WO2017107857A1 - 一种含有二胺衍生物或其盐的固体药物组合物 - Google Patents

一种含有二胺衍生物或其盐的固体药物组合物 Download PDF

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WO2017107857A1
WO2017107857A1 PCT/CN2016/110260 CN2016110260W WO2017107857A1 WO 2017107857 A1 WO2017107857 A1 WO 2017107857A1 CN 2016110260 W CN2016110260 W CN 2016110260W WO 2017107857 A1 WO2017107857 A1 WO 2017107857A1
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pharmaceutical composition
solid pharmaceutical
composition according
cellulose
hypromellose
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PCT/CN2016/110260
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English (en)
French (fr)
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郭辰宁
潘凯
刘凯
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江苏恒瑞医药股份有限公司
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Priority to CN201680013039.4A priority Critical patent/CN107405342B/zh
Publication of WO2017107857A1 publication Critical patent/WO2017107857A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to a solid pharmaceutical composition having improved dissolution characteristics, which comprises a compound which exhibits an inhibitory effect on activated blood coagulation factors and which is useful as a prophylactic and/or therapeutic drug for thrombotic diseases.
  • Isoxazaban is a factor X (FXa) blocker that exhibits an effective inhibitory effect on activated factor FXa and can be used to prevent and/or treat thrombosis.
  • FXa factor X
  • Edesaban is a basic compound that exhibits good solubility in acidic aqueous solutions, but decreases in neutral solutions (eg, neutral pH 6.8 buffer).
  • neutral solutions eg, neutral pH 6.8 buffer.
  • the poor dissolution of edoxaban in neutral medium may also affect the absorption of the drug in the intestinal tract, which may lead to a decrease in bioavailability, which is not conducive to clinical treatment.
  • Patent CN102791271B discloses a preparation method comprising edoxaban granules, further comprising a coating step.
  • the method adopts fluidized bed granulation, and by strictly controlling the maximum water content between the granules during the granulation process to be less than 10%, finally, the edoxaban tablets which are well-dissolved under neutral conditions can be prepared.
  • the preparation method of this patent is very demanding on the parameters of the granulating equipment and the preparation process. It is not conducive to the expansion of production scale and the control of the production process.
  • Patent WO 2008/129846 discloses that coating a tablet with one or two or more coating agents selected from the group consisting of cellulose derivatives, polyvinyl compounds, acrylic acid derivatives and sugars can improve the formulation of edoxaban tablets.
  • Neutral zone dissolution method can increase the weight of the tablet coating by 5% or more, which is far beyond the range of 2 to 3% of the weight of the general coated tablet coating, which inevitably leads to a large increase in coating time and an increase in the production time. Energy consumption.
  • 5% of the weight gain of the coating is also not conducive to the parameter control of the coating process. Therefore, the disclosed method of this patent is not conducive to the expansion of the production scale and the control of the production process.
  • the object of the present invention is to provide a solid pharmaceutical composition which can be rapidly dissolved in different pH ranges, and the preparation process of the solid pharmaceutical composition is simple, adapts to different preparation processes, the parameters are easy to control, and is more suitable for large-scale production. .
  • the present invention provides a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising N 1 -(5-chloropyridin-2-yl)-N 2 -[(1S,2R,4S)-4-(N, represented by the following formula (I) N-dimethylcarbamoyl)]-2-[(5-methyl-4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]-pyridine-2-yl Amido)cyclohexyl]ethanediamide:
  • a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient and two or more kinds of cellulose derivatives, and containing no coating or coating containing no cellulose derivative.
  • the active ingredient in the solid pharmaceutical composition provided by the present invention is a solvate (including a hydrate) of an edoxaban solvate (including a hydrate) or a pharmaceutically acceptable salt or a salt.
  • the pharmaceutically acceptable salt may be hydrochloride, sulfate, hydrobromide, citrate, hydroiodide, phosphate, nitrate, benzoate, methanesulfonate, besylate, 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, Malay Acid salts, fumarates, malates and mandelates.
  • p-toluenesulfonate is preferred, and monohydrate of p-toluenesulfonate is particularly preferred.
  • the cellulose derivative in the solid pharmaceutical composition provided by the present invention is selected from the group consisting of methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cyanoethyl cellulose, hydroxypropyl cellulose, and Two or more of hydroxypropylmethylcellulose.
  • a combination of two celluloses is preferred, with the most preferred combination being hydroxypropyl cellulose and hypromellose.
  • the total content of two or more kinds of cellulose derivatives in the solid pharmaceutical composition provided by the present invention is from 0.1% to 60%, preferably from 1% to 40%, more preferably from 5 to 30% (in the present invention, the content is The calculation is based on the total weight of the composition).
  • the mass ratio of hydroxypropylcellulose to hypromellose in the solid pharmaceutical composition provided by the present invention is selected from 1:100 to 1:0.01, preferably from 1:10 to 1:0.1, and most preferably from 1:5 to 1: 0.2.
  • the hydroxypropylcellulose content of the solid pharmaceutical compositions provided herein is selected from the group consisting of from 0.05% to 30%; preferably from 0.5% to 20%, more preferably from 1% to 15%, most preferably from 2% to 15%.
  • the hypromellose content of the solid pharmaceutical composition provided by the present invention is selected from 0.05% to 30%; preferably from 0.5% to 20%, more preferably from 1% to 15%, most preferably from 2% to 15%.
  • the hydroxypropylcellulose in the solid pharmaceutical composition provided by the present invention is selected from the group consisting of high substituted hydroxypropyl cellulose or low substituted hydroxypropyl cellulose, preferably high substituted hydroxypropyl cellulose, most preferably having a viscosity of 50 cP (concentration 5 %Time)
  • the following low viscosity models of high substituted hydroxypropyl cellulose are selected from the group consisting of high substituted hydroxypropyl cellulose or low substituted hydroxypropyl cellulose, preferably high substituted hydroxypropyl cellulose, most preferably having a viscosity of 50 cP (concentration 5 %Time)
  • the following low viscosity models of high substituted hydroxypropyl cellulose are examples of high substituted hydroxypropyl cellulose.
  • the hypromellose in the solid pharmaceutical composition provided by the present invention is selected from low viscosity or high viscosity hypromellose, preferably low viscosity hypromellose, most preferably having a viscosity in the range of 200 cP (concentration 5%) The following hypromellose.
  • the solid pharmaceutical compositions of the present invention can be prepared by a variety of processes including, but not limited to, granulation tableting and powder direct compression.
  • the granulation method when the granulation tableting method is selected, the granulation method may be selected from wet granulation and dry granulation.
  • the invention adopts the scheme of wet granulation and then tableting, it can be granulated by fluidized bed granulation or high shear wet granulation, and the cellulose derivative can be added in any manner, including adding, adding or adding separately.
  • the cellulose derivative can be dissolved in water and other premixed excipients can be prepared by a high shear wet granulation process. It is also possible to pre-mix the cellulose derivative with the remaining raw materials and then add water to granulate. Further, after the granulation of the remaining components, the cellulose derivative may be added in a powder form and mixed to prepare a tablet.
  • the invention has no strict control on the water content of the particles in the wet granulation process, and the water content can be more than 10%, and the desired effect of the invention can be achieved.
  • the cellulose derivative when the method of dry granulation and then tableting is selected, can be added before or after granulation.
  • one or both of the cellulose derivatives can be added to the pre-mixed other excipients to mill the pellets. It is also possible to grind the remaining raw materials together and then add the cellulose derivatives in a powder form and mix them to achieve the desired effects of the present invention.
  • silica it is also possible to add silica to improve the flowability of the final particles, which is advantageous for the tableting process.
  • the solid pharmaceutical composition of the present invention is prepared by directly compressing the powder, the cellulose derivative is directly added to the same raw material and mixed uniformly, and then the tablet is pressed.
  • the problem of poor powder flow it is usually solved by adding 2% silica as a flow aid.
  • the present invention may be coated with a polyvinyl alcohol polyethylene glycol copolymer, such as Kollicoat IR, but is not limited thereto.
  • the tablets prepared by the present invention have an average dissolution percentage of edoxaban 30% or more after 30 minutes from the start of the dissolution test in a dissolution medium having a rotation speed of 50 rpm in a tablet prepared by the present invention. high.
  • the average dissolution percentage of edoxaban was 60% or higher 60 minutes after the start of the dissolution test.
  • the tablets prepared by the present invention have an average dissolution percentage of edoxaban 80% or more after 30 minutes from the start of the dissolution test in a dissolution medium having a rotation speed of 50 rpm in a tablet prepared by the present invention. high.
  • the average dissolution percentage of edoxaban was 60% or more 60 minutes after the start of the dissolution test.
  • the invention effectively improves the ydoxaban system by simultaneously adding hydroxypropyl cellulose and hypromellose.
  • Figure 1 shows the dissolution profile of the edoxaban tablet of Example 1 in phosphate buffer pH 6.8.
  • Figure 2 shows the dissolution profile of the edoxaban tablets of Example 2 in phosphate buffer pH 6.8.
  • Figure 3 shows the dissolution profile of the edoxaban tablet of Example 3 in phosphate buffer pH 6.8.
  • Figure 4 shows the dissolution profile of the edoxaban tablet of Example 4 in phosphate buffer pH 6.8.
  • the dissolution of the edoxaban tablets of Example 1 was examined.
  • 900 mL of a phosphate buffer solution of pH 6.8 was used as the dissolution medium, and the dissolution rate of the tablets was examined.
  • the dissolution medium temperature was 37 ⁇ 0.5 ° C, and the paddle speed was 50 rpm. Samples were taken at 5, 10, 15, 30, 45, 60 min and measured by UV spectrometer at 290 nm.
  • the dissolution measurement results and dissolution profiles of the edoxaban tablets of each of the examples 1 are shown in Fig. 1.
  • the ordinate shows the dissolution rate of edoxaban and the abscissa shows the time (min).
  • the results show that the edoxaban tablet (Prescription D) prepared by the composition provided by the present invention dissolves rapidly and can be dissolved more than 70% in 30 minutes, which is superior to the tablet of the present invention.
  • edoxaban toluene sulfonate, mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose (SL), hypromellose (E50) The granulation method is subjected to dry granulation, and the obtained granules are subjected to dry granulation, and then a prescribed amount of magnesium stearate is added.
  • magnesium stearate may be added to improve the fluidity of the granules.
  • Mixing is carried out using a rotary total mixer. The resulting total mixed granules were tableted and coated with Kollicoat IR.
  • the dissolution of the edoxaban tablets of Example 2 was examined.
  • the second method of paddle method using 900 mL of phosphate buffer solution of pH 6.8 as the dissolution medium for tableting
  • the dissolution rate was examined, the dissolution medium temperature was 37 ⁇ 0.5 ° C, and the paddle speed was 50 rpm. Samples were taken at 5, 10, 15, 30, 45, 60 min and measured by UV spectrometer at 290 nm.
  • the dissolution measurement results and the dissolution profiles of the edoxaban tablets of each of the examples 2 are shown in Fig. 2.
  • the ordinate shows the dissolution rate of edoxaban and the abscissa shows the time (min).
  • the results show that the edoxaban tablet (prescription G) prepared by the composition provided by the present invention dissolves rapidly and can be dissolved more than 70% in 30 minutes, which is superior to the tablet which does not use the present invention.
  • Etozaban toluene sulfonate, mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose (SL), hypromellose (E50), magnesium stearate according to Table 3 The ratio is mixed using a rotary total mixer. The resulting total mixed granules were tableted and coated with Kollicoat IR.
  • the dissolution of the edoxaban tablets of Example 3 was carried out.
  • 900 mL of a phosphate buffer solution of pH 6.8 was used as the dissolution medium, and the dissolution rate of the tablets was examined.
  • the dissolution medium temperature was 37 ⁇ 0.5 ° C, and the paddle speed was 50 rpm. Samples were taken at 5, 10, 15, 30, 45, 60 min and measured by UV spectrometer at 290 nm.
  • the dissolution measurement results and dissolution profiles of the edoxaban tablets in each of Example 3 are shown in the figure. III.
  • the ordinate shows the dissolution rate of edoxaban and the abscissa shows the time (min).
  • the results show that the edoxaban tablets (prescriptions K and L) prepared by the composition provided by the present invention dissolve rapidly and dissolve more than 70% in 30 minutes, which is superior to the tablets not using the present invention.
  • the preparation process of ydoxaban toluene sulfonate, mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate adopts the preparation process similar to that of the third embodiment
  • the wet granulation prescription adopts the preparation process similar to that of the first embodiment
  • the dry granulation prescription adopts the process similar to the embodiment 2
  • the fluidized bed granulation process refers to the preparation method in the patent CN102791271B) .
  • the resulting total mixed granules were tableted and coated with Opadry containing HPMC.
  • the dissolution of the edoxaban tablets of Example 4 was examined.
  • 900 mL of a phosphate buffer solution of pH 6.8 was used as the dissolution medium, and the dissolution rate of the tablets was examined.
  • the dissolution medium temperature was 37 ⁇ 0.5 ° C, and the paddle speed was 50 rpm. Samples were taken at 5, 10, 15, 30, 45, 60 min and measured by UV spectrometer at 290 nm.
  • the dissolution measurement results and dissolution profiles of the edoxaban tablets of each of the examples 4 are shown in Fig. 4.
  • the ordinate shows the dissolution rate of edoxaban and the abscissa shows the time (min).
  • the results show that the formulation in the patent CN102791271B can not be prepared well in the fluidized bed granulation process with powder direct pressure process, high shear wet granulation, dry granulation and maximum water content of more than 10% during granulation. tablet.

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Abstract

一种含有二胺衍生物或其盐的固体药物组合物。所述固体药物组合物含有式(I)所示的N 1-(5-氯吡啶-2-基)-N 2-[(1 S,2R,4S)-4-(N,N-二甲基氨甲酰基)]-2-[(5-甲基-4,5,6,7-四氢-1,3-噻唑并[5,4-c]-吡啶-2-甲酰胺基)环己基]乙二酰胺或其药理学上可接受的盐或其溶剂合物作为活性成分，和两种或两种以上的纤维素衍生物，且不含包衣或者包衣中不含纤维素衍生物。本发明的固体药物组合物具有在宽的pH范围内溶出迅速、稳定性良好的特点。

Description

一种含有二胺衍生物或其盐的固体药物组合物 技术领域
发明涉及一种溶出特性改善的固体药物组合物，其含有对活化的凝血因子显示抑制作用和可用作血栓性疾病的预防和/或治疗药物的化合物。
背景技术
依度沙班，化学名N1-(5-氯吡啶-2-基)-N2-[(1S,2R,4S)-4-(N,N-二甲基氨甲酰基)]-2-[(5-甲基-4,5,6,7-四氢-1,3-噻唑并[5,4-c]-吡啶-2-甲酰胺基)环己基]乙二酰胺结构如下图所示:
Figure PCTCN2016110260-appb-000001
依度沙班为凝血因子X(FXa)阻滞剂，对活化的凝血因子FXa显示有效的抑制作用，可用来预防和/或治疗血栓。
依度沙班是一种碱性化合物，其在酸性水溶液中表现良好溶解度，但在中性溶液(如中性pH6.8的缓冲液)中溶解度下降。依度沙班在中性条件的介质中溶出度差还可能影响药物在肠道内的吸收，进而会导致生物利用度降低，不利于临床治疗。
专利CN102791271B公开了一种含有依度沙班颗粒的制备方法，进一步包含包衣步骤。该方法采用流化床制粒，通过严格控制制粒过程中颗粒间的最大含水量小于10％，最终可制备出在中性条件下溶出良好的依度沙班片。但是该专利的制备方法对制粒设备及制备过程的参数要求非常苛刻。不利于生产规模的扩大和生产过程的控制。
专利WO2008/129846公开了用一种或两种或多种选自纤维素衍生物、聚乙烯化合物、丙烯酸衍生物和糖的包衣剂对片剂进行包衣，可以改善依度沙班片在中性区域溶出度的方法。但是，该方法对片剂包衣增重在5％或以上，远远超出了一般包衣片包衣增重2～3％的范围，在生产中势必会导致包衣时间大大增加，增大能源消耗。同时，5％的包衣增重也不利于包衣过程的参数控制。因此，该专利的公开的方法不利于生产规模的扩大和生产过程的控制。
发明内容
本发明的目的在于提供一种在不同pH范围内均可迅速溶出的固体药物组合物，并且该固体药物组合物的制备工艺简单，适应不同的制备工艺，参数易于控制，更适合工艺化大生产。
本发明提供了一种固体药物组合物，含有下式(Ⅰ)表示的N1-(5-氯吡啶-2-基)-N2-[(1S,2R,4S)-4-(N,N-二甲基氨甲酰基)]-2-[(5-甲基-4,5,6,7-四氢-1,3-噻唑并[5,4-c]-吡啶-2-甲酰胺基)环己基]乙二酰胺：
Figure PCTCN2016110260-appb-000002
或其药理学上可接受的盐或其溶剂合物作为活性成分，和两种或两种以上的纤维素衍生物，且不含包衣或者包衣中不含纤维素衍生物。
本发明提供的固体药物组合物中活性成分是依度沙班溶剂合物(包括水合物)或者药学上可接受的盐或者盐的溶剂合物(包括水合物)。药学上可接受的盐可以是盐酸盐、硫酸盐、氢溴酸盐、柠檬酸盐、氢碘酸盐、磷酸盐、硝酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、己二酸盐、酒石酸盐、马来酸盐、富马酸盐、苹果酸盐和扁桃酸盐。在上述依度沙班的盐的种类中，优选对甲苯磺酸盐，特别优选对甲苯磺酸盐的一水合物。
Figure PCTCN2016110260-appb-000003
本发明提供的固体药物组合物中的纤维素衍生物选自甲基纤维素、羧甲基纤维素、乙基纤维素、羟乙基纤维素、氰乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素中的两种或两种以上。优选两种纤维素的组合，最优选组合为羟丙基纤维素和羟丙甲纤维素。
本发明提供的固体药物组合物中的两种或者两种以上的纤维素衍生物的总含量为0.1％～60％，优选1％～40％，更优选5～30％(本发明中涉及含量时，计算方式是基于组合物的总重来计算)。
本发明提供的固体药物组合物中的羟丙基纤维素和羟丙甲纤维素质量比选自1:100～1:0.01，优选1:10～1:0.1，最优选1:5～1:0.2。
本发明提供的固体药物组合物中的羟丙基纤维素含量选自0.05％-30％；优选0.5％-20％，更优选1％-15％，最优选2％-15％。
本发明提供的固体药物组合物中的羟丙甲纤维素含量选自0.05％-30％；优选0.5％-20％，更优选1％-15％，最优选2％-15％。
本发明提供的固体药物组合物中所述羟丙基纤维素选自高取代羟丙基纤维素或低取代羟丙基纤维素，优选高取代羟丙基纤维素，最优选粘度50cP(浓度5％时) 以下的低粘度型号的高取代羟丙基纤维素。
本发明提供的固体药物组合物中所述羟丙甲纤维素选自低粘度或者高粘度的羟丙甲纤维素，优选低粘度的羟丙甲纤维素，最优选粘度范围在200cP(浓度5％时)以下的羟丙甲纤维素。
本发明所述的固体药物组合物可以选用多种工艺进行制备，包括但不限于制粒压片法以及粉末直接压片法。
本发明在选用制粒压片法的方案时，制粒方式可选用湿法制粒和干法制粒。本发明选用湿法制粒后再压片的方案时，可以采用流化床制粒或高剪切湿法制粒，纤维素衍生物可以选任意方式加入，包括内加，外加或者分别内外加。例如，可以将纤维素衍生物溶解在水中加入预混好的其他辅料采用高剪切湿法制粒工艺制备。也可以将纤维素衍生物直接与其余原辅料一起预混后加入水制粒，还可以在其余组分制粒完成后将纤维素衍生物以粉末形式加入后混合，以备制片。
本发明对于湿法制粒过程中颗粒的含水量并没有严格的控制，含水量可以大于10％，均可达到本发明的预期效果。
本发明选用干法制粒后再压片的方案时，纤维素衍生物可以在干法制粒前或制粒后加入。例如，可以将一种或两种纤维素衍生物加入预混好的其他辅料碾压制粒。也可以将其余原辅料一起碾压制粒后将纤维素衍生物以粉末形式加入后混合，均可达到本发明的预期效果。另外，还可以加入二氧化硅改善最终颗粒的流动性，有利于压片过程。
本发明所述的固体药物组合物，当采用粉末直接压片制得时，纤维素衍生物直接加入同其余原辅料混合均匀后压片即可。针对粉末流动性较差的问题，通常加入2％的二氧化硅作为助流剂即可解决。
本发明可以采用聚乙烯醇聚乙二醇共聚物包衣，例如Kollicoat IR，但是不限此。
通过本发明制备的片剂，在进行转速为50rpm的桨法溶出试验时，在pH为6.8的溶出介质中，在溶出试验开始后30分钟后依度沙班的平均溶出百分数为70％或更高。在溶出试验开始后60分钟后依度沙班的平均溶出百分数为85％或更高。通过本发明制备的片剂，在进行转速为50rpm的桨法溶出试验时，在pH为6.0的溶出介质中，在溶出试验开始后30分钟后依度沙班的平均溶出百分数为80％或更高。在溶出试验开始后60分钟后依度沙班的平均溶出百分数为90％或更高。
本发明通过同时添加羟丙基纤维素和羟丙甲纤维素有效的改善了依度沙班制 剂在pH接近中性的缓冲盐中的溶出行为。
附图说明
图1显示实施例1的依度沙班片在pH6.8的磷酸盐缓冲液中的溶出曲线。
图2显示实施例2的依度沙班片在pH6.8的磷酸盐缓冲液中的溶出曲线。
图3显示实施例3的依度沙班片在pH6.8的磷酸盐缓冲液中的溶出曲线。
图4显示实施例4的依度沙班片在pH6.8的磷酸盐缓冲液中的溶出曲线。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1
将甲苯磺酸依度沙班、甘露醇、预胶化淀粉、交联聚维酮、羟丙基纤维素(SL)、羟丙甲纤维素(E50)，按表1中的比例，采用高速剪切湿法制粒工艺，以纯化水进行制粒，然后干燥处理，将干颗粒(水分小于2％)进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒压片，以Kollicoat IR进行包衣。
表1
Figure PCTCN2016110260-appb-000004
将实施例1的依度沙班片进行溶出度考察。采用中国药典溶出度测定方法第二法桨法，使用900mL的pH6.8的磷酸盐缓冲间溶液作为溶出介质，进行片剂的溶出度考察，溶出介质温度37±0.5℃，桨速度为50rpm。在5，10，15，30，45，60min采集样品，并通过紫外光谱仪在290nm进行测定。
实施例1中各处方的依度沙班片的溶出度测定结果及溶出曲线显示在图一中。纵坐标显示依度沙班的溶出率，横坐标显示时间(min)。结果显示通过本发明提供的组合物制备的依度沙班片(处方D)溶出迅速，在30min即可溶出70％以上，优于未使用本发明片剂。
实施例2
将甲苯磺酸依度沙班、甘露醇、预胶化淀粉、交联聚维酮、羟丙基纤维素(SL)、羟丙甲纤维素(E50)，按表2中的比例，采用碾压制粒法进行干法制粒，将制得的颗粒进行干整粒，再加入处方量的硬脂酸镁，部分实施例还可添加二氧化硅改善颗粒的流动性。采用旋转总混机进行混合。将得到的总混颗粒压片，以Kollicoat IR进行包衣。
表2
Figure PCTCN2016110260-appb-000005
将实施例2的依度沙班片进行溶出度考察。采用中国药典溶出度测定方法第二法桨法，使用900mL的pH6.8的磷酸盐缓冲间溶液作为溶出介质，进行片剂的 溶出度考察，溶出介质温度37±0.5℃，桨速度为50rpm。在5，10，15，30，45，60min采集样品，并通过紫外光谱仪在290nm进行测定。
实施例2中各处方的依度沙班片的溶出度测定结果及溶出曲线显示在图二中。纵坐标显示依度沙班的溶出率，横坐标显示时间(min)。结果显示通过本发明提供的组合物制备的依度沙班片(处方G)溶出迅速，在30min即可溶出70％以上，优于未使用本发明的片剂。
实施例3
将甲苯磺酸依度沙班、甘露醇、预胶化淀粉、交联聚维酮、羟丙基纤维素(SL)、羟丙甲纤维素(E50)，硬脂酸镁按表3中的比例，采用旋转总混机进行混合。将得到的总混颗粒压片，以Kollicoat IR进行包衣。
表3
Figure PCTCN2016110260-appb-000006
将实施例3的依度沙班片进行溶出度考察。采用中国药典溶出度测定方法第二法桨法，使用900mL的pH6.8的磷酸盐缓冲间溶液作为溶出介质，进行片剂的溶出度考察，溶出介质温度37±0.5℃，桨速度为50rpm。在5，10，15，30，45，60min采集样品，并通过紫外光谱仪在290nm进行测定。
实施例3中各处方的依度沙班片的溶出度测定结果及溶出曲线显示在图中。三中。纵坐标显示依度沙班的溶出率，横坐标显示时间(min)。结果显示通过本发明提供的组合物制备的依度沙班片(处方K及L)溶出迅速，在30min即可溶出70％以上，优于未使用本发明的片剂。
实施例4
将甲苯磺酸依度沙班、甘露醇、预胶化淀粉、交联聚维酮、羟丙基纤维素、，硬脂酸镁按表4中的比例，采用相应的制备工艺(粉末直压处方采用类似实施例3的制备工艺，湿法制粒处方采用类似实施例1的制备工艺，干法制粒处方采用类似实施例2的工艺，流化床制粒工艺参考采用专利CN102791271B中的制备方法)。将得到的总混颗粒压片，以含有HPMC的欧巴代进行包衣。
表4
Figure PCTCN2016110260-appb-000007
将实施例4的依度沙班片进行溶出度考察。采用中国药典溶出度测定方法第二法桨法，使用900mL的pH6.8的磷酸盐缓冲间溶液作为溶出介质，进行片剂的溶出度考察，溶出介质温度37±0.5℃，桨速度为50rpm。在5，10，15，30，45，60min采集样品，并通过紫外光谱仪在290nm进行测定。
实施例4中各处方的依度沙班片的溶出度测定结果及溶出曲线显示在图4中。纵坐标显示依度沙班的溶出率，横坐标显示时间(min)。结果显示专利CN102791271B中的处方在采用粉末直压工艺、高剪切湿法制粒、干法制粒及制粒期间最大含水量大于10％的流化床制粒工艺时，均不能制得溶出良好的片剂。

Claims (13)

  1. 一种固体药物组合物，含有下式(Ⅰ)表示的N1-(5-氯吡啶-2-基)-N2-[(1S,2R,4S)-4-(N,N-二甲基氨甲酰基)]-2-[(5-甲基-4,5,6,7-四氢-1,3-噻唑并[5,4-c]-吡啶-2-甲酰胺基)环己基]乙二酰胺：
    Figure PCTCN2016110260-appb-100001
    或其药理学上可接受的盐或其溶剂合物为活性成分，和两种或两种以上的纤维素衍生物，其特征在于所述固体组合物不含包衣或者包衣中不含纤维素衍生物。
  2. 根据权利要求1所述的固体药物组合物，其特征在于所述的纤维素衍射物选自甲基纤维素、羧甲基纤维素、乙基纤维素、羟乙基纤维素、氰乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素中的两种或两种以上，优选自两种的组合，更优选组合为羟丙基纤维素和羟丙甲纤维素。
  3. 根据权利要求1所述的固体药物组合物，其特征在于所述的两种或者两种以上的纤维素衍生物的总含量选自0.1％～60％，优选1％～40％，更优选5～30％。
  4. 根据权利要求2所述的固体药物组合物，其特征在于所述羟丙基纤维素和羟丙甲纤维素质量比选自1:100～1:0.01，优选1:10～1:0.1，最优选1:5～1:0.2。
  5. 根据权利要求2所述的固体药物组合物，其特征在于所述羟丙基纤维素的含量选自0.05％-30％；优选0.5％-20％，更优选1％-15％，最优选2％-15％。
  6. 根据权利要求2所述的固体药物组合物，其特征在于所述羟丙甲纤维素的含量选自0.05％-30％；优选0.5％-20％，更优选1％-15％，最优选2％-15％。
  7. 根据权利要求2所述的固体药物组合物，其特征在于所述羟丙基纤维素选自高取代羟丙基纤维素或低取代羟丙基纤维素，优选高取代羟丙基纤维素，最优选粘度范围在50cP以下的低粘度型号的高取代羟丙基纤维素。
  8. 根据权利要求2所述的固体药物组合物，其特征在于所述羟丙甲纤维素选 自低粘度或者高粘度的羟丙甲纤维素，优选低粘度的羟丙甲纤维素，最优选粘度范围在200cP以下的羟丙甲纤维素。
  9. 根据权利要求1-7任一项所述的固体药物组合物，其特征在于化合物为N1-(5-氯吡啶-2-基)-N2-[(1S,2R,4S)-4-(N,N-二甲基氨甲酰基)]-2-[(5-甲基-4,5,6,7-四氢-1,3-噻唑并[5,4-c]-吡啶-2-甲酰胺基)环己基]乙二酰胺对甲苯磺酸盐的一水合物。
  10. 一种制备权利要求1-7任一项所述的固体药物组合物的方法，包括将所述活性成分与纤维素衍生物混合的步骤，还包括制粒的步骤，其特征是混合步骤在制粒前或者制粒后。
  11. 根据权利要求9所述的方法，制粒步骤方法选自湿法制粒和干法制粒，优选湿法制粒，且湿法制粒过程中颗粒含水量大于10％。
  12. 根据权利要求9所述的方法，进一步包括压片的步骤。
  13. 一种制备权利要求1-7任一项所述的固体药物组合物的方法，所述方法为粉末直接压片法。
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