WO2012006965A1

WO2012006965A1 - Tablet with improved comprehensive performance and preparation method therefor

Info

Publication number: WO2012006965A1
Application number: PCT/CN2011/077211
Authority: WO
Inventors: 钟术光
Original assignee: Zhong Shuguang
Priority date: 2010-07-16
Filing date: 2011-07-15
Publication date: 2012-01-19
Also published as: CN101919822A; CN101919822B

Abstract

A tablet with improved comprehensive performance and a preparation method therefor. The tablet comprises an active ingredient, a water-soluble crystalline diluent as particles or as a powder, a meltable binder, and a meltable mechanical performance improving agent, and comprises/or does not comprise a pharmaceutically acceptable additive, wherein the diluent and/or the active ingredient are bound and bridged by a solidified melt of the binder and the mechanical performance improving agent, the ratio of the mechanical performance improving agent/(the binder + mechanical performance improving agent) is 0.25-0.70, the ratio of the diluent/(the binder + the mechanical performance improving agent + the diluent) is 0.40-0.93, the weight content of the diluent in the tablet is no less than 25%, the weight content of the binder and the mechanical performance improving agent in the tablet is no less than 5%. The mechanical performance, the weathering resistance, the hydrophilicity, the porosity, and the disintegrability of the tablet are improved.

Description

综合性能改善的片剂及其制备方法 Comprehensive performance improving tablet and preparation method thereof

技术领域 Technical field

本发明涉及一种综合性能改善的片剂。更具体地说一种机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂。本发明还涉及该片剂的制备方法。发明背景 The present invention relates to a tablet having improved overall performance. More specifically, a hydrophilic tablet having a higher mechanical properties and a higher porosity and a higher weather resistance. The invention also relates to a process for the preparation of the tablet. Background of the invention

片剂的孔隙率与机械强度在片剂起非常重要的作用。高的孔隙率有利于片剂中的药物，尤其是难溶性药物的溶出释放，特别是口腔内迅速崩解 /溶解片剂。高的机械强度有利于片剂在生产、运输等过程中维护其形态，保证单个剂量的准确，从而保证用药安全。 The porosity and mechanical strength of the tablet play a very important role in the tablet. The high porosity facilitates the release of the drug in the tablet, especially the poorly soluble drug, especially the rapid disintegration/dissolution of the tablet in the mouth. The high mechanical strength is conducive to the maintenance of the shape of the tablet during production, transportation, etc., to ensure the accuracy of a single dose, thus ensuring the safety of medication.

然而，片剂高的孔隙率常常导致片剂的机械强度不足等问题，如硬度不高、脆碎度不好，从而可能出现载药量（单个剂量）下降、裂片、碎片等质量问题，并进一步加剧湿气、空气 (氧气)及光等对片剂的影响，降低其稳定性；而片剂高的机械强度又常常导致片剂的孔隙率不足，片剂崩解或药物溶出变慢等问题。 However, the high porosity of the tablet often leads to problems such as insufficient mechanical strength of the tablet, such as low hardness and poor friability, which may cause quality problems such as drop in drug loading (single dose), lobes, fragments, etc., and Further aggravating the influence of moisture, air (oxygen) and light on the tablet and reducing its stability; while the high mechanical strength of the tablet often leads to insufficient porosity of the tablet, tablet disintegration or slow dissolution of the drug, etc. problem.

近年来，已有人们发明了一些获得较高孔隙率的片剂技术。例如，特开平 11-35451所揭示的口腔内溶解型片剂：药效成分、糖类等和聚乙二醇类、脂类如羊毛脂、羊毛脂醇，天然蜡类如巴西棕榈蜡等低熔点物质混合，该混合物低压下压片，所得的片剂在熔融该低熔点物质的温度下加温，之后自然冷却为特征的口腔内溶解型片剂及其制造方法。 In recent years, some tablet technologies have been invented to obtain higher porosity. For example, the orally dissolvable tablet disclosed in JP-A-11-35451: medicinal ingredients, saccharides, and the like, and polyethylene glycols, lipids such as lanolin, lanolin alcohol, natural waxes such as carnauba wax, etc. The melting point substance is mixed, the mixture is tableted at a low pressure, and the obtained tablet is heated at a temperature at which the low-melting point substance is melted, and then naturally cooled to characterize an orally dissolved tablet and a method for producing the same.

再如， US5853758 揭示了一种多孔的片剂：此片剂在制备时，使用脂类如羊毛脂、羊毛脂醇，天然蜡类如巴西棕榈蜡，天然或合成聚合物如 PEG200〜20000，麦芽糊精，糖类如葡萄糖等热熔固化作为交接剂或粘合剂及碳酸氢铵、樟脑等挥发或可分解的成分作致孔剂；其制作过程如下：（a)将可熔化性粘合剂、至少一种赋形剂及医药的活性剂组合在片剂中，（b) 将前述的可熔化性粘合剂在上述片剂中使其熔化及 (c)使上述可熔化性粘合剂凝固。 As another example, US Pat. No. 5,853,758 discloses a porous tablet: This tablet is prepared by using a lipid such as lanolin, lanolin alcohol, a natural wax such as carnauba wax, a natural or synthetic polymer such as PEG200~20000, malt. Dextrin, saccharide such as glucose, etc. as a porogen as a crosslinking agent or binder and a volatile or decomposable component such as ammonium bicarbonate or camphor; the preparation process is as follows: (a) bonding the meltability a combination of at least one excipient and a pharmaceutically active agent in a tablet, (b) melting the aforementioned meltable binder in the tablet, and (c) bonding the meltable bond The agent solidifies.

上述技术在实际应用中，均不同程度地表现出机械强度不够理想的缺点，如硬度不够高、脆碎度不够好，在生产及运输等过程中易出现裂片、碎片等问题。其机械性能仍有较大的改善余地。此外，由于一般所揭示的亲水性较好的可熔化性粘合剂熔点较低，使用该熔点为粘合剂的制剂在没充分配备夏季空调设备的室内保存情况下，粘合剂可能熔化，片剂***，使片剂强度及口腔内崩解时间等发生变化，耐候性或耐较高气温的能力变差。而所用熔点相对较高的亲脂性的可熔化性粘合剂亲水性不好，制备的上述制剂崩解或药物溶出相对较慢。亲水性与耐候性在此常常不是有机统一的，而是相互矛盾的。 In the practical application, the above-mentioned technologies all have disadvantages such as insufficient mechanical strength, such as insufficient hardness and insufficient friability, and problems such as cracks and fragments are likely to occur during production and transportation. There is still much room for improvement in its mechanical properties. In addition, since the generally disclosed hydrophilicity of the meltable adhesive has a lower melting point, the formulation using the melting point as the binder may be melted in the case of indoor storage in which the air conditioner is not fully equipped. The tablet becomes soft, and the strength of the tablet and the disintegration time in the oral cavity are changed, and the weather resistance or the ability to withstand higher temperatures is deteriorated. On the other hand, the lipophilic fusible binder having a relatively high melting point is not hydrophilic, and the above-mentioned preparation prepared for disintegration or drug dissolution is relatively slow. Hydrophilicity and weatherability are often not organically unified, but contradictory.

因此，现实中还需要机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂。发明目的 Therefore, in reality, a hydrophilic tablet having a high porosity and a high weather resistance which is further enhanced in mechanical properties is required. Purpose of the invention

本发明的目的之一，提供一种机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂及其制备方法。其他目的见下面的说明书及实施例。发明内容 SUMMARY OF THE INVENTION One object of the present invention is to provide a hydrophilic tablet having a high porosity and a high porosity which is further enhanced in mechanical properties and a process for producing the same. For other purposes, see the following description and examples. Summary of the invention

为了达到上述目的，本发明者进行了深入的研究，结果发现，多孔的片剂的机械性能与下列几个因素有较大关系， 1 )、被可熔化的粘合剂粘合的颗粒物自身的机械性能； 2)、可熔化的粘合剂自身的机械性能； 3)、被可熔化的粘合剂粘合的颗粒物与可熔化的粘合剂间的粘附力或亲合性； 4)、被可熔化的粘合剂粘合的颗粒物与可熔化的粘合剂间的比例及被可熔化性粘合剂粘合的颗粒物在整个片剂中所占的比例。其中，被可熔化的粘合剂粘合的颗粒物及可熔化的粘合剂的亲水性对制剂的亲水性起重大甚至决定性的关系，可熔化的粘合剂的融变性决定或主要影响制剂的耐候性。 In order to achieve the above object, the inventors conducted intensive studies and found that the mechanical properties of the porous tablet are largely related to the following factors: 1) the particles themselves bonded by the meltable binder Mechanical properties; 2), the mechanical properties of the meltable adhesive itself; 3) the adhesion or affinity between the particles bonded by the meltable adhesive and the meltable adhesive; 4) The ratio between the particulate material bound by the meltable binder and the meltable binder and the proportion of particulate matter bound by the meltable binder throughout the tablet. Wherein, the hydrophilicity of the particles bound by the meltable binder and the hydrophilicity of the meltable binder are significant or even decisive for the hydrophilicity of the formulation, and the melt densification of the meltable binder determines or primarily affects The weatherability of the formulation.

经本发明者进行了深入的研究，结果还发现：较低熔点的亲水性的聚乙二醇酯或醚类表面活性剂及糖酯类表面活性剂等物质（以下简称熔融粘合剂，此类物质通常具有较好的亲水性及亲脂性）分别与较高熔点的亲脂性的物质（以下简称机械性能增强剂）熔融后再冷却，固化后的熔融物的机械性能有较大幅度的提高，以熔融粘合剂与机械性能增强剂的比例为横坐标与以测得的机械性能参数值为纵坐标绘制而成的比例-机械性能参数（如硬度或姽碎度）相图通常可得上凸或下凹的曲线；此等处理后，较低熔点的亲水性的聚乙二醇酯或醚类表面活性剂及糖酯类表面活性剂等物质的耐候性或耐较高气温的能力被提高。 The inventors conducted intensive studies and found that: lower melting hydrophilic polyethylene glycol ester or ether table Surfactants and sugar ester surfactants (hereinafter referred to as melt binders, which usually have good hydrophilicity and lipophilicity) and higher melting point lipophilic substances (hereinafter referred to as mechanical properties) Reinforcing agent) After melting and then cooling, the mechanical properties of the solidified melt are greatly improved. The ratio of the molten binder to the mechanical performance enhancer is plotted on the abscissa and the measured mechanical property parameter is plotted on the ordinate. The ratio drawn - mechanical properties (such as hardness or mash) phase diagram usually gives a convex or concave curve; after these treatments, lower melting hydrophilic polyethylene glycol ester or ether The weather resistance or resistance to higher temperatures of substances such as surfactants and sugar ester surfactants is improved.

在此基础上，本发明人把一定量的亲水性的原辅料特别可溶于水的结晶态的辅料如糖类物质（结晶态颗粒物或粉未机械性能一般较无定型粉未好），及上述两种可熔融的成分掺和到片剂原、辅料中，在较低压力下压片或不进行压片，然后加热使上述两种可熔融的成分熔化，再冷却，使上述两种可熔融的成分的熔融固化物在上述亲水性的原辅料特别可溶于水的结晶态的辅料如糖类物质颗粒间形成交联。结果发明，上述孔隙率较高的亲水性的片剂的机械强度、耐候性可大幅度地提高。在上述片剂中，亲水性及亲脂性较好的聚乙二醇酯或醚类表面活性剂及糖酯类表面活性剂一端较好粘附亲水性的原辅料特别可溶于水的结晶态的辅料如糖类物质，另一端较好地粘合较高熔点的亲脂性的物质。 On the basis of this, the inventors have made a certain amount of hydrophilic raw materials particularly soluble in water-crystalline auxiliary materials such as saccharides (crystalline particles or powders are generally not mechanically better than amorphous powders). And the above two meltable components are blended into the tablet raw materials and auxiliary materials, pressed or not pressed at a lower pressure, and then heated to melt the above two meltable components, and then cooled to make the above two kinds The molten solidified product of the meltable component forms a crosslink between the above-mentioned hydrophilic raw material and a water-soluble crystalline auxiliary material such as a saccharide substance particle. As a result, the mechanical strength and weather resistance of the hydrophilic tablet having a high porosity can be greatly improved. In the above tablets, the hydrophilic and lipophilic polyethylene glycol ester or ether surfactant and the sugar ester surfactant are preferably adhered at one end to the hydrophilic raw material, particularly soluble in water. A crystalline excipient such as a saccharide, the other end preferably binds a higher melting point lipophilic material.

在上述基础上，本发明人制造出机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂，并完成了本发明。 On the basis of the above, the inventors have produced a hydrophilic tablet having a higher porosity and a higher porosity, which has been further enhanced in mechanical properties, and has completed the present invention.

具体说来，一方面，本发明涉及一种机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂，该片剂包含： Specifically, in one aspect, the present invention relates to a hydrophilic tablet having a higher porosity and a higher porosity, which is further enhanced in mechanical properties, the tablet comprising:

1 ) 、一种活性成分； 1) an active ingredient;

2 ) 、一种药学上可接受的、可溶于水的结晶态的颗粒状或粉未状的稀释剂； 2) a pharmaceutically acceptable, water-soluble crystalline particulate or powdery diluent;

3 )、一种可熔融的粘合剂，该可熔融的粘合剂为药学上可接受的、熔点较上述可溶于水的结晶态的颗粒状或粉未状的稀释剂低的更佳地还较上述活性成分低的、常温下为固体（熔点不低于 25°C ) 且可溶于水的可熔融的表面活性剂； 3) a meltable binder which is preferably pharmaceutically acceptable, having a lower melting point than the above-mentioned water-soluble crystalline particulate or powdery diluent a meltable surfactant which is lower in solidity than the above active ingredient and which is solid at room temperature (melting point not lower than 25 ° C) and soluble in water;

4)、一种可熔融的机械性能增强剂，该可熔融的机械性能增强剂为药学上可接受的、熔点不低于 45°C且较上述可溶于水的结晶态的颗粒状或粉未状的稀释剂低更佳地还较上述活性成分的熔点低但较上述可熔融的粘合剂的熔点高的、脂溶性的且不可溶于水的可熔融的和 /或无 4) a meltable mechanical property enhancer, wherein the meltable mechanical property enhancer is a pharmaceutically acceptable granule or powder having a melting point of not lower than 45 ° C and being more soluble in a water-soluble crystalline form The unshaped diluent is preferably lower than the melting point of the above active ingredient but higher than the melting point of the above meltable binder, fat-soluble and water-insoluble, meltable and/or absent

5 )、一种药学上可接受的添加剂； 5), a pharmaceutically acceptable additive;

其中，上述的可溶于水的结晶态的颗粒状或粉未状的稀释剂和 /或上述的活性成分被上述的可熔融的粘合剂及上述的机械性能增强剂的固化熔融物粘合桥连；且上述组分用量满足下列关系：上述机械性能增强剂的重量 / (上述可熔融的粘合剂的重量 +上述机械性能增强剂的重量）位于 0. 25至 0. 70之间（含端点）（此处 "/"表示比例关系，等同于 " ÷ " )，且上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量 / (上述可熔融的粘合剂的重量 +上述机械性能增强剂的重量 +上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量)位于 0. 40 至 0. 93之间（含端点）（此处 "/"表示比例关系，等同于 " ÷ " ) ; 且上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量占整个片剂总重量的比例为不低于 25%; 且上述的熔融粘合剂与上述的机械性能增强剂的重量和占整个片剂总重量的比例不低于 5%; 当上述活性成分和 /或上述药学上可接受的添加剂为可溶于水的结晶态的颗粒状或粉未状的物质时，其重量合计于上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量，并以此合计重量计算上述相关比例；当上述活性成分和 /或上述药学上可接受的添加剂为可溶于水的结晶态的颗粒状或粉未状的物质且用量满足上述关系时，上述可溶于水的结晶态的颗粒状或粉未状的稀释剂用量可以为 0。 Wherein the above-mentioned water-soluble crystalline particulate or powdery diluent and/or the above-mentioned active ingredient are bonded by the above-mentioned meltable binder and the cured melt of the above-mentioned mechanical property enhancer至之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间。 Including the endpoint) (here "/" means a proportional relationship, equivalent to "÷"), and the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent / (the above meltable binder) The weight of the above-mentioned mechanical property enhancer + the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent is between 0.40 and 0.93 (inclusive) (here) /" indicates a proportional relationship, which is equivalent to "÷"); and the ratio of the above-mentioned water-soluble crystalline particulate or powdery diluent to the total weight of the entire tablet is not less than 25%; The above molten binder and the above mechanical property enhancer The ratio of the weight to the total weight of the entire tablet is not less than 5%; when the above active ingredient and/or the above pharmaceutically acceptable additive is a water-soluble crystalline granular or powdery substance, The weight is added to the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent, and the above relevant ratio is calculated by the total weight; when the above active ingredient and/or the above pharmaceutically acceptable additive is When the particulate or powdery substance in a crystalline state is dissolved in water and the amount satisfies the above relationship, the amount of the particulate or powdery diluent which is soluble in water may be 0.

另一方面，本发明涉及一种机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂的制备方法，该方法包含三个基本的工序：（1 )、如下所述的成形工序：为了将含有活性成分、药学上可接受的可溶于水的结晶态的颗粒状或粉未状的稀释剂、可熔融的粘合剂、可熔融的机械性能增强剂和 /或无药学上可接受的添加剂的片剂原料在制药上呈基本均一分散的状态并使其具有药学上可接受的空间形态（片剂）即维持片剂形式的工序，其中，上述的可熔融的粘合剂为药学上可接受的、熔点较上述可溶于水的结晶态的颗粒状或粉未状的稀释剂低的更佳地还较上述活性成分低的、常温下为固体（熔点不低于 25°C ) 且可溶于水的可熔融的表面活性剂；上述的可熔融的机械性能增强剂为药学上可接受的、熔点不低于 45°C且较上述可溶于水的结晶态的颗粒状或粉未状的稀释剂低更佳地还较上述的活性成分的熔点低但较上述可熔融的粘合剂的熔点高的、脂溶性的且不可溶于水的可熔融的物质；且上述组分用量满足下列关系：上述机械性能增强剂的重量 / (上述可熔融的粘合剂的重量 +上述机械性能增强剂的重量）位于 0. 25至 0. 70之间（含端点）（此处 "/"表示比例关系），上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量 / (上述可熔融的粘合剂的重量 +上述机械性能增强剂的重量 +上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量)位于 0. 40至 0. 93 之间（含端点）（此处 "/"表示比例关系）；且上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量占整个片剂总重量的比例为不低于 25%; 且上述的熔融粘合剂与上述的机械性能增强剂的重量和占整个片剂总重量的比例不低于 5%; 当上述活性成分和 /或上述药学上可接受的添加剂为可溶于水的结晶态的颗粒状或粉未状的物质时，其重量合计于上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量，并以此合计重量计算上述相关比例；当上述活性成分和 /或上述药学上可接受的添加剂为可溶于水的结晶态的颗粒状或粉未状的物质且用量满足上述关系时，上述可溶于水的结晶态的颗粒状或粉未状的稀释剂用量可以为 0; ( 2)、如下所述的加热工序：将由工序（1)得到的片剂成形物加热到上述可熔融的机械性能增强剂的熔融温度以上（含熔融温度）的温度使上述粘合剂 (C)及上述机械性能增强剂 (D)熔化的工序;In another aspect, the present invention relates to a method for preparing a hydrophilic tablet having a higher porosity and a higher porosity and having a higher mechanical property, the method comprising three basic steps: (1), as follows The forming step described: in order to contain a granular or powdery diluent, a meltable binder, containing an active ingredient, a pharmaceutically acceptable water-soluble crystalline form, The meltable mechanical performance enhancer and/or the tablet material without the pharmaceutically acceptable additive is in a substantially uniformly dispersed state of pharmacy and has a pharmaceutically acceptable morphological form (tablet), ie, maintains the tablet form And the above-mentioned meltable binder is preferably a pharmaceutically acceptable lower than the above-mentioned active ingredient having a melting point lower than that of the above-mentioned water-soluble crystalline particulate or powdery diluent a low meltable surfactant which is solid at room temperature (melting point not lower than 25 ° C) and soluble in water; the above meltable mechanical property enhancer is pharmaceutically acceptable, having a melting point of not less than 45 °C and lower than the above-mentioned water-soluble crystalline particulate or powdery diluent, preferably lower than the melting point of the above active ingredient but higher than the melting point of the above meltable binder a meltable substance which is soluble and insoluble in water; and the amount of the above components satisfies the following relationship: The weight of the above mechanical property enhancer / (the weight of the above meltable binder + the weight of the above mechanical property enhancer) is located 0. 25 Between 70 and 70 (inclusive) (here "/" indicates the proportional relationship), the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent / (the above meltable binder The weight + the weight of the above-mentioned mechanical property enhancer + the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent is between 0.40 and 0.93 (inclusive) (here "/ "representing a proportional relationship"; and the ratio of the above water-soluble crystalline particulate or powdery diluent to the total weight of the entire tablet is not less than 25%; and the above-mentioned molten binder and The above mechanical property enhancer has a weight ratio of not less than 5% by weight based on the total weight of the whole tablet; when the above active ingredient and/or the above pharmaceutically acceptable additive is a water-soluble crystalline granular or powder In the case of an unexposed substance, the weight thereof is a total of the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent, and the above relevant ratio is calculated by the total weight; when the above active ingredient and/or the above pharmacy An acceptable additive is a particulate form that is soluble in water. When the powdery substance is used in an amount satisfying the above relationship, the amount of the particulate or powdery diluent in the water-soluble crystalline state may be 0; (2), the heating process as described below: the process (1) a step of heating the obtained binder (C) and the mechanical property enhancer (D) by heating the obtained tablet molded article to a temperature higher than a melting temperature (including a melting temperature) of the meltable mechanical property enhancer;

( 3)、如下所述的冷却工序：将由工序 (2)得到的片剂成形物中的熔化的上述粘合剂 (C)及上述机械性能增强剂 (D)凝固的工序。本发明使用的术语 "片剂"是指含一种或一种以上的活性成分的经加压或其他非加压工艺制成的扁平或上下面稍为凸起的圆片状、棒状、支状、丸状、块状、锥状、或其他药学上可接受的形状的内部各成分分散基本均匀的主要供内服、也可以外用的固体剂型以及在此基础上进一步处理制成的胶囊剂及其他药学上可接受的剂型，在本发明中， "片剂 "较佳地为口腔内迅速崩解 /溶解片剂。 (3) A cooling step as follows: a step of solidifying the melted binder (C) and the above-mentioned mechanical property enhancer (D) in the tablet molded article obtained in the step (2). The term "tablet" as used in the present invention refers to a flat or slightly convex, disc-shaped, rod-like, branched shape made of a pressurized or other non-pressurized process containing one or more active ingredients. , the internal components of the pellets, lumps, cones, or other pharmaceutically acceptable shapes are substantially uniformly dispersed, and the solid dosage forms are mainly for internal use, and can also be used externally, and capsules prepared by further processing on this basis and others A pharmaceutically acceptable dosage form, in the present invention, the "tablet" is preferably a rapidly disintegrating/dissolving tablet in the oral cavity.

本发明使用的术语 "口腔内迅速崩解 /溶解片剂"是指为服用片剂不摄取水，在口腔内基本上只用唾液于 1分以内（较佳地在约 30秒以内，更佳地在约 10秒以内）崩解 /溶解的片剂。 The term "rapidly disintegrating/dissolving the tablet in the mouth" as used in the present invention means that the tablet is not ingested for taking the tablet, and the saliva is substantially only within 1 minute (preferably within about 30 seconds, preferably in the oral cavity). A tablet that disintegrates/dissolves within about 10 seconds.

本发明使用的术语 "多孔"是指片剂的多孔性结构，通常其孔隙率是约 10至约 95%，满意的是约 20至约 80%，更满意的是约 30至约 50%的意思。 As used herein, the term "porous" refers to the porous structure of a tablet, typically having a porosity of from about 10 to about 95%, desirably from about 20 to about 80%, more desirably from about 30 to about 50%. meaning.

本发明使用的术语 "孔隙率 (Porosity) "是指片剂中微粒内孔隙及微粒间空隙所占容积与片剂容积之比，通常用百分数表示。 The term "Porosity" as used in the present invention means the ratio of the volume of pores in the microparticles in the tablet to the volume of the interparticle voids to the volume of the tablet, usually expressed as a percentage.

本发明使用的术语 "熔点"是指物质从固态转化为液态的温度，当熔点用熔程表示时，特别是比较两种物质的熔点大小时，在本发明中是特指熔程的起点值与终点值的算术平均值 (中点值）。 As used herein, the term "melting point" refers to the temperature at which a substance is converted from a solid state to a liquid state. When the melting point is expressed by a melting range, particularly when comparing the melting points of the two substances, in the present invention, the starting point of the melting point is specifically referred to. The arithmetic mean (midpoint value) with the endpoint value.

本发明使用的术语"可熔融的"指物质能在不高于温度 150°C，尤其是不高于温度 120°C，特别是不高于温度 10CTC的条件下熔化的意思。 The term "meltable" as used in the present invention means that the substance can be melted at a temperature not higher than 150 ° C, especially not higher than 120 ° C, particularly not higher than 10 CTC.

本发明使用的术语 "机械性能增强剂"是指可以改善固态熔融物或片剂机械性能如提高硬度（Hardness )、拉伸强度（tensi le strength)或推片力（Ejection Force ), 降低姽碎度 (Friabi l ity) 等的物质。 The term "mechanical performance enhancer" as used herein means that the solid melt or tablet mechanical properties such as increased hardness, tensile strength or Ejection Force can be improved, and mashing can be reduced. Substances such as Friabiity.

本发明使用的术语 "机械性能参数"是指反映片剂的机械性能的参数，包括但不限于硬度（Hardness )、姽碎度（Friabi l ity)、拉伸强度（tensi le strength)、推片力（Ejection Force )。本发明使用的术语 "可溶于水的"或 "水溶性的"是指物质在水（温度 25°C )或温水（温度 37°C ) 中的平衡溶解量不低于 33m_g/lml (溶解质 /水），较佳地不低于 lOOmg/lml (溶解质 / 水），更佳地不低于 200mg/lml (溶解质 /水），最佳地不低于 500mg/lml (溶解质 /水）。 The term "mechanical performance parameter" as used herein refers to a parameter that reflects the mechanical properties of a tablet, including but not limited to hardness (hardness), fragrantness (tensi le strength), tensile strength (tensi le strength), push film. Ejection Force. The term "water-soluble" or "water-soluble" as used in the present invention means that the equilibrium dissolved amount of the substance in water (temperature 25 ° C) or warm water (temperature 37 ° C) is not less than 33 m _g /l ml ( Solute/water), preferably not lower than 100 mg/lml (solute/water), more preferably not lower than 200 mg/lml (solute/water), optimally not lower than 500 mg/lml (solute /water).

本发明使用的术语 "脂溶性的且不可溶于水的"是指物质可溶解或分散于一种或数种如植物油、天然脂肪、矿物油或石油醚、苯、 ***、四氯化碳等非极性溶剂或分散剂但在水（温度 25°C ) 或温水（温度 37°C ) 中的平衡溶解量低于 33m_g/lml (溶解质 /水），且该平衡溶解量不超过上述可溶于水的可熔融的粘合剂在同一温度下的水中的平衡溶解量十分之一，较佳地不超过其三十分之一，更佳地不超过其百分之一，最佳地不超过其千分之一。 The term "lipid-soluble and insoluble in water" as used herein means that the substance is soluble or dispersible in one or more of such as vegetable oil, natural fat, mineral oil or petroleum ether, benzene, diethyl ether, carbon tetrachloride, etc. a non-polar solvent or dispersant, but the equilibrium dissolved amount in water (temperature 25 ° C) or warm water (temperature 37 ° C) is less than 33 m _g / lml (solute / water), and the equilibrium dissolved amount does not exceed the above The water-soluble meltable binder is one-tenth of the equilibrium dissolved amount in water at the same temperature, preferably not more than one-thirtieth, more preferably not more than one-hundredth, most The best place is no more than one thousandth.

本发明使用的术语 "平衡溶解量"是指在一定条件下如一定的温度下，物质溶解于单位体积溶剂并达到平衡（饱和）所需的量。 The term "equilibrium dissolved amount" as used in the present invention means an amount required to dissolve a substance in a unit volume of a solvent and reach equilibrium (saturation) under certain conditions such as a certain temperature.

本发明使用的术语 "溶解"是指物质以分子状态和 /或离子状态或表面活性剂以胶束状态和 /或分子状态和 /或离子状态分散于分散介质即溶剂的过程。 The term "dissolving" as used in the present invention means a process in which a substance is dispersed in a molecular state and/or an ionic state or a surfactant in a micelle state and/or a molecular state and/or an ionic state in a dispersion medium, i.e., a solvent.

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。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。 The terms "active ingredient", "biologically active ingredient", "pharmaceutically active ingredient", "active substance", "active agent" and "biologically active substance", "drug" and the like as used herein mean any substance as it Detectable biological effects when administered to a living body include any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any pharmaceutically, therapeutic, prophylactic, nutritional material.

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。 The terms "comprising" and "containing", as used in the present invention, are meant to include, but not limited to, or in addition to the meaning of other components and the like.

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。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。发明具体实施方式 The term "a" as used in the present invention means at least one, and may be one type or two or more types. The term "pharmaceutically acceptable" as used in the present invention means that it can be mixed with each other in the preparation without adverse effects on each other without deteriorating the stability and/or efficacy of the preparation and is suitable for topical or systemic administration. DETAILED DESCRIPTION OF THE INVENTION

作为本发明所用的稀释剂，要求是可溶于水（其定义见上文）的结晶态的颗粒状或粉未状的物质，该稀释剂应易于成形处理，且制成片剂时片剂应在口腔内可迅速崩解或溶解。用于本发明的稀释剂较佳地为方晶形或者被粉细的结晶态颗粒或粉未。用于本发明的稀释剂较佳地为在可溶于水的结晶态的颗粒物或粉未状，更佳地为可溶于水的结晶态的糖类物质。可用于本发明的稀释剂的实例如结晶态的糖类、氧化钠、氯化钾、可溶性氨基酸及其混合物，其中糖类为更优选。可用于本发明的糖类包括但不限于结晶态的赤藻糖醇、葡萄糖、异麦芽糖醇、拉克替醇、乳糖、麦芽糖醇、麦芽糖、甘露醇、蔗糖、海藻糖、木糖醇、果糖、棉子糖、偶联糖、低聚糖及其混合物。结晶态的颗粒状或粉未状的稀释剂用于本发明有利于提高片剂的机械性能，因其具有相对较高的机械性能，特别是相对于无定型粉未。可溶于水的稀释剂有利于其与亲水性的可熔融的粘合剂亲合性或结合力，有利于提高片剂的机械性能。 As the diluent used in the present invention, it is required to be a crystalline or granulated substance which is soluble in water (as defined above), which should be easily formed into a tablet and made into tablets. It should disintegrate or dissolve rapidly in the mouth. The diluent used in the present invention is preferably in the form of a cubic crystal or a finely divided crystalline particle or powder. The diluent used in the present invention is preferably a particulate or powdery form in a water-soluble crystalline state, more preferably a water-soluble crystalline substance. Examples of the diluent which can be used in the present invention are crystalline saccharides, sodium oxide, potassium chloride, soluble amino acids and mixtures thereof, with saccharides being more preferred. The saccharides useful in the present invention include, but are not limited to, crystalline erythritol, glucose, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sucrose, trehalose, xylitol, fructose, Raffinose, conjugated sugars, oligosaccharides, and mixtures thereof. The use of a crystalline particulate or powdered diluent for use in the present invention advantageously enhances the mechanical properties of the tablet due to its relatively high mechanical properties, particularly relative to amorphous powder. The water-soluble diluent facilitates its affinity or binding force with the hydrophilic meltable binder, which is advantageous for improving the mechanical properties of the tablet.

本发明所用的上述稀释剂的掺合量可以按药物的用量及 /或片剂的大小进行适当的调整，但一般上述可溶于水的结晶态的颗粒状或粉未状的稀释剂通常占整个片剂的比例不低于 25% (wt/wt ), 更佳地不低于 34% (wt/wt ) 且不高于 80% (wt/wt ), 最佳地不低于 40% (wt/wt ) 且不高于 70% (wt/wt ) , 以上重量百分比是基于片剂的总重量。这是因为较高的上述稀释剂的掺合量有利于提高片剂的亲水性特别是机械性能。 The blending amount of the above diluent used in the present invention may be appropriately adjusted depending on the amount of the drug and/or the size of the tablet, but generally the above-mentioned water-soluble crystalline granular or powder-form diluent usually accounts for The proportion of the entire tablet is not less than 25% (wt/wt), more preferably not less than 34% (wt/wt) and not more than 80% (wt/wt), and most preferably not less than 40% ( The wt% is not more than 70% (wt/wt), and the above weight percentage is based on the total weight of the tablet. This is because the higher amount of the above diluent is added to enhance the hydrophilicity, particularly the mechanical properties of the tablet.

本发明涉及的可熔融的粘合剂（以下简称熔融粘合剂）为药学上可接受的、熔点较上述可溶于水的结晶态的颗粒状或粉未状的稀释剂低更佳地还较上述的活性成分低的、常温下为固体（熔点不低于 25°C ) 且可溶于水的可熔融的表面活性剂。上述熔融粘合剂的熔点较佳地比上述稀释剂更佳地还较活性成分的熔点至少低 10°C (含），更佳地至少低 20°C (含）。用于本发明的可熔融的粘合剂通常是熔点为 25至 10CTC (含端点），优选 35至 80°C (含端点），更优选 40至 80°C (含端点）。上述熔融粘合剂的熔点通常不低于 25°C，因为各组分的混合通常在此温度进行并且粘合剂在此混合温度应保持固体形态。上述熔融粘合剂的熔点温度一般不高于 100°C，因为粘合剂应当在药用活性组分的活性不受不利影响的温度下熔化。例如，粘合剂应当在低于药用活性组分以及任意含有的赋形剂分解的温度下熔化。 The meltable binder (hereinafter referred to as a molten binder) according to the present invention is preferably a pharmaceutically acceptable low-particle granule or powder-like diluent having a melting point higher than that of the above-mentioned water-soluble crystalline form. A meltable surfactant which is lower than the above-mentioned active ingredient and which is solid at a normal temperature (melting point of not lower than 25 ° C) and soluble in water. The melting point of the above molten binder is preferably at least 10 ° C (inclusive), more preferably at least 20 ° C (inclusive) lower than the melting point of the active ingredient. The meltable binder used in the present invention usually has a melting point of 25 to 10 CTC (inclusive), preferably 35 to 80 ° C (inclusive), more preferably 40 to 80 ° C (inclusive). The melting point of the above molten binder is usually not lower than 25 ° C because the mixing of the components is usually carried out at this temperature and the binder should maintain a solid form at this mixing temperature. The melting temperature of the above molten binder is generally not Above 100 ° C, because the binder should melt at a temperature at which the activity of the pharmaceutically active component is not adversely affected. For example, the binder should be melted at a temperature below the decomposition of the pharmaceutically active component and any excipients contained therein.

示例性的合适用于本发明的可熔融的粘合剂包括但不限于下列的药学上可接受的、常温下为固体（熔点不低于 25°C ) 且可溶于水的可熔融的表面活性剂的实例如，但不局限于此，聚氧乙烯垸基醚（Polyoxyethylene Alkyl Ethers ) 类表面活性剂、聚氧乙烯蓖麻油衍生物 Exemplary meltable binders suitable for use in the present invention include, but are not limited to, the following pharmaceutically acceptable meltable surfaces which are solid at room temperature (melting point not lower than 25 ° C) and soluble in water Examples of the active agent are, but not limited to, polyoxyethylene Alkyl Ethers surfactants, polyoxyethylene castor oil derivatives

( Polyoxyethylene Castor Oi l Derivatives ) 类表面活性剂、聚氧乙烯山梨糖醇酐脂肪酸酯（Polyoxyethylene Sorbitan Fatty Acid Esters ) 类表面活性剂、乙氧基化脂肪酸如聚氧乙烯硬脂酸酯（Polyoxyethylene Stearates ) 类表面活性剂、乙氧基化脂肪醇如聚氧乙烯月桂酸酯（Polyoxyethylene Stearates ) 类表面活性剂、聚氧乙烯一聚氧丙烯醇共聚物（泊洛沙姆），及它们的混合物。 (Polyoxyethylene Castor Oi l Derivatives ) Surfactant, Polyoxyethylene Sorbitan Fatty Acid Esters Surfactant, Ethoxylated Fatty Acids such as Polyoxyethylene Stearates Surfactants, ethoxylated fatty alcohols such as polyoxyethylene Stearates surfactants, polyoxyethylene-polyoxypropylene alcohol copolymers (poloxamers), and mixtures thereof.

可用于本明的聚氧乙烯垸基醚类表面活性剂的实例如商品名为下列的产品： Volpo S10 Examples of polyoxyethylene decyl ether surfactants which can be used in the present invention are as follows: Volpo S10

( mp, 35 - 38 °C )、 Volpo S20 ( mp , 42 - 48 °C )、 Volpo C20 ( mp, 40 - 45 °C )、 Volpo CS10(mp, 35 - 38 °C), Volpo S20 (mp, 42 - 48 °C), Volpo C20 (mp, 40 - 45 °C), Volpo CS10

(mp, 35 - 38°C )、 Volpo CS20 (mp, 44°C )、 Volpo L23 (mp, 37°C )、 Brij 35 (mp, 33°C )、 Bri j 56 (mp, 31。C )、 Brij 58 (mp, 38。C )、 Cremophor A6 (mp, 41_45。C )、 Cremophor A25(mp, 35 - 38°C), Volpo CS20 (mp, 44°C), Volpo L23 (mp, 37°C), Brij 35 (mp, 33°C), Bri j 56 (mp, 31.C) , Brij 58 (mp, 38.C), Cremophor A6 (mp, 41_45.C), Cremophor A25

(mp, 44 - 48°C )、 Ethylan 2560 (mp, 45°C )、 Rito 721 (mp, 35°C)、 Texofor A1P (mp, 40°C)、 Texofor A10 (mp, 30°C)、 Texofor A14 (mp, 35°C)、 Texofor A30 (mp, 43°C)、 Texofor A45 (mp, 47°C)、 Texofor A60 (mp, 48°C)，及它们的混合物，及它们的混合物（ r j'_: ICI Surfactants 公司供应； Volpo: Croda Chemicals公司供应； Cremophor-. BASF Corporation公司供应； Ritox: Rita Corporation公司供应)。 (mp, 44 - 48°C), Ethylan 2560 (mp, 45°C), Rito 721 (mp, 35°C), Texofor A1P (mp, 40°C), Texofor A10 (mp, 30°C), Texofor A14 (mp, 35 ° C), Texofor A30 (mp, 43 ° C), Texofor A45 (mp, 47 ° C), Texofor A60 (mp, 48 ° C), and mixtures thereof, and mixtures thereof ( Rj' _: supplied by ICI Surfactants; Volpo: supplied by Croda Chemicals; Cremophor-. supplied by BASF Corporation; Ritox: supplied by Rita Corporation).

可用于本明的聚氧乙烯蓖麻油衍生物类表面活性剂的实例如：聚乙二醇（60 ) 氢化蓖麻油（Polyoxyl 60 hydrogenated castor oi l) (mp, 40 °C)、聚乙二醇（40)氢化蓖麻油（Polyoxyl 40 hydrogenated castor oi l ) (mp, 30°C)，及它们的混合物。 Examples of polyoxyethylene castor oil derivative surfactants which can be used in the present invention are as follows: polyethylene glycol (60) hydrogenated castor oil (Polyoxyl 60 hydrogenated castor oi l) (mp, 40 ° C), polyethylene glycol (40) Hydroxyl 40 hydrogenated castor oi l (mp, 30 ° C), and mixtures thereof.

可用于本明的聚氧乙烯山梨糖醇酐脂肪酸酯类表面活性剂的实例如：聚山梨酯 61 (mp, 35 - 49°C ) 、聚山梨酯 65，及它们的混合物。 Examples of the polyoxyethylene sorbitan fatty acid ester surfactant which can be used in the present invention are: polysorbate 61 (mp, 35 - 49 ° C), polysorbate 65, and a mixture thereof.

可用于本明的乙氧基化脂肪酸或聚氧乙烯硬脂酸酯类表面活性剂的实例如：聚氧乙烯（12) 硬脂酸酯 (mp， 37°C)、聚氧乙烯 (20)硬脂酸酯 (mp， 28°C)、聚氧乙烯 (40)硬脂酸酯 (mp， 38°C)、聚氧乙烯（50)硬脂酸酯 (mp， 52°C)、聚氧乙烯（100)硬脂酸酯 (mp， 46°C)、聚氧乙烯（32)双硬脂酸酯 (mp， 45°C)、聚氧乙烯（150)双硬脂酸酯 (mp， 53 - 57°C)，及它们的混合物。 Examples of ethoxylated fatty acid or polyoxyethylene stearate surfactants which can be used in the present invention are: polyoxyethylene (12) stearate (mp, 37 ° C), polyoxyethylene (20) Stearate (mp, 28 ° C), polyoxyethylene (40) stearate (mp, 38 ° C), polyoxyethylene (50) stearate (mp, 52 ° C), polyoxygen Ethylene (100) stearate (mp, 46 ° C), polyoxyethylene (32) distearate (mp, 45 ° C), polyoxyethylene (150) distearate (mp, 53 - 57 ° C), and mixtures thereof.

可用于本明的乙氧基化脂肪醇或聚氧乙烯月桂酸酯类表面活性剂的实例如，聚氧乙烯 (23) 月桂酸酯（mp， 38〜40°C)。 Examples of the ethoxylated fatty alcohol or polyoxyethylene laurate surfactant which can be used in the present invention are, for example, polyoxyethylene (23) laurate (mp, 38 to 40 ° C).

可用于本明的聚氧乙烯一聚氧丙烯醇共聚物（泊洛沙姆）的实例如 poloxamer 188 (熔点 52〜57°C)、 poloxamer 237 (熔点 49°C)、 poloxamer 338 (熔点 57°C)、 poloxamer 407 (熔点 52〜57°C)。 Examples of polyoxyethylene-polyoxypropylene alcohol copolymers (poloxamers) which can be used in the present invention are poloxamer 188 (melting point 52 to 57 ° C), poloxamer 237 (melting point 49 ° C), poloxamer 338 (melting point 57 °) C), poloxamer 407 (melting point 52 to 57 ° C).

此外，常温下为固体（熔点不低于 25°C ) 且可溶于水的可熔融的糖酯类表面活性剂还可用于本明，如：蔗糖单硬脂酸酯（熔点 53〜57°C)、蔗糖单棕榈酸酯 (mp， 43〜48°C)。 In addition, a meltable sugar ester surfactant which is solid at room temperature (melting point not lower than 25 ° C) and soluble in water can also be used in the present invention, such as: sucrose monostearate (melting point 53 to 57 °) C), sucrose monopalmitate (mp, 43~48 ° C).

本发明涉及的可熔融的机械性能增强剂（以下简称机械性能增强剂)为药学上可接受的、熔点不低于 45°C且较上述稀释剂低更佳地还较上述的活性成分低且较上述可熔融的粘合剂高的、脂溶性的且不可溶于水的可熔融的物质。上述机械性能增强剂在水（温度 25°C ) 或温水 (温度 37°C ) 中的平衡溶解量通常不超过上述可溶于水的可熔融的粘合剂在同一温度下的水中的平衡溶解量十分之一，较佳地不高于其三十分之一，更佳地不超过其百分之一，最佳地不超过其千分之一，这是因为二者的水溶性相差俞大，二者的亲脂性基团的结合力俞强，俞有利于提高片剂的机械性能及耐候性。上述可熔融的机械性能增强剂较佳地为药学上可接受的、熔点不低于 50°C且较上述稀释剂低及上述的活性成分至少低 5°C (含）且较可熔融的粘合剂至少高 5°C (含）的、脂溶性的且不可溶于水的可熔融的物质。上述机械性能增强剂的熔点较佳地不低于 60°C，更佳地不低于 70°C，最更佳地不低于 80°C，但较佳地不高于 120°C，更佳地不高于 ioo°c _; 上述机械性能增强剂的熔点较佳地比上述稀释剂及上述活性成分的熔点至少低 10°C (含），更佳地至少低 20°C (含）；上述机械性能增强剂的熔点较佳地比上述熔融粘合剂的熔点至少高 10°C (含），更佳地至少高 20°C (含），最佳地至少高 30°C (含）。 The meltable mechanical property enhancer (hereinafter referred to as mechanical property enhancer) according to the present invention is pharmaceutically acceptable, has a melting point of not lower than 45 ° C and is lower than the above-mentioned diluent, and is also lower than the above-mentioned active ingredient. a fat-soluble, water-insoluble, meltable material that is higher than the above meltable binder. The equilibrium dissolution amount of the above mechanical property enhancer in water (temperature 25 ° C) or warm water (temperature 37 ° C) generally does not exceed the equilibrium dissolution of the above water-soluble meltable binder in water at the same temperature One tenth of a quantity, preferably not more than one third of its thickness, more preferably not more than one hundredth thereof, and optimally not more than one thousandth thereof, because the water solubility of the two is different. Yu Da, the combination of the lipophilic groups of the two, Yu Qiang, Yu is beneficial to improve the mechanical properties and weather resistance of the tablets. The above meltable mechanical property enhancer is preferably pharmaceutically acceptable, has a melting point of not less than 50 ° C and is at least 5 ° C lower than the above-mentioned diluent and is at least 5 ° C (inclusive) and more meltable. A mixture of at least 5 ° C (inclusive), fat-soluble and water-insoluble, meltable material. Mechanical strength enhancer as described above The melting point is preferably not lower than 60 ° C, more preferably not lower than 70 ° C, most preferably not lower than 80 ° C, but preferably not higher than 120 ° C, more preferably not higher than ioo °c _; the melting point of the above mechanical property enhancer is preferably at least 10 ° C (inclusive), more preferably at least 20 ° C lower (inclusive) than the melting point of the above diluent and the above active ingredient; The melting point is preferably at least 10 ° C (inclusive), more preferably at least 20 ° C (inclusive), and most preferably at least 30 ° C (inclusive) above the melting point of the molten binder.

可用于本发明的可熔融的机械性能增强剂包括但不限于药学上可接受的熔点不低于 45°C 的脂溶性的且不可溶于水的可熔融的动植物油脂类、半合成油脂、高级烃类、天然或人工蜡类、高级脂肪酸、高级脂肪酸酯、高级垸基醇及其混合物，其优选的示例性的化合物包括但不限于硬脂酸（熔点约 54°C )、乙二醇单硬脂酸酯（熔点 54〜57°C )、二乙二醇二硬脂酸酯（熔点 54〜55°C )、微晶蜡（熔点 54〜102°C )、甘油三硬脂酸酯（熔点 55°C )、硬脂醇（熔点 55〜 60°C )、单硬脂酸甘油酯（熔点 55〜60°C )、甘油单癸酸酯（熔点 56〜57°C )、氢化植物油（熔点 57〜85°C )、白蜂蜡（熔点 61〜65°C )、黄蜂蜡（熔点 61〜65°C )、甘油三棕榈酸酯（熔点 62〜68°C )、山嵛酸（熔点 80°C )、巴西棕榈蜡（熔点 80〜88°C )、虫白蜡（熔点 81〜85°C )、胆固醇硬脂酸酯 (熔点 82. 5°C )、氢化蓖麻油（熔点 85〜88°C )、胆固醇棕榈酸酯 (熔点 90. 5°C )，及它们的混合物。其中，硬脂酸、氢化蓖麻油为更优选，因为它们质地较为坚硬，有利于提高片剂机械性能，氢化蓖麻油为特别优选，因为它还具有较高的熔点，有利于改善或提高片剂的机械性能特别是耐候性。此外，优选的可熔融的机械性能增强剂还包括但不限于熔点不低于 45°C的脂溶性的且不可溶于水的乳酸脂肪酸丙二醇酯、乳酸脂肪酸甘油酯、脂肪酸乳酰酯，及它们的混合物，尤其优选的是上述硬质的物质，特别是硬度不低于氢化蓖麻油的硬度的 70%的上述物质。 Meltable mechanical property enhancers useful in the present invention include, but are not limited to, pharmaceutically acceptable fat-soluble and water-insoluble meltable animal and vegetable oils, semi-synthetic fats, having a melting point of not lower than 45 ° C, Higher hydrocarbons, natural or artificial waxes, higher fatty acids, higher fatty acid esters, higher mercapto alcohols, and mixtures thereof, preferred exemplary compounds of which include, but are not limited to, stearic acid (melting point about 54 ° C), ethylene Alcohol monostearate (melting point 54~57 ° C), diethylene glycol distearate (melting point 54~55 ° C), microcrystalline wax (melting point 54~102 ° C), glyceryl tristearic acid Ester (melting point 55 ° C), stearyl alcohol (melting point 55~60 ° C), glyceryl monostearate (melting point 55~60 ° C), glycerol monodecanoate (melting point 56~57 ° C), hydrogenation Vegetable oil (melting point 57~85 ° C), white beeswax (melting point 61~65 ° C), yellow beeswax (melting point 61~65 ° C), glyceryl tripalmitate (melting point 62~68 ° C), behenic acid ( Melting point 80 ° C), carnauba wax (melting point 80~88 ° C), insect white wax (melting point 81~85 ° C), cholesterol stearate (melting point 82. 5 ° C), hydrogenated castor oil (melting point 85-88 ° C), cholesterol palmitate (melting point 90. 5 ° C), and mixtures thereof. Among them, stearic acid and hydrogenated castor oil are more preferred because they are harder in texture and are advantageous for improving the mechanical properties of the tablet. Hydrogenated castor oil is particularly preferred because it also has a high melting point, which is advantageous for improving or improving the tablet. The mechanical properties are especially weather resistant. Further, preferred meltable mechanical property enhancers include, but are not limited to, fat-soluble and water-insoluble lactic acid fatty acid propylene glycol esters, lactic acid fatty acid glycerides, fatty acid lactyl esters having a melting point of not lower than 45 ° C, and Particularly preferred are the above-mentioned hard substances, particularly those having a hardness of not less than 70% of the hardness of hydrogenated castor oil.

"熔融粘合剂 "及"机械性能增强剂"较佳地选择比稀释剂及活性成分的熔点至少低 10°C，更佳地至少低 20°C的可熔融的物质的优势在于：当这些物质全部熔化时，仅小量或微量的上述稀释剂及活性成分熔化，大量的上述稀释剂及活性成分以原来的形态存在，这样有利于提高固体熔融物及片剂的强度，同时还不影响片剂的崩解性能。 The advantages of the "melt binder" and the "mechanical performance enhancer" which are preferably at least 10 ° C lower than the melting point of the diluent and active ingredient, more preferably at least 20 ° C lower, are: When the substance is completely melted, only a small amount or a small amount of the above diluent and active ingredient are melted, and a large amount of the above diluent and active ingredient exist in the original form, which is advantageous for improving the strength of the solid melt and the tablet without affecting The disintegration performance of the tablet.

"机械性能增强剂"为熔点不低于 45°C或 50°C或更高且较上述可熔融的粘合剂高的可熔融的物质，其优势在于：有利于片剂能耐受更高气温及提高固体熔融物及片剂的机械性能。 "机械性能增强剂"为脂溶性的且不可溶于水的物质，不仅有利于发挥其桥连可溶性的熔融粘合剂等作用而且有利于发挥且不降低可溶于水的可熔融的粘合剂（即可溶于水的表面活性剂）的粘连（可溶于水的结晶态的颗粒状或粉未状的稀释剂）作用。 "Mechanical performance enhancer" is a meltable substance having a melting point of not lower than 45 ° C or 50 ° C or higher and higher than the above meltable binder, and has the advantages of: facilitating the tablet to withstand higher Temperature and improve the mechanical properties of solid melts and tablets. "Mechanical performance enhancer" is a fat-soluble and water-insoluble substance, which not only contributes to the action of bridging a soluble molten binder but also contributes to the function and does not reduce the water-soluble meltable bond. The adhesion of the agent (ie, a water-soluble surfactant) to a water-soluble crystalline particulate or powdery diluent.

当上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的量固定不变且熔融粘合剂与机械性能增强剂总量固定不变，仅熔融粘合剂与机械性能增强剂间的比例变化时，以熔融粘合剂与机械性能增强剂的比例（即机械性能增强剂的重量 / (熔融粘合剂的重量 +机械性能增强剂的重量））为横坐标与以测得的机械性能参数值为纵坐标绘制而成的比例-机械性能参数（如硬度或姽碎度）相图通常为上凸或下凹幅度较大的曲线（参见实施例 1的附图 1-2)。其中，熔融粘合剂与机械性能增强剂相溶性俞好，上述相图上凸或下凹幅度俞大，图中出现的最值俞大（或小）（为本发明的最优选值）。 When the amount of the above-mentioned water-soluble crystalline particulate or powdery diluent is fixed and the total amount of the molten binder and the mechanical performance enhancer is fixed, only the molten binder and the mechanical property enhancer When the ratio between the melt is changed, the ratio of the molten binder to the mechanical performance enhancer (ie, the weight of the mechanical performance enhancer / (the weight of the molten binder + the weight of the mechanical performance enhancer)) is measured on the abscissa The mechanical performance parameter values are plotted on the ordinate - mechanical properties (such as hardness or mash). The phase diagram is usually a curve with a large convex or concave width (see Figure 1-2 of Example 1). ). Among them, the compatibility of the molten binder with the mechanical performance enhancer is good, and the above-mentioned phase diagram has a convex or concave amplitude, and the maximum value appearing in the figure is Yuda (or small) (which is the most preferable value of the present invention).

由于端值如 0-0. 20及 0. 8-1处的机械性能参数改善幅度不如中间值的机械性能参数好，故在本发明熔融粘合剂与机械性能增强剂间的量的比例关系取中间段的比例，而又由于比例过高的机械性能增强剂使制剂亲脂高，亲水性不好，熔融粘合剂与机械性能增强剂间的量的比例关系进一步取偏前段（亲水段）的比例，此外，比例过高的熔融粘合剂又使制剂耐候性不好，因此，上述熔融粘合剂与上述机械性能增强剂间的量的比例关系较佳地为：上述机械性能增强剂 / (上述熔融粘合剂 +上述机械性能增强剂)位于 0. 25至 0. 70 (重量比）之间（含端点），较佳地位于 0. 35至 0. 60 (重量比）（含端点）之间，更佳地位于 0. 40至 0. 55 (重量比）之间（含端点）。 Since the mechanical properties of the end values such as 0-0. 20 and 0.8-1 are not improved as well as the mechanical properties of the intermediate value, the proportional relationship between the amount of the molten binder and the mechanical performance enhancer of the present invention is Taking the proportion of the middle section, and because the mechanical property enhancer is too high, the formulation has high lipophilicity and poor hydrophilicity, and the proportional relationship between the amount of the molten binder and the mechanical performance enhancer is further taken before the pro In addition, the proportion of the molten binder which is too high in proportion makes the formulation less resistant to weathering. Therefore, the ratio of the amount of the above-mentioned molten binder to the above-mentioned mechanical property enhancer is preferably: The ratio of the weight ratio of the above-mentioned sizing agent (the above-mentioned sizing agent + the above-mentioned mechanical property-enhancing agent) is between 0.25 and 0.70 (weight ratio) (including the end point), preferably from 0.35 to 0.60 (weight ratio) Between (including the endpoints), more preferably between 0.40 and 0.55 (by weight) (inclusive).

作为本发明所用的活性成分，可以是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，就没有特别的限制。本发明可用的活性成分实例列举如下：一中枢神经***药物： The active ingredient to be used in the present invention may be any pharmaceutically or nutritionally therapeutic or preventive substance, and is not particularly limited. Examples of active ingredients useful in the present invention are listed below: A central nervous system drug:

一中枢兴奋药：艾地苯醌、苯甲曲秦、吡拉西坦、吡硫醇、长春西丁、二甲弗林、茴拉西坦、甲氯芬酯、咖啡因、 ***、戊四氮。 A central stimulant: idebenone, benzopyridin, piracetam, pyrithione, vinpocetine, dimethylformin, aniracetam, meclofenoxate, caffeine, modafinil , pentylenetetrazol.

一镇痛药：布桂嗪、丁丙诺啡、二氢埃托啡、夫洛非宁、荷包牡丹碱、可待因、罗通定、 ***、麦角胺、美普他酚、 ***、奈福泮、哌替啶、匹米诺定、羟考酮、氢***醇、曲马多、舒马普坦、四氢帕马丁、右丙氧芬、右美沙芬、左啡诺、左吗拉胺。 An analgesic: chlorpheniramine, buprenorphine, dihydroetorphine, florofinine, bicuculline, codeine, rotundine, morphine, ergotamine, meptazin, methadone, nai Fructus, pethidine, pirimidin, oxycodone, hydromorphol, tramadol, sumatriptan, tetrahydropalmatine, dextropropoxyphene, dextromethorphan, levonorol, left mala amine.

一解热镇痛药：阿司匹林、对乙酰氨基酚、非那西丁、羟布宗、噻拉米特、水杨酸镁、水杨酸咪唑、异丙安替比林。 An antipyretic analgesic: aspirin, acetaminophen, phenacetin, hydroxybzon, thiaramite, magnesium salicylate, imidazole salicylate, isopropyl antipyrine.

一抗炎镇痛药：阿明洛芬、阿西美辛、阿扎丙宗、安吡昔康、奥古蛋白、奥沙拉秦、贝诺酯、吡洛芬、布洛芬、布西拉明、醋氯芬酸、丁苯羟酸、二氟尼柳、芬布芬、氟比洛芬、氟芬那酸、胍西替柳、环氯茚酸、甲芬那酸、甲氯芬那酸、金硫葡糖、金诺芬、来氟米特、氯芬那酸、洛索洛芬、马兜铃酸、美洛昔康、美沙拉秦、萘丁美酮、萘普生、尼氟酸、依托度酸、扎托洛芬、愈创蓝油烃、依托芬那酯、伊索昔康、酮洛芬、替诺昔康。 An anti-inflammatory analgesic: aminclofen, acemetacin, azaprozin, ampoxicam, augusin, olsalazine, benolyl ester, pirfen, ibuprofen, buxila Ming, aceclofenac, butyl hydroxy acid, diflunisal, fenbufen, flurbiprofen, flufenamic acid, citrictin, cyclohexanoic acid, mefenamic acid, meclofena Acid, gold thioglucose, auranofin, leflunomide, chlorpheniric acid, loxoprofen, aristolochic acid, meloxicam, mesalazine, nabumetone, naproxen, ni Fluoric acid, etodolac, zaltoprofen, guaiac blue hydrocarbon, etofenamate, escitoxicam, ketoprofen, tenoxicam.

一抗痛风药：氨基葡萄糖、苯溴马隆、别嘌醇、秋水仙碱、丙磺舒、伊替马唑。 An anti-gout drug: glucosamine, benzbromarone, allopurinol, colchicine, probenecid, etimabazole.

一抗震颤麻痹药：苯海索、比哌立登、多瑞肽、恩他卡朋、金刚垸胺、卡比多巴、喹高利特、雷沙吉兰、美金刚、司来吉兰、托卡朋、溴隐亭、左旋多巴、莫非吉兰、莫西芬辛、帕立太特、多奈哌齐。 An anti-shock paralysis drug: trihexyphenidate, biperiden, dorepeptide, entacapone, adamantamine, carbidopa, quetiapine, rasagiline, memantine, selegiline, Tokapeng, bromocriptine, levodopa, mobilis, moxifensin, palitide, donepezil.

一抗精神病药：阿立必利、阿尼哌醇、阿扎哌隆、安哌齐特、氨磺必利、奥卡哌酮、奥沙氟嗪、奥昔哌汀、丙氯拉嗪、氟奋乃静、氟哌啶醇、氟哌利多、氟哌噻吨、氟司必林、利培酮、林卡唑、硫必利、硫利达嗪、氯氮平、氯哌帕生、氯哌噻吨、氯普噻吨、洛沙平、莫沙帕明、奈莫必利、哌泊噻嗪、匹莫齐特、普拉克索、瑞莫必利、舒必利、五氟利多、佐替平、溴哌利多、奥氮平。 Primary antipsychotic drugs: alipidide, anibirdolol, azaipone, ampicillate, amisulpride, oxaporone, oxaflurazine, oxybuterazine, prochlorperazine, Fluphenazine, haloperidol, droperidol, flupentixol, flupristen, risperidone, linacazole, thiopril, thioridazine, clozapine, clopipapine, Clopidogrel, clopidogrel, loxapine, mazapamine, nemiride, piperazine, pimozide, pramipexole, rimopride, sulpiride, penfluridol, zo Telpine, epoprazol, olanzapine.

一抗焦虑药：阿普***、艾司***、丁螺环酮、氟他***、劳拉西泮、氯美扎酮、美他沙酮、珠氯噻醇、依替***、氟***。 An anti-anxiety drug: alprazolam, estazolam, buspirone, flazodazole, lorazepam, clomiprazole, metaxalone, beta chlorophenidate, etidazolam, Fludisazine.

一抗抑郁症药：阿米替林、阿莫沙平、安非他酮、奥匹哌醇、地昔帕明、地美替林、氟伏沙明、氟西汀、卡匹帕明、氯米帕明、马普替林、米安色林、帕罗西汀、哌甲酯、普罗替林、曲米帕明、舍曲林、圣 ·约翰草提取物片、维洛沙秦、文拉法辛、 ***、西酞普兰、异卡波肼。 An antidepressant: amitriptyline, amoxapine, bupropion, opipramol, desipramine, dexmedeline, fluvoxamine, fluoxetine, carbipipamine, Clomipramine, maprotiline, mianserin, paroxetine, methylphenidate, protriptyline, trimipramine, sertraline, St. John's wort extract, veroshaqin, wenla Fasin, sibutramine, citalopram, isocarbomer.

一抗癫痫药：奥卡西平、贝克拉胺、苯妥英、丙戊酸及其钠、镁盐、甲乙双酮、卡马西平、卡西尼特、拉莫三嗪、利鲁唑、扑米酮、托吡酯、依沙双酮、依他西平、乙苯妥英、乙琥胺、唑尼沙胺、噻加宾、美芬妥英。 An antiepileptic drug: oxcarbazepine, bequesamine, phenytoin, valproic acid and its sodium, magnesium salt, methyl ethyl ketone, carbamazepine, casinitide, lamotrigine, riluzole, primidone , Topiramate, esadiazepine, ethecoxibine, etoposide, ethosuxamine, zonisamide, tiagabin, mefentoin.

一镇静药、催眠药、抗惊厥药及其他：奥沙***、巴比妥、 ***、格鲁米特、喹硫平、尼唑苯酮、天麻素、溴米索伐、依托咪酯、乙酰天麻素、扎来普隆、佐匹克隆、唑吡坦、倍他司汀、长春胺、氟桂利嗪、氟美烯酮、氟替尔、环扁桃酯、己酮可可碱、甲磺双氢麦角胺、利扎曲普坦、美西麦角、那拉曲坦、尼可占替诺、尼麦角林、血管舒缓素、烟酸、伊普吲哚、依来曲普坦、依前列醇、异丙佐罗、罂粟碱、佐米曲普坦、左乙拉西坦。 A sedative, hypnotic, anticonvulsant and others: oxazuron, barbital, phenobarbital, glutamine, quetiapine, niazophenone, gastrodin, bromoisoval, relying on Mimidate, acetyl gastrodin, zaleplon, zopiclone, zolpidem, betahistine, vincamine, flunarizine, flumethenone, fluentil, cyclomandelate, pentoxifylline , meglumine dihydroergotamine, rizatriptan, mesalamine, naratriptan, nicotinol, nigralin, kallikrein, niacin, iripusone, eletriptan , epoprostenol, isoprozol, papaverine, zolmitriptan, levetiracetam.

一植物神经***药物：阿罗洛尔、阿普洛尔、阿替洛尔、艾司洛尔、苯扎托品、比索洛尔、东莨菪碱、酒石酸美托洛尔、卡替洛尔、卡维地洛、拉贝洛尔、美托洛尔、莫普洛尔、莫西赛利、纳多洛尔、山莨菪碱、塞利洛尔、塞他洛尔、噻吗洛尔、坦洛新、索他洛尔、育亨宾、樟柳碱、卡维地洛、坦洛新、托吡卡胺、溴丙胺太林。 An autonomic nervous system drug: arololol, aplolol, atenolol, esmolol, benzaltropine, bisoprolol, scopolamine, metoprolol tartrate, carteolol, carvey Dilo, Labetalol, Metoprolol, Moplelol, Moxicelli, Nadolol, Anisodamine, Celilol, Cetalol, Thiololol, Tamsulosin , sotalol, yohimbine, anisodine, carvedilol, tamsulosin, tropicamide, bromopropylamine.

一循环***药物： A circulatory system drug:

一钙拮抗药：阿尼帕米、巴尼地平、贝尼地平、苄普地尔、地伐帕米、法利帕米、桂利嗪、拉西地平、马尼地平、噻帕米、维拉帕米、右维拉帕米。 One calcium antagonist: anipamil, benidipine, benidipine, bepridil, valparaprin, faripamil, cinnarizine, lacidipine, manidipine, thiophane, dimension Lapami, right Vera Paimi.

一治疗慢性心功能不全的药物：布拉地新、地高辛、地诺帕明、毒毛花苷^多巴酚丁胺、多卡巴胺、黄夹苷、米力农、依诺昔酮、左西孟旦、阿利非君。一抗心律失常药：阿普林定、胺碘酮、吡西卡尼、丙吡胺、氟卡尼、奎尼丁、莫地卡尼、莫雷西嗪、普鲁卡因胺、普罗帕酮、伊伐布雷定、伊曲卡尼、托西溴苄铵、美西律、司替卡尼。 A drug for the treatment of chronic cardiac insufficiency: budexin, digoxin, denomamine, venom glycosides, dobutamine, docarbaamine, paclitaxel, milrinone, enoxacin , Zuo Xi Meng Dan, Ali Fei Jun. An antiarrhythmic drug: aprilin, amiodarone, pyridoxine, propiamine, flecainide, quinidine, modicani, orexizine, procainamide, propa Ketone, ivabradine, itraconi, tocic bromide, mexiletine, stenicai.

一防治心绞痛药：奥昔非君、单硝酸异山梨酯、川芎嗪、地尔硫卓、丁四硝酯、海索苯定、环磷腺苷、利多氟嗪、麝香酮、双嘧达莫、戊四硝酯、 ***、伊莫拉明、依他苯酮、环磷腺苷。 A drug for preventing and treating angina pectoris: oxyxitox, isosorbide mononitrate, ligustrazine, diltiazem, tetrabutyl nitrite, hysopidine, cyclophosphamide, levopraz, musk ketone, dipyridamole, pentaerythritol Nitrate, nitroglycerin, imoramin, etanoterone, cyclic adenosine.

一周围血管扩张药：阿扑长春胺、长春胺、吡那地尔、长春考酯、长春培醇、达加帕米、丁咯地尔、法舒地尔、戈洛帕米、肼屈嗪、卡屈嗪、米诺地尔、尼可地尔、萘呋胺、曲匹地尔、双肼屈嗪、乌拉地尔、溴长春胺、烟酸肌醇、依那地平、异丙地、异丙沙明、罂粟林、甾伐地尔、左依莫帕米、佐勒汀。 Peripheral vasodilator: apovinamine, vincamine, pinacidil, vinpocet, vinorelbine, dagapamil, buflomedil, fasudil, golopamil, hydralazine , kalazine, minoxidil, nicorandil, naproxil, tripidil, diterpenoid, urapidil, bromo-vincoamine, nicotinic acid inositol, enalappine, isopropanol, Isosaramine, poppy peony, valvadil, left emolim, zoelepine.

一降血压药：阿夫唑嗪、阿拉普利、阿那立肽、氨氯地平、倍他尼定、贝那普利、八厘麻毒素、布那唑嗪、地巴唑、地拉普利、地来洛尔、丁吡考胺、多沙唑嗪、厄贝沙坦、非洛地平、福辛普利、粉防己碱、甲基多巴、黄豆苷元、酒石酸喷托铵、卡托普利、坎地沙坦、喹那普利、可乐定、赖诺普利、雷米普利拉、利美尼定、利舍平、螺普利、洛非西定、美卡拉明、尼伐地平、尼卡地平、尼莫地平、尼群地平、尼索地平、帕吉林、培哚普利、群多普利、特拉唑嗪、替莫普利、托洛尼定、西拉普利、硝苯地平、缬沙坦、伊拉地平、依利沙坦、依那吉仑、依那普利、依那普利拉、依普罗沙坦、吲哚拉明、左洛非西定、佐芬普利、佐芬普利拉、替米沙坦。 A blood pressure lowering drug: alfuzosin, alapril, analipide, amlodipine, betaxetidine, benazepril, octapeptide, bunazosin, diazepam, dilapid Lee, Delilorol, Butyzolamine, Doxazosin, Irbesartan, Felodipine, Fosinopril, Tetrandrine, Methyldopa, Daidzein, Tartrate Tartrate, Card Topily, candesartan, quinapril, clonidine, lisinopril, ramipril, limonidine, lishepine, spiropril, lofexidine, mecaramine, Nilvadipine, nicardipine, nimodipine, nitrendipine, nisoldipine, pagilin, perindopril, trandolapril, terazosin, temocapril, tolonedine, sira Puli, nifedipine, valsartan, isradipine, elishartan, enalapril, enalapril, enalapril, eprosartan, valeramine, zolofexine , Zofenopril, Zofenpril, Telmisartan.

一调节血脂药及抗动脉粥样硬化药：阿托伐他汀、阿昔莫司、苯丙醇胺、苯赖加压素、苯扎贝特、吡卡酯、苄氯贝特、达伐他汀、弹性酶、多巴胺、多培沙明、非诺贝特、氟伐他汀、环丙贝特、吉非贝齐、考来替泊、考来烯胺、克伐他汀、克利贝特、来西贝特、氯贝丁酯、氯贝酸铝、洛伐他汀、美伐他汀、尼卡那汀、尼可贝特、普伐他汀、普罗布考、西立伐他汀、辛伐他汀、亚油酸、益多酯、右甲状腺素钠、猪去氧胆酸。 A regulation of blood lipids and anti-atherosclerosis drugs: atorvastatin, acixil, phenylpropanolamine, benzepressin, bezafibrate, pyracarbyl ester, benzyl chloride, darvastatin , elastase, dopamine, docepramine, fenofibrate, fluvastatin, ciprofibrate, gemfibrozil, colestipol, cholestyramine, kevastatin, clebate, lysine Bate, clofibrate, clofibrate, lovastatin, mevastatin, nicaratin, niketabate, pravastatin, probucol, cerivastatin, simvastatin, linoleum Acid, polydextrose, dextrothyroxine, hyodeoxycholic acid.

一呼吸***药物：氨茶碱、氨溴索、奥西那林、奥昔拉定、苯丙哌林、比托特罗、苯佐那酯、吡布特罗、地布酸钠、地美索酯、地普托品、厄多司坦、非诺特罗、福尔可定、海索那林、克仑特罗、氯丁替诺、马布特罗、孟鲁司特、匹考哌林、特布他林、愈创甘油醚、愈创木酚磺酸钾、扎莫特罗、左丙氧芬、异米尼尔、乙酰半胱氨酸、酮替芬、特布他林、妥洛特罗、依普拉酮、萜品醇。 A respiratory system drug: aminophylline, ambroxol, oxycin, oxicillin, benproperine, bitoterol, benzonatate, pyrbuterol, sodium zoate, dimethoate Ester, putotropine, erdosteine, fenoterol, forcodine, hexolin, clenbuterol, chlorobutano, mabuterol, montelukast, picotazide Lin, terbutaline, guaifenesin, guaiacol sulfonate, zaloterol, levopropoxyphene, isomirier, acetylcysteine, ketotifen, terbutaline, Trolotrol, epradolone, terpineol.

一消化***药物： A digestive system drug:

一抗酸药及治疗消化性溃疡病药：奥美拉唑、巴柳氮、奥诺前列素、恩前列素、法莫替丁、甘羟铝、枸橼酸铋钾、兰索拉唑、雷贝拉唑、硫糖铝、铝镁加、铝酸铋、铝碳酸镁、罗沙前列醇、罗沙替丁、米索前列醇、尼扎替丁、哌仑西平、普劳诺托、泮托拉唑、曲昔派特、索法酮、替仑西平、维生素 u、伊索拉定、依卡倍特。 An antacid and a peptic ulcer drug: omeprazole, balsalazide, ornoprost, enprostin, famotidine, galac aluminum, bismuth potassium citrate, lansoprazole, Rabeprazole, sucralfate, aluminum-magnesium plus, barium aluminate, magnesium aluminum carbonate, rosaprost, roxatidine, misoprostol, nizatidine, pirenzepine, Pronoto, Pantoprazole, Traxapat, Sophorone, Tirenoxapine, Vitamin U, Isoladine, Ekabit.

一胃肠解痉药：阿地芬宁。 A gastrointestinal antispasmodic drug: adifenin.

一助消化药：奥西肽、促胰酶素淀粉酶、枸橼酸、卡尼汀、胃蛋白酶、西沙必利、胰蛋白酶、胰酶、胰脂肪酶。 A helper digestive drug: oxcarbin, trypsin amylase, citric acid, carnitine, pepsin, cisapride, trypsin, trypsin, pancreatic lipase.

一止吐药、催吐药及肠胃推动药：昂丹司琼、多潘立酮、格拉司琼、甲氧氯普胺、氯波必利、托垸司琼、伊托必利、岩白菜素、左舒必利、四羟黄酮、来立司琼、林托必利、莫吉司坦、莫沙必利。 An antiemetic, emetic, and gastrointestinal drug: ondansetron, domperidone, granisetron, metoclopramide, clopirol, tolztron, itopride, bergenin, sulpiride , quercetin, lystron, lintobili, mojistan, mosapride.

一肝胆疾病辅助用药：奥拉米特、鹅去氧胆酸、非布丙醇、茴三硫、肌醇、肌苷、联苯双酯、亮菌甲素、硫普罗宁、硫辛酸、马洛替酯、葡醛内酯、齐墩果酸、羟甲香豆素、羟甲烟胺、去氢胆酸、去氢胆酸钠、去氧胆酸、乳果糖、水飞蓟宾、水飞蓟素、西阿尼醇、腺苷蛋氨酸、熊去氧胆酸、原卟啉钠。 A hepatobiliary disease adjuvant medication: olamimet, chenodeoxycholic acid, non-bupropanol, anthranil trioxide, inositol, inosine, biphenyl diester, leucovorin, tiopronin, lipoic acid, horse Loctinate, glucurolactone, oleanolic acid, hydroxymethyl coumarin, hydroxymethanolamine, dehydrocholic acid, sodium dehydrocholate, deoxycholic acid, lactulose, silybin, silymarin , ceaniol, adenosylmethionine, ursodeoxycholic acid, sodium protoporphyrin.

一泌尿***药物：阿米洛利、阿佐塞米、氨苯蝶啶、贝美噻嗪、泊利噻嗪、布美他尼、吡咯他尼、呋塞米、环戊噻嗪、氯索隆、螺利酮、美替拉酮、螺内酯、美夫西特、赖氨加压素、吲达帕胺、依匹噻嗪、依索唑胺、依他尼酸、依他尼酸钠、依托唑啉、乙噻嗪、乙酰唑胺、异丙碘铵、异波帕胺、去氨加压素、双氯非那胺、替普瑞酮、美替拉酮。 A urinary system drug: amiloride, azosemide, triamterene, bethiazine, poritizine, bumetanide, pyrrhotanib, furosemide, cyclopentazine, cloxasolone , spirronone, melilone, spironolactone, mefsett, lysine , indapamide, epilizide, eszolate, ethenic acid, sodium citrate, etazozoline, thiazide, acetazolamide, isopropyl iodide, isopamine, Desmopressin, diclofenac, teprenone, metyrapone.

一影响血液及造血***的药物：沙格雷酯、乙双香豆素、乙双豆乙酯、华法林、苯茚二酮、醋硝香豆素、硫酸亚铁、葡萄糖酸亚铁、亚叶酸钙、叶酸、右旋糖酐铁、甲钴胺、富马酸亚铁、葡庚糖酐铁、阿魏酸钠、核苷酸、茴香脑、茜草双酯、鲨肝醇、小檗胺、阿卡地新、阿那格雷、阿前列素、奥扎格雷、贝前列素、吡吗格雷、达美格雷、达唑氧苯、呋格雷酸、利马前列素、氯吡格雷、罗拉格雷、咪唑格雷、莫地帕泛、那法格雷、帕米格雷、前列地尔、曲克芦丁、噻氯匹定、三苯格雷、沙替格雷、舒那格雷、西洛他唑、西前列烯、烟格雷酯、氧格雷酯、伊他格雷、羟苯磺酯钙。 A drug that affects the blood and hematopoietic system: sarpogrelate, bis-coumarin, ethyl acetophenone, warfarin, benzoquinone, acenocoumarol, ferrous sulfate, ferrous gluconate, ar Calcium folate, folic acid, iron dextran, mecobalamin, ferrous fumarate, iron glucoheptone, sodium ferulate, nucleotides, anethole, valerate, squalyl alcohol, chloramine, aca Dixin, anagrelide, aprostin, ozagrel, beraprost, picogreline, dalgregre, dazooxaphene, furoic acid, limatoprost, clopidogrel, rolagrel, imidazole , motodipine, narfagre, pamidrex, alprostadil, trox rutin, ticlopidine, tribexyrene, sartrimrel, sultagreride, cilostazol, cisprost, tobacco Greg ester, oxydresyl ester, iptagrel, calcium hydroxybenzene sulfonate.

一抗***反应药物： Primary anti-allergic drugs:

一抗组胺药：阿伐斯汀、阿利马嗪、阿司咪唑、奥沙米特、奥索马嗪、苯海拉明、苯茚胺、丙酰马嗪、布克力嗪、茶苯海明、茶氯酸异丙嗪、氮卓斯汀、丁夫罗林、多拉斯汀、多西拉敏、恩布拉敏、非尼拉敏、非索非那定、二甲茚定、氯雷他定、氯马斯汀、氯哌斯汀、马来酸氯苯那敏、美海屈林、美克洛嗪、美喹他嗪、尼普拉嗪、赛庚啶、司他斯汀、依巴斯汀、依美斯汀、依匹斯汀、右溴苯那敏、扎鲁司特、左卡巴斯汀。 Primary antihistamines: avastin, alimazine, astemizole, oxapramine, oxomamycin, diphenhydramine, benzoguanamine, propionylazine, bupizine, tea benzene Hamming, promethazine tea, azelastine, diflupromide, dolastatin, doxylamine, embramin, febrinamide, fexofenadine, dimethylformidine , loratadine, clemastine, cloperastine, chlorpheniramine maleate, mepyrazine, meclozine, mequitazine, niprazine, cyproheptadine, stastatin, Ebastine, estramustine, epilin, bromophenamine, zafirlukast, levocabastine.

一过敏反应介质阻释剂及其他：阿扎他定、氨来咕诺、洛度沙胺、曲尼司特、色甘酸钠、西替利嗪、扎普司特、普克罗米、普昔罗米、他扎司特。 An allergic reaction medium release agent and others: azastatin, amlexanox, lodosamide, tranilast, cromolyn, cetirizine, zapastast, plucomi, pu Hydrazine, his zastel.

一肾上腺皮质激素及促肾上腺皮质激素：地夫可特、 ***、甲泼尼龙、甲***、可的松、曲安西龙。 An adrenocortical hormone and adrenocorticotropic hormone: difluxate, dexamethasone, methylprednisolone, prednisone, cortisone, triamcinolone.

一性激素及促性激素：比卡鲁胺、雌酮、雌三醇、醋酸甲羟孕酮、达那唑、夫拉扎勃、氟他胺、己二烯雌酚、己垸雌酚、己烯雌酚、甲地孕酮、甲羟孕酮、雷洛昔芬、尼鲁米特、孕三烯酮、托瑞米芬、司坦唑醇、炔诺孕酮。 A sex hormone and gonadotropin: bicalutamide, estrone, estriol, medroxyprogesterone acetate, danazol, prazzab, flutamide, diethylstilbestrol, hexaerythritol, diethylstilbestrol, Megestrol, medroxyprogesterone, raloxifene, nilutamide, gestrinone, toremifene, stanozolol, norgestrel.

一胰岛激素及其它影响血糖的药物：阿卡波糖、吡格列酮、二甲双胍、伏格列波糖、格列本脲、格列吡脲、格列吡嗪、格列丙唑、格列波脲、格列喹酮、格列美脲、格列齐特、甲苯磺丁脲、米格列醇、曲格列酮、瑞格列奈、妥拉磺脲。 An islet hormone and other drugs that affect blood sugar: acarbose, pioglitazone, metformin, voglibose, glibenclamide, glibenclamide, glipizide, glibenclamide, glibenclamide, Glequinolidone, glimepiride, gliclazide, tolbutamide, miglitol, troglitazone, repaglinide, tolazamide.

一甲状腺激素类药物及抗甲状腺药物：奥替瑞林、泊替瑞林、氮替瑞林、碘塞罗宁、二溴酪氨酸、甲状丙酸、甲状米登、甲状球蛋白、孟替瑞林、咪匹马唑、双碘酪氨酸、替拉曲考、左甲状腺素、左甲状腺素钠、氨噻唑、丙硫氧嘧啶、碘硫氧嘧啶、甲硫氧嘧啶、甲巯咪唑、卡比马唑、硫苯唑林。 A thyroid hormone drug and an antithyroid drug: oltipreline, botinidrine, nitrexine, liothyronine, dibromotyrosine, thyropropionate, thyroidine, thyroglobulin, montetine Relin, miprazole, diiodotyrosine, telazocine, levothyroxine, levothyroxine sodium, aminothiazole, propylthiouracil, iodothiouracil, methylthiouracil, methimazole, Carbazole, thiazoline.

一抗微生物药物 /抗生素： An antimicrobial drug / antibiotic:

一青霉素类：阿莫西林、氨苄西林、巴氨西林、苯唑西林、氟氯西林、海他西林、环己西林、磺苄西林、卡茚西林、氯唑西林、仑氨西林、萘夫西林、匹氨西林、匹美西林、青霉、舒他西林、双氯西林、酞氨西林。 A penicillin: amoxicillin, ampicillin, bamcillin, oxacillin, flucloxacillin, hetacillin, cyclohexillin, sulfacillin, carbocillin, cloxacillin, lenazocillin, nafcillin , pirazicillin, pimecillin, penicillium, sultamicillin, diclocillin, and acesulfame.

一头孢菌素类：氯碳头孢、头孢氨苄、头孢丙烯、头孢泊肟、头孢布烯、头孢克洛、头孢克肟、头孢拉定、头孢拉宗、头孢来星、头孢羟氨苄、头孢沙定、头孢特仑、头孢地尼。 A cephalosporin: chlorocarbon cephalosporin, cephalexin, cefprozil, cefpodoxime, ceftibuten, cefaclor, cefixime, cefradine, cefradine, ceftriaxone, cefadroxil, cefafloxacin, Ceftriaxone, cefdinir.

一 β _内酰胺酶抑制剂：克拉维酸、舒巴坦、溴巴坦。 A beta-lactamase inhibitor: clavulanic acid, sulbactam, brombata.

一氨基糖苷类：巴龙霉素、卡那霉素、庆大霉素、新霉素。 An aminoglycoside: paromomycin, kanamycin, gentamicin, neomycin.

一四环素类及其他：地美环素、多西环素、胍甲环素、美他环素、米诺环素、土霉素、四环素、氯霉素。 One tetracyclines and others: dimecycline, doxycycline, indomethacin, metacycline, minocycline, oxytetracycline, tetracycline, chloramphenicol.

一大环内酯类：阿奇霉素、醋竹桃霉素、地红霉素、红霉素、琥乙红霉素、吉他霉素、交沙霉素、克拉霉素、罗红霉素、罗他霉素、螺旋霉素、麦白霉素、麦迪霉素、司丙红霉素、依托红霉素、乙酰螺旋霉素。 Large ring lactones: azithromycin, oleandomycin, dirithromycin, erythromycin, erythromycin ethylsuccinate, guitarmycin, josamycin, clarithromycin, roxithromycin, rosta Neomycin, spiramycin, melamycin, medimycin, erythromycin, erythromycin, acetylspiramycin.

一其他抗细菌感染药：左氧氟沙星、氧氟沙星、环丙沙星、诺氟沙星、多粘菌素£、克林霉素、林可霉素、磷霉素、米卡霉素、制霉素、黄藤素、小檗碱、雪胆素、鱼腥草素钠。 A other antibacterial agent: levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, polymyxin, clindamycin, lincomycin, fosfomycin, micammycin, Stomycin, yellow vine, berberine, gentian, houttuyfonate sodium.

一抗结核病药：吡嗪酰胺、对氨水杨酸、对氨水杨酸钠、丙硫异烟胺、环丝氨酸、利福布汀、利福喷汀、利福平、乙胺丁醇、异烟肼。 Primary anti-tuberculosis drugs: pyrazinamide, sodium salicylic acid, sodium salicylate, propionamide, cycloserine, rifamp Butin, rifapentine, rifampicin, ethambutol, isoniazid.

一抗真菌药：氟胞嘧啶、氟康唑、灰黄霉素、咪康唑、伊曲康唑、酮康唑、制霉菌素。一抗病毒药：阿昔洛韦、泛昔洛韦、伐昔洛韦、拉米夫定、利巴韦林、吗啉胍、齐多夫定、去氧氟尿苷、去羟肌苷、扎西他滨。 An antifungal drug: flucytosine, fluconazole, griseofulvin, miconazole, itraconazole, ketoconazole, nystatin. An antiviral drug: acyclovir, famciclovir, valaciclovir, lamivudine, ribavirin, morpholinium, zidovudine, deoxyfluorouridine, didanosine, zhaxi coast.

一抗肿瘤药物：白消安、环磷酰胺、洛莫司汀、司莫司汀、硫鸟嘌呤、巯嘌呤、伊达比星、氨鲁米特、他莫昔芬、阿那曲唑、丙卡巴肼、斑蝥素、卡培他滨、来曲唑、美法仑。 An anti-tumor drug: busulfan, cyclophosphamide, lomustine, semustine, thioguanine, guanidine, idarubicin, aminoglutethimide, tamoxifen, anastrozole, c Carbachol, cantharidin, capecitabine, letrozole, melphalan.

一影响机体免疫功能的药物：阿克他利、丙帕锗、硫唑嘌呤、咪唑立宾、他克莫司。一蛋白质： DNA酶、藻酸酶、超氧化物歧化酶及脂肪酶、多肽、寡肽。 A drug that affects the body's immune function: akitali, propacetam, azathioprine, imidazolyn, tacrolimus. A protein: DNase, alginate, superoxide dismutase and lipase, peptide, oligopeptide.

一核苷酸。 One nucleotide.

一维生素及营养类药：维生素 A、 B、 C, D、 E、 K等及其衍生物、氨基酸； A vitamin and nutraceutical: vitamins A, B, C, D, E, K, etc. and their derivatives, amino acids;

一减肥药：阿米雷司、安非拉酮、安非雷司、安非氯醛、奥替他明、苯氟雷司、苯托雷司、苄非他明、丙己君、对氯苯丁胺、非尼雷司、芬布酯芬、氟拉明、芬美曲秦、芬普雷司、芬特明、呋芬雷司。 A diet pill: Amiris, amfepramone, amphetamine, amphetamine, oltipamine, fenfluramine, phenyltol, benzethetamine, propylhexidine, p-chloro Phentermine, non-Nyles, fenbufen, fluramine, fenmetrazine, fenpres, phentermine, furfurex.

一其他药物：非那雄胺、阿仑膦酸钠、阿洛司琼、奥利司他、依立雄胺、依帕司他、托特罗定、托瑞司他，中草药提取物。 One other drug: finasteride, alendronate, alosetron, orlistat, eric acid, epalrestat, tolterodine, torista, herbal extracts.

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、各种晶型及光学异构体。 The actives useful in the present invention include the pharmaceutically acceptable salt forms, free acid forms, free base forms, hydrates, various crystal forms, and optical isomers of the following active ingredients.

本发明更适合可压性较差的活性成分，如粘性较差的药物（实例如矽炭银、硫酸亚铁、硫轻奎宁及溴本辛），粘性很大的药物（如蛋白质类：酵母片和多酶片、中草药浸膏），弹性较大的药物如中草药粉未。 The invention is more suitable for active components with poor compressibility, such as poorly viscous drugs (examples such as bismuth carbon silver, ferrous sulfate, sulfur quinine and bromobenzine), and highly viscous drugs (such as protein: Yeast tablets and multi-enzyme tablets, Chinese herbal extracts), more flexible drugs such as Chinese herbal medicine powder.

对相关活性成分的配合量，一般只要是在治疗上安全有效的量则没有特别限定，但相对于片剂重量，较好是在治疗上安全有效剂量以上， 80%w/w以下的片剂重量，更好的是在治疗上安全有效剂量以上、 50%w/w以下的片剂重量。由于本发明可在保持原有的多孔性结构的同时、获得足够的片剂强度，因此可提高相对于片剂重量的药物掺入量。当药物的颗粒直径大的情况下，由于口腔内崩解时有不光滑感的缘故，因而较理想的是平均颗粒直径在 250 μ πι以下。必要时，可对药物预先用适当的粉碎机设备粉碎至平均颗粒直径约 1至约 200 μ πι大小，较好地粉碎至平均颗粒直径约 5至约 100 μ m大小，更好地至约 5至约 30 μ m大小。 The amount of the active ingredient to be added is generally not particularly limited as long as it is therapeutically safe and effective, but it is preferably a safe and effective dose or more, and a tablet of 80% w/w or less or less based on the weight of the tablet. The weight is more preferably the weight of the tablet above 50% w/w above the safe and effective dose. Since the present invention can attain sufficient tablet strength while maintaining the original porous structure, the amount of drug incorporation relative to the weight of the tablet can be increased. When the particle diameter of the drug is large, it is preferable that the average particle diameter is 250 μm or less due to the unsmooth feeling in disintegration in the oral cavity. If necessary, the drug may be pulverized in advance with an appropriate pulverizer apparatus to an average particle diameter of from about 1 to about 200 μm, preferably pulverized to an average particle diameter of from about 5 to about 100 μm, more preferably to about 5 Up to a size of about 30 μm.

对于稳定性不好的活性成分，可用高分子成膜材料、腊等进行包衣。对易挥发的及化学不稳定性等的活性成分可用环糊精及其衍生物进行包合。这样的包衣材料可列举作为高分子物质的水不溶性高分子、胃溶性高分子、肠溶性高分子或者蜡状物质等。 For the active ingredient having poor stability, it may be coated with a polymer film-forming material, wax or the like. The active ingredient for volatile and chemical instability can be encapsulated with cyclodextrin and its derivatives. Examples of such a coating material include a water-insoluble polymer, a gastric-soluble polymer, an enteric polymer, or a waxy substance as a polymer material.

本发明涉及的 "药学上可接受的添加剂"是指固态制剂包含的一种或多种能彼此混合且无相互作用而不会发生降低固态制剂稳定性和 /或效力的固态或液态的且适用于局部或全身给药的药用辅助材料（含其胶囊化物）。本发明涉及的添加剂的选择及其用量的选择根据具体的剂型、固态制剂实际情况、制备方法和主观需求等来确定，不完全局限于本文的限制。作为在本发明所用的其它添加剂，只要是医药上所允许的，可作为添加物使用的各种赋形剂，则没有特别的限制。例如有崩解剂、粘合剂、润滑剂、增塑剂、甜味剂、芳香剂、着色剂、酸味调料、发泡剂、稳定剂等。这样的添加剂可使用 1种或多种组合使用。在酸味料中，例如有柠檬酸、洒石酸、苹果酸等。在发泡剂中，例如有小苏打等。稳定剂可在药物上进行各种研究来选择。这些添加剂能够适当地适量添加，使某 1种和 2种以上组合使用。 The term "pharmaceutically acceptable additive" as used in the present invention means that the solid preparation contains one or more solid or liquid substances which can be mixed with each other without interaction without reducing the stability and/or effectiveness of the solid preparation. A pharmaceutical auxiliary material (including its encapsulated compound) for topical or systemic administration. The selection of the additive and the amount thereof to be used in the present invention are determined according to the specific dosage form, the actual state of the solid preparation, the preparation method, and the subjective requirements, etc., and are not completely limited to the limitations herein. As the other additives used in the present invention, various excipients which can be used as an additive are not particularly limited as long as they are pharmaceutically acceptable. For example, there are disintegrators, binders, lubricants, plasticizers, sweeteners, fragrances, colorants, sour sauces, foaming agents, stabilizers, and the like. Such additives may be used in combination of one or more kinds. Among the sour materials, there are, for example, citric acid, tartaric acid, malic acid and the like. Among the foaming agents, for example, baking soda or the like. Stabilizers can be selected for various studies on drugs. These additives can be appropriately added in an appropriate amount, and one type or two or more types can be used in combination.

上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量与（熔融粘合剂与机械性能增强剂的重量和）间的比例也较大程度地影响片剂的机械性能。 The ratio of the weight of the above water-soluble crystalline particulate or powdery diluent to the weight of the molten binder and the mechanical strength enhancer also affects the mechanical properties of the tablet to a large extent.

当上述可溶于水的结晶态的颗粒状或粉未状的稀释剂、熔融粘合剂及机械性能增强剂的总量固定不变且上述可溶于水的结晶态的颗粒状或粉未状的稀释剂间的比例及熔融粘合剂与机械性能增强剂间的比例固定不变，仅上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量与上述熔融粘合剂与上述机械性能增强剂的总量间的比例变化时，以此比例即上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量 / (上述熔融粘合剂的重量 +上述机械性能增强剂的重量 +上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量）为横坐标与以测得的机械性能参数值为纵坐标绘制而成的比例-机械性能参数（如硬度或姽碎度）相图通常为上凸或下凹幅度较大的曲线（参见实施例 2的附图 3-4)。其中，上述熔融粘合剂与上述可溶于水的成分亲合性俞好，上述相图上凸或下凹幅度俞大，图中出现的最值俞大（或小）（为本发明的最优选值）；图中出现的最值通常向熔点较高的可溶于水的成分方向偏移。 When the above-mentioned water-soluble crystalline particulate or powdery diluent, molten binder and mechanical property enhancer are fixed in total, and the above-mentioned water-soluble crystalline particulate or powder is not present. The ratio between the diluents and the ratio between the molten binder and the mechanical property enhancer are fixed, and only the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent is melt-bonded with the above. When the ratio between the agent and the total amount of the mechanical performance enhancer is changed, the ratio is the above soluble The weight of the particulate or powdery diluent in the crystalline state of water / (the weight of the above molten binder + the weight of the above mechanical property enhancer + the above-mentioned water-soluble crystalline form of granular or powdery The weight of the diluent is plotted on the abscissa and the ratio of the measured mechanical properties to the ordinate - the mechanical properties (such as hardness or mash) phase diagram is usually convex or concave. Curve (see Figures 3-4 of Example 2). Wherein, the above-mentioned molten binder has good affinity with the above-mentioned water-soluble component, and the above-mentioned phase diagram has a convex or concave amplitude, and the maximum value of Yu Da (or small) appears in the figure (which is the present invention) Most preferred values); The most significant values appearing in the graph are generally offset toward the water soluble component having a higher melting point.

由于端值如 0-0. 25及 0. 93-1处的机械性能参数改善幅度不如中间值的机械性能参数好，故在本发明上述的比例关系取中间段的比例，而又由于相对较高比例量的上述可溶于水的结晶态的颗粒状或粉未状的稀释剂有利于提高片剂的亲水性及机械性能，故在本发明上述的比例关系进一步取中间偏后段（亲水段）的比例，即上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量 / (上述熔融粘合剂的重量 +上述机械性能增强剂的重量 +上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量）位于 0. 40至 0. 93之间（含端点），较佳地位于 0. 50 至 0. 87之间（含端点），更佳地位于 0. 55至 0. 80之间（含端点）。 Since the mechanical properties of the end values such as 0-0. 25 and 0.93-1 are not improved as well as the mechanical properties of the intermediate value, the ratio of the above-mentioned proportional relationship in the present invention is taken as the ratio of the middle segment, and relatively A high proportion of the above-mentioned water-soluble crystalline particulate or powdery diluent is advantageous for improving the hydrophilicity and mechanical properties of the tablet, so that the above-mentioned proportional relationship in the present invention is further taken in the middle of the back ( The ratio of the hydrophilic segment), that is, the weight of the above-mentioned water-soluble crystalline particulate or powdery diluent / (the weight of the above molten binder + the weight of the above mechanical property enhancer + the above soluble Between 0. 50 and 0. 87 (inclusive), preferably between 0. 40 and 0.87 (inclusive), More preferably between 0.55 and 0.80 (inclusive).

上述片剂中的上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量在整个片剂总重量中的比例也较大程度地影响片剂的机械性能及其亲水性；同样，上述的熔融粘合剂与机械性能增强剂的总量在整个片剂中的比例也较大程度地影响片剂的机械性能。为了不让片剂处方中的其他成分（非水溶性结晶态物质或非熔融固化剂）对上述可溶于水的结晶态的颗粒状或粉未状的稀释剂及上述熔融粘合剂与上述机械性能增强剂等熔融固化剂作过度稀释，降低其作用，参照上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量 / (上述熔融粘合剂的重量 +上述机械性能增强剂的重量 +上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量）为横坐标与以测得的机械性能参数值为纵坐标绘制而成的比例-机械性能参数（如硬度或姽碎度）相图（参见实施例 2的附图 3-4)，上述片剂中的上述可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量占整个片剂总重量的比例不低于 25% ( wt/wt ) , 更佳地不低于 34% The proportion of the above water-soluble crystalline particulate or powdery diluent in the above tablet in the total weight of the tablet also affects the mechanical properties and hydrophilicity of the tablet to a large extent. Similarly, the above ratio of the total amount of the molten binder to the mechanical performance enhancer in the entire tablet also affects the mechanical properties of the tablet to a large extent. In order to prevent other components in the tablet formulation (water-insoluble crystalline material or non-melting curing agent) from being in the above-mentioned water-soluble crystalline particulate or powdery diluent and the above-mentioned molten binder and the above Toluene curing agent such as mechanical performance enhancer is excessively diluted to reduce its effect. Refer to the weight of the above-mentioned water-soluble crystalline granular or powdery diluent / (weight of the above molten binder + mechanical properties mentioned above) The weight of the reinforcing agent + the weight of the above-mentioned water-soluble crystalline granular or powdery diluent is the ratio of the abscissa and the measured mechanical property parameter value to the ordinate - mechanical property parameter (such as hardness or mash) phase diagram (see Figures 3-4 of Example 2), the above water-soluble crystalline particulate or powder-form diluent in the above tablet accounts for the entire weight The ratio of the total weight of the tablet is not less than 25% (wt/wt), more preferably not less than 34%

(wt/wt ) 且不高于 80% (wt/wt ), 最佳地不低于 40% (wt/wt ) 且不高于 70% (wt/wt ); 且上述的熔融粘合剂与机械性能增强剂占整个片剂的比例不低于 5% (wt/wt ), 更佳地不低于 8%(wt/wt) and not higher than 80% (wt/wt), optimally not lower than 40% (wt/wt) and not higher than 70% (wt/wt); and the above-mentioned molten binder and The mechanical performance enhancer accounts for not less than 5% (wt/wt), more preferably not less than 8%, of the entire tablet.

(wt/wt ), 以上重量百分比是基于片剂的总重量。 (wt/wt), the above weight percentages are based on the total weight of the tablet.

特别说明的是，当上述活性成分和 /或上述药学上可接受的添加剂为可溶于水的结晶态的颗粒状或粉未状的物质时，其重量合计于可溶于水的结晶态的颗粒状或粉未状的稀释剂的重量，并以此合计重量计算上述相关比例。此外，当上述活性成分和 /或上述药学上可接受的添加剂为可溶于水的结晶态的颗粒状或粉未状的物质时，上述可溶于水的结晶态的颗粒状或粉未状的稀释剂用量可以为 0。另一方面，本发明还涉及制备上述机械性能被进一步强化的孔隙率较高的耐候性较好的亲水性的片剂的方法。下面对相关制备工序作详细地说明。 In particular, when the above active ingredient and/or the above pharmaceutically acceptable additive is a water-soluble crystalline particulate or powdery substance, the weight thereof is in a water-soluble crystalline state. The weight of the granulated or powdered diluent is used to calculate the above relevant ratio based on the total weight. Further, when the above-mentioned active ingredient and/or the above pharmaceutically acceptable additive is a particulate or powdery substance in a water-soluble crystalline state, the above-mentioned water-soluble crystalline granular or powdery form The amount of diluent can be zero. On the other hand, the present invention also relates to a method for producing a hydrophilic tablet having a high porosity and a high porosity which is further enhanced by the above mechanical properties. The relevant preparation steps will be described in detail below.

( 1 )、成形工序 (1), forming process

本工序是使本发明涉及的上述制剂原辅料：稀释剂、活性成分、熔融粘合剂、机械性能增强剂及添加剂在制药上呈基本均一分散的状态并使其具有药学上可接受的空间形态即片剂形式，除此外没有特别的限制。对本发明涉及的制剂原辅料通过下列的调制方法，如，采用物理混合、湿法制粒、干法制粒、喷雾干燥法、流化床造粒、搅拌造粒法、转动造粒法、熔化冷却粉碎、浇铸、辗压造粒法等各种方法造粒；或者将不含活性成分的小球或含活性成分的颗粒与粉末或颗粒相结合；或者对的含有约 100%的生物活性物质粉末和晶体或上述成形物通过铺展、喷雾等方法包衣造粒；或者完成上述工艺后再进一步经压制工艺成形为片状；或者已混匀的制剂原辅料直接压片、干粉压片；或者已混匀的制剂原辅料熔化、浇铸制成片剂，或者烧结制拉、挤压及随后圆形化、或者直接制成丸或片剂 (如，通过平板），或者完成上述工艺后再进一步制成片剂。其中，从生产性方面来看，使熔融粘合剂、机械性能增强剂均匀分散在成形物表面上，流化床造粒法是满意的。如一实施例，在流化床造粒法中，将稀释剂、活性成分、熔融粘合剂、机械性能增强剂与溶解及 /或混悬于制药上所允许的溶剂中，作为粘合剂喷雾、包衣及 /或造粒，完成上述工艺后再进一步制成片剂。用于包衣的成形物的颗拉、小丸或者晶体的尺寸在 0. 01至 2. 5 之间。包衣厚度在 1至 100 μ m之间，优选 10至 50 μ m 在常见片剂中，该厚度与使用 0. 5至 5%重量的聚合物相对应，在具体应用中可适当增减。 The present process is to make the above-mentioned preparation raw materials of the present invention: a diluent, an active ingredient, a molten binder, a mechanical property enhancer and an additive are substantially uniformly dispersed in a pharmaceutical state and have a pharmaceutically acceptable space form. That is, the tablet form is not particularly limited unless otherwise. The preparation raw materials of the present invention are prepared by the following preparation methods, for example, physical mixing, wet granulation, dry granulation, spray drying, fluidized bed granulation, stirring granulation, rotary granulation, and melt cooling pulverization. , granulation by various methods such as casting, rolling granulation, or combining the active ingredient-free pellet or the active ingredient-containing granule with powder or granule; or the pair containing about 100% of the bioactive substance powder and The crystal or the above-mentioned shaped product is coated and granulated by spreading, spraying or the like; or after the above process is completed, further formed into a sheet by a pressing process; or the mixed preparation of the original raw material is directly compressed, and the dry powder is compressed; or The uniform preparation of the raw materials is melted, cast into tablets, or sintered, extruded, and subsequently rounded, or directly into pellets or tablets (for example, through a flat plate), or further processed after the above process is completed. tablet. Among them, from the aspect of productivity, the molten binder and the mechanical performance enhancer are evenly distributed. Dispersed on the surface of the formed body, the fluidized bed granulation method was satisfactory. As an embodiment, in a fluidized bed granulation method, a diluent, an active ingredient, a molten binder, a mechanical property enhancer is dissolved and/or suspended in a pharmaceutically acceptable solvent as an adhesive spray , coating and / or granulation, after the above process is completed, further into tablets.至之间。 The size of between 0. 01 to 2. 5 between. The thickness of the coating is between 1 and 100 μm, preferably between 10 and 50 μm. In a common tablet, the thickness corresponds to the use of 0.5 to 5% by weight of the polymer, and may be appropriately increased or decreased in a specific application.

在成形工艺中，常采用压制工艺。这样的压制工艺，通常是预先在片剂原辅料掺合润滑剂后采用压片机进行压片。为使片剂的形状维持，压制工艺必需使用不低于最低压力限度的压力，同时，为了获得满意的孔隙率，又需采用较低的压力，此时压片压力通常是 10_700kg/ 杵，满意的是 30_400kg/杵，更满意的是 50_250kg/杵。 In the forming process, a pressing process is often employed. Such a pressing process is usually carried out by a tableting machine after the lubricant is blended in advance with the tablet raw material. In order to maintain the shape of the tablet, the pressing process must use a pressure not lower than the minimum pressure limit, and at the same time, in order to obtain a satisfactory porosity, a lower pressure is required, and the tableting pressure is usually 10 - 700 kg / 杵, satisfactory It is 30_400kg/杵, and more satisfactory is 50_250kg/杵.

本发明涉及的固体制剂制备方法中的成形工序较佳地采用非压制工艺。 The forming step in the method for producing a solid preparation according to the present invention preferably employs a non-pressing process.

如一实施例，把制剂原料：上述的稀释剂、添加剂、活性成分、熔融粘合剂及机械性能增强剂等混匀后或者溶解和 /或混悬于制药上所允许的溶剂中后直接分装于制剂模孔 (moulds ) 或包装材料模压泡眼（bl isters of final pack)中，加热，有溶剂时可一并挥去，熔融，冷却。这种工艺无需使用压力。具体操作参见参见 US6083531 W00247607 As an embodiment, the preparation raw material: the above diluent, additive, active ingredient, molten binder, mechanical property enhancer, etc. are mixed or dissolved and/or suspended in a pharmaceutically acceptable solvent, and then directly dispensed. In the molds or the bl isters of final pack, it is heated, and when it is solvent, it can be swept away, melted, and cooled. This process does not require the use of pressure. For details, see US6083531 W00247607

如另一实施例，把上述的制剂原料装入可加热的词料斗或其他适当容器，加热熔化制剂原料，将熔化物引入有二反向模制辊的压延机内模制成片剂，而此二反向模制辊表面有互相相反的凹陷以接受并模制片剂组合物。具体操作参见 US4880585 As another embodiment, the above-mentioned preparation raw materials are charged into a heatable word hopper or other suitable container, and the preparation material is heated and melted, and the melt is introduced into a calender having two reverse molding rolls to form a tablet. The surfaces of the two reverse molding rolls have mutually opposite depressions to receive and mold the tablet composition. For details, see US4880585

( 2 )、加热工序 (2), heating process

在本发明的 "加热"，用已公知的方法进行，用工序（2 ) 所得的成形物，只要是加热能使在本发明所用的熔融粘合剂、机械性能增强剂全部溶化，在熔化过程中无物质在加热时降解（降解致孔剂可除外）或活性成分的挥发，更佳地，上述可溶于水的结晶态的颗粒状或粉未状的稀释剂及上述的活性成分不熔化的方法就没有特别的限制。这样的 "加热"工序，例如可以采用通风炉、烘箱、恒温箱进行。温度条件根据本发明所用的稀释剂、活性成分、熔融粘合剂、机械性能增强剂的种类适当地决定的，只要在通常本发明所用的熔融粘合剂及机械性能增强剂全部溶化，无物质在加热时降解（降解致孔剂除外）或活性成分的挥发，上述可溶于水的结晶态的颗粒状或粉未状的稀释剂及上述的活性成分不熔化就没有特别的限制。在本发明所用的温度通常高于上述机械性能增强剂的熔点，所用的温度通常是约 45 至约 130°C，较佳地是约 60至约 110°C，更佳地是约 70至约 90°C。时间条件根据所用稀释剂、活性成分、熔融粘合剂及机械性能增强剂的种类、所希望的固体制剂强度、固体制剂崩解性能等来适当地决定，通常是 0. 5至 120分，较佳地是 1至 60分，更佳地是 2至 30分。 In the "heating" of the present invention, it is carried out by a known method, and the molded article obtained by the step (2) can be melted by melting the binder and the mechanical property enhancer used in the present invention as long as it is heated. No substance is degraded upon heating (except for degrading porogen) or volatilization of active ingredient, more preferably, the above-mentioned water-soluble crystalline granular or powdery diluent and the above active ingredient are not melted. There is no particular limitation on the method. Such a "heating" process can be carried out, for example, in a ventilating oven, an oven, or an incubator. The temperature conditions are appropriately determined according to the type of the diluent, the active ingredient, the melt binder, and the mechanical property enhancer used in the present invention, as long as the melt binder and the mechanical property enhancer used in the present invention are all dissolved, no substance. The degradation is carried out upon heating (except for the degradation of the porogen) or the volatilization of the active ingredient, and the above-mentioned water-soluble crystalline particulate or powdery diluent and the above-mentioned active ingredient are not melted, and are not particularly limited. The temperature used in the present invention is usually higher than the melting point of the above mechanical property enhancer, and the temperature used is usually from about 45 to about 130 ° C, preferably from about 60 to about 110 ° C, more preferably from about 70 to about 90 ° C. 5至120分分, compared with the diluent, the active ingredient, the type of the melt binder and the mechanical property enhancer, the desired strength of the solid preparation, the disintegration performance of the solid preparation, etc., usually 0.5 to 120 minutes. The best is 1 to 60 minutes, more preferably 2 to 30 minutes.

本发明的 "加热"工序，也可在成型物的表面或邻近其表面加热，使表层如 0. 1至 2mm 的深度的熔融粘合剂及机械性能增强剂溶化，而内部的熔融粘合剂、机械性能增强剂维持原状，这样可得到更快速崩解的固体制剂。具体操作参见 US6258381 The "heating" process of the present invention may also be heated on the surface of the molded article or adjacent to the surface thereof to melt the surface of the molten adhesive and the mechanical property enhancer at a depth of 0.1 to 2 mm, and the internal molten adhesive. The mechanical performance enhancer is maintained as it is, so that a solid formulation which disintegrates more rapidly can be obtained. For details, see US6258381

( 3 )、冷却工序 (3), cooling process

在本发明所谓 "冷却"，用已公知的方法进行，只要是本发明所用的熔融粘合剂及机械性能增强剂熔融后固化 (凝固）的方法就没有特别的限制。这样的 "冷却"，例如能够采用在室温下放置和冷藏库等低温环境下保存来进行。 The "cooling" of the present invention is carried out by a known method, and the method of curing (solidifying) the molten binder and the mechanical property enhancer used in the present invention after melting is not particularly limited. Such "cooling" can be carried out, for example, by storage at a room temperature and in a low temperature environment such as a refrigerator.

在本发明的具体实施方案中，片剂中还可以含有挥发性组分和 /或可降解成无害气体的组分，以获得更大孔隙率的片剂。挥发性组分和 /或可降解成无害气体的组分掺合混合到片剂原辅料中制成片剂后，通过在常压或减压条件下加热，将挥发性组分从片剂中挥发除去以形成多孔片剂。挥发性组分优选在熔化阶段挥发除去。在一个优选的制备方法中，将片剂在连续氮气吹洗下加热到 45至 110°C，较佳地 50至 80°C，直到挥发性组分全部经升华挥发出去。使用氮气吹洗有助于保护不稳定的活性成分在这些条件下免于降解。然而，对于稳定的活性成分，在温度 45至 110°C，较佳地 50至 80°C下，也可使用空气吹洗。合适的挥发性组分及可降解成无害气体的组分包括能升华的物质以及在等于或低于粘合剂和 /或机械性能增强剂的熔点能分解的物质，可用于本发明的实例如苯甲酸（mpl21.5〜123.5°C， 100°C开始升华 (latm))、苯甲酸酯及苯甲酸盐类化合物（如苯甲酸乙脂、苯甲酸苯酯、苯甲酸丙脂、苯甲酸苄酯、苯甲酸甲酯、苯甲酸盐如钠盐）、香草醛（mp81〜83°C)、乙基香草醛（πιρ76〜8Γ〇，纯品 mp77〜78°C) 、天然或合成樟脑（天然樟脑 mpl76〜181°C，合成樟脑 mpl74〜179°C ) 、右旋樟脑（mp约 179.8°C， 204°C开始升华（latm) ) 、左旋樟脑（mp约 178.6°C， 204°C开始升华（latm) ) 、外消旋薄荷脑（醇）（mp42〜44°C) 、左旋薄荷醇（mp41〜45°C) 、天然或合成冰片（mp205-210°C)、右旋龙脑（mp约 208°C)、左旋龙脑（mp约 204°C)、右旋异龙脑（mp约 214°C)、左旋异龙脑（mp约 214°C)、外消旋异龙脑（mp约 212°C)、二硫代草酰胺（二硫代二酰胺）（mp约 4ΓΟ、 6 甲基一 2—硫脲嘧啶（甲基硫氧嘧啶）（mp约 330°C， 326〜331°C分解）、奥磺酸盐如钠盐、叔丁基对羟基茴香醚（mp57〜65°C) 、二特丁基羟基甲苯（2, 6 二特丁基对甲酚）（mp69〜71°C) 、水杨酸（mpl58°C， 76°C开始升华）、阿司匹林、乙水杨胺、咖啡因类化合物（如咖啡因 1水合物（mp 238° ， 178° 升华）、咖啡因无水物、柠檬酸咖啡因、咖啡因苯甲酸盐如钠盐）、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、尿素、乌拉坦、 ^化铵如氯化铵、碳酸氢铵、碳酸铵、醋酸铵及其混合物，优选乌拉坦、碳酸氢铵。挥发性组分的用量为 1%至 95%重量比，较佳地 20%至 70%，更佳地 30%至 50%，这是基于混合时的片剂组分的重量。 In a particular embodiment of the invention, the tablet may also contain volatile components and/or components that degrade into harmless gases to obtain tablets of greater porosity. The volatile component and/or the component degradable into a harmless gas are blended and mixed into the tablet raw material to form a tablet, and the volatile component is removed from the tablet by heating under normal pressure or reduced pressure. The volatilization is removed to form a porous tablet. The volatile components are preferably removed by evaporation during the melting stage. In a preferred method of preparation, the tablets are heated to 45 to 110 ° C, preferably 50 to 80 ° C under continuous nitrogen purge until the volatile components are all sublimed and volatilized. The use of nitrogen purge helps to protect the unstable active ingredient from degradation under these conditions. However, for stable active ingredients, air purging can also be used at a temperature of 45 to 110 ° C, preferably 50 to 80 ° C. Suitable volatile components and components which degrade into harmless gases include sublimable materials and at or below binder and/or mechanical property enhancers a substance capable of decomposing at a melting point, which can be used in the examples of the present invention such as benzoic acid (mpl 21.5 to 123.5 ° C, 100 ° C to start sublimation (latm)), benzoic acid esters and benzoate compounds (such as benzoic acid B) Fat, phenyl benzoate, propyl benzoate, benzyl benzoate, methyl benzoate, benzoate such as sodium salt), vanillin (mp 81~83 ° C), ethyl vanillin (πιρ76~8Γ〇) , pure mp77~78°C), natural or synthetic camphor (natural camphor mpl76~181°C, synthetic camphor mpl74~179°C), right-handed camphor (mp about 179.8°C, 204°C begins to sublimate (latm) ), left-handed brain (mp about 178.6 ° C, 204 ° C began to sublimate (latm)), racemic menthol (alcohol) (mp42 ~ 44 ° C), L-menthol (mp41 ~ 45 ° C), natural or Synthetic borneol (mp205-210°C), right-handed borneol (mp about 208°C), left-handed borneol (mp about 204°C), right-handed borneol (mp about 214°C), left-handed dragon brain (mp about 214 ° C), racemic isoborne brain (mp about 212 ° C), dithiooxamide (dithiodiamide) (mp about 4 ΓΟ, 6 methyl 2- thiouracil (A Thiothiopyrimidine (mp about 330 ° C, 326 ~ 331 ° C decomposition), sulfonate salt such as sodium salt, tert-butyl p-hydroxyanisole (mp57 ~ 65 ° C), di-tert-butyl hydroxy toluene (2, 6 two Tert-butyl-p-cresol) (mp69~71°C), salicylic acid (mpl58°C, sub-sublimation at 76°C), aspirin, salicylamine, caffeine (eg caffeine 1 hydrate (mp) 238°, 178° sublimation), caffeine anhydrate, caffeine citrate, caffeine benzoate such as sodium salt), alanine, leucine, isoleucine, valine, phenylalanine Acid, urea, urethane, ammonium, such as ammonium chloride, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate and mixtures thereof, preferably urethane, ammonium hydrogencarbonate. The volatile component is used in an amount of 1% to 95% by weight. Preferably, it is from 20% to 70%, more preferably from 30% to 50%, based on the weight of the tablet component when mixed.

依照上述各种方法制备的片剂是 "多孔 " 的，通常其孔隙率是约 10至约 95%，满意的是约 20至约 90%，更满意的是约 40至约 80%。 Tablets prepared according to the various methods described above are "porous" and typically have a porosity of from about 10 to about 95%, desirably from about 20 to about 90%, more desirably from about 40 to about 80%.

用上述任一方法制备的片剂都可以包上一薄层包衣材料以改善片刑的表面整体性。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，以免妨碍片剂在口中的迅速崩解能力。 Tablets prepared by any of the above methods may be coated with a thin layer of coating material to improve the surface integrity of the tablet. Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrin and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, any coating It should be sufficiently thin and water soluble so as not to interfere with the rapid disintegration ability of the tablet in the mouth.

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。本发明涉及的片剂与片剂中的可熔融的成分单独应用制备的片剂相比具有下列优势：一有更强的机械性能，维护片剂的完整性，防止片剂在生产、运输等过程中出现细微或大的裂缝、磨损、破碎，防止不稳定的物质重新暴露于不利的环境中； The present invention has been described in detail, and it is obvious to those skilled in the art that various modifications may be made without departing from the scope of the invention. The tablet according to the invention has the following advantages over the tablet prepared by the meltable component in the tablet alone: one has stronger mechanical properties, maintains the integrity of the tablet, prevents the tablet from being produced, transported, etc. Fine or large cracks, abrasion, and breakage during the process to prevent unstable materials from being re-exposed to adverse environments;

一能在夏季耐受更高的气温，在更高的气温下，片剂不会软化，其片剂强度及崩解时间等也不会因此发生变化； One can tolerate higher temperatures in the summer, and at higher temperatures, the tablets will not soften, and the strength and disintegration time of the tablets will not change.

一较好的亲水性及较高的孔隙率，有较好的崩解或释药性能； A better hydrophilicity and higher porosity, better disintegration or release properties;

一可在在相对较低的温度下生产，节能，降低生产成本，有利于热不稳定的成分的稳定。附图说明 It can be produced at relatively low temperatures, save energy, reduce production costs, and contribute to the stability of thermally unstable components. DRAWINGS

图 1 机械性能增强剂的重量 /(熔融粘合剂的重量 +机械性能增强剂的重量) 硬度相图，其中，稀释剂（1为甘露醇 +蔗糖（比例为 2 : 3) ，简称稀 1; 2为异麦芽糖醇 +赤藻糖醇 Figure 1 Weight of mechanical performance enhancer / (weight of molten binder + weight of mechanical performance enhancer) Hardness phase diagram, where diluent (1 is mannitol + sucrose (ratio 2: 3), referred to as lean 1 2 is isomalt + erythritol

(比例为 1 : 1)，简称稀 2)的量不变，熔融粘合剂（1为聚氧乙烯 (40)硬脂酸酯，简称粘 1; 2为聚乙二醇（60) 氢化蓖麻油，简称粘 2) 与机械性能增强剂（1为单硬脂酸甘油酯，简称增 1; 2为氢化蓖麻油，简称增 2) 总量不变，且稀 1重 / (稀 1重 +粘 1重 +增 1重） =0.85，稀 2重 / (稀 2重 +粘 2重 +增 2重） =0.60。 (The ratio is 1:1), abbreviated as dilute 2), the amount of molten binder (1 is polyoxyethylene (40) stearate, referred to as sticky 1; 2 is polyethylene glycol (60) Sesame oil, abbreviated as 2) and mechanical performance enhancer (1 is glyceryl monostearate, abbreviated as 1; 2 is hydrogenated castor oil, abbreviated as 2). The total amount is constant, and it is 1 weight / (thin 1 weight + Sticking 1 weight + increasing 1 weight) = 0.85, thin 2 weight / (rare 2 weight + sticky 2 weight + increasing 2 weight) =0.60.

图 2 机械性能增强剂的重量 /(熔融粘合剂的重量 +机械性能增强剂的重量)一姽碎度相图，其中，稀释剂（1为甘露醇 +蔗糖（比例为 2 : 3) ，简称稀 1; 2为异麦芽糖醇 +赤藻糖醇 Figure 2 The weight of the mechanical performance enhancer / (weight of the molten adhesive + weight of the mechanical performance enhancer) - a phase diagram of the mash, wherein the diluent (1 is mannitol + sucrose (ratio 2: 3), Referred to as dilute 1; 2 is isomalt + erythritol

(比例为 1 : 1)，简称稀 2)的量不变，熔融粘合剂（1为聚氧乙烯 (40)硬脂酸酯，简称粘 1; 2为聚乙二醇（60) 氢化蓖麻油，简称粘 2) 与机械性能增强剂（1为单硬脂酸甘油酯，简称增 1; 2为氢化蓖麻油，简称增 2) 总量不变，且稀 1重 / (稀 1重 +粘 1重 +增 1重） =0.85，稀 2重 / (稀 2重 +粘 2重 +增 2重） =0.60。 (The ratio is 1:1), abbreviated as dilute 2), the amount of molten binder (1 is polyoxyethylene (40) stearate, referred to as sticky 1; 2 is polyethylene glycol (60) Sesame oil, abbreviated as 2) and mechanical performance enhancer (1 is glyceryl monostearate, abbreviated as 1; 2 is hydrogenated castor oil, abbreviated as 2). The total amount is constant, and it is 1 weight / (thin 1 weight + Sticking 1 weight + increasing 1 weight) = 0.85, Dilute 2 weight / (thin 2 weight + viscosity 2 weight + increase 2 weight) =0.60.

图 3 稀释剂的重量 / (熔融粘合剂的重量 +机械性能增强剂的重量 +稀释剂的重量）一硬度相图，其中，稀释剂（1为甘露醇 +蔗糖（比例为 2： 3) ，简称稀 1; 2为异麦芽糖醇 +赤藻糖醇（比例为 1 : 1) ，简称稀 2) 间的比例及熔融粘合剂（1为聚氧乙烯 (40)硬脂酸酯，简称粘 1; 2为聚乙二醇（60) 氢化蓖麻油，简称粘 2) 与机械性能增强剂（1为单硬脂酸甘油酯，简称增 1; 2为氢化蓖麻油，简称增 2) 间的比例不变，即增 1重 / (粘 1重 +增 1重） = 0.40，增 2重 / (粘 2重 +增 2重） =0.60，且稀释剂、熔融粘合剂及机械性能增强剂的总量不变。 Figure 3 Weight of diluent / (weight of molten binder + weight of mechanical performance enhancer + weight of diluent) - Hardness phase diagram, where diluent (1 is mannitol + sucrose (2: 3 ratio) , referred to as dilute 1; 2 is the ratio of isomalt + erythritol (ratio: 1), referred to as dilute 2) and molten binder (1 is polyoxyethylene (40) stearate, abbreviation Sticking 1; 2 is polyethylene glycol (60) hydrogenated castor oil, abbreviated as 2) and mechanical performance enhancer (1 is glyceryl monostearate, abbreviated as 1; 2 is hydrogenated castor oil, abbreviated as 2) The ratio is the same, that is, increase 1 weight / (stick 1 weight + increase 1 weight) = 0.40, increase 2 weight / (stick 2 weight + increase 2 weight) = 0.60, and the diluent, molten binder and mechanical properties are enhanced The total amount of the agent is unchanged.

图 4 稀释剂的重量 / (熔融粘合剂的重量 +机械性能增强剂的重量 +稀释剂的重量）一姽碎度相图，其中，稀释剂（1为甘露醇 +蔗糖（比例为 2： 3) ，简称稀 1; 2为异麦芽糖醇 +赤藻糖醇（比例为 1 : 1) ，简称稀 2) 间的比例及熔融粘合剂（1为聚氧乙烯 (40)硬脂酸酯，简称粘 1; 2为聚乙二醇（60) 氢化蓖麻油，简称粘 2) 与机械性能增强剂（1为单硬脂酸甘油酯，简称增 1; 2为氢化蓖麻油，简称增 2) 间的比例不变，即增 1重 / (粘 1重 +增 1重） =0.40, 增 2重 / (粘 2重 +增 2重） =0.60，且稀释剂、熔融粘合剂及机械性能增强剂的总量不变。优选实施例 Figure 4 The weight of the diluent / (weight of the molten binder + weight of the mechanical performance enhancer + weight of the diluent) a mash phase diagram, wherein the diluent (1 is mannitol + sucrose (ratio 2: 3), abbreviated as dilute 1; 2 is the ratio of isomalt + erythritol (ratio: 1), referred to as dilute 2) and molten binder (1 is polyoxyethylene (40) stearate , referred to as sticky 1; 2 is polyethylene glycol (60) hydrogenated castor oil, referred to as sticky 2) and mechanical performance enhancer (1 is glyceryl monostearate, abbreviated as 1; 2 is hydrogenated castor oil, referred to as 2 The ratio between the two is the same, that is, increase 1 weight / (stick 1 weight + increase 1 weight) = 0.40, increase 2 weight / (stick 2 weight + increase 2 weight) = 0.60, and thinner, melt adhesive and machinery The total amount of performance enhancer is unchanged. Preferred embodiment

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。在本发明的范围内这些实施例还可有许多变化。实施例 1 The following non-selective examples further describe preferred embodiments within the scope of the invention. Many variations of these embodiments are possible within the scope of the invention. Example 1

取固定量的稀释剂、固定总量的熔融粘合剂及机械性能增强剂，按稀释剂的重量：熔融粘合剂的重量：机械性能增强剂的重量= ： (1-p-z) ： z比例配制混合物（其中， 0 p<l， z = (l-p) Xn/20, 且 n=0、 1、 2、 3、 ……、 20， p为常量， z为变量），其中，稀释剂、熔融粘合剂及机械性能增强剂依次为①：（甘露醇 +蔗糖）（2 : 3，比例固定不变） /聚氧乙烯 (40) 硬脂酸酯 /单硬脂酸甘油酯（其中， p=0.85)、 ②：（异麦芽糖醇 +赤藻糖醇）（1 : 1，比例固定不变） /聚乙二醇（60) 氢化蓖麻油 /氢化蓖麻油（其中， p=0.60)。将上述混匀的混合物 500mg在压力约 150kg/杵下压制成直径为 12mm的片剂，把上述片剂加热至机械性能增强剂熔点以上的一定的温度（①： 75。C、 ②： 90°C) 60分钟，使片剂中的熔融粘合剂及机械性能增强剂全部熔化，并在室温下自然冷却凝固，测定片剂的硬度及脆碎度等机械性能参数，绘制组成 X-硬度相图及组成 X-脆碎度相图，其中， x = z/ (1-ρ) =η/20=0.05η, 且 η=0、 1、 2、 3、 ……、 20。每一个比例下的硬度及脆碎度分别测定 9-11次，取平均值。结果分别见图 1 及图 2。实施例 2 Take a fixed amount of diluent, a fixed amount of molten binder and a mechanical strength enhancer, by weight of diluent: weight of molten binder: weight of mechanical performance enhancer = : (1-pz) : z ratio Formulating a mixture (where 0 p < l, z = (lp) Xn / 20, and n = 0, 1, 2, 3, ..., 20, p is a constant, z is a variable), wherein, diluent, melting The binder and mechanical strength enhancer are 1: (mannitol + sucrose) (2: 3, fixed ratio) / polyoxyethylene (40) stearate / glyceryl monostearate (where p =0.85), 2: (Isomalt + erythritol) (1:1, fixed ratio) / Polyethylene glycol (60) Hydrogenated castor oil / hydrogenated castor oil (where p = 0.60). 500 mg of the above-mentioned mixed mixture was compressed to a tablet having a diameter of 12 mm under a pressure of about 150 kg/min, and the tablet was heated to a certain temperature above the melting point of the mechanical performance enhancer (1:75.C, 2:90°). C) 60 minutes, the melt adhesive and mechanical performance enhancer in the tablet are all melted, and naturally cooled and solidified at room temperature, and the mechanical properties such as hardness and friability of the tablet are determined, and the composition X-hard phase is drawn. Figure and composition X-brittle phase diagram, where x = z / (1 - ρ) = η / 20 = 0.05 η, and η = 0, 1, 2, 3, ..., 20. The hardness and friability at each ratio were determined 9-11 times and averaged. The results are shown in Figure 1 and Figure 2, respectively. Example 2

取实施例 1中的稀释剂、熔融粘合剂及机械性能增强剂（三者总量固定），按（稀释剂的重量）：（熔融粘合剂 +机械性能增强剂的重量） =y : (1-y)的比例配制混合物，其中， y = 0.05 Xn, 且 n=l、 2、 3、 ……、 19，（机械性能增强剂的重量）：（熔融粘合剂 +机械性能增强剂的重量） =0.40 (①）或 0.60 (②）（即熔融粘合剂及机械性能增强剂间的比例固定不变）。将上述混匀的混合物 500mg在压力约 150kg/杵下压制成直径为 12隱的片剂，把上述片剂加热至机械性能增强剂熔点以上的一定的温度（①： 75。C、 ②： 90°C) 60分钟，使片剂中的熔融粘合剂及机械性能增强剂全部熔化，并在室温下自然冷却凝固，测定片剂的硬度及脆碎度等机械性能参数，绘制组成比例 y_硬度相图及组成比例 y_脆碎度相图，其中， y = 0.05 Xn, 且 n=0、 1、 2、 3、 ……、 20。每一个比例下的硬度及脆碎度分别测定 9_11次，取平均值。组成比例 y_硬度相图及组成比例 y_脆碎度相图见图 3、图 4。实施例 3 Take the diluent, the molten binder and the mechanical property enhancer in Example 1 (the total amount of the three is fixed), according to (the weight of the diluent): (the weight of the molten binder + mechanical performance enhancer) = y: a mixture of (1-y) ratios, where y = 0.05 Xn, and n = 1, 2, 3, ..., 19, (weight of mechanical performance enhancer): (melt binder + mechanical strength enhancer) Weight) =0.40 (1) or 0.60 (2) (ie the ratio between the molten binder and the mechanical strength enhancer is fixed). 500 mg of the above-mentioned mixed mixture was compressed to a tablet having a diameter of 12 at a pressure of about 150 kg/min, and the tablet was heated to a temperature above the melting point of the mechanical performance enhancer (1:75.C, 2:90). °C) 60 minutes, the melt adhesive and mechanical performance enhancer in the tablet are all melted, and naturally cooled and solidified at room temperature, the mechanical properties such as hardness and friability of the tablet are determined, and the composition ratio y_ is drawn. Hardness phase diagram and composition ratio y_ friability phase diagram, where y = 0.05 Xn, and n = 0, 1, 2, 3, ..., 20. The hardness and friability at each ratio were measured 9-11 times, respectively, and averaged. The composition ratio y_hardness phase diagram and composition ratio y_ friability degree phase diagram are shown in Fig. 3 and Fig. 4. Example 3

根据实施例 1、 2中的实验结果，取离最佳较近并稍偏亲水性成分的比例值 x = (机械性能增强剂的重量）：（熔融粘合剂 +机械性能增强剂的重量） =0. 5，及 = (稀释剂的重量) ： (熔融粘合剂 +机械性能增强剂的重量 +稀释剂的重量） = 0. 75，其中，熔融粘合剂为聚氧乙烯 (40)硬脂酸酯，机械性能增强剂为单硬脂酸甘油酯，稀释剂为 (甘露醇 +蔗糖）（2 : 3 ) ，进行组方如下： According to the experimental results in Examples 1 and 2, the ratio value x (the weight of the mechanical performance enhancer) which is the closest and slightly hydrophilic component is taken: (the weight of the molten binder + mechanical strength enhancer) =0. 5, and = (weight of diluent): (weight of melt binder + mechanical strength enhancer + weight of diluent) = 0.75, wherein the molten binder is polyoxyethylene (40) Stearate, the mechanical property enhancer is glyceryl monostearate, and the diluent is (mannitol + sucrose) (2:3). The composition is as follows:

组分 mg/片 Component mg/tablet

双嘧达莫 25 Dipyridamole 25

D-甘露醇 67. 5 D-mannitol 67. 5

蔗糖 101. 25 Sucrose 101. 25

聚氧乙烯 (40)硬脂酸酯 28. 125 Polyoxyethylene (40) stearate 28. 125

单硬脂酸甘油酯 28. 125 Glyceryl monostearate 28. 125

羟丙基纤维素 11 Hydroxypropyl cellulose 11

交联羧甲纤维素钠 25 Croscarmellose sodium 25

二氧化硅 4 Silica 4

硬脂酰延胡索酸钠 5 Sodium stearyl fumarate 5

硬脂酸镁 5 Magnesium stearate 5

总计 300 Total 300

将组分 D-甘露醇、蔗糖、羟丙基纤维素磨碎并用乙醇制成湿颗粒，干燥，并磨细；所得干颗粒依次与双嘧达莫、聚氧乙烯 (40)硬脂酸酯、单硬脂酸甘油酯、交联羧甲纤维素钠、二氧化硅、硬脂酰延胡索酸钠混合混合；最后，将硬脂酸镁与得到的混合物混合。将最终的混合物在压力约 50kg/杵下压制成直径为 9mm的片剂。将片剂在温度 75°C下加热 60分钟，之后在室温下自然冷却，即可。实施例 4 The components D-mannitol, sucrose, hydroxypropyl cellulose are ground and made into wet granules with ethanol, dried, and ground; the obtained dry granules are sequentially combined with dipyridamole, polyoxyethylene (40) stearate And glyceryl monostearate, croscarmellose sodium, silica, sodium stearyl fumarate are mixed and mixed; finally, magnesium stearate is mixed with the obtained mixture. The final mixture was compressed to a tablet having a diameter of 9 mm under a pressure of about 50 kg/min. The tablets were heated at a temperature of 75 ° C for 60 minutes and then allowed to cool naturally at room temperature. Example 4

把实施例 3处方中的聚氧乙烯 (40)硬脂酸酯的量由 28. 125mg/片换成 35. 438mg/片，单硬脂酸甘油酯由 28. 125mg/片换成 20. 812mg/片（即 x = 0. 37)，其他不变，按上述方法制备实施例 4。实施例 5 The amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg / tablet to 35. 438 mg / tablet, glyceryl monostearate was changed from 28. 125 mg / tablet to 20. 812 mg / Sheet (i.e., x = 0.37), the others were unchanged, and Example 4 was prepared as described above. Example 5

把实施例 3处方中的聚氧乙烯（40)硬脂酸酯的量由 28. 125mg/片换成 22. 5mg/片，单硬脂酸甘油酯由 28. 125mg/片换成 33. 75mg/片（即 x = 0. 6)，其他不变，按上述方法制备实施例 5。实施例 6 The amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg/tablet to 22.5 mg/tablet, and glyceryl monostearate was changed from 28.125 mg/tablet to 33.75 mg. / Sheet (i.e., x = 0.6), the others were unchanged, and Example 5 was prepared as described above. Example 6

把实施例 3 处方中的 D-甘露醇由 67. 5mg/片换成 45mg/片，蔗糖由 101. 25mg/片换成 67. 5mg/片，聚氧乙烯（40)硬脂酸酯及单硬脂酸甘油酯的量由 28. 125mg/片换成 56. 25mg/片 (即 x=0. 50， y=0. 50), 其他不变，按上述方法制备实施例 6。实施例 7 The D-mannitol in the formulation of Example 3 was changed from 67.5 mg/tablet to 45 mg/tablet, and sucrose was changed from 101. 25 mg/tablet to 67. 5 mg/tablet, polyoxyethylene (40) stearate and single The amount of glyceryl stearate was changed from 28.125 mg/tablet to 56.25 mg/tablet (i.e., x = 0.50, y = 0.50), and the others were unchanged. Example 6 was prepared as described above. Example 7

把实施例 3处方中的 D-甘露醇由 67. 5mg/片换成 78. 3mg/片，蔗糖由 101. 25mg/片换成 117. 45mg/片，聚氧乙烯（40)硬脂酸酯及单硬脂酸甘油酯的量由 28. 125mg/片换成 14. 625mg/ 片（即 x=0. 50， y=0. 87 ), 其他不变，按上述方法制备实施例 7。实施例 8 根据实施例 1、 2中的实验结果，取离最佳较近或并稍偏亲水性成分的比例值 x = (机械性能增强剂的重量）：（熔融粘合剂 +机械性能增强剂的重量） = 0. 55， Ά = (稀释剂的重量）：（熔融粘合剂 +机械性能增强剂的重量 +稀释剂的重量） = 0. 70，其中，熔融粘合剂为聚乙二醇（60 ) 氢化蓖麻油，机械性能增强剂为氢化蓖麻油，稀释剂为（异麦芽酮糖醇 +异麦芽进行组方如下： The D-mannitol in the formulation of Example 3 was changed from 67.5 mg/tablet to 78.3 mg/tablet, and sucrose was changed from 101.25 mg/tablet to 117.45 mg/tablet, polyoxyethylene (40) stearate. And the amount of glyceryl monostearate was changed from 28.125 mg/tablet to 14.625 mg/tablet (i.e., x=0.50, y=0.87), and the others were unchanged. Example 7 was prepared as described above. Example 8 According to the experimental results in Examples 1 and 2, the ratio of the nearest or slightly more hydrophilic component is taken x = (weight of mechanical performance enhancer): (melt adhesive + mechanical performance enhancer Weight) = 0. 55, Ά = (weight of diluent): (weight of melt binder + mechanical strength enhancer + weight of diluent) = 0. 70, where the molten binder is polyethylene glycol (60) Hydrogenated castor oil, the mechanical performance enhancer is hydrogenated castor oil, and the diluent is (isomalt + iso malt is as follows):

组分 mg/片 Component mg/tablet

盐酸罂粟碱 30 Papaverine hydrochloride 30

异麦芽酮糖醇 122. 5 Isomalt 122. 5

赤藻糖醇 122. 5 Erythritol 122. 5

聚乙二醇（60 )氢化蓖麻油 47. 25 Polyethylene glycol (60) hydrogenated castor oil 47. 25

氢化蓖麻油 57. 75 Hydrogenated castor oil 57. 75

交联羧甲纤维素钠 15 Croscarmellose sodium 15

阿斯帕坦 1 Aspartan 1

二氧化硅 4 Silica 4

总计 400 Total 400

将盐酸罂粟碱、异麦芽酮糖醇、赤藻糖醇、聚乙二醇（60 ) 氢化蓖麻油、氢化蓖麻油、交联羧甲纤维素钠、阿斯帕坦、二氧化硅分别研磨，过 60目筛，用等量递加法混匀。在冲压包装膜材料中的小泡眼中装入 400mg的上述混合物，用铝箔压封。将封压的包装膜带在温度 90°C加热 60分钟，在室温下冷却，即可。实施例 9 Papaverine hydrochloride, isomalt, erythritol, polyethylene glycol (60) hydrogenated castor oil, hydrogenated castor oil, croscarmellose sodium, aspartame, silica, respectively, After passing through a 60 mesh sieve, mix by equal amount addition. 400 mg of the above mixture was placed in a small bubble in a stamping and packaging film material, and sealed with an aluminum foil. The sealed packaging film is heated at a temperature of 90 ° C for 60 minutes and cooled at room temperature. Example 9

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 96. 25mg/片，聚乙二醇 ( 60 ) 氢化蓖麻油的量由 47. 25mg/片换成 70. 875mg/片，氢化蓖麻油由 57. 75mg/片换成 86. 625mg/片（即 x=0. 55， y=0. 55)，其他不变，按上述方法制备实施例 9。实施例 10 The amount of the hydrogenated castor oil was changed from 47.5 mg/tablet to the amount of the polyethylene glycol (60) hydrogenated castor oil. 70. 875 mg / piece, hydrogenated castor oil was changed from 57.75 mg / piece to 86. 625 mg / piece (ie x = 0.55, y = 0.55), the other unchanged, Example 9 was prepared as described above. Example 10

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 148. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 ) 氢化蓖麻油换成 31. 5mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 21mg/片的胆固醇硬脂酸酯（即 x=0. 40， y=0. 85 ) , 其他不变，按上述方法制备实施例 10。实施例 11 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 148.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 31. 5 mg / piece of polysorbate 61, 57. 75 mg / piece of hydrogenated castor oil was replaced by 21 mg / piece of cholesterol stearate (ie x = 0.40, y = 0.85), the other unchanged, according Example 10 was prepared by the above method. Example 11

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 87. 5mg/片， 47. 25mg/ 片的聚乙二醇（60 )氢化蓖麻油换成 105mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 70mg/片的胆固醇硬脂酸酯（即 x=0. 40， y=0. 50 ) , 其他不变，按上述方法制备实施例 11。实施例 12 The isomal wasol and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 87. 5 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 105 mg. / tablets of polysorbate 61, 57. 75mg / piece of hydrogenated castor oil replaced with 70mg / tablet of cholesterol stearate (ie x = 0.40, y = 0.50), other unchanged, as above Preparation Example 11. Example 12

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 113. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 ) 氢化蓖麻油换成 73. 5mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 49mg/片的胆固醇硬脂酸酯 (即 x=0. 40， y=0. 65)，其他不变，按上述方法制备实施例 12。参照例： The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 113.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 73. 5 mg / tablet of polysorbate 61, 57. 75 mg / piece of hydrogenated castor oil was changed to 49 mg / piece of cholesterol stearate (ie x = 0.40, y = 0.65), other unchanged, according Example 12 was prepared by the above method. Reference example:

把实施例 3处方中单硬脂酸甘油酯换成同等重量的聚氧乙烯 (40)硬脂酸酯，其他不变，按上述方法制备参照品 1。 The glyceryl monostearate in the formulation of Example 3 was replaced with the equivalent weight of polyoxyethylene (40) stearate, and the others were unchanged. Reference material 1 was prepared as described above.

把实施例 3处方中聚氧乙烯 (40)硬脂酸酯换成同等重量的单硬脂酸甘油酯，其他不变，按上述方法制备参照品 2。把实施例 3处方中的聚氧乙烯 (40)硬脂酸酯的量由 28. 125mg/片换成 50. 625mg/片，单硬脂酸甘油酯由 28. 125mg/片换成 5. 625mg/片（即 x = 0. 1 )，其他不变，按上述方法制备参照品 3。 The polyoxyethylene (40) stearate in the formulation of Example 3 was changed to an equivalent weight of glyceryl monostearate, and the others were unchanged. Reference product 2 was prepared as described above. The amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg/tablet to 50.625 mg/tablet, and glyceryl monostearate was changed from 28.125 mg/tablet to 5.625 mg. /Piece (i.e., x = 0.1), otherwise unchanged, reference product 3 was prepared as described above.

把实施例 3处方中的聚氧乙烯（40)硬脂酸酯的量由 28. 125mg/片换成 5. 625mg/片，单硬脂酸甘油酯由 28. 125mg/片换成 50. 625mg/片（即 x = 0. 9)，其他不变，按上述方法制备参照品 4。 The amount of polyoxyethylene (40) stearate in the formulation of Example 3 was changed from 28.125 mg/tablet to 5.625 mg/tablet, and glyceryl monostearate was changed from 28.125 mg/tablet to 50. 625 mg. / Sheet (i.e., x = 0.9), the others were unchanged, and Reference 4 was prepared as described above.

把实施例 3处方中的 D-甘露醇由 67. 5mg/片换成 18mg/片，蔗糖由 101. 25mg/片换成 27mg/ 片，聚氧乙烯 (40)硬脂酸酯及单硬脂酸甘油酯的量由 28. 125mg/片换成 90mg/片（即 x=0. 50， y=0. 2)，其他不变，按上述方法制备参照品 5。 The D-mannitol in the formulation of Example 3 was changed from 67.5 mg/tablet to 18 mg/tablet, and sucrose was changed from 101.25 mg/tablet to 27 mg/tablet, polyoxyethylene (40) stearate and mono-hard fat. The amount of the acid glyceride was changed from 28.125 mg/tablet to 90 mg/tablet (i.e., x = 0.50, y = 0.2), and the others were unchanged. Reference product 5 was prepared as described above.

把实施例 3处方中的 D-甘露醇由 67. 5mg/片换成 85. 5mg/片，蔗糖由 101. 25mg/片换成 128. 25mg/片，聚氧乙烯（40)硬脂酸酯及单硬脂酸甘油酯的量由 28. 125mg/片换成 5. 625m_g/ 片（即 x=0. 50， y=0. 95 ) , 其他不变，按上述方法制备参照品 6。 The amount of D-mannitol in the formulation of Example 3 was changed from 67.5 mg/tablet to 85.5 mg/tablet, and sucrose was changed from 101.25 mg/tablet to 128.25 mg/tablet, polyoxyethylene (40) stearate. And the amount of glyceryl monostearate was changed from 28.125 mg/tablet to 5.625 m _g / piece (i.e., x = 0.50, y = 0.95), and the others were unchanged. Reference product 6 was prepared as described above.

把实施例 8处方中氢化蓖麻油换成同等重量的聚乙二醇（60 ) 氢化蓖麻油，其他不变，按上述方法制备参照品 7。 The hydrogenated castor oil in the formulation of Example 8 was replaced with polyethylene glycol (60) hydrogenated castor oil of the same weight, and the others were unchanged. Reference material 7 was prepared as described above.

把实施例 8处方中聚乙二醇（60 ) 氢化蓖麻油换成同等重量的氢化蓖麻油，其他不变，按上述方法制备参照品 8。 The polyethylene glycol (60) hydrogenated castor oil in the formulation of Example 8 was replaced with hydrogenated castor oil of the same weight, and the others were unchanged. Reference material 8 was prepared as described above.

把实施例 8处方中的聚乙二醇（60 )氢化蓖麻油的量由 47. 25mg/片换成 78. 25mg/片，氢化蓖麻油由 57. 75mg/片换成 26. 25mg/片（即 x = 0. 25)，其他不变，按上述方法制备参照品 9。 The amount of the polyethylene glycol (60) hydrogenated castor oil in the formulation of Example 8 was changed from 47.5 mg/tablet to 78.25 mg/tablet, and hydrogenated castor oil was changed from 57.75 mg/tablet to 26.25 mg/tablet ( That is, x = 0. 25), and the others are unchanged, and the reference product 9 is prepared as described above.

把实施例 8处方中的聚乙二醇（60 ) 氢化蓖麻油的量由 47. 25mg/片换成 21mg/片，氢化蓖麻油由 57. 75mg/片换成 84mg/片（即 x = 0. 8)，其他不变，按上述方法制备参照品 10。 The amount of polyethylene glycol (60) hydrogenated castor oil in the formulation of Example 8 was changed from 47.5 mg/tablet to 21 mg/tablet, and hydrogenated castor oil was changed from 57.75 mg/tablet to 84 mg/tablet (ie, x = 0). 8), other unchanged, reference product 10 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 66. 5mg/片，聚乙二醇 ( 60 ) 氢化蓖麻油的量由 47. 25mg/片换成 97. 65mg/片，氢化蓖麻油由 57. 75mg/片换成 119. 35mg/片（即 x=0. 55， y=0. 38)，其他不变，按上述方法制备参照品 11。 The amount of the hydrogenated castor oil was changed from 47.5 mg/tablet to the amount of the ethylene glycol (60) hydrogenated castor oil. The amount of the isomal wasol and the erythritol in the formulation of Example 8 was changed from 12.5 mg/tablet to 66.5 mg/tablet. 97. 65 mg / piece, hydrogenated castor oil was changed from 57.75 mg / piece to 119. 35 mg / piece (ie x = 0.55, y = 0.38), other unchanged, reference product 11 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 162. 725mg/片，聚乙二醇（60 ) 氢化蓖麻油的量由 47. 25mg/片换成 11. 025mg/片，氢化蓖麻油由 57. 75mg/片换成 13. 475mg/片（即 x=0. 55， y=0. 93)，其他不变，按上述方法制备参照品 12。 The amount of the isomal wasol and the erythritol in the formulation of Example 8 was changed from 122.5 mg/tablet to 162.725 mg/tablet, and the amount of polyethylene glycol (60) hydrogenated castor oil was changed from 47. 25 mg/tablet. 11. 025 mg / piece, hydrogenated castor oil from 57. 75 mg / piece to 13. 475 mg / piece (ie x = 0.55, y = 0.93), the other unchanged, the reference product 12 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 169. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 )氢化蓖麻油换成 6. 3mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 4. 2mg/片的胆固醇硬脂酸酯 (即 x=0. 40， y=0. 97)，其他不变，按上述方法制备实参照品 13。 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 169.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 6 3 mg / piece of polysorbate 61, 57. 75 mg / piece of hydrogenated castor oil was changed to 4. 2 mg / piece of cholesterol stearate (ie x = 0.40, y = 0.97), the other unchanged The real reference 13 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 8. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 )氢化蓖麻油换成 199. 5mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 133mg/片的胆固醇硬脂酸酯（即 x=0. 40， y=0. 05)，其他不变，按上述方法制备参照品 14。 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 8.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 199. 5 mg / piece of polysorbate 61, 57. 75 mg / piece of hydrogenated castor oil was replaced by 133 mg / piece of cholesterol stearate (ie x = 0.40, y = 0.05), the other unchanged, according to The reference 14 was prepared by the above method.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 148. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 )氢化蓖麻油换成 47. 25mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 5. 25mg/片的胆固醇硬脂酸酯（即 x=0. 10， y=0. 85)，其他不变，按上述方法制备参照品 15。 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 148.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 47. 25 mg / piece of polysorbate 61, 57. 75 mg / piece of hydrogenated castor oil was replaced by 5. 25 mg / piece of cholesterol stearate (ie x = 0.10, y = 0.85), the other unchanged , Reference 15 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 148. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 ) 氢化蓖麻油换成 5. 25mg/片的聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 47. 25mg/片的胆固醇硬脂酸酯（即 x=0. 90， y=0. 85)，其他不变，按上述方法制备参照品 16。 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 148.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 5 25 mg / piece of polysorbate 61, 57. 75 mg / piece of hydrogenated castor oil was replaced by 47. 25 mg / piece of cholesterol stearate (ie x = 0.90, y = 0.85), the other unchanged Reference material 16 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 148. 75mg/片， 47. 25mg/ 片的聚乙二醇（60 ) 氢化蓖麻油换成 52. 5mg/片的聚山梨酯 61，氢化蓖麻油去掉，且不加入胆固醇硬脂酸酯，其他不变，按上述方法制备参照品 17。 The isomalt and erythritol in the formulation of Example 8 were changed from 122.5 mg/tablet to 148.75 mg/tablet, 47.25 mg/tablet of polyethylene glycol (60) hydrogenated castor oil was changed to 52. 5 mg/tablet of polysorbate 61, hydrogenated castor oil was removed, and cholesterol stearate was not added, and the others were unchanged. Reference product 17 was prepared as described above.

把实施例 8处方中的异麦芽酮糖醇及赤藻糖醇由 122. 5mg/片换成 148. 75mg/片，聚乙二醇（60 ) 氢化蓖麻油去掉，且不加入聚山梨酯 61， 57. 75mg/片的氢化蓖麻油换成 52. 5mg/片的胆固醇硬脂酸酯，其他不变，按上述方法制备参照品 18。 The isomalt and erythritol in the formulation of Example 8 were replaced by 122.5 mg/tablet to 148.75 mg/tablet, polyethylene glycol (60) hydrogenated castor oil was removed, and no polysorbate 61 was added. 5mg/片片。 57. 75mg / piece of hydrogenated castor oil was replaced by 52.5 mg / piece Cholesterol stearate, other unchanged, reference product 18 was prepared as described above.

检测例 Test case

测定实施例的样品及参照品的硬度、姽碎度、口腔内崩解时间；对实施例样品及参照品缓缓加热，观察并计录片剂开始软化时的温度；计算孔隙率（以上均测定 9次，取平均值）。 The hardness, mash, and intraoral disintegration time of the samples and reference samples of the examples were measured. The sample samples and the reference materials were slowly heated, and the temperature at which the tablets began to soften was observed and recorded; the porosity was calculated (above Determined 9 times and averaged).

其中，口腔内崩解时间通过下列试验测定： Among them, the intraoral disintegration time was determined by the following tests:

在健康成为男子的口腔内即口内不含有水分的口腔内使其含有本发明片剂，测定片剂只用唾液完全崩解、直至溶解的时间。 The tablet of the present invention is contained in an oral cavity which is healthy in the mouth of a man, i.e., which does not contain water in the mouth, and the time during which the tablet is completely disintegrated by saliva until dissolution is measured.

其中，片剂的孔隙率（Poros ity ) 通过以下的计算式（I)计算出，记载 9片的平均值。计算式 (I) : Here, the porosity of the tablet was calculated by the following calculation formula (I), and the average value of the nine pieces was described. Calculation formula (I):

— y w/ — y w/

Porosity = 式中， V：片剂的体积片剂组分的重量， Ρ : 构成片剂组分的比重。 Porosity = where V: the volume of the tablet The weight of the tablet component, Ρ : The specific gravity of the tablet component.

结果见表 1-3，结果显示，实施例样品有较好的整体性能：机械性能被进一步强化，且同时具有较高的孔隙率，具有较好的耐候性（较高的熔点）且也同时具有较好的亲水性及口腔内崩解性能。 The results are shown in Tables 1-3. The results show that the sample samples have better overall properties: mechanical properties are further enhanced, and at the same time have higher porosity, better weatherability (higher melting point) and at the same time Has good hydrophilicity and oral disintegration properties.

表 1 实施例 3-7与参照品 1-6的硬度、姽碎度、口腔内崩解时间 Table 1 Examples 3-7 and reference products 1-6 hardness, mash, oral disintegration time

、开始软化的温度及孔隙率的测定结果 , the temperature at which softening starts and the measurement result of porosity

表 2 实施例 8-9与参照品 7- 12的硬度、姽碎度、口腔内崩解时间

Table 2 Hardness, mashing, and intraoral disintegration time of Examples 8-9 and References 7-12

参照品 12 3. 9 0. 84 约 67 14 55 表 3 实施例 10-12与参照品 12-18的硬度、姽碎度、口腔内崩解时间

Reference 12 3. 9 0. 84 Approx 67 14 55 Table 3 Hardness, mash, and intraoral disintegration time of Examples 10-12 and 12-18

Claims

WO 2012/006965 权利要求书 PCT/CN2011/077211 WO 2012/006965 Claim PCT/CN2011/077211

1. 一种机械性能强化的孔隙率较高的耐候性较好的亲水性的片剂，其特征在于该片剂包含： A hydrophilic sheet having a higher mechanical properties and a higher porosity and a higher weatherability, characterized in that the tablet comprises:

1 ) 、一种活性成分 (A) ; 1 ) , an active ingredient (A);

2) 、一种药学上可接受的、可溶于水的结晶态的颗粒状或粉未状的稀释剂 (B) ; 2) a pharmaceutically acceptable, water-soluble crystalline particulate or powdery diluent (B);

3)、一种可熔融的粘合剂 (0，该粘合剂为药学上可接受的、熔点不低于 25°C的且较上述的稀释剂 (B)低的、且在水（温度 25 °C ) 或温水（温度 37 °C ) 中的平衡溶解量不低于 33mg/lml (溶解质 /水）的可熔融的表面活性剂； 3), a meltable binder (0, the binder is pharmaceutically acceptable, having a melting point of not lower than 25 ° C and lower than the above diluent (B), and in water (temperature a meltable surfactant having an equilibrium dissolved amount of not less than 33 mg/lml (solute/water) in 25 ° C or warm water (temperature 37 ° C);

4)、一种可熔融的机械性能增强剂 (D)，该机械性能增强剂为药学上可接受的、熔点不低于 45°C且较上述的稀释剂 (B)的熔点低但较上述的粘合剂 (C)的熔点高的、在水（温度 25°C ) 或温水（温度 37°C ) 中的平衡溶解量低于 33m_g/lml (溶解质 /水）的且该平衡溶解量不超过上述的粘合剂 (C)在同一温度下的水中的平衡溶解量的十分之一的可熔融的脂溶性的物质；和 / 或无 4), a meltable mechanical property enhancer (D), the mechanical property enhancer is pharmaceutically acceptable, having a melting point of not lower than 45 ° C and lower than the melting point of the above diluent (B) but higher than The binder (C) has a high melting point, an equilibrium dissolved amount in water (temperature 25 ° C) or warm water (temperature 37 ° C) of less than 33 m _g /lml (solute/water) and the equilibrium dissolves a meltable fat-soluble substance in an amount not exceeding one tenth of the equilibrium dissolved amount of the above binder (C) in water at the same temperature; and/or

5)、一种药学上可接受的添加剂 (E) ; 5), a pharmaceutically acceptable additive (E);

其中，上述的稀释剂 (B)和 /或上述的活性成分 (A)被上述的粘合剂 (C)及上述的机械性能增强剂 (D)的固化熔融物粘合桥连；且上述组分用量满足下列关系：比例关系 1即上述机械性能增强剂 (D)的重量 / (上述粘合剂 (C)的重量十上述机械性能增强剂 (D)的重量）位于 0. 25至 0. 70之间（含端点），比例关系 2即上述稀释剂 (B)的重量 / (上述粘合剂 (C)的重量 +上述机械性能增强剂 (D)的重量 +上述稀释剂 (B)的重量)位于 0. 40至 0. 93之间（含端点）；且上述稀释剂 (B)的重量占整个片剂总重量的比例为不低于 25%; 且上述熔融粘合剂 (C)与上述机械性能增强剂 (D)的重量和占整个片剂总重量的比例不低于 5%; 当上述活性成分 (A)和 /或上述的添加剂 (E)为可溶于水的结晶态的颗粒状或粉未状的物质时，其重量合计于上述的稀释剂 (B)的重量，并以此合计重量计算上述相关比例；当上述活性成分 (A)和 /或上述的添加剂 (E)为可溶于水的结晶态的颗粒状或粉未状的物质且用量满足上述关系时，上述稀释剂 (B)的用量可以为 0。 Wherein the above diluent (B) and/or the above-mentioned active ingredient (A) are bridged by the above-mentioned binder (C) and the cured melt of the above-mentioned mechanical property enhancer (D); 5至0. The ratio of the weight of the above-mentioned mechanical property enhancer (D) / (the weight of the above-mentioned adhesive (C), the weight of the above mechanical properties enhancer (D)) is located at 0.25 to 0. Between 70 (inclusive), the proportional relationship 2 is the weight of the above diluent (B) / (the weight of the above binder (C) + the weight of the above mechanical property enhancer (D) + the above diluent (B) The weight) is between 0.40 and 0.93 (inclusive); and the ratio of the above diluent (B) to the total weight of the entire tablet is not less than 25%; and the above molten adhesive (C) The ratio of the weight of the mechanical property enhancer (D) to the total weight of the whole tablet is not less than 5%; when the above active ingredient (A) and/or the above additive (E) is a water-soluble crystalline state When the granular or powdery substance is used, the weight thereof is the total weight of the above diluent (B), and the above weight is calculated by the total weight Corresponding ratio; when the above-mentioned active ingredient (A) and/or the above-mentioned additive (E) is a particulate or powdery substance in a water-soluble crystalline state and the amount satisfies the above relationship, the above diluent (B) The amount can be 0.

2. 根据权利要求 1的片剂，其特征在于所述的比例关系 1位于 0. 35至 0. 60之间（含端点），且所述的比例关系 2位于 0. 50至 0. 87之间（含端点），且所述的稀释剂 (B)的重量占整个片剂总重量的比例为 34%至 80% (含端点）。 The singularity of the ratio 2 is between 0. 50 and 0. 87. The ratio of the diluent (B) to the total weight of the whole tablet is 34% to 80% (inclusive).

3.根据权利要求 1或 2的片剂，其特征在于所述的比例关系 1位于 0. 40至 0. 55之间（含端点），且所述的比例关系 2位于 0. 55至 0. 80之间（含端点），且所述的稀释剂 (B)的重量占整个片剂总重量的比例为 40%至 70% (含端点）。 5至0. The ratio of the ratio 2 is between 0.55 and 0. 55 to 0. 55 to 0. Between 80 (inclusive), and the ratio of the diluent (B) to the total weight of the entire tablet is 40% to 70% (inclusive).

4. 根据前述权利要求中任意一项的片剂，其特征在于所述的粘合剂 (C)和所述的机械性能增强剂 (D)的熔点较所述的活性成分 (A)的熔点低。 The tablet according to any one of the preceding claims, characterized in that the binder (C) and the mechanical property enhancer (D) have a melting point higher than the melting point of the active ingredient (A) low.

5. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)的熔点为 50°C至 120°C (含端点）且较所述的稀释剂 (B)及所述的活性成分 (A)的熔点低 10°C (含）但较所述的粘合剂 (C)的熔点高 10°C (含）。 The tablet according to any of the preceding claims, characterized in that the mechanical property enhancer (D) has a melting point of from 50 ° C to 120 ° C (inclusive) and is more than the diluent (B) And the active ingredient (A) has a melting point of 10 ° C (inclusive) but 10 ° C (inclusive) higher than the melting point of the binder (C).

6. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)的熔点为 60°C至 10CTC (含端点）且较所述的稀释剂 (B)及所述的活性成分 (A)的熔点低 20°C (含）但较所述的粘合剂 (C)的熔点高 20°C (含）。 The tablet according to any one of the preceding claims, characterized in that the mechanical property enhancer (D) has a melting point of from 60 ° C to 10 CTC (inclusive) and is more than the diluent (B) and The active ingredient (A) has a melting point of 20 ° C (inclusive) but is 20 ° C (inclusive) higher than the melting point of the binder (C).

7.根据前述权利要求中任意一项的片剂，其特征在于所述的粘合剂 (C)熔点为 35至 80°C (含端点）。 Tablet according to any of the preceding claims, characterized in that the binder (C) has a melting point of 35 to 80 ° C (inclusive).

8. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)的平衡溶解量不超过所述的粘合剂 (C)在同一温度下的水中的平衡溶解量的三十分之一。 The tablet according to any one of the preceding claims characterized in that the equilibrium dissolution amount of the mechanical property enhancer (D) does not exceed the balance of the binder (C) in water at the same temperature. One-thirtieth of the dissolved amount.

9. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)的平衡溶解量不超过所述的粘合剂 (C)在同一温度下的水中的平衡溶解量的一百分之一。 The tablet according to any one of the preceding claims characterized in that the equilibrium dissolution amount of the mechanical property enhancer (D) does not exceed the balance of the binder (C) in water at the same temperature. One hundredth of the dissolved amount.

10. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)的平衡 WO 2012/006965 权利要求书 PCT/CN2011/077211 溶解量不超过所述的粘合剂 (c)在同一温度下的水中的平衡溶解量的一千分之一。 Tablet according to any of the preceding claims, characterized in that the balance of the mechanical property enhancer (D) WO 2012/006965 Claim PCT/CN2011/077211 The amount of dissolution does not exceed one thousandth of the equilibrium dissolved amount of the binder (c) in water at the same temperature.

11. 根据前述权利要求中任意一项的片剂，其特征在于所述的粘合剂 (C)选自熔点不低于 25°C的且可溶于水的聚氧乙烯垸基醚（Polyoxyethylene Alkyl Ethers ) 类表面活性剂、聚氧乙烯蓖麻油衍生物（Polyoxyethylene Castor Oi l Derivatives ) 类表面活性剂、聚氧乙烯山梨糖醇酐脂肪酸酯（Polyoxyethylene Sorb i tan Fatty Acid Esters ) 类表面活性剂、乙氧基化脂肪酸如聚氧乙烯硬脂酸酯（Polyoxyethylene Stearates ) 类表面活性剂、乙氧基化脂肪醇如聚氧乙烯月桂酸酯（Polyoxyethylene Stearates ) 类表面活性剂、聚氧乙烯一聚氧丙烯醇共聚物（泊洛沙姆）、糖酯类表面活性剂及它们的混合物。 The tablet according to any of the preceding claims, characterized in that the binder (C) is selected from water-soluble polyoxyethylene decyl ether (Polyoxyethylene) having a melting point of not lower than 25 ° C. Alkyl Ethers Surfactant, Polyoxyethylene Castor Oi l Derivatives Surfactant, Polyoxyethylene Sorb i tan Fatty Acid Esters Surfactant , ethoxylated fatty acids such as polyoxyethylene stearates surfactants, ethoxylated fatty alcohols such as polyoxyethylene Stearates surfactants, polyoxyethylene aggregates An oxypropenol copolymer (poloxamer), a sugar ester surfactant, and mixtures thereof.

12. 根据前述权利要求中任意一项的片剂，其特征在于所述的粘合剂 (C)选自聚乙二醇 ( 60 ) 氢化蓖麻油（Polyoxyl 60 hydrogenated castor oi l) 聚乙二醇（40) 氢化蓖麻油 (Polyoxyl 40 hydrogenated castor oi l )、聚山梨酯 61、聚山梨酯 65、聚氧乙烯（12)硬脂酸酯、聚氧乙烯 (20)硬脂酸酯、聚氧乙烯 (40)硬脂酸酯、聚氧乙烯 (50)硬脂酸酯、聚氧乙烯 (100)硬脂酸酯、聚氧乙烯（32)双硬脂酸酯、聚氧乙烯（150)双硬脂酸酯、 poloxamer 188、 poloxamer 237、 poloxamer 338、 poloxamer 407、蔗糖单硬脂酸酯和 /或蔗糖单棕榈酸酯及它们的混合物。 The tablet according to any of the preceding claims, characterized in that the binder (C) is selected from the group consisting of polyethylene glycol (60) hydrogenated castor oil (Polyoxyl 60 hydrogenated castor oi l) polyethylene glycol (40) Hydroxy castor oil (Polyoxyl 40 hydrogenated castor oi l ), polysorbate 61, polysorbate 65, polyoxyethylene (12) stearate, polyoxyethylene (20) stearate, polyoxyethylene (40) stearate, polyoxyethylene (50) stearate, polyoxyethylene (100) stearate, polyoxyethylene (32) distearate, polyoxyethylene (150) double hard Fatty acid ester, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, sucrose monostearate and/or sucrose monopalmitate and mixtures thereof.

13. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)选自动植物油脂、半合成油脂、高级烃、天然或人工蜡、高级脂肪酸、高级脂肪酸酯、高级垸基醇及它们的混合物。 The tablet according to any of the preceding claims, characterized in that the mechanical property enhancer (D) is selected from the group consisting of automatic vegetable fats, semi-synthetic fats, higher hydrocarbons, natural or artificial waxes, higher fatty acids, higher fatty acids. Esters, higher mercapto alcohols and mixtures thereof.

14. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)选自硬脂酸、乙二醇单硬脂酸酯、二乙二醇二硬脂酸酯、微晶蜡、甘油三硬脂酸酯、硬脂醇、单硬脂酸甘油酯、甘油单癸酸酯、氢化植物油、白蜂蜡、黄蜂蜡、甘油三棕榈酸酯、山嵛酸、巴西棕榈蜡、虫白蜡、胆固醇硬脂酸酯、氢化蓖麻油、胆固醇棕榈酸酯及它们的混合物。 The tablet according to any of the preceding claims, characterized in that the mechanical property enhancer (D) is selected from the group consisting of stearic acid, ethylene glycol monostearate, diethylene glycol distearate Ester, microcrystalline wax, glyceryl tristearate, stearyl alcohol, glyceryl monostearate, glycerol monodecanoate, hydrogenated vegetable oil, white beeswax, yellow beeswax, glyceryl tripalmitate, behenic acid, Brazil Palm wax, insect white wax, cholesterol stearate, hydrogenated castor oil, cholesterol palmitate, and mixtures thereof.

15. 根据前述权利要求中任意一项的片剂，其特征在于所述的机械性能增强剂 (D)选自氢化蓖麻油。 Tablet according to any of the preceding claims, characterized in that the mechanical property enhancer (D) is selected from the group consisting of hydrogenated castor oil.

16. 根据前述权利要求中任意一项的片剂，其特征在于所述的稀释剂 (B)选自赤藻糖醇、葡萄糖、异麦芽糖醇、拉克替醇、乳糖、麦芽糖醇、麦芽糖、甘露醇、蔗糖、海藻糖、木糖醇、果糖、棉子糖、偶联糖、低聚糖及其混合物。 Tablet according to any of the preceding claims, characterized in that the diluent (B) is selected from the group consisting of erythritol, glucose, isomalt, lactitol, lactose, maltitol, maltose, nectar Alcohol, sucrose, trehalose, xylitol, fructose, raffinose, conjugated sugars, oligosaccharides, and mixtures thereof.

17. 根据前述权利要求中任意一项的片剂，其特征在于所述的活性成分 (A)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、钙拮抗药、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***用药物、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***药物、影响血液及造血***的药物、抗 ***反应药物、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、影响血糖的药物、甲状腺激素类药物及抗甲状腺药物、抗微生物药物 /抗生素、抗肿瘤药物、影响机体免疫功能的药物、蛋白质类药物、维生素及营养类药、减肥药、中草药粉未及中草药提取物。 The tablet according to any of the preceding claims, characterized in that the active ingredient (A) is selected from the group consisting of central stimulants, analgesics, antipyretic analgesics, anti-inflammatory analgesics, anti-gout drugs Anti-shock palsy, antipsychotics, anxiolytics, antidepressants, antiepileptics, sedatives, hypnotics, anticonvulsants, calcium antagonists, drugs for the treatment of chronic heart failure, antiarrhythmic drugs, Prevention and treatment of angina pectoris, peripheral vasodilators, blood pressure lowering drugs, regulating blood lipids and anti-atherosclerosis drugs, respiratory drugs, antacids and peptic ulcer drugs, gastrointestinal antispasmodics, digestive drugs, Antiemetics, emetics and gastrointestinal drugs, hepatobiliary diseases, urinary system drugs, drugs that affect blood and hematopoietic system, antiallergic drugs, allergic mediators, adrenocortical hormones and adrenocorticotropic hormones, sex hormones And gonadotropins, drugs that affect blood sugar, thyroid hormones and antithyroid drugs, antibiotics/antibiotics, anti-tumor Tumor drugs, drugs that affect the body's immune function, protein drugs, vitamins and nutrients, diet pills, herbal powders and herbal extracts.

18. 根据前述权利要求中任意一项的片剂，其特征在于该片剂的孔隙率为约 10至约 95%。 Tablet according to any of the preceding claims, characterized in that the tablet has a porosity of from about 10 to about 95%.

19. 根据前述权利要求中任意一项的片剂，其特征在于该片剂为服用不摄取水，在口腔内基本上只用唾液于 1分以内崩解和 /或溶解的片剂。 A tablet according to any one of the preceding claims, characterized in that the tablet is a tablet which is disintegrated and/or dissolved in the oral cavity by substantially only saliva within 1 minute without taking up water.

20. 根据前述权利要求中任意一项的片剂，其特征在于该片剂为服用不摄取水，在口腔内基本上只用唾液于约 30秒以内崩解和 /或溶解的片剂。 A tablet according to any one of the preceding claims characterized in that the tablet is a tablet which is disintegrated and/or dissolved in the oral cavity by substantially only saliva within about 30 seconds without taking up water.

21. 根据前述权利要求中任意一项的片剂，其特征在于该片剂为服用不摄取水，在口腔内基本上只用唾液于约 10秒以内崩解和 /或溶解的片剂。 A tablet according to any one of the preceding claims characterized in that the tablet is a tablet which is disintegrated and/or dissolved in the oral cavity by substantially only saliva within about 10 seconds without taking up water.

22. 根据前述权利要求中任意一项的片剂的制备方法，其特征在于该方法包含： WO 2012/006965 权利要求书 PCT/CN2011/077211 22. A method of preparing a tablet according to any of the preceding claims, characterized in that the method comprises: WO 2012/006965 Claim PCT/CN2011/077211

( 1 )、为了将含有所述的稀释剂 (B)、粘合剂 (C)、机械性能增强剂 (D)和 /或无药学上可接受的添加剂 (E)及活性成分 (A)的片剂原料维持片剂形式的工序； (1), in order to contain the diluent (B), the binder (C), the mechanical property enhancer (D) and/or the pharmaceutically acceptable additive (E) and the active ingredient (A) The step of maintaining the tablet material in the form of a tablet;

( 2 )、将由工序（1)得到的片剂成形物加热到所述的机械性能增强剂 (D)的熔融温度以上 (含熔融温度）的温度使所述的粘合剂 (C)及所述的机械性能增强剂 (D)熔化的工序； (2) heating the tablet shaped article obtained in the step (1) to a temperature higher than a melting temperature (including a melting temperature) of the mechanical property enhancer (D) to cause the binder (C) and the The process of melting the mechanical performance enhancer (D);

( 3 )、将由工序 (2)得到的片剂成形物中的熔化的所述的粘合剂 (C)及所述的机械性能增强剂 (D)凝固的工序。 (3) A step of solidifying the melted binder (C) and the mechanical performance enhancer (D) in the tablet molded article obtained in the step (2).

23. 根据权利要求 22的方法，其特征在于所述的工序（1)采用非压制工艺。 23. A method according to claim 22, characterized in that said step (1) employs a non-pressing process.

24. 根据权利要求 22的方法，其特征在于所述的工序 (2)中由工序（1)得到的片剂成形物在所述机械性能增强剂 (D)的熔融温度以上（含熔融温度）及所述的稀释剂 (B)及所述活性成分 (A)的熔融温度以下的温度下加热。 The method according to claim 22, characterized in that the tablet shaped article obtained in the step (1) in the step (2) is above the melting temperature of the mechanical property enhancer (D) (including a melting temperature) And heating at the temperature below the melting temperature of the diluent (B) and the active component (A).

25. 根据权利要求 22的方法，其特征在于所述的工序 (2)中在由工序（1)得到的片剂成型物的表面或邻近其表面加热，使表层如 0. 1至 2隱的深度的熔融粘合剂及机械性能增强剂溶化，而内部的熔融粘合剂、机械性能增强剂维持原状。 And the surface layer is 0. 1 to 2 hidden. The method of the present invention is characterized in that the surface of the tablet is formed by the process (1). The deep molten binder and the mechanical performance enhancer dissolve, while the internal molten binder and mechanical performance enhancer remain intact.

26. 根据权利要求 22的方法，其特征在于所述的成形工序（1)中掺合将除去的挥发性组分和 /或可降解成无害气体的组分。 A method according to claim 22, characterized in that said forming step (1) incorporates a volatile component to be removed and/or a component which degrades into a harmless gas.

27. 根据权利要求 26的方法，其特征在于所述的挥发性组分和 /或可降解成无害气体的组分选自苯甲酸、苯甲酸酯、苯甲酸盐类化合物、香草醛、乙基香草醛、天然或合成樟脑、右旋樟脑、左旋樟脑、外消旋薄荷脑（醇）、左旋薄荷醇、天然或合成冰片、右旋龙脑、左旋龙脑、右旋异龙脑、左旋异龙脑、外消旋异龙脑、二硫代草酰胺（二硫代二酰胺）、 6—甲基一 2—硫脲嘧啶（甲基硫氧嘧啶）、奥磺酸盐、叔丁基对羟基茴香醚、二特丁基羟基甲苯（2， 6 一二特丁基对甲酚）、水杨酸、阿司匹林、乙水杨胺、咖啡因类化合物、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、尿素、乌拉坦、卤化铵、碳酸氢铵、碳酸铵、醋酸铵或它们混合物。 27. The method according to claim 26, characterized in that said volatile component and/or component degradable to a harmless gas is selected from the group consisting of benzoic acid, benzoic acid esters, benzoate compounds, vanillin, Ethyl vanillin, natural or synthetic camphor, dextrothymolin, levo-ephedo, racemic menthol (alcohol), levo-menthol, natural or synthetic borneol, dextro-dragon, left-handed cerebral, right-handed borneol, L-isobornanol, racemic isoborneol, dithiooxamide (dithiodiamide), 6-methyl-2-thiouracil (methylthiouracil), sulfonate, tert-butyl Hydroxyanisole, di-tert-butylhydroxytoluene (2,6-di-tert-butyl-p-cresol), salicylic acid, aspirin, salicylamine, caffeine, alanine, leucine, Isoleucine, valine, phenylalanine, urea, urethane, ammonium halide, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate or a mixture thereof.