English:
[0016] In detail, the enteric-coated solid dosage form of the present invention is acid resistant (gastric resistant) and shows less than 10 percent drug release and preferably essentially no drug release in a hydrochloride solution pH 1.2 for at least 120 min, before it, for example, is placed into a phosphate buffer of higher pH, for example of pH 5.6. The present inventors have shown that the use of an inner coating which is located between the outer enteric coating and the core of the solid dosage form helps to disintegrate and to release the drug at a certain pH earlier compared to a solid dosage form having an enteric coating without inner coating. The intended effect is that in vivo the solid dosage form according to the invention releases its active substance "earlier", namely already at the entry of the intestine. The term "earlier" here means that the solid dosage form according to the invention starts to release the active substance already at lower pH value compared to the normal pH of the intestine, namely when the solid dosage form is transferred from the stomach having low pH e.g. 1.2 to the entry of the intestine (e.g. pH 5.6) which is having a higher pH compared to the stomach, but not as high as it is the case in more distal sections of the intestine.
[0060] It is known to employ anionic (meth)acrylate copolymers in partially neutralized form as single layer in order to improve the stability of acid-labile active agents. An improved solubility of the polymer in water and a stabilization of the polymer dispersions is achieved thereby. Bases which can be used for the partial neutralization are normally substances such as NaOH, KOH, ammonium hydroxide or organic bases such as, for example, triethanolamine.
[0072] Additionally suitable is a copolymer composed of
[0073] Additionally suitable is a copolymer composed of
[0075] Glass transition temperature means in this connection in particular the midpoint temperature Tmg according to ISO 11357-2, subsection 3.3.3. Measurement takes place without added plasticizer, with residual monomer contents (REMO) of less than 100 ppm, with a heating rate of 10°C/min and under a nitrogen atmosphere.
[0076] The copolymer preferably consists essentially to exclusively of 90, 95 or 99 to 100% by weight of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the ranges of amounts indicated above.
[0087] The non-neutralized or the partially neutralized (meth)acrylate copolymer may be for example in the form of an aqueous dispersion with a solids content of from 10 to 50 percent.
[0092] The dispersion may also for example be spray dried or freeze dried in a manner known per se and be provided in the form of a redispersible powder (see, for example, EP-A 0 262 326). Alternative processes are freeze drying or coagulation and squeezing out the water in an extruder with subsequent granulation (see, for example, EP-A 0 683 028).
[00102] The invention further relates to a process for producing the pharmaceutical form according to the invention in a manner known per se by pharmaceutically customary processes such as direct compression, compression of dry, wet or sintered granules, extrusion and subsequent rounding off, wet or dry granulation or direct pelleting or by binding powders (powder layering) onto active ingredient-free beads or neutral cores (nonpareilles) or active ingredient- containing particles and by applying the polymer coating in a spray process or by fluidized bed granulation.
[00120] Details are to be found in the customary textbooks, for example:
[00137] 6% HP-55 solution was prepared by dissolving in ethonal/water (80:20). 5mg/cm2 of polymer was applied. 4.2 Coating conditions
[00147] Inlet air temperature: 40.0-45.0 0C; product temperature: 28-30 0C; Exhaust air temperature: 22-27 0C; exhaust air humidity: 40-45%; micro climate: 0.4 bar; airflow: 16.0-18.0 m3/h; atomizing air pressure: 0.6-0.8 bar; spray rate: 2.2 g/min.
[00152] Table 4 summarizes a comparison of different citric acid concentrations in the inner coat. The drug releases from 10% by weight citric acid double coated tablets were faster than from 10% adipic acid double coated tablets (s. table 5). In pH 5.6 buffer, the drug release differences of 10, 15, 20, 30% citric acid formulations were very small.
[00153] In buffer having pH 5.5 15% the citric acid formulation showed faster drug release than 10% citric acid (data not shown).
[00158] The experiment shows a slight increase of drug release when the pH of inner coating solution was increased from pH 5.6 to pH 5.8. When neutralizing the inner coating solution to pH 6.0 the drug release rate was further significantly increased (see table 6). Here, the lag time of drug release in pH 5.6 phosphate buffer was reduced from 40 min to 5 min.
[00166] In particular the drug released from 10% citric acid and 10% adipic acid double coated tablets in pH 5.5, 5.6 and 5.8 buffer were tested (table 8 only shows the double coated tablets in pH 5.6 buffer). In all of the test pH values, double coated tablets containing an organic acid (either citric acid or adipic acid) showed faster drug release than control coated tablets. In all of these three pH values, 10% citric acid formulation showed faster drug release rates than 10% adipic acid formulation.
[00183] The double coated tablet having an inner coat formulation with 20% NaCI and also neutralized to pH 5.6 showed a drug release which was similar to the 10% citric acid pH 5.6 formulation (table 13).

中文:
[0016]详细地说,本发明的肠溶包衣固体剂型是耐酸的(胃耐受性),并且显示了少于10%的药物释放,并且优选,在将它例如放入较高pH值例如pH5.6的磷酸盐缓冲液中之前,在pH1.2的盐酸溶液中经过至少120min基本上没有药物释放。本发明人已经表明,使用位于外肠溶包衣和固体剂型的核之间的内包衣,相比于具有肠溶包衣而没有内包衣的固体剂型,可以在某些pH值下帮助更早地崩解和释放药物。预期效果是,按照本发明的固体剂型“更早地”,即在肠管的入口处已经,在体内释放它的活性物质。本文中,术语“更早地”是指:相比于肠管的正常pH值,按照本发明的固体剂型在更低的pH值下已经开始释放活性物质,即,当固体剂型从具有低pH值例如1.2的胃移动到具有比胃更高pH值(但不是和肠管的更远端部分一样高)的肠管入口(例如pH5.6)时开始释放。
[0060]已知的是,以单层形式使用部分中和形式的阴离子型(甲基)丙烯酸酯共聚物,以便提高对酸不稳定的活性剂的稳定性。由此获得聚合物在水中的提高的溶解性和聚合物分散体的稳定化。可以用于部分中和的碱通常是下列物质:例如NaOH,KOH,氢氧化铵,或有机碱,例如三乙醇胺。
[0072]另外合适的是由下列组成的共聚物:
[0073]另外合适的是由下列组成的共聚物:
[0075]在玻璃态转化温度这一点上,尤其是指按照ISO 11357-2的3.3.3小节的中点温度Tmg。在不加入增塑剂、剩余单体含量(REMO)小于100ppm、采用10°C/min的加热速率的条件下和在氮气氛下进行测定。
[0076]优选,共聚物基本上至仅只地,90、95或99至100%重量由上述数量范围的单体甲基丙烯酸、丙烯酸甲酯、丙烯酸乙酯和甲基丙烯酸丁酯组成。
[0087]未中和的或部分中和的(甲基)丙烯酸酯共聚物可以例如是具有10至50%固体含量的水分散体形式。
[0092]还可以例如用本身已知的方式将分散体喷雾干燥或冷冻干燥,并以可再分散粉末的形式提供(参见例如EP-A 0262326)。替代性方法是冷冻干燥或凝结,并在挤出机中挤出水,随后造粒(参见例如EP-A0683028)。
[00102]本发明进一步涉及以本身已知的方式制备按照本发明的药物形式的方法,该方法利用药学通常的方法进行,例如直接压制,干法、湿法或烧结颗粒的压制,挤出和随后的修圆磨光,湿式或干法成粒,或直接造粒,或将粉末(粉末层合)结合到不含活性组分的珠粒或中性核(nonpareilles)或包含活性组分的颗粒上,在喷涂过程中应用聚合物包衣,或通过流化床造粒法。
[00120]在通常的教科书中可以找到详细内容,例如:
[00137]通过溶于乙醇/水(80∶20)中来制备6%HP-55溶液。施加5mg/cm2的聚合物。
[00147]入口空气温度:40.0-45.0°C;产品温度:28-30°C;排放空气温度:22-27°C;排放空气湿度:40-45%;微气候:0.4bar;空气流量:16.0-18.0m3/h;雾化空气压力:0.6-0.8bar;喷涂速度:2.2g/min。
[00152]表4总结了内包衣中不同柠檬酸浓度的比较。与10%己二酸双包衣片剂相比,药物从10%重量柠檬酸双包衣片剂中释放得更快(参见表5)。在pH5.6缓冲液中,10、15、20、30%柠檬酸制剂的药物释放差别是很细微的。
[00153]在具有pH5.5的缓冲液中,15%柠檬酸制剂显示了比10%柠檬酸更快的药物释放率(数据未显示)。
[00158]实验显示,当内包衣溶液的pH值从pH5.6提高至pH5.8时,轻微提高了药物释放。当将内包衣溶液中和至pH6.0时,药物释放速度进一步显著地提高(参见表6)。这里,在pH5.6磷酸盐缓冲液中,药物释放的滞后时间从40min减少至5min。
[00166]尤其是,试验了10%柠檬酸和10%己二酸双包衣片剂在pH5.5、5.6和5.8缓冲液中的药物释放(表8只显示了在pH5.6缓冲液中的双包衣片剂)。在所有试验pH值下,包含有机酸(柠檬酸或己二酸)的双包衣片剂显示了比对照物包衣片剂更快的药物释放。在所有这三个pH值下,10%柠檬酸制剂显示了比10%己二酸制剂更快的药物释放速度。
[00183]具有内包衣制剂(含有20%NaCl以及中和至pH5.6)的双包衣片剂显示了与10%柠檬酸(pH5.6)制剂相似的药物释放(表13)。