有被消化液可溶的但水不溶的聚合物包覆的水溶性颗粒的实施例样品均有较好的药物释放稳定性,相对于控释衣膜中含有未包衣的水溶性颗粒及消化液可溶的但水不溶的聚合物的对照品,实施例的药物释放稳定性被改善。 [0393] The test results show, but the embodiment sample coated water-insoluble polymer particles are preferably water-soluble pharmaceutical digestive juice containing the soluble release stability with respect to the controlled release coating film containing uncoated and water-soluble granules digestive clothes soluble but water-insoluble polymer of reference, the stability of the drug release embodiments is improved.

[0394] 另外,在相对湿度90%的环境下稳定性考查中,结果观察到控释衣膜含未包衣的水溶性的颗粒的对照品(2、4、6)均有部分样品出现了“泛霜”现象,即水溶性致孔物质从控释衣膜中析出;实施例样品未观察到此现象。 [0394] Further, in the stability test at 90% relative humidity environment was observed in the reference the water-soluble film coating containing controlled release particles of uncoated (2,4,6) are part of the sample appeared "efflorescence" phenomenon, i.e., water-soluble porogenic material from a controlled release coating deposited film; Example sample this was not observed.

[0395] 测试例2控释衣膜机械性能测试 [0395] Test Example 2 Test release the mechanical properties of coating film

[0396] 用实施例1-3及对照品2、4、6中配制的控释膜包衣液在聚四氟乙烯板上浇铸制成厚度为150 μ m的薄膜,把薄膜切成IX 7cm的大小。 [0396] with a controlled release film coating solution in Example 1-3 and Reference Sample formulated embodiment 2,4,6 cast film having a thickness of 150 μ m in the Teflon plate, the film was cut IX 7cm the size of. 然后在INSTR0N抗张强度测试器下测定抗张强度。 Determination of tensile strength and tensile strength tester INSTR0N next. 结果见表7。 The results are shown in Table 7.

[0397] 表7聚合物膜抗张强度测定结果[0398] [0397] Table 7 Polymer film tensile strength measurement result [0398]

Figure CN101987081AD00531

[0399] 结果表明,实施例机械性能优于对照品,控释膜包衣液中的水溶性颗粒(致孔剂) 被聚合物包衣后相对于未包衣的颗粒,控释膜衣膜的机械性能被改善。 [0399] The results show that the mechanical properties superior to the reference embodiment, controlled release of water-soluble film coating liquid (porogen) is a polymer coating with respect to the uncoated granules, controlling membrane coating film mechanical performance is improved.

[0400] 测试例3体内药物释放测试 [0400] Test Example 3 Test drug release in vivo

[0401] 12名雄性健康受试者,随机交叉一次口服实施例(1-3,7-9)样品和对照例样品(1、3、5)各1片,进行体内药物释放测试(生物利用度研究),血药浓度用液相色谱法(HPLC)或液-质联用法HPLC-MS/MS)测定。 [0401] 12 healthy male subjects, a randomized crossover Example orally (1-3,7-9) each of one pair of samples and sample Comparative Example (1,3,5), the test performed in vivo drug release (bioavailability degree of) plasma concentrations by liquid chromatography (HPLC) or LC - MS usage HPLC-MS / MS) assay. 结果见表8、9、10。 The results are shown in Table 8,9,10.

[0402] 表8辛伐他汀体内释放测试结果(平均值士SD,η = 6) [0402] Table 8 Test results of simvastatin released in vivo (average persons SD, η = 6)

[0403] [0403]

Figure CN101987081AD00532

[0404[0405] 表9盐酸地尔硫卓体内释放测试结果(平均值士SD,η = 6) [0404 [0405] Table 9 diltiazem hydrochloride release in vivo test results (average persons SD, η = 6)

[0406] [0406]

Figure CN101987081AD00541

[0407] 表10盐酸二甲双胍体内释放测试结果(平均值士SD,η = 6) [0407] Table 10 Test Results of in vivo release of metformin hydrochloride (average persons SD, η = 6)

[0408] [0408]

Figure CN101987081AD00542

[0409] 结果表明,实施例体内释药性行为优于对照品,在体内受影响程度低于对照品;实施例药物溶出时滞更小,特别是含可在体内反应的致孔剂。 [0409] The results show that Example vivo release behavior superior to the reference in the body below the reference level of the affected; Example Delay smaller drug dissolution embodiments, particularly those containing porogen may react in vivo.

Claims (55)

  1. 一种性能改善的控释制剂,其特征在于该控释制剂包括:a)、含有一种药物的核芯;b)、外覆于上述核芯的控释衣膜,其中,该控释衣膜包含药学上可接受的增塑剂、药学上可接受的不溶于或几乎不溶于水及胃和肠消化液的聚合物及包埋于其中的作为致孔剂的被含有药学上可接受的增塑剂或不含有增塑剂的药学上可接受的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物,上述可溶于水的药用添加剂与上述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物在体内消化液中不能发生化学反应或者能发生化学反应但不生成不溶于水且常温(25℃)下为固体或液体的产物及药学上不可接受的产物,且上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量不超过上述可溶于水 Such an improved controlled release formulation, wherein the controlled release formulation comprising: a), a drug containing core; B), the outer cover to the core of the controlled release coating film, wherein the controlled release coating film comprising a pharmaceutically acceptable plasticizer, and the pharmaceutically acceptable insoluble or almost insoluble in water and digestive juices of the stomach and intestines and embedded in a polymer which is used as a porogen comprising a pharmaceutically acceptable acceptable soluble stomach and / or intestinal digestive juices of the plasticizer or plasticizer, but does not contain a pharmaceutically-insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble pharmaceutically acceptable additives particles, the above-described water-soluble pharmaceutical additives may be dissolved in the above-mentioned gastric and / or intestinal digestive juices but do not chemically or hardly soluble in water-insoluble polymer should not chemically react or in vivo digestive fluids can occur the reaction without generating water insoluble and at room temperature (25 ℃) of the product and a solid or liquid pharmaceutically unacceptable product and said soluble in the stomach and / or intestine digestive juice but insoluble or hardly soluble in water the amount of the polymer coating film is not more than the above-described water-soluble 药用添加剂的用量的700%(重量/重量)。 700% The amount of pharmaceutically acceptable additive (wt / wt).
  2. 2.根据权利要求1的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量不超过所述的可溶于水的药用添加剂的用量的300% (重量/重量)。 2. A controlled-release formulation according to claim 1, wherein said soluble soluble in the stomach and / or intestinal digestive juices but the amount is insoluble or hardly water-insoluble polymer coating film is not more than the 300% in a pharmaceutically acceptable aqueous additive amount (wt / wt).
  3. 3.根据权利要求1的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量为所述的可溶于水的药用添加剂的用量的约2〜 约200% (重量/重量)。 The controlled release formulation according to claim 1, wherein the amount of soluble but insoluble or hardly water-insoluble polymer coating film in the stomach and / or intestine of the digestive soluble the amount of pharmaceutical additives water from about 2 ~ to about 200% (wt / wt).
  4. 4.根据权利要求1的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量为所述的可溶于水的药用添加剂的用量的约2〜 约100% (重量/重量)。 The controlled release formulation according to claim 1, wherein the amount of soluble but insoluble or hardly water-insoluble polymer coating film in the stomach and / or intestine of the digestive soluble the amount of pharmaceutical additives water from about 2 ~ to about 100% (wt / wt).
  5. 5.根据权利要求1的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量为所述的可溶于水的药用添加剂的用量的约3〜 约50% (重量/重量)。 The controlled-release formulation according to claim 1, wherein the amount of soluble but insoluble or hardly water-insoluble polymer coating film in the stomach and / or intestine of the digestive soluble the amount of pharmaceutical additives of about 3 ~ about 50% water (wt / wt).
  6. 6.根据权利要求1的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜的用量为所述的可溶于水的药用添加剂的用量的约3〜 约30% (重量/重量)。 6. The controlled-release formulation according to claim 1, wherein the amount of soluble but insoluble or hardly water-insoluble polymer coating film in the stomach and / or intestine of the digestive soluble the amount of pharmaceutical additives of about 3 ~ about 30% water (wt / wt).
  7. 7.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物在所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜中的用量为35 %至100 % (重量/重量),这是基于该衣膜的干总重量。 7. The controlled release formulation of any one of the preceding claims, characterized in that said soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer in the soluble stomach and / or intestinal digestive juices but the polymer coating film is insoluble or hardly soluble in water in an amount of 35-100% (wt / wt), based on the total weight of the dry coating film.
  8. 8.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物在所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜中的用量为50 %至100 % (重量/重量),这是基于该衣膜的干总重量。 8. The controlled release formulation of any one of the preceding claims, characterized in that said soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer in the soluble stomach and / or intestinal digestive juices but the polymer coating film is insoluble or hardly soluble in water in an amount of 50-100% (wt / wt), based on the total weight of the dry coating film.
  9. 9.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物在所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜中的用量为65 %至100 % (重量/重量),这是基于该衣膜的干总重量。 9. The controlled release formulation of any one of the preceding claims, characterized in that said soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer in the soluble stomach and / or intestinal digestive juices but the polymer coating film is insoluble or hardly soluble in water in an amount of 65-100% (wt / wt), based on the total weight of the dry coating film.
  10. 10.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物与所述的不溶于或几乎不溶于水及胃和肠消化液的聚合物相容或完全相容。 10. The controlled release formulation of any one of the preceding claims, characterized in that said soluble in the stomach and / or intestine digestive juice but insoluble insoluble or almost insoluble in water or the polymer almost insoluble in water and digestive juices of the stomach and intestine or a compatible polymer is fully compatible.
  11. 11.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于水的药用添加剂选自可溶于水的氨基酸、寡肽(2-10肽),可溶于水的单糖及其药学上可接受的衍生物、寡糖(2-6糖)及其药学上可接受的衍生物,可溶于水的钠、钾或铵离子的无机盐,可溶于水的碳原子数不超过6的有机酸及其可溶于水的钠、钾或铵离子盐,可溶于水的碳原子数不超过6的有机碱及其可溶于水的盐,可溶于水的非离子型表面活性剂,药学上可接受的可溶于水的非离子型聚合物以及它们的混合物。 11. The controlled release formulation of any one of the preceding claims, characterized in that said water-soluble additive is selected from pharmaceutically acceptable water-soluble amino acid, an oligopeptide (2-10 peptide), soluble water monosaccharides and pharmaceutically acceptable derivatives thereof, oligosaccharides (sugar 2-6) and pharmaceutically acceptable derivatives thereof, water-soluble sodium, potassium or ammonium ion salts, soluble number of carbon atoms does not exceed the water-soluble organic acids and water-sodium, potassium or ammonium salt of 6 carbon atoms, water-soluble organic base is not more than 6 and its water-soluble salts, water soluble non-ionic surface active agent, a pharmaceutically acceptable water-soluble nonionic polymers, and mixtures thereof.
  12. 12.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于水的药用添加剂选自丙氨酸,甘氨酸,丝氨酸,缬氨酸,天冬酰胺,赖氨酸,谷氨酰胺,甲硫氨酸,精氨酸, 羟脯氨酸,脯氨酸,力肽(L-丙氨酰-L-谷胺酰胺),谷胱甘肽,D-赤藓糖,D-赤藓酮糖,赤藻糖醇,D-核糖,D-2-脱氧核糖,D-木糖,L-阿拉伯糖,D-核酮糖,D-木酮糖,木糖醇,葡萄糖,半乳糖,甘露醇,甘露糖,果糖,山梨糖,D-甘露庚酮糖,D-景天庚酮糖,麦芽糖,乳糖, 蔗糖,纤维二糖,龙胆二糖,蜜二糖,海藻二糖,异麦芽糖醇,麦芽糖,拉克替醇,海藻糖,壳聚二糖,棉子糖,壳聚三糖,水苏糖,脱乙酰壳聚四糖,毛蕊花糖,麦芽五糖,麦芽六糖,己二酸、 反/顺丁烯二酸、苹果酸、枸橼酸、洒石酸、植酸、琥珀酸及甘醇酸以及它们可溶于水的钠、 钾或铵离子盐, 12. The controlled release formulation of any one of the preceding claims, characterized in that said water soluble pharmaceutically acceptable additives selected from alanine, glycine, serine, valine, asparagine, lysine , glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L- alanyl -L- glutamine), glutathione, D- erythrose, D- erythrulose, erythritol, D- ribose, D-2- deoxyribose, D- xylose, L- arabinose, D- ribulose, D- xylulose, xylitol, glucose , galactose, mannitol, mannose, fructose, sorbose, D- mannoheptulose, D- sedoheptulose, maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose, alginic disaccharides, isomalt, maltitol, lactitol, trehalose, chitosan disaccharides, raffinose, chitosan trisaccharide, stachyose, chitosan polytetramethylene sugar, verbascose, maltopentaose, maltohexaose sugar, adipic acid, trans / maleic acid, malic acid, citric acid, tartaric acid, phytic acid, succinic acid and glycolic acid, and their water soluble sodium, potassium or ammonium salts, 溶性碱性氨基酸、葡甲胺及其可溶于水的盐,氯离子、溴离子、氟离子、磷酸根、磷酸氢根、硫酸根、硫酸氢根、亚硫酸根、亚硫酸氢根、焦亚硫酸根、硝酸根、碳酸根、碳酸氢根及过碳酸根的钠、钾或铵离子盐,可溶于水的聚氧乙烯烷基醚类表面活性剂,可溶于水的聚氧化乙烯蓖麻油类表面活性剂,可溶于水的聚氧乙烯硬脂酸酯类表面活性剂,可溶于水的环糊精及环糊精衍生物,可溶于水的低聚糖(聚合度7-20),可溶于水的葡聚糖、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、低粘度甲基纤维素、聚乙烯醇、聚维酮、分子量为2000-20000的PEG (聚乙二醇)及它们的混合物。 Soluble basic amino acid, meglumine, and water-soluble salts, chloride, bromide, fluoride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, bisulfite, pyrosulfate sulfite, nitrate, carbonate, bicarbonate and carbonate over sodium, potassium or ammonium salts, water-soluble polyoxyethylene alkyl ether surfactants, water soluble polyoxyethylene castor oil based surfactant, water-soluble polyoxyethylene stearate ester surfactant, water-soluble cyclodextrin and cyclodextrin derivatives, water-soluble oligosaccharides (degree of polymerization 7-20), water-soluble dextran, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low viscosity methyl cellulose, polyvinyl alcohol, povidone, a molecular weight of 2000 to 20000 in PEG (polyethylene glycol), and mixtures thereof.
  13. 13.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于水的药用添加剂的平均粒径为5〜250 μ m。 13. The controlled release formulation of any one of the preceding claims, characterized in that the average particle diameter of the water soluble pharmaceutically acceptable additives are 5~250 μ m.
  14. 14.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于水的药用添加剂在水中的溶解度(温度25°C )不小于100mg/ml。 14. The controlled release formulation of any one of the preceding claims, characterized in that said water soluble pharmaceutically acceptable additive solubility (temperature 25 ° C) in water of not less than 100mg / ml.
  15. 15.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于水的药用添加剂中还含有崩解剂。 15. The controlled release formulation of any one of the preceding claims, characterized in that said water-soluble pharmaceutical additives further contain a disintegrant.
  16. 16.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自胃溶性聚合物、肠溶性聚合物、既可肠溶又可胃溶的聚合物、生物可降解的聚合物、酶和/或微生物可降解的聚合物及它们的混合物。 16. The controlled release formulation of any one of the preceding claims, characterized in that said soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer is selected from polymers soluble in the stomach, enteric polymers, stomach soluble polymers, biodegradable polymers, enzymes and / or microorganisms and biodegradable polymer but also a mixture thereof can enteric.
  17. 17.根据权利要求16的控释制剂,其特征在于所述的胃溶性聚合物选自具有单或二取代氨基的纤维素衍生物、具有单或二取代氨基的聚乙烯衍生物、具有单取代的氨基的丙烯酸聚合物、聚氨基葡糖(Chitosan)及它们的混合物。 17. The controlled release formulation according to claim 16, wherein the stomach-soluble polymer selected from the mono or disubstituted amino cellulose derivative having mono- or di-substituted amino derivatives of polyethylene, having a mono-substituted amino acrylic polymer, chitosan (chitosan), and mixtures thereof.
  18. 18.根据权利要求16的控释制剂,其特征在于所述的胃溶性聚合物选自苄基氨基甲基纤维素、二乙基氨基甲基纤维素、哌啶基乙基羟乙基纤维素、醋酸纤维素二乙基氨基醋酸酯、乙烯基二乙基胺_醋酸乙烯酯共聚物、乙烯苄基胺_醋酸乙烯酯共聚物、聚乙缩醛醋酸二乙基氨基乙烯酯、乙烯哌啶基-乙酰乙缩醛乙烯共聚物、聚二乙基氨基甲基苯乙烯、甲基丙烯酸甲酯-甲基丙烯酸丁酯-甲基丙烯酸二甲基氨基乙酯共聚物(即Eudragit E, Rohm-Pharma的商品名)、聚甲基丙烯酸二甲基氨基乙酯、聚氨基葡糖(Chitosan)及它们的混合物。 18. A controlled-release formulation according to claim 16, wherein the stomach-soluble polymer is selected from benzylamino methyl cellulose, diethylaminomethyl cellulose, piperidyl ethyl hydroxyethyl cellulose , cellulose acetate diethylamino acetate, vinyl diethylamine _ vinyl acetate copolymer, vinyl benzylamine _ vinyl acetate copolymer, polyvinyl acetal diethylamino acetate, vinyl esters, vinyl piperidine yl - acetyl acetal copolymer, polydiethyl aminomethyl styrene, methyl methacrylate - butyl methacrylate - dimethylaminoethyl methacrylate copolymer (i.e. Eudragit E, Rohm- Pharma's trade name), polymethyl methacrylate-dimethylaminoethyl methacrylate, chitosan (chitosan), and mixtures thereof.
  19. 19.根据权利要求16的控释制剂,其特征在于所述的胃溶性聚合物选自Eudragit E。 19. The controlled release formulation according to claim 16, wherein the stomach-soluble polymer is selected from Eudragit E.
  20. 20.根据权利要求16的控释制剂,其特征在于所述的肠溶性聚合物选自羧烷基纤维素、具有二元酸的单酯键的纤维素衍生物、具有二元酸单酯键的聚乙烯基衍生物、马来酸-乙烯其聚物、丙烯酸类聚合物及它们的混合物。 20. A controlled-release formulation according to claim 16, wherein said enteric polymer is selected from carboxyalkyl cellulose, cellulose derivative having monoester bond of dibasic acid, a dibasic acid having a monoester bond polyvinyl derivatives, maleic acid - ethylene copolymer thereof, acrylic polymers, and mixtures thereof.
  21. 21.根据权利要求16的控释制剂,其特征在于所述的肠溶性聚合物选自羧甲基纤维素、羧甲基乙基纤维素、邻苯二甲酸酯酸纤维素、琥珀酸醋酸纤维素酯、邻苯二甲酸甲基纤维素酯、邻苯二甲酸羟甲基乙基纤维素酯、邻苯二酸羟丙基甲基纤维素酯、琥珀酸羟丙基甲基纤维素酯、乙烯基聚合物的二元酸单酯、邻苯二甲酸聚乙烯醇酯、邻苯二甲酸聚乙烯丁酯、乙酰基乙缩醛邻苯二甲酸聚乙烯酯、醋酸乙烯酯-马来酸酐共聚物、丁基乙烯醚_马来酸酐共聚物、苯乙烯_马来酸单酯共聚物、丙烯酸甲酯_甲基丙烯酸共聚物、苯乙烯_丙烯酸共聚物、丙烯酸甲酯-甲基丙烯酸-丙烯酸辛酯共聚物、Eudragit L、Eudragit S、 Eudragit FS、虫胶及它们的混合物。 21. The controlled release formulation according to claim 16, wherein said enteric polymer is selected from carboxymethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acetate succinate cellulose phthalate, methylcellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropylmethyl cellulose acid succinate, hydroxypropylmethylcellulose ester dibasic acid monoesters of vinyl polymers, polyvinyl acetate phthalate, butyl phthalate, polyvinyl acetyl phthalate, polyvinyl acetal esters, vinyl acetate - maleic anhydride copolymers, butyl vinyl ether maleic anhydride copolymer _, _ styrene-maleic acid monoester copolymer, methyl acrylate-methacrylic acid copolymer _, _ styrene-acrylic acid copolymer, methyl acrylate - methacrylic acid - octyl acrylate copolymer, Eudragit L, Eudragit S, Eudragit FS, shellac, and mixtures thereof.
  22. 22.根据权利要求16的控释制剂,其特征在于所述的肠溶性聚合物选自Eudragit S、 Eudragit FS及它们的混合物。 22. A controlled-release formulation according to claim 16, wherein said enteric polymer is selected from Eudragit S, Eudragit FS, and mixtures thereof.
  23. 23.根据权利要求16的控释制剂,其特征在于所述的既可肠溶又可胃溶的聚合物选自乙烯基吡啶-丙烯酸类共聚物、具有单或二取代的氨基的羧甲基多糖、聚乙烯氨基酸类衍生物及它们的混合物。 23. A controlled-release formulation according to claim 16, wherein both of said enteric-soluble polymer is selected from the stomach but also vinylpyridine - acrylic copolymer, having a mono- or di-substituted carboxymethyl amino polysaccharides, polyvinyl amino acid derivatives, and mixtures thereof.
  24. 24.根据权利要求16的控释制剂,其特征在于所述的既可肠溶又可胃溶的聚合物选自2-甲基-5-乙烯基吡啶/甲基丙烯酸甲基/甲基丙烯酸共聚物、2-甲基-5-乙烯基吡啶/ 丙烯酸甲酯/甲基丙烯酸共聚物、2-乙烯基-5-乙烯基吡啶/甲基丙烯酸/苯乙烯共聚物、 2-乙烯基-5-乙烯基吡啶/甲基丙烯酸/甲基丙烯酸甲酸共聚物、2-乙烯基吡啶/甲基丙烯酸/甲基丙烯酸共聚物、2-乙烯基吡啶/甲基丙烯酸/丙烯腈共聚物、羧甲基哌啶基淀粉、羧甲基苄基氨基纤维素、聚_2-(乙烯基苯基)甘氨酸、N-乙烯基甘氨酸-苯乙烯共聚物及它们的混合物。 24. A controlled-release formulation according to claim 16, wherein both the enteric polymer but also a gastric selected from 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid copolymers, 2-methyl-5-vinylpyridine / methyl acrylate / methacrylic acid copolymer, 2-vinyl-5-vinylpyridine / methacrylic acid / styrene copolymer, 2-vinyl -5 - vinylpyridine / methacrylic acid / methacrylic acid copolymer, 2-vinylpyridine / methacrylic acid / methacrylic acid copolymer, 2-vinylpyridine / methacrylic acid / acrylonitrile copolymers, carboxymethylcellulose piperidyl starch, carboxymethyl cellulose, benzylamino, _2- poly (vinylphenyl) glycine, N- vinyl glycine - styrene copolymers, and mixtures thereof.
  25. 25.根据权利要求16的控释制剂,其特征在于所述的生物可降解的聚合物选自天然的生物降解聚合物、脂肪族聚酯类、聚氨及其共聚物、聚氨基酸、聚原酸酯、聚氰基丙烯酸酉旨、聚丙炼酸类、poly (3-hydroxybutyrate)及其共聚物、polyanhydries、poly (methyl vinylether-maleic acid)、聚氨基甲酸酯类及它们的混合物。 25. The controlled release formulation according to claim 16, wherein said biodegradable polymer is selected from natural biodegradable polymers, aliphatic polyesters, polyurethanes and copolymers thereof, polyaminoacids, polyorthoesters ester, polycyanoacrylate unitary purpose, polyacrylic acid refining, poly (3-hydroxybutyrate) and copolymers thereof, polyanhydries, poly (methyl vinylether-maleic acid), polyurethanes, and mixtures thereof.
  26. 26.根据权利要求16的控释制剂,其特征在于所述的酶和/或微生物可降解的聚合物选自含偶氮键或二硫键的聚合物。 26. A controlled-release formulation according to claim 16, characterized in that the polymer of said azo bond or a disulfide bond enzyme and / or microorganism-containing polymer is selected from degradable.
  27. 27.根据权利要求16的控释制剂,其特征在于所述的酶和/或微生物可降解的聚合物选自果胶、右旋糖酐、半乳甘露聚糖、9-右旋葡萄糖苷酸及它们的混合物。 27. The controlled release formulation according to claim 16, wherein said enzyme and / or microorganism degradable polymer is selected from pectin, dextran, galactomannan, 9- dextrose glucuronide thereof, and mixture.
  28. 28.根据权利要求1至10中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自胃溶性的聚合物,所述的可溶于水的药用添加剂选自与上述的胃溶性的聚合物能在体内消化液中发生中和反应但不生成不溶于水且常温(25°C )下为固体或液体的产物及药学上不可接受的产物的可溶于水的常温(25°C)下为固态的药学上可接受的酸性物质;或者所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自肠溶性的聚合物,所述的可溶于水的药用添加剂选自与上述的肠溶性的聚合物能在体内消化液中发生中和反应但不生成不溶于水且常温(25°C ) 下为固体或液体的产物及药学上不可接受的产物的可溶于水的常温(25°C )下为固态的药学上可接受的碱性物质。 28. A controlled-release formulation of any one of claims 1 to 10, wherein said soluble in the stomach and / or intestine digestive juice but insoluble or hardly soluble in water soluble polymer is selected from the stomach polymer, the water soluble pharmaceutically acceptable additives are selected from the above-described polymer soluble in the stomach, but can not generate insoluble in water and at room temperature (25 ° C) as a solid and the reaction occurs in vivo digestive fluids at room temperature or water-soluble liquid product and a pharmaceutically unacceptable product (25 ° C) to a pharmaceutically acceptable solid acidic substance; the soluble or gastric and / or intestinal digestive juices but is insoluble or hardly water-soluble polymer is selected from an enteric polymer, the water soluble additive is selected from pharmaceutically acceptable and capable of reacting with the above-mentioned enteric polymer in vivo digestive fluids but does not produce the water-insoluble and at room temperature (25 ° C) of the product and a solid or liquid pharmaceutically unacceptable product is soluble in water at room temperature (25 ° C) of the pharmaceutically acceptable basic solid substance.
  29. 29.根据权利要求28的控释制剂,其特征在于所述的酸性物质选自可溶于水的碳原子数不超过6的常温(25°C)下为固态的有机酸(如己二酸、反/顺丁烯二酸、苹果酸、枸橼酸、 洒石酸、琥珀酸)或其呈酸性的钠、钾或铵离子的酸式盐及它们的混合物;或者所述的碱性物质选自可溶于水的钠、钾或铵离子的无机碱性盐、可溶于水的碳原子数不超过6的常温(250C )下为固态的有机碱或其呈碱性的盐、可溶于水的碳原子数不超过6的有机多元酸的呈碱性的钠、钾或铵离子的盐及它们的混合物。 29. A controlled-release formulation according to claim 28, wherein the solid organic acid number of the acidic substance is selected from water-soluble carbon atoms not more than 6 at room temperature (25 ° C) (such as adipic acid , trans / maleic acid, malic acid, citric acid, tartaric acid, succinic acid) or acidic sodium, potassium or ammonium salts of acid ions and mixtures thereof; or the alkaline substance is selected from water-soluble alkaline inorganic salts of sodium, potassium or ammonium ions, the number of water-soluble carbon atoms not more than 6 at room temperature (250C of) is solid organic base or alkaline salt thereof, may be carbon atoms not more than 6 water-soluble organic polybasic acid alkaline sodium, potassium or ammonium salts and mixtures thereof.
  30. 30.根据权利要求1至10中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自肠溶性的聚合物,所述的可溶于水的药用添加剂选自能与上述的肠溶性的聚合物在体内消化液中反应产生气体但不生成不溶于水且常温(25°C )下为固体或液体的产物及药学上不可接的产物的可溶于水的药用添加剂。 30. The controlled release formulation according to any of claims 1 to 10, wherein said soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer is selected from enteric the polymer, the water-soluble pharmaceutical additives may be selected to produce a reaction in vivo digestive fluids of the enteric polymer but does not produce said gas and water-insoluble at room temperature (25 ° C) or as a solid product can not contact the liquid product and a pharmaceutically acceptable water-soluble additives.
  31. 31.根据权利要求1至10中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物选自肠溶性的聚合物,所述的可溶于水的药用添加剂选自碳酸氢根的钠、钾或铵盐,碳酸根的钠、钾或铵盐,甘氨酸碳酸盐,L-赖氨酸的碳酸盐,精氨酸的碳酸盐,氨基酸钠、钾或铵碳酸盐,含钠、钾或铵糖基的碳酸盐,亚硫酸根的钠、钾或铵盐,亚硫酸氢根的钠、钾或铵盐,焦亚硫酸根的钠、钾或铵盐,钠、钾或铵的过碳酸盐,及它们的混合物。 31. A controlled-release formulation of any one of claims 1 to 10, wherein said soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer is selected from enteric polymer, the water soluble pharmaceutically acceptable additives are selected from sodium bicarbonate, potassium or ammonium salts, sodium carbonate, potassium or ammonium salts, glycine carbonate, L- lysine carbonate sodium salt, arginine carbonate, sodium amino acids, potassium or ammonium carbonates, sodium, potassium or ammonium carbonate glycosyl groups, of sodium sulfite, potassium or ammonium salts, the sulfate bisulfite , potassium or ammonium salts, sodium pyrosulfite root, potassium or ammonium salts, sodium, potassium or ammonium percarbonates, and mixtures thereof.
  32. 32.根据前述权利要求中任意一项的控释制剂,其特征在于所述的致孔剂即被含有药学上可接受的增塑剂或不含有增塑剂的药学上可接受的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的可溶于水的药用添加剂的颗粒物在所述的控释衣膜中的用量为5%〜95% (重量比或体积比),基于控释衣膜的干总重量或体积。 32. The controlled release formulation of any one of the preceding claims, characterized in that said porogen i.e. contain pharmaceutically acceptable plasticizers or pharmaceutically acceptable soluble plasticizer containing no stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film may be coated with water-soluble pharmaceutically acceptable amount of the additive particles in the coating film in the controlled release of 5 ~ 95 % (by weight or volume), based on the total dry weight of the controlled release film coat or volume.
  33. 33.根据前述权利要求中任意一项的控释制剂,其特征在于所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜中还含有调节药物释放速率的酸或碱性药用添加剂。 33. The controlled release formulation of any one of the preceding claims, characterized in that said soluble in the stomach and / or intestinal digestive juices but the polymer coating film is insoluble or almost insoluble in water is adjusted medicament further contains release rate of a pharmaceutically acceptable acid or basic additives.
  34. 34.根据前述权利要求中任意一项的控释制剂,其特征在于所述的不溶于或几乎不溶于水及胃和肠消化液的聚合物选自不溶于或几乎不溶于水及胃和肠消化液的纤维素酯类、 丙烯酸(酯)类聚合物、聚醋酸乙烯酯类、聚氯乙烯类及其组合物。 34. The controlled release formulation of any one of the preceding claims, characterized in that said insoluble or almost insoluble in water and a polymer selected from the gastric and intestinal digestive juices is insoluble or almost insoluble in water and gastric and intestinal digestive cellulose esters, acrylic (ester) polymer, polyvinyl acetate, polyvinyl chloride, and combinations thereof.
  35. 35.根据前述权利要求中任意一项的控释制剂,其特征在于所述的不溶于或几乎不溶于水及胃和肠消化液的聚合物选自乙基纤维素、醋酸纤维素、丙酸纤维素、醋酸丁酸纤维素、醋酸丙酸纤维素(cellulose acetate propionate)、硝酸纤维素、三戊酸纤维素、 三十二酸纤维素、三棕榈酸纤维素、二琥珀酸纤维素、二棕榈酸纤维素、聚乙烯乙酸酯、甲基丙烯酸(酯)聚合物、氯乙烯-乙烯醇-醋酸乙烯酯的三元共聚物、聚碳酸酯、聚甲基丙烯酸甲酯、丙烯酸乙酯-间丙烯酸甲酯聚合物、乙烯乙酸酯-氯乙烯共聚物、聚氯乙烯、聚乙烯、聚异丁炼、poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylate hloride)及其组合物。 35. The controlled release formulation of any one of the preceding claims, characterized in that said insoluble or hardly water-soluble polymers and gastric and intestinal digestive juices selected from ethyl cellulose, cellulose acetate propionate, cellulose, cellulose acetate butyrate, cellulose acetate propionate (cellulose acetate propionate), cellulose nitrate, cellulose valerate three, thirty acid cellulose, cellulose tripalmitate, cellulose disuccinate, di palmitic acid, polyvinyl acetate, methacrylic acid (ester) polymer, a vinyl chloride - vinyl alcohol - vinyl acetate terpolymer, polycarbonate, polymethyl methacrylate, ethyl acrylate - Room methacrylate polymer, an ethylene acetate - vinyl chloride copolymer, polyvinyl chloride, polyethylene, polyisobutylene refining, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylate hloride) and combinations thereof.
  36. 36.根据权利要求1至35中任意一项的控释制剂,其特征在于所述的不溶于或几乎不溶于水及胃和肠消化液的聚合物选自醋酸纤维素、醋酸丁酸纤维素、醋酸丙酸纤维素(eelluloseacetate propionate)及它们的混合物。 36. The controlled release formulation of any one of 1 to 35 claims, characterized in that said insoluble or hardly water-soluble polymers and gastric and intestinal digestive juices selected from cellulose acetate, cellulose acetate butyrate , cellulose acetate propionate (eelluloseacetate propionate), and mixtures thereof.
  37. 37.根据权利要求1至35中任意一项的控释制剂,其特征在于所述的不溶于或几乎不溶于水及胃和肠消化液的聚合物选自含80〜95%的聚氯乙烯、0.5〜19%的聚乙烯乙酸酯及0. 5〜10%聚乙烯醇的三元共聚物、含50〜100%的聚氯乙烯及O〜50%的聚乙烯乙酸酯共聚物及它们的混合物。 37. The controlled release formulation according to any one of claims 35, wherein said insoluble or almost insoluble in water and digestive juices of the stomach and intestines polymer is selected from polyvinyl chloride containing 80~95% terpolymers 0.5~19% of polyvinyl acetate and 0. 5 to 10% of polyvinyl alcohol, polyvinyl chloride and containing 50~100% O~50% of polyvinyl acetate copolymer and mixtures thereof.
  38. 38.根据前述权利要求中任意一项的控释制剂,其特征在于所述的控释衣膜还含有药学上可接受的聚合物的增强剂和/或增韧剂。 38. The controlled release formulation of any one of the preceding claims, characterized in that said coating film further comprises a release enhancing agent and / or a pharmaceutically acceptable toughener polymer.
  39. 39.根据前述权利要求中任意一项的控释制剂,其特征在于所述的核芯选自规则或不规则形式的片、颗粒、丸、晶体或载药树脂。 39. The controlled release formulation of any one of the preceding claims, characterized in that the core is selected from the regular or irregular form of tablets, granules, pellets, crystals or medicated resin.
  40. 40.根据前述权利要求中任意一项的控释制剂,其特征在于所述的药物选自中枢兴奋药、镇痛药、解热镇痛药、抗炎镇痛药、抗痛风药、抗震颤麻痹药、抗精神病药、抗焦虑药、抗抑郁症药、抗癫痫药、镇静药、催眠药、抗惊厥药、植物神经系统药物、、钙拈抗药、治疗慢性心功能不全的药物、抗心律失常药、防治心绞痛药、周围血管扩张药、降血压药、调节血脂药及抗动脉粥样硬化药、呼吸系统药物、抗酸药及治疗消化性溃疡病药、胃肠解痉药、助消化药、止吐药、催吐药及肠胃推动药、肝胆疾病辅助用药、泌尿系统药物、影响血液及造血系统的药物、抗组胺药、过敏反应介质阻释剂、肾上腺皮质激素及促肾上腺皮质激素、性激素及促性激素、胰岛激素及其它影响血糖的药物、甲状腺激素类药物及抗甲状腺药物、青霉素类、头孢菌素类、内酰胺酶 40. The controlled release formulation of any one of the preceding claims, characterized in that said selected central stimulant drugs, analgesics, antipyretic analgesics, antiinflammatory analgesics, anti-gout agents, anti-tremor paralysis, antipsychotics, anxiolytics, antidepressants, antiepileptics, sedatives, hypnotics, anticonvulsants, calcium autonomic nervous system drugs ,, twist resistant, the treatment of chronic heart failure drugs, anti antiarrhythmics, control angina drugs, peripheral vasodilators, antihypertensive drugs, lipid regulating drugs and anti-atherosclerotic drugs, respiratory system drugs, antacid drugs, and treatment of peptic ulcer disease, gastrointestinal antispasmodics, help digestion, anti-emetics, drugs to promote and gastrointestinal emetic, auxiliary liver disease drug, urinary tract drugs, blood and affect the hematopoietic system drugs, antihistamines, hyper-media retarded release agents, adrenocortical hormone and adrenocorticotropic hormone, gonadotropin and sex hormones, insulinotropin and other drugs affect blood sugar, thyroid hormone drugs, and anti-thyroid drugs, penicillins, cephalosporins, lactamase 制剂、氨基糖苷类、四环素类、大环内酯类、抗结核病药、抗真菌药、抗病毒药、抗肿瘤药物、影响机体免疫功能的药物、维生素及营养类药、减肥药或中草药提取物或其混合物。 Formulation, aminoglycosides, tetracyclines, macrolides, anti-tuberculosis drugs, antifungal agents, antiviral agents, antineoplastic agents, drugs affect immune function, vitamins and nutritional drugs, antiobesity drugs or herbal extracts or mixtures thereof.
  41. 41.根据前述权利要求中任意一项的控释制剂,其特征在于所述的药物选自LEC0Z0TAN (SRA-333)、阿莫西林、阿莫西林-克拉维酸钾复方、阿司达莫、阿司匹林-磷酸川芎嗪复方、阿司匹林-双嘧达莫复方、阿魏酸哌嗪、阿昔洛韦、扑热息痛-盐酸伪麻黄碱-顺丁烯二酸右旋溴苯吡胺复方、别嘌醇、丙硫氧嘧啶、丙戊酸镁、布洛芬、醋氯芬酸、单硝酸异山梨酯_阿司匹林复方、单硝酸异山梨酯、地西泮、二甲双胍-罗格列酮复方、泛昔洛韦、非洛地平、非诺贝特、盐酸非索那定-盐酸伪麻黄碱复方、氟伐他汀钠、阿昔莫司及复方、非洛地平_酒石酸美托洛尔复方、洛伐他汀_烟酸复方、维生素Β6复方、西替利嗪-盐酸伪麻黄碱复方、盐酸非索非那定_盐酸伪麻黄碱复方、愈创甘油醚_伪麻黄碱_右美沙芬复方、富马酸喹硫平、富马酸美托洛尔、富马酸依美斯汀、格列吡嗪-盐酸 41. The controlled release formulation of any one of the preceding claims, characterized in that said medicament is selected LEC0Z0TAN (SRA-333), amoxicillin, amoxicillin - clavulanate potassium compound, astemizole dipyridamole, aspirin - tetramethylpyrazine phosphate compound, aspirin - dipyridamole compound, piperazine ferulic acid, acyclovir, acetaminophen - pseudoephedrine hydrochloride - maleic dextrose brompheniramine compound, allopurinol, propylthiouracil alloxan, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate compound _ aspirin, isosorbide mononitrate, diazepam, metformin - rosiglitazone compound, famciclovir, felodipine, fenofibrate, fexofenadine hydrochloride - compound pseudoephedrine hydrochloride, fluvastatin sodium, acipimox and compound, felodipine metoprolol tartrate _, _ lovastatin niacin compound, vitamin Β6 compound, cetirizine - compound pseudoephedrine hydrochloride, fexofenadine hydrochloride _ compound pseudoephedrine hydrochloride, guaifenesin, pseudoephedrine _ _ dextromethorphan compound, quetiapine fumarate, metoprolol fumarate, fumaric acid emedastine, glipizide - hydrochloric acid 二甲双胍复方、格列喹酮、 格列美脲-二甲双胍复方、格列齐特、枸橼酸钾、枸橼酸他莫昔芬、枸橼酸他莫昔芬、琥珀酸去甲文拉法辛、环丙沙星、茴拉西坦、己酮可可碱、甲硝唑、酒石酸托特罗定、酒石酸唑吡坦、 克拉霉素、苦参素、雷诺嗪、利巴韦林、磷酸苯丙哌林、磷酸川芎嗪、硫普罗宁、硫酸吗啡、硫酸沙丁胺醇、氯雷他定_扑热息痛_伪麻黄碱复方、氯雷他定_伪麻黄碱复方、罗格列酮、 罗红霉素、洛伐他汀、马来酸曲美布汀、马来酸依那普利-非洛地平复方、美沙拉嗪、美托法宗、咪唑斯汀、萘哌地尔、萘普生钠、尼可他汀、尼美舒利、尼群地平、尼索地平、帕潘立酮、帕普拉唑、氢溴酸达非那新、氢溴酸加兰他敏、石杉碱甲、双环醇、司他夫定、天麻素、酮洛芬、头孢克洛、头孢克肟、维生素C阴道控释片、维生素E烟酸酯、伪麻黄碱_萘 Compound Metformin, gliquidone, glimepiride - compound metformin, gliclazide, potassium citrate, tamoxifen citrate, tamoxifen citrate, desvenlafaxine succinate , ciprofloxacin, aniracetam, pentoxifylline, metronidazole, tolterodine tartrate, zolpidem tartrate, clarithromycin, oxymatrine, ranolazine, ribavirin, benzenepropanoic acid Lin piperazine, tetramethylpyrazine phosphate, tiopronin, morphine sulfate, albuterol sulfate, loratadine, acetaminophen _ _ compound pseudoephedrine, loratadine _ compound pseudoephedrine, rosiglitazone, roxithromycin, lovastatin, MA trimebutine maleate, enalapril maleate - felodipine compound, mesalamine, the United States and France were entrusted, mizolastine, naftopidil, naproxen sodium, Nico statins, nimesulide Lee, nitrendipine, nisoldipine, paliperidone, Pa Pula oxazole, darifenacin hydrobromide, galantamine hydrobromide, huperzine, bicyclic alcohols, stavudine, Gastrodia Su, ketoprofen, cefaclor, cefixime, controlled release vaginal tablets of vitamin C, vitamin E nicotinate, naphthyl pseudoephedrine _ 生钠复方、乌拉地尔、烟酸、烟酸-辛伐他汀复方、盐酸安非他酮、盐酸氨溴索、盐酸奥昔布宁、盐酸倍他司汀、盐酸二甲双胍、盐酸伐昔洛韦、盐酸环丙沙星、盐酸拉贝洛尔、盐酸尼卡地平、盐酸帕罗西汀、盐酸哌唑嗪、盐酸普罗帕酮、盐酸普萘洛尔、盐酸氢吗啡酮、盐酸曲马多、盐酸曲美他嗪、盐酸坦洛新、盐酸坦索罗辛、盐酸左旋沙丁胺醇、盐酸左氧氟沙星、氧氟沙星、依托度酸、吲达帕胺、愈创甘油醚、愈创甘油醚-盐酸伪麻黄碱复方、左羟丙哌嗪、苯扎贝特、吡贝地尔、茶碱、长春胺、甲磺酸二氢麦角碱、甲磺酸多沙唑嗪、酒石酸美托洛尔、酒石酸双氢可待因、卡比多巴-左旋多巴复方、硫酸吗啡、硫酸庆大霉、硫酸亚铁、氯化钾、吗多明、萘呋胺、尼莫地平、双氯芬酸钠、维拉帕米、维铁、硝苯地平、盐酸地尔硫卓、盐酸普萘洛尔、格列 Raw sodium compound, urapidil, nicotinic acid, nicotinic acid - simvastatin compound, a ketone bupropion hydrochloride, ambroxol hydrochloride, oxybutynin hydrochloride, betahistine hydrochloride, metformin hydrochloride, valacyclovir hydrochloride , ciprofloxacin hydrochloride, labetalol hydrochloride, nicardipine hydrochloride, paroxetine hydrochloride, methylphenidate hydrochloride, prazosin, propafenone hydrochloride, propranolol hydrochloride, hydromorphone hydrochloride, tramadol hydrochloride, tramadol hydrochloride trimetazidine, tamsulosin hydrochloride, tamsulosin, levalbuterol hydrochloride, levofloxacin, ofloxacin, etodolac, indapamide, guaifenesin, guaifenesin - compound pseudoephedrine hydrochloride, left Dropropizine, bezafibrate, piribedil, theophylline, vincamine, ergoloid mesylate, doxazosin mesylate, metoprolol tartrate, dihydrocodeine tartrate , carbidopa - levodopa compound, morphine sulfate, Qing Trappe sulfate, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, iron dimension, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glibenclamide 吡嗪、盐酸地尔硫、吲哚美辛、阿西美辛、茶碱-沙丁胺醇复方、地塞米松、对乙酰氨基酚、格列齐特、琥珀酸亚铁、卡马西平、磷酸可待因、洛芬待因、马洛替酯、萘普生、碳酸锂、头孢氨苄、盐酸阿夫唑嗪、盐酸丁咯地尔、盐酸噻氯匹啶、异丁司特、右美沙芬、青藤碱、5-单硝异山梨醇酯、丙戊酸钠、多巴丝胼、硫酸庆大霉素_ 二氧化锆复方、马来酸氯苯那敏、巴尼地平、 布那唑嗪、戈洛帕米、盐酸哌甲酯、盐酸羟考酮。 Pyrazine, diltiazem hydrochloride, indomethacin, acemetacin, theophylline - Compound salbutamol, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate because, ibuprofen codeine, malotilate, naproxen, lithium carbonate, cephalexin, alfuzosin hydrochloride, alprostadil slightly butyrate hydrochloride, ticlopidine hydrochloride, piperidine, ibudilast, dextromethorphan, green vine base, 5-isosorbide mono nitrate, sodium valproate, Duo Basi corpus, gentamicin sulfate _ zirconia compound, chlorpheniramine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride.
  42. 42.根据权利要求17至19中任意一项的控释制剂,其特征在于所述的药物选自对碱不稳定的、酸易溶的、胃或胃近端如十二指肠有吸收窗的或对胃或近胃端局部起治疗作用的药物。 42. A controlled-release formulation of any one of claims 17 to claim 19, wherein said agent is selected from alkali-labile, acid-soluble, such as the stomach or duodenum proximal absorption window or on the stomach or gastric lesion near the end play the role of medicine.
  43. 43.根据权利要求17至19中任意一项的控释制剂,其特征在于所述的药物选自环丙沙星、卡托普利、速尿、熊去氧胆酸、复方消化酶、中药妇科千金、厄贝沙坦、格列美脲、来氟米特、麦迪霉素、伊贝沙坦、阿莫西林、头孢氨呋肟、头孢三嗪、头孢泊肟、克拉霉素、氯碳头孢、 阿奇霉素、头孢克肟、头孢羟氨苄、阿昔洛韦、地尔硫D、卡托普利、辛伐他汀、洛伐他汀、依托度酸、酮咯酸、雷尼替丁、法莫替丁、非索非那定、伪麻黄碱、苯丙醇胺、右美沙芬、右扑尔敏、 溴隐亭、环孢素、巴氧芬、别嘌醇、(+)_α-氨甲基-2-甲氧基磺酸胺基苯甲醇或3' -(2-氨基-1-羟乙基-4'-氟甲磺酸苯胺(NS49)、灭吐灵、维拉必利、阿立必利、氯波必利、、氨磺必禾IJ、硫必利、舒必利及其盐、特拉唑嗪、阿夫唑嗪以及它们的盐。 43. The controlled release formulation of any one of claims 17 to claim 19, wherein said medicament is selected from ciprofloxacin, captopril, furosemide, ursodeoxycholic acid, digestive enzymes of Compound CHINESE Qianjinpian, irbesartan, glimepiride, leflunomide, midecamycin, irbesartan, amoxicillin, cefuroxime, ceftriaxone, cefpodoxime, clarithromycin, chlorocarbons cephalosporins, azithromycin, cefixime, cefadroxil, acyclovir, diltiazem D, captopril, simvastatin, lovastatin, etodolac, ketorolac, ranitidine, Farmer nizatidine, fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine and right, bromocriptine, cyclosporine, Finland bar oxygen, allopurinol, (+) _ α- aminomethyl - 2-methoxy benzyl alcohol or amino acid 3 '- (2-amino-4'-fluoro-hydroxyethyl aniline acid (NS49), metoclopramide, cisapride Vera, aripiprazole will Lee, clebopride ,, Wo IJ amisulpride, tiapride, sulpiride and salts thereof, terazosin, alfuzosin and their salts.
  44. 44.根据权利要求20至21或30至31中任意一项的控释制剂,其特征在于所述的药物选自对酸不稳定的、碱易溶的、对胃较强毒副作用的、对胃有较强刺激作用的、在肠局部直接起治疗作用的、在肠段基本吸收良好的、以肠段为基本吸收部位的或需延时释放的药物。 44. A controlled-release formulation of any one of 20 to 21 or 30 to claim 31, wherein said drug is selected from acid-labile, base soluble, strong side effects on the stomach, on a strong stimulation of the stomach, directly from the treatment of locally in the intestine, in the intestine basic well absorbed, absorption site in the intestine is substantially or delayed release of the drug required.
  45. 45.根据权利要求20至21或30至31中任意一项的控释制剂,其特征在于所述的药物选自5-氨基水杨酸及其盐、阿坎酸钙、阿雷地平、阿仑膦酸钠、阿奇霉素、阿嗪米特及其复方制剂、阿司匹林、埃索美拉唑及其盐、艾普拉唑、桉柠菔、氨糖美辛、奥美拉唑及其盐、奥沙普秦、吡美拉唑、苯酰甲硝唑、比沙可啶、吡罗昔康、丙硫氧嘧啶、菠萝蛋白酶及其复方制齐U、促肝细胞生长素、醋氯芬酸、头孢氨苄甲氧苄啶、大蒜素、弹性酶、胞磷胆碱钠、地红霉素、丁二磺酸腺苷蛋氨酸、丁二磺酸硫代腺苷蛋氨酸、托西腺苷蛋氨酸、腺苷蛋氨酸、对氨基水杨酸钠、法罗培南钠、非诺洛芬钙、呋喃妥因、辅酶Q10、牛胎肝提取及其复方制剂、谷氨酰胺及其复方制剂、双炔失碳酯及其复方制剂、复合磷酸酯酶、格列吡嗪二甲双胍复方制剂、 谷胱甘肽、还原型谷胱甘肽、骨 45. A controlled release formulation of any one of 20 to 21 or 30 to claim 31, wherein said medicament is selected from 5-aminosalicylic acid and its salts, calcium acamprosate, aranidipine, A Lun alendronate, azithromycin, azintamide its compound preparation, aspirin, esomeprazole and salts thereof, ilaprazole, lemon eucalyptus turnip, Glucosamine indomethacin, omeprazole and salts thereof, Austria Sharpe Qin, pyrazole esomeprazole, benzoyl metronidazole, bisacodyl, piroxicam, propylthiouracil, bromelain and made homogeneous compound U, hepatocyte growth factor, aceclofenac, cephalexin A oxygen trimethoprim, allicin, elastase, citicoline sodium, erythromycin, succinic acid adenosyl methionine, adenosylmethionine thio succinic acid, Tosi adenosyl methionine, adenosylmethionine, for aminosalicylate sodium, faropenem sodium, fenoprofen calcium, nitrofurantoin, coenzyme Q10, and its compound preparation, glutamine, and fetal bovine liver extract compound preparation, and bis Anordrin compound, phosphoric acid compound esterase, glipizide metformin compound, glutathione, reduced glutathione, bone 、甘草酸二铵、桂美辛、环磷酰胺及其复方制剂、红霉素、己酮可可碱、甲砜霉素、吉他霉素、甲巯咪唑、甲芬那酸、精氨酸酮洛芬、克拉霉素、苦参碱、重组B亚单位/菌体霍乱菌苗复方制剂、枯草杆菌二联活菌复方制剂、双歧三联活菌、赖氨匹林、雷贝拉唑钠、雷尼替丁、硫普罗宁、硫酸庆大霉素、硫酸亚铁甘氨酸复合物、诺氟沙星、芦氟沙星、洛美沙星、氯克罗孟、柳氮磺吡啶、六甲蜜胺、罗红霉素、麦考酚钠、磷霉素及其盐、 美帕曲星、美洛昔康、美他卡韦、美他环素、盐酸门冬氨酸镁、帕罗西汀、米非司酮、米索前列醇、木瓜酶、萘普生、脑蛋白水解物、尼美舒利、尿嘧啶替加氟复方制剂、帕普拉唑、泮托拉唑及其盐、七叶皂苷钠、曲克芦丁脑蛋白水解物复方制剂、去羟肌苷、溶菌酶、三磷酸腺苷、三苯双脒、舍雷肽酶、司帕沙星、替 , Diammonium glycyrrhizinate, Gui indomethacin, cyclophosphamide and compound preparation, erythromycin, pentoxifylline, thiamphenicol, kitasamycin, methimazole, mefenamic acid, arginine ketorolac Fen, clarithromycin, matrine, recombinant B subunit / cell cholera vaccine compound preparation, bacillus subtilis subtilisin compound preparation, probiotics, aspisol, rabeprazole sodium, Ray Nepal nizatidine, tiopronin, gentamicin sulfate, ferrous glycine sulfate complex, norfloxacin, rufloxacin, lomefloxacin, chloro Ke Luomeng, sulfasalazine, altretamine, Luo erythromycin, mycophenolate sodium, fosfomycin and its salts, mepartricin, meloxicam, the United States and he abacavir, metacycline, hydrochloric acid, aspartic acid, magnesium, paroxetine, mifepristone , misoprostol, papain, naproxen, brain protein hydrolyzate, nimesulide, tegafur uracil compound, Pa Pula oxazole, pantoprazole and their salts, sodium aescinate, Qu troxerutin brain protein hydrolyzate compound, didanosine, lysozyme, adenosine triphosphate, tribendimidine, serrapeptase, sparfloxacin, for 沙坦、双氯芬酸钠、酮基布洛芬、硫酸钠、细胞色素C、胸腺肽、度洛西汀、多西环素、二甲双胍、氟西汀、青藤碱、乙酰左卡尼汀、乙酰螺旋霉素、左旋咪唑、胰激肽原酶、胰酶、胰岛素、乙酰水杨酸、己酮可可碱、辛伐他汀、银耳孢糖、胶体果胶铋、 牛磺酸、小牛血去蛋白提取物、吲哚拉辛、蚓激酶、右旋酮洛芬、扎托布洛芬、中性蛋白酶、左炔诺孕酮、左炔诺孕酮炔雌醚、叶绿素铜钠、依立拉唑、依托度酸、青藤碱、异甘草酸镁或维生素E烟酸酯。 Losartan, diclofenac sodium, ketoprofen, sodium, cytochrome C, thymosin, duloxetine, doxycycline, metformin, fluoxetine, sinomenine, acetyl L-carnitine, acetyl spiral mold Su, levamisole, pancreatic kallikrein, trypsin, insulin, acetylsalicylic acid, pentoxifylline, simvastatin, tremella sugar, colloidal bismuth pectin, taurine, calf blood extract protein , indole Racine, lumbrokinase, ketoprofen, zaltoprofen, neutral protease, levonorgestrel, levonorgestrel quinestrol, sodium copper chlorophyll, irinotecan omeprazole, relying etodolac, sinomenine, magnesium isoglycyrrhizinate or vitamin E nicotinate.
  46. 46.根据权利要求20至21或30至31中任意一项的控释制剂,其特征在于所述的药物选自大蒜提取物、刺五加提取物、熊胆、虫草菌丝体、龙血竭、米曲菌胰酶(慷彼申)、至灵菌丝、华蟾素或商品名为标准桃金娘油、鼻渊舒、消炎利胆、妇痛宁、龙芪溶栓、慈丹、芙朴感冒、复方杜仲、复方黄连素、感冒康、惠血生、降酶灵、降糖甲、雷丸、浙水调脂、龙香平喘、 脑脉泰、平喘抗炎、七生静、七生力、心脑康、脉血康、帕朱丸、启脾、前列平、芩暴红止咳、叶下珠、益阴消渴、薏参、脂脉康、吉如心、芪龙、三七通舒、男宝、春血安、治感佳、苓桂咳喘宁、 百宝丹、丹黄祛瘀、复方杜仲健骨、更年安、抗痨、六味地黄、六味木香、溶栓脑通、神安、血塞通、止咳、复方红豆杉、消栓、感冒清热、芩连、克痹骨泰、脑立清或云芝肝泰的中成药。 46. ​​A controlled release formulation of any one of 20 to 21 or 30 to claim 31, wherein said medicament is selected from garlic extract, Acanthopanax extract, bear bile, Cordyceps, Dracaena dried up, m aspergillosis trypsin (generous He Shen), to the spirit of the mycelium, or trade name cinobufotalin standard myrtle oil, Biyuanshu, Xiaoyanlidan, FuTongNing, Longqi thrombolysis, Cidan , Fu Park colds, gutta compound, compound berberine, cold Kang Hui blood born, JiangMei spirit, hypoglycemic armor, Lei Wan, Zhejiang water lipid, dragon incense and asthma, Naomaitai, asthma and inflammatory, seven students static, seven San Miguel, heart and brain, veins Xuekang, Pa Zhu Wan, Kai spleen, prostate level, skullcap violent red cough, Phyllanthus, Yin diabetes, Yi Senate Zhimaikang, Kyrgyzstan such as heart, Qilong Panax Tongshu, men and treasure, spring blood safety, Zhiganjia, Linggui Kechuanning, Babolat Dan, Dan Huang stasis, compound duzhong bone, Gengnian'an, anti-tuberculosis, Liu Wei Di Huang, Liu Wei wood, naotong thrombolysis, ShenAn, XUESAITONG, cough, compound yew, Xiaoshuan, cold heat, Qinlian, g Bi Autograft, or proprietary Naoliqing of Glucurolactone versicolor.
  47. 47.根据权利要求22、26或27中任意一项的控释制剂,其特征在于所述的药物选自对消化酶敏感的、用于(局部或直接)治疗结肠部位疾病的、对消化道上部(如胃、小肠)有较强毒副作用的或有较强刺激作用的或需延时释放的药物。 22, 26 or 47. A controlled release formulation according to any one of claim 27, wherein said medicament is selected digestive enzymes sensitive to (directly or topical) treatment of colonic disease site, digestive tract an upper portion (e.g., stomach, small intestine) or strong toxic side effects of a strong stimulation or the need to delay release of the drug.
  48. 48.根据权利要求22、26或27中任意一项的控释制剂,其特征在于所述的药物选自柳氮,柳氮磺吡啶,偶氮水杨酸、5-氨基水杨酸及其盐、布洛芬、氢化波尼松、地塞米松、布地缩松、倍氯米松、氟替卡松、替可的松(tioxocortal)、氢化可的松、甲硝唑、替硝唑、甲硝哒唑、 环饱菌素、甲氨蝶呤、哌双咪酮、5-氟尿嘧啶、双乙酰氧苯基甲基吡啶、番泻(senna)、胸腺肽、胰岛素、后叶加压素、生长激素、菌落刺激因子、降血钙素、免疫球蛋白、格列本脲、硫氮酮、异搏定、硝苯地平、硫甲丙脯氨酸、贝那普禾IJ、依那普禾IJ、茶碱、萘普生、环氟拉嗪、阿昔洛韦、奥美拉唑、洛伐它丁、阿仑特罗、去氨加压素、二甲双胍、甲氧乙心安、西沙必利、四氢氨基吖啶或微生态调节剂(probiotics)。 22, 26, 27 or 48. A controlled release formulation according to any one of the preceding claims, wherein the medicament is selected from sulfasalazine, sulfasalazine, olsalazine, 5-aminosalicylic acid and salt, ibuprofen, prednisolone, dexamethasone, budesonide, beclomethasone, fluticasone, tixocortol (tioxocortal), hydrocortisone, metronidazole, tinidazole, metronidazole , saturated ring streptozotocin, methotrexate, piperazine bis-one microphone, 5-fluorouracil, phenylmethyl bis acetoxymethyl pyridine, senna (Senna), thymosin, insulin, vasopressin, growth hormones, colony stimulating factors, calcitonin, immunoglobulin, glyburide, diltiazem, verapamil, nifedipine, sulfur methylpropyl proline, benazepril IJ P Wo, Wo IJ enalapril, theophylline, naproxen, ring-fluoro fluphenazine, acyclovir, omeprazole, lovastatin, alendronate, desmopressin, metformin, metoprolol, cisapride, tetrahydro-aminoacridine piperidine or microorganism modulator (probiotics).
  49. 49.根据权利要求25的控释制剂,其特征在于所述的药物选自需延时释放的药物。 49. A controlled-release formulation according to claim 25, wherein said medicament is selected from the need to delay release of the drug.
  50. 50.根据权利要求25的控释制剂,其特征在于所述的药物选自吉哌隆(Gepirone)、利塞膦酸盐、帕罗西汀及其盐、莫索尼定、硫辛酸及其衍生物、二甲双胍及其盐、加巴喷丁、 1R,2S-甲氧胺、克拉霉素、兰索拉唑及其盐、奥美拉唑及其盐、泮托拉唑及其盐、雷贝拉唑及其盐、埃索美拉唑及其盐、泰妥拉唑及其盐)。 50. The controlled release formulation according to claim 25, wherein said medicament is selected gepirone (gepirone), risedronate, paroxetine and salts thereof, moxonidine, lipoic acid and derivatives thereof, metformin and its salts, gabapentin, 1R, 2S- methoxamine, clarithromycin, and salts lansoprazole, omeprazole and salts thereof, and salts thereof pantoprazole, rabeprazole and salts thereof , esomeprazole and its salts, tenatoprazole and its salts).
  51. 51.根据前述权利要求中任意一项的控释制剂的制备方法,该方法包括下列基本步骤:1)、制备含有一种药物的芯料;2)、对所述的可溶于水的药用添加剂的颗粒物用含有药学上可接受的增塑剂或不含有增塑剂的药学上可接受的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的溶液或分散液包覆所述范围内用量的衣膜;3)、对上述含有一种药物的芯料用含有药学上可接受的增塑剂的药学上可接受的不溶于或几乎不溶于水及胃和肠消化液的聚合物的溶液或分散液包覆控释衣膜,其中,该聚合物的溶液或分散液中分散有作为致孔剂的被上述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的上述的可溶于水的药用添加剂的颗粒物,该聚合物的溶液或分散液不溶解或不降解或几乎不溶解或几乎不降解所述的可溶于胃和/或肠消化 51. The method for preparing a controlled release formulation of any one of the preceding claims, the method comprising the following basic steps: 1), a pharmaceutical preparation containing core material; 2), the water-soluble drug was treated with particulate additive with pharmaceutically acceptable pharmaceutically acceptable plasticizer containing no or containing a plasticizer is soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymers or an amount within the range of the coating dispersion coating film; 3), of a drug-containing core material comprising a pharmaceutically acceptable pharmaceutically acceptable plasticizer is insoluble or almost insoluble in water and a solution or dispersion of polymer film coated with a controlled release coating gastric and intestinal digestive juices, wherein a solution or dispersion of the polymer was dispersed as described above are soluble in the stomach and / or intestinal digestive juices porogen However, the above-described water-soluble pharmaceutically-insoluble or hardly water-insoluble polymer coating film coated with the additive particles, a solution or dispersion of the polymer does not dissolve or degrade or hardly soluble or hardly the degradation may be soluble in the stomach and / or intestinal digestion 的但不溶于或几乎不溶于水的聚合物。 But it is insoluble or hardly water-soluble polymers.
  52. 52.根据权利要求51的制备方法,其特征在于所述的方法还进一步将所述的控释衣膜包覆含有一种药物的芯料置于高于所述的控释衣膜的玻璃化转变温度的温度下愈合处理, 直至该包衣芯料具有稳定的溶出特性,愈合处理终点通过比较刚结束愈合处理的包衣芯料与在40士2°C的温度及70% -80%的相对湿度下的加速贮存条件中放置3个月和/或6个月的包衣芯料的溶出特性而确定。 52. A production method according to claim 51, characterized in that the method further coating the film-coated controlled release of a drug having a glass frit positioned above the core of the controlled release film coating a transition temperature of the healing process, until the coated core material having a stable dissolution profile, the end of the healing process by comparing the coated core material immediately after the healing process at a temperature of 40 persons and a 2 ° C of 70% -80% 3 months and / or dissolution characteristics of the coated core material is placed for 6 months under accelerated storage conditions of relative humidity determined.
  53. 53.根据权利要求28至31中任意一项的控释制剂的的制备方法,其特征在于包括将被所述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的所述的可溶于水的药用添加剂的颗粒物分散并混悬于所述的含有药学上可接受的增塑剂的不溶于或几乎不溶于水及胃和肠消化液的聚合物的水分散液(体)之前,将被所述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆的所述的可溶于水的药用添加剂的颗粒物置于高于所述衣膜的玻璃化转变温度的温度下愈合,直至下述的所述衣膜对水的渗透性能为0的状态终点,在该状态终点下所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物与所述的可溶于水的药用添加剂在所述的水分散液(体)中不发生化学反应,或者至少要在对所述含有一种药物的芯料用所述的含有 Soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymeric 53. A method for preparing a controlled release formulation of any one of claims 28 to 31, characterized by comprising the water-soluble pharmaceutical composition of the coating film of the coated additive particles are dispersed and suspended in the pharmaceutically acceptable containing a plasticizer is insoluble or almost insoluble in water and digestive juices of the stomach and intestines before an aqueous dispersion of polymer (bulk), it will be soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film coated with the water soluble pharmaceutically acceptable additive particles placed healing glass transition temperature is higher than the temperature of the coating film, the coating film performance until the permeability to water is below the end of the state 0, the state at the end soluble in the stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymer and the water soluble pharmaceutically acceptable additive which does not react chemically in the aqueous dispersion liquid (volume) in the or contain at least one drug-containing core material with said 学上可接受的增塑剂的不溶于或几乎不溶于水及胃和肠消化液的聚合物的水分散液(体)包覆控释衣膜的过程中不发生化学反应。 Chemical reaction occurs during insoluble or hardly water-soluble polymers and water gastric and intestinal digestive juices dispersion (volume) of the coating film coated with a controlled release agriculturally acceptable plasticizer.
  54. 54.根据权利要求28至31中任意一项的控释制剂的的制备方法,其特征在于包括用所述的含有药学上可接受的增塑剂或不含有增塑剂的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物的不含水的有机溶液或分散液对所述的可溶于水的药用添加剂包覆衣膜及将被所述可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物衣膜包覆所述的可溶于水的药用添加剂的颗粒物分散并混悬于所述的含有药学上可接受的增塑剂的不溶于或几乎不溶于水及胃和肠消化液的聚合物的不含水的有机溶液或分散液中, 该有机溶液或分散液不溶解或不降解或几乎不溶解或几乎不降解所述的可溶于胃和/或肠消化液的但不溶于或几乎不溶于水的聚合物。 54. A method for preparing a controlled release formulation of any one of claims 28 to 31, characterized by comprising a gastric-soluble plasticizer comprising a pharmaceutically acceptable or not containing a plasticizer and the / intestinal digestive juices or organic solution or dispersion, but no water-insoluble or hardly water-soluble polymer will be on the water soluble film coat covering a pharmaceutical additives may be dissolved in the stomach and / or intestine digestive juice but insoluble or hardly water-insoluble polymer coating film covering the water soluble pharmaceutically acceptable additive particles dispersed and suspended in the pharmaceutically acceptable containing organic solution or dispersion is insoluble or almost insoluble in water and non-aqueous polymer gastric and intestinal digestive juices of the plasticizer, the organic solution or dispersion does not dissolve or degrade or hardly soluble or hardly degrade the soluble stomach and / or intestine digestive juice but insoluble or hardly water-soluble polymers.
  55. 55.根据权利要求51至54中任意一项的制备方法,其特征在于进一步把制备的控释制剂用计量设备装入胶囊、袋(小药囊)或合适的多计量容器中或进一步制成片剂或进一步制备成栓剂或进一步用半球形容器或多剂量容器包装。 51 to 55. The production method as claimed in any one of claim 54, further characterized in that the metering device with a controlled release formulation encapsulated prepared bags (sachets) or multiple dosing suitable container or further prepared tablets or suppositories, or further be prepared with a hemispherical further packaging multi-dose containers.
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