技术领域technical field
本发明涉及一种抗糖尿病的药物组合物，更具体而言，是涉及一种包含DPP-4抑制剂和盐酸二甲双胍的药物组合物及其制备方法，属于药物制剂技术领域。The invention relates to an anti-diabetic pharmaceutical composition, more specifically to a pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
背景技术Background technique
糖尿病是一种具有多种病理表现的慢性疾病，同时伴有脂质代谢紊乱、循环失调和糖代谢紊乱。结果在许多情况下，糖尿病易发展为多种并发症。因此，有必要针对每个人的病情选择出适用于占主导地位的疾病阶段的药物。然而，这一选择在临床实施时通常是较难的，这是因为单独使用一种药物在某些疾病状态时不能产生足够的疗效，同时增加剂量或长期服药会带来如副作用等的多种问题。Diabetes mellitus is a chronic disease with multiple pathological manifestations, accompanied by disorders of lipid metabolism, circulation and glucose metabolism. As a result, diabetes is prone to develop multiple complications in many cases. Therefore, it is necessary to select the drug suitable for the dominant disease stage for each individual's condition. However, this option is often difficult to implement clinically, because single use of a drug cannot produce sufficient efficacy in certain disease states, and increasing the dose or taking the drug for a long time will bring various side effects such as side effects. question.
二肽基肽酶-4(DPP-4)抑制剂和盐酸二甲双胍均为治疗糖尿病用药，包含这两种活性成分的药物组合物具有极高的临床用途。本发明人在尝试制备包含这两种活性成分的药物组合物时发现，DPP-4抑制剂(尤其是利格列汀)与盐酸二甲双胍或多种制剂辅料(如乳糖、微晶纤维素等)易发生杂质反应，进而严重影响药物组合物的稳定性。因此，急需提供一种包含DPP-4抑制剂和盐酸二甲双胍作为活性成分的稳定的药物组合物。Both dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride are medicines for treating diabetes, and the pharmaceutical composition containing these two active ingredients has extremely high clinical application. The inventors found that DPP-4 inhibitors (especially linagliptin) and metformin hydrochloride or various preparation auxiliary materials (such as lactose, microcrystalline cellulose, etc.) Impurity reactions are prone to occur, which seriously affects the stability of the pharmaceutical composition. Therefore, there is an urgent need to provide a stable pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride as active ingredients.
发明内容Contents of the invention
发明概述Summary of the invention
本发明经过深入的研究，出人意料地发现在包含DPP-4抑制剂和盐酸二甲双胍的药物组合物中加入葡甲胺，可显著提高组合物的稳定性，这可能是葡甲胺对上述的杂质反应产生抑制作用。此外，在制备过程中，采取对DPP-4抑制剂和盐酸二甲双胍分开单独制粒的方法，通过物理隔离方式，减少DPP-4抑制剂与盐酸二甲双胍直接接触，可进一步提高组合物稳定性。After in-depth research, the present invention has unexpectedly found that adding meglumine to a pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride can significantly improve the stability of the composition, which may be due to the reaction of meglumine to the above-mentioned impurities. produces an inhibitory effect. In addition, during the preparation process, the DPP-4 inhibitor and metformin hydrochloride are granulated separately, and the direct contact between the DPP-4 inhibitor and metformin hydrochloride is reduced through physical isolation, which can further improve the stability of the composition.
因此，本发明一方面提供一种包含DPP-4抑制剂和盐酸二甲双胍的药物组合物，该组合物包含DPP-4抑制剂和盐酸二甲双胍两种活性成分。所述药物组合物具有优异的保存稳定性和优异的溶出特性。Therefore, one aspect of the present invention provides a pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride, the composition comprising two active ingredients of the DPP-4 inhibitor and metformin hydrochloride. The pharmaceutical composition has excellent storage stability and excellent dissolution properties.
本发明另一方面提供一种包含DPP-4抑制剂和盐酸二甲双胍的药物组合物，其包含含有DPP-4抑制剂和葡甲胺的第一颗粒(下文称第一颗粒)以及含有盐酸二甲双胍的第二颗粒(下文称第二颗粒)。Another aspect of the present invention provides a pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride, which comprises a first granule (hereinafter referred to as the first granule) comprising a DPP-4 inhibitor and meglumine and a granule comprising metformin hydrochloride. Second particles (hereinafter referred to as second particles).
本发明还提供制备第一方面和第二方面所述药物组合物的方法，该制备工艺辅料易得，价格低廉，适合工业化生产。The present invention also provides a method for preparing the pharmaceutical composition described in the first aspect and the second aspect. The auxiliary materials of the preparation process are readily available and cheap, and are suitable for industrial production.
术语定义Definition of Terms
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
发明详述Detailed description of the invention
第一方面，本发明经过深入的研究，出人意料地发现在包含DPP-4抑制剂和盐酸二甲双胍的药物组合物中加入葡甲胺，可显著提高组合物的稳定性，因此本发明涉及一种包含DPP-4抑制剂和盐酸二甲双胍的具有高稳定性的药物组合物，该组合物包含DPP-4抑制剂和盐酸二甲双胍两种活性成分，还包含葡甲胺作为稳定剂。In the first aspect, after in-depth research, the present invention has unexpectedly found that adding meglumine to a pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride can significantly improve the stability of the composition, so the present invention relates to a composition comprising A pharmaceutical composition with high stability of DPP-4 inhibitor and metformin hydrochloride, the composition contains two active ingredients of DPP-4 inhibitor and metformin hydrochloride, and also contains meglumine as a stabilizer.
本发明所述的DPP-4抑制剂是具有伯氨基或仲氨基的DPP-4抑制剂，其包括但不限于利格列汀、阿格列汀、西格列汀、沙格列汀、维格列汀药学上可接受的盐，这些DPP-4抑制剂对应的结构式如下：The DPP-4 inhibitors of the present invention are DPP-4 inhibitors with primary or secondary amino groups, including but not limited to linagliptin, alogliptin, sitagliptin, saxagliptin, The pharmaceutically acceptable salts of Gliptin, the corresponding structural formulas of these DPP-4 inhibitors are as follows:
除非另有所指，根据本发明应理解上面列举的DPP-4抑制剂也包括它们的药学上可接受的盐以及水合物、溶剂合物及多晶型形式。Unless otherwise indicated, it should be understood according to the present invention that the above-listed DPP-4 inhibitors also include their pharmaceutically acceptable salts as well as hydrates, solvates and polymorphic forms.
在一些实施方案中，本发明的药物组合物中葡甲胺的质量相对盐酸二甲双胍的质量比例为1:10～1:200；DPP-4抑制剂的质量相对盐酸二甲双胍的质量比例为1:5～1:400。In some embodiments, the mass ratio of the mass of meglumine to metformin hydrochloride in the pharmaceutical composition of the present invention is 1:10 to 1:200; the mass ratio of the mass of DPP-4 inhibitor to metformin hydrochloride is 1:5 ~1:400.
在一些实施方案中，所述的药物组合物还任选地包含可药用的药物赋形剂，所述药物赋形剂选自填充剂、粘合剂、崩解剂、润滑剂、助流剂、增塑剂、膜包衣剂、色素或其组合。在一些实施方案中，所述可药用的药物赋形剂包括填充剂、粘合剂、润滑剂、助流剂。In some embodiments, the pharmaceutical composition optionally further comprises pharmaceutically acceptable pharmaceutical excipients selected from fillers, binders, disintegrants, lubricants, glidants agents, plasticizers, film coating agents, pigments or combinations thereof. In some embodiments, the pharmaceutically acceptable excipients include fillers, binders, lubricants, glidants.
本发明所述填充剂选自微晶纤维素、预胶化淀粉、玉米淀粉、糊精、乳糖、蔗糖、甘露醇、硫酸钙、磷酸氢钙或其组合；在一些实施方案中，所述填充剂选自玉米淀粉、甘露醇、预胶化淀粉、微晶纤维素或其组合。所述填充剂的用量在整个药物组合物中的重量百分比为2.00％～30.00％。在一些实施方案中，所述填充剂的用量为2.00％～10.00％。The filler of the present invention is selected from microcrystalline cellulose, pregelatinized starch, corn starch, dextrin, lactose, sucrose, mannitol, calcium sulfate, calcium hydrogen phosphate or combinations thereof; in some embodiments, the filler The agent is selected from cornstarch, mannitol, pregelatinized starch, microcrystalline cellulose or combinations thereof. The weight percentage of the filler in the whole pharmaceutical composition is 2.00%-30.00%. In some embodiments, the filler is used in an amount of 2.00%-10.00%.
本发明所述粘合剂选自聚乙烯吡咯烷酮、淀粉浆、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠或其组合；在一些实施方案中，所述填充剂选自聚乙烯吡咯烷酮。所述粘合剂的用量在整个药物组合物中的重量百分比为3.00％～10.00％。The binder of the present invention is selected from polyvinylpyrrolidone, starch slurry, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or combinations thereof; In some embodiments, the filler is selected from polyvinylpyrrolidone. The weight percentage of the adhesive is 3.00%-10.00% in the whole pharmaceutical composition.
本发明所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、聚乙二醇6000、富马酸钠、山嵛酸甘油酯或其组合。在一些实施方案中，所述润滑剂选自硬脂酸镁。所述润滑剂的用量在整个药物组合物中的重量百分比为0.50％～3.00％。The lubricant in the present invention is selected from stearic acid, magnesium stearate, calcium stearate, polyethylene glycol 6000, sodium fumarate, glyceryl behenate or combinations thereof. In some embodiments, the lubricant is selected from magnesium stearate. The usage amount of the lubricant is 0.50%-3.00% by weight in the whole pharmaceutical composition.
本发明所述助流剂选自微粉硅胶、滑石粉、硬脂酸镁或其组合。在一些实施方案中，所述助流剂选自微粉硅胶。所述助流剂的用量在整个药物组合物中的重量百分比为0.50％～3.00％。The glidant in the present invention is selected from micropowder silica gel, talcum powder, magnesium stearate or combinations thereof. In some embodiments, the glidant is selected from micronized silica gel. The dosage of the glidant is 0.50%-3.00% by weight in the whole pharmaceutical composition.
在一些实施方式中，本发明所述的DPP-4抑制剂是利格列汀。In some embodiments, the DPP-4 inhibitor of the present invention is linagliptin.
在一些实施方案中，本发明的药物组合物中葡甲胺的质量相对盐酸二甲双胍的质量比例为1:10～1:200；利格列汀的质量相对盐酸二甲双胍的质量比例为1:200～1:400。In some embodiments, the mass ratio of the mass of meglumine relative to metformin hydrochloride in the pharmaceutical composition of the present invention is 1:10～1:200; the mass ratio of the mass of linagliptin relative to metformin hydrochloride is 1:200～ 1:400.
在一些实施方案中，按单位剂量计，本发明的药物组合物包括利格列汀2.5mg、盐酸二甲双胍500mg～1000mg和葡甲胺5～50mg。In some embodiments, the pharmaceutical composition of the present invention includes 2.5 mg of linagliptin, 500 mg-1000 mg of metformin hydrochloride and 5-50 mg of meglumine in unit dosage.
在一些实施方式中，本发明的药物组合物，包括利格列汀、盐酸二甲双胍、葡甲胺和药用赋形剂；所述赋形剂是填充剂、粘合剂、润滑剂、助流剂或其组合。In some embodiments, the pharmaceutical composition of the present invention includes linagliptin, metformin hydrochloride, meglumine and pharmaceutical excipients; agents or combinations thereof.
在一些实施方式中，所述的药物组合物，按各组分按重量百分含量计，包括利格列汀0.10％～0.50％、盐酸二甲双胍50.00％～88.00％、葡甲胺1.00％～10.00％、填充剂0％～30.00％、粘合剂0％～10.00％、润滑剂0％～3.00％和助流剂0％～3.00％。In some embodiments, the pharmaceutical composition includes 0.10% to 0.50% of linagliptin, 50.00% to 88.00% of metformin hydrochloride, and 1.00% to 10.00% of meglumine according to the weight percentage of each component. %, filler 0% to 30.00%, binder 0% to 10.00%, lubricant 0% to 3.00%, and glidant 0% to 3.00%.
在一些实施方式中，所述的药物组合物，按各组分按重量百分含量计，包括利格列汀0.20％～0.50％、盐酸二甲双胍78.00％～88.00％、葡甲胺2.00％～5.00％、填充剂8.00％～30.00％、粘合剂3％～10.00％、润滑剂0.50％～3.00％和助流剂0％～3.00％。In some embodiments, the pharmaceutical composition includes 0.20% to 0.50% of linagliptin, 78.00% to 88.00% of metformin hydrochloride, and 2.00% to 5.00% of meglumine according to the weight percentage of each component. %, fillers 8.00% to 30.00%, binders 3% to 10.00%, lubricants 0.50% to 3.00%, and glidants 0% to 3.00%.
在一些实施方式中，所述的药物组合物，按各组分按重量百分含量计，包括利格列汀0.20％～0.45％、盐酸二甲双胍78.00％～85.00％、葡甲胺2.00％～3.00％、填充剂8.00％～20.00％、粘合剂3％～5.00％、润滑剂0.50％～2.00％和助流剂0％～2.00％。In some embodiments, the pharmaceutical composition includes 0.20% to 0.45% of linagliptin, 78.00% to 85.00% of metformin hydrochloride, and 2.00% to 3.00% of meglumine according to the weight percentage of each component. %, fillers 8.00% to 20.00%, binders 3% to 5.00%, lubricants 0.50% to 2.00%, and glidants 0% to 2.00%.
在一些实施方式中，所述的药物组合物，按各重量组分百分含量计，包括利格列汀0.21％、盐酸二甲双胍83.33％、葡甲胺2.00％、玉米淀粉2.00％、甘露醇7.86％、聚乙烯吡咯烷酮3.60％和硬脂酸镁1.00％。In some embodiments, the pharmaceutical composition includes linagliptin 0.21%, metformin hydrochloride 83.33%, meglumine 2.00%, cornstarch 2.00%, mannitol 7.86%, based on the percentage of each weight component. %, polyvinylpyrrolidone 3.60% and magnesium stearate 1.00%.
在一些实施方式中，涉及的药物组合物，按各组分重量百分含量计，包括利格列汀0.23％、盐酸二甲双胍78.20％、葡甲胺2.10％、预胶化淀粉5.60％、微晶纤维素8.05％、聚乙烯吡咯烷酮3.82％、硬脂酸镁1.50％和微粉硅胶0.5％。In some embodiments, the pharmaceutical composition involved includes linagliptin 0.23%, metformin hydrochloride 78.20%, meglumine 2.10%, pregelatinized starch 5.60%, microcrystalline Cellulose 8.05%, polyvinylpyrrolidone 3.82%, magnesium stearate 1.50% and micronized silica gel 0.5%.
在一些实施方式中，涉及的药物组合物，按各组分重量百分含量计，包括利格列汀0.42％、盐酸二甲双胍84.00％、葡甲胺2.30％、微晶纤维素2.80％、甘露醇5.29％、聚乙烯吡咯烷酮4.37％和硬脂酸镁0.82％。In some embodiments, the pharmaceutical composition involved includes linagliptin 0.42%, metformin hydrochloride 84.00%, meglumine 2.30%, microcrystalline cellulose 2.80%, mannitol 5.29%, polyvinylpyrrolidone 4.37%, and magnesium stearate 0.82%.
本发明第一方面所述的药物组合物，采用葡甲胺作为稳定剂可以对DPP-4抑制剂，尤其是利格列汀，与盐酸二甲双胍易发生的杂质反应产生抑制作用，显著提高了组合物的稳定性。In the pharmaceutical composition described in the first aspect of the present invention, using meglumine as a stabilizer can inhibit DPP-4 inhibitors, especially linagliptin, from impurity reactions that are prone to occur with metformin hydrochloride, and significantly improve the combination Stability of things.
本发明第一方面所述的药物组合物，最终可以制成口服固体制剂，所述口服固体制剂包括但不限于颗粒剂、散剂、片剂、胶囊剂、混悬剂、缓释片、普通片、丸剂。在一些实施例中，所述的口服固体制剂为片剂。The pharmaceutical composition described in the first aspect of the present invention can finally be made into oral solid preparations, which include but not limited to granules, powders, tablets, capsules, suspensions, sustained-release tablets, ordinary tablets ,pill. In some embodiments, the oral solid preparation is a tablet.
本发明在第一方面研究的基础上，还发现在制备过程中，采取对DPP-4抑制剂和盐酸二甲双胍分开单独制粒的方法，通过物理隔离方式，减少DPP-4抑制剂与盐酸二甲双胍直接接触，可进一步提高组合物稳定性。On the basis of the research of the first aspect, the present invention also finds that in the preparation process, the DPP-4 inhibitor and metformin hydrochloride are separately granulated separately, and by physical isolation, the direct contact between the DPP-4 inhibitor and metformin hydrochloride is reduced. contact, the stability of the composition can be further improved.
因此，本发明第二方面提供一种包含DPP-4抑制剂和盐酸二甲双胍的药物组合物，其其包含第一颗粒以和第二颗粒。Therefore, the second aspect of the present invention provides a pharmaceutical composition comprising a DPP-4 inhibitor and metformin hydrochloride, which comprises a first granule and a second granule.
本发明所述第一颗粒，包含DPP-4抑制剂、葡甲胺，还可包含可药用的赋形剂。所述药物赋形剂选自填充剂、粘合剂、崩解剂、润滑剂、助流剂、增塑剂、膜包衣剂、色素或其组合。在一些实施方案中，所述可药用的药物赋形剂包括填充剂、崩解剂、粘合剂。The first granules of the present invention include DPP-4 inhibitors, meglumine, and pharmaceutically acceptable excipients. The pharmaceutical excipient is selected from fillers, binders, disintegrants, lubricants, glidants, plasticizers, film coating agents, pigments or combinations thereof. In some embodiments, the pharmaceutically acceptable excipients include fillers, disintegrants, binders.
本发明所述第二颗粒，包含盐酸二甲双胍以及可药用的赋形剂。所述赋形剂选自填充剂、粘合剂、崩解剂、润滑剂、助流剂、增塑剂、膜包衣剂、色素或其组合。在一些实施方案中，所述可药用的药物赋形剂包括粘合剂。The second granule of the present invention comprises metformin hydrochloride and pharmaceutically acceptable excipients. The excipient is selected from fillers, binders, disintegrants, lubricants, glidants, plasticizers, film coating agents, pigments or combinations thereof. In some embodiments, the pharmaceutically acceptable excipient includes a binder.
本发明第一方面所述的药物组合物，最终的药物制剂形式为口服固体制剂，所述口服固体制剂包括但不限于颗粒剂、散剂、片剂、胶囊剂、混悬剂、缓释片、普通片、丸剂。在一些实施例中，所述的口服固体制剂为片剂。The pharmaceutical composition described in the first aspect of the present invention, the final pharmaceutical preparation form is an oral solid preparation, and the oral solid preparation includes but not limited to granules, powders, tablets, capsules, suspensions, sustained-release tablets, Ordinary tablets, pills. In some embodiments, the oral solid preparation is a tablet.
第三方面，本发明还提供制备本发明的药物组合物的方法，包括：In a third aspect, the present invention also provides a method for preparing the pharmaceutical composition of the present invention, comprising:
1)制备第一颗粒：采用流化床制粒机或高速剪切制粒机将处方量的DPP-4抑制剂、葡甲胺和其他可药用的赋形剂混合，制备得到第一颗粒；1) Preparing the first granules: using a fluidized bed granulator or a high-speed shear granulator to mix the prescribed amount of DPP-4 inhibitor, meglumine and other pharmaceutically acceptable excipients to prepare the first granules ;
2)制备第二颗粒：采用流化床制粒机将处方量的盐酸二甲双胍与其他的可药用的赋形剂混合，制备得到第二颗粒；2) Preparation of the second granule: using a fluidized bed granulator to mix the prescribed amount of metformin hydrochloride with other pharmaceutically acceptable excipients to prepare the second granule;
3)整粒及混合：第一颗粒和第二颗粒整粒并混合均匀，得到混合颗粒；3) granulation and mixing: the first granule and the second granule are sized and mixed uniformly to obtain mixed granules;
4)混合颗粒与可选地其他赋形剂制成胶囊剂、颗粒剂、散剂、片剂、胶囊剂、混悬剂等。4) Mixing granules and optionally other excipients to make capsules, granules, powders, tablets, capsules, suspensions and the like.
所述其他赋形剂包括填充剂、粘合剂、崩解剂、润滑剂或其组合。所述填充剂选自选自微晶纤维素、预胶化淀粉、玉米淀粉、糊精、乳糖、蔗糖、甘露醇、硫酸钙、磷酸氢钙或其组合；所述粘合剂选自聚乙烯吡咯烷酮、淀粉浆、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠或其组合；所述崩解剂选自羧甲基淀粉钠、干淀粉、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、低取代羟丙基纤维素或其组合；所述润滑剂选自硬脂酸、硬脂酸镁、滑石粉、聚乙二醇6000、富马酸钠、山嵛酸甘油酯或其组合。Such other excipients include fillers, binders, disintegrants, lubricants or combinations thereof. The filler is selected from microcrystalline cellulose, pregelatinized starch, cornstarch, dextrin, lactose, sucrose, mannitol, calcium sulfate, calcium hydrogen phosphate or combinations thereof; the binder is selected from polyethylene Pyrrolidone, starch slurry, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or a combination thereof; the disintegrant is selected from carboxymethyl starch Sodium, dry starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or a combination thereof; the lubricant is selected from stearic acid, magnesium stearate, talc, poly Ethylene Glycol 6000, Sodium Fumarate, Glyceryl Behenate, or combinations thereof.
在一些具体实施方式中，制备所述药物组合物的方法，包括：In some specific embodiments, the method for preparing the pharmaceutical composition includes:
1)制备第一颗粒：采用流化床制粒机或高速剪切制粒机将处方量的利格列汀、葡甲胺和其他的可药1) Preparation of the first granules: use a fluidized bed granulator or a high-speed shear granulator to prepare the prescribed amount of linagliptin, meglumine and other medicaments
用的赋形剂混合，制备得到第一颗粒；The excipients used are mixed to prepare the first granules;
2)制备第二颗粒：采用流化床制粒机将处方量的盐酸二甲双胍与其他的可药用的赋形剂混合，制备得到第二颗粒；2) Preparation of the second granule: using a fluidized bed granulator to mix the prescribed amount of metformin hydrochloride with other pharmaceutically acceptable excipients to prepare the second granule;
3)整粒及混合：第一颗粒和第二整粒并混合均匀；3) Sizing and mixing: the first granulation and the second sizing and mixing evenly;
4)混合颗粒可选地与其他赋形剂制成胶囊剂、颗粒剂、散剂、片剂、胶囊剂、混悬剂等。4) The mixed granules are optionally prepared with other excipients into capsules, granules, powders, tablets, capsules, suspensions and the like.
在一些具体实施方式中，本发明药物组合物可以是片剂，该片剂还经薄膜进行包衣；薄膜包衣包含膜包衣剂、助流剂、增塑剂、色素；所述薄膜包衣剂可以是羟丙基甲基纤维素/羟丙基纤维素/乙基纤维素，所述助流剂可以是滑石粉/微粉硅胶，所述增塑剂可以是丙二醇/聚乙二醇/柠檬酸三乙酯/聚山梨酯/蓖麻油，所述色素可以是氧化铁红/氧化铁黄/二氧化钛；在一些实施例中，这种额外薄膜包衣可占所述药物组合物总重量的1-4％。In some specific embodiments, the pharmaceutical composition of the present invention can be a tablet, and the tablet is also coated with a film; the film coating includes a film coating agent, a glidant, a plasticizer, and a pigment; the film coating Coating agent can be hydroxypropyl methyl cellulose/hydroxypropyl cellulose/ethyl cellulose, described glidant can be talcum powder/micropowder silica gel, and described plasticizer can be propylene glycol/polyethylene glycol/ Triethyl citrate/polysorbate/castor oil, the pigment can be iron oxide red/iron oxide yellow/titanium dioxide; in some embodiments, this additional film coating can account for the total weight of the pharmaceutical composition 1-4%.
在一些具体实施方式中，制备所述药物组合物的方法，包括：In some specific embodiments, the method for preparing the pharmaceutical composition includes:
1)制备第一颗粒：将处方量利格列汀、葡甲胺和粘合剂加入水中制成包含粘合剂的混合溶液，通过流化床制粒机，将包含粘合剂的混合溶液喷至预混合好的填充剂中，制备得到第一颗粒；1) Preparation of the first granules: add the prescription amount of linagliptin, meglumine and the binder into water to make a mixed solution containing the binder, pass through a fluidized bed granulator, and mix the mixed solution containing the binder Spray into the pre-mixed filler to prepare the first granules;
2)制备第二颗粒：将处方量粘合剂溶于水中配制成溶液后，通过流化床制粒机，喷至盐酸二甲双胍中，制备得到第二颗粒；2) Preparation of the second granule: after dissolving the prescribed amount of binder in water to prepare a solution, spray it into metformin hydrochloride through a fluidized bed granulator to prepare the second granule;
3)整粒及混合：第一颗粒和第二整粒并混合均匀；3) Sizing and mixing: the first granulation and the second sizing and mixing evenly;
4)压片：将混合颗粒与处方量润滑剂混合，采用压片机进行压片；4) Tablet compression: mix the mixed granules with the prescribed amount of lubricant, and use a tablet press to perform tablet compression;
5)包衣：配置薄膜包衣溶液，于包衣机中进行包衣。5) Coating: Prepare a film coating solution and perform coating in a coating machine.
本发明还提供所定义的药物组合物在制备药物中的用途，所述药物用于治疗和/或预防代谢疾病，尤其是Ⅱ型糖尿病和与其相关的病症(例如糖尿病并发症)。The present invention also provides the use of the defined pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of metabolic diseases, especially type 2 diabetes and disorders related thereto (eg diabetic complications).
具体实施方式Detailed ways
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.
本发明中，min表示分钟，mg表示毫克，LOD表示干燥失重。In the present invention, min means minute, mg means milligram, and LOD means loss on drying.
实施例1Example 1
处方组成prescription composition
制备方法：Preparation:
1)制备第一颗粒：将处方量利格列汀、葡甲胺和聚乙烯吡咯烷酮加入水制得包含粘合剂的混合溶液，采用流化床制粒，设定进风温度50℃～60℃，物料温度37℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的甘露醇和玉米淀粉加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥颗粒的干燥失重(LOD)至2.0％～3％；1) Preparation of the first granule: add the prescribed amount of linagliptin, meglumine and polyvinylpyrrolidone to water to prepare a mixed solution containing the binder, use a fluidized bed for granulation, and set the inlet air temperature at 50°C to 60°C ℃, the material temperature is 37 ℃, the air volume of the fan is adjusted according to the fluidization state of the material; after the inlet air temperature reaches the set value, add the pre-mixed mannitol and corn starch and preheat for 5-10 minutes, and start spraying the adhesive solution , the loss on drying (LOD) of the dried particles after spraying is 2.0% to 3%;
2)制备第二颗粒：将处方量聚乙烯吡咯烷酮加入水中制得粘合剂溶液，采用流化床制粒，设定进风温度45℃～55℃，物料温度34℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将盐酸二甲双胍加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥LOD至1.0％～1.5％；2) Prepare the second granule: Add the prescribed amount of polyvinylpyrrolidone into water to prepare a binder solution, use a fluidized bed to granulate, set the inlet air temperature at 45°C to 55°C, and the material temperature at 34°C. The air volume of the fan depends on the material flow Adjust the chemical state; after the inlet air temperature reaches the set value, add metformin hydrochloride and preheat it for 5-10 minutes, start spraying the binder solution, and dry the LOD to 1.0%-1.5% after the spraying is completed;
3)整粒及混合：将第一颗粒和第二颗粒整粒并混合均匀；3) Sizing and mixing: sizing and mixing the first granule and the second granule;
4)压片：混合颗粒与处方量硬脂酸镁混合，采用压片机进行压片；4) Tablet compression: the mixed granules are mixed with the prescribed amount of magnesium stearate, and a tablet press is used for tablet compression;
5)包衣：配置薄膜包衣溶液，于包衣机中进行包衣。5) Coating: Prepare a film coating solution and perform coating in a coating machine.
实施例2Example 2
处方组成prescription composition
制备方法：Preparation:
1)制备第一颗粒：将处方量利格列汀、葡甲胺和聚乙烯吡咯烷酮加入水制得包含粘合剂的混合溶液，采用流化床制粒，设定进风温度50℃～60℃，物料温度37℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的预胶化淀粉和微晶纤维素加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥颗粒的干燥失重(LOD)至2.0％～3％；1) Preparation of the first granule: add the prescribed amount of linagliptin, meglumine and polyvinylpyrrolidone to water to prepare a mixed solution containing the binder, use a fluidized bed for granulation, and set the inlet air temperature at 50°C to 60°C ℃, the material temperature is 37 ℃, the air volume of the fan is adjusted according to the fluidization state of the material; after the inlet air temperature reaches the set value, add the pre-mixed pregelatinized starch and microcrystalline cellulose and preheat for 5-10 minutes, start Spray the binder solution, and the loss on drying (LOD) of the dried particles after spraying is 2.0% to 3%;
2)制备第二颗粒：将处方量聚乙烯吡咯烷酮加入水中制得粘合剂溶液，采用流化床制粒，设定进风温度45℃～55℃，物料温度34℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的盐酸二甲双胍和预胶化淀粉混合物加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥LOD至1.0％～1.5％；2) Prepare the second granule: Add the prescribed amount of polyvinylpyrrolidone into water to prepare a binder solution, use a fluidized bed to granulate, set the inlet air temperature at 45°C to 55°C, and the material temperature at 34°C. The air volume of the fan depends on the material flow Adjust the chemical state; after the air inlet temperature reaches the set value, add the pre-mixed metformin hydrochloride and pregelatinized starch mixture and preheat it for 5-10 minutes, start spraying the binder solution, and dry the LOD to 1.0%～1.5%;
3)整粒及混合：将第一颗粒和第二颗粒整粒并混合均匀；3) Sizing and mixing: sizing and mixing the first granule and the second granule;
4)压片：混合颗粒与处方量微粉硅胶和硬脂酸镁混合，采用压片机进行压片；4) Tablet compression: the mixed granules are mixed with the prescribed amount of micropowder silica gel and magnesium stearate, and are compressed by a tablet machine;
5)包衣：配置薄膜包衣溶液，于包衣机中进行包衣。5) Coating: Prepare a film coating solution and perform coating in a coating machine.
实施例3Example 3
处方组成prescription composition
制备方法：Preparation:
1)制备第一颗粒：将处方量利格列汀、葡甲胺和聚乙烯吡咯烷酮加入水制得包含粘合剂的混合溶液，采用流化床制粒，设定进风温度50℃～60℃，物料温度37℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的微晶纤维素和甘露醇加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥颗粒的干燥失重(LOD)至2.0％～3％；1) Preparation of the first granule: add the prescribed amount of linagliptin, meglumine and polyvinylpyrrolidone to water to prepare a mixed solution containing the binder, use a fluidized bed for granulation, and set the inlet air temperature at 50°C to 60°C ℃, the material temperature is 37 ℃, the air volume of the fan is adjusted according to the fluidization state of the material; after the inlet air temperature reaches the set value, add the pre-mixed microcrystalline cellulose and mannitol into it and preheat for 5-10 minutes, and start spraying For the mixture solution, the loss on drying (LOD) of the dried particles after spraying is 2.0% to 3%;
2)制备第二颗粒：将处方量聚乙烯吡咯烷酮加入水中制得粘合剂溶液，采用流化床制粒，设定进风温度45℃～55℃，物料温度34℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将盐酸二甲双胍加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥LOD至1.0％～1.5％；2) Prepare the second granule: Add the prescribed amount of polyvinylpyrrolidone into water to prepare a binder solution, use a fluidized bed to granulate, set the inlet air temperature at 45°C to 55°C, and the material temperature at 34°C. The air volume of the fan depends on the material flow Adjust the chemical state; after the inlet air temperature reaches the set value, add metformin hydrochloride and preheat it for 5-10 minutes, start spraying the binder solution, and dry the LOD to 1.0%-1.5% after the spraying is completed;
3)整粒及混合：将第一颗粒和第二颗粒整粒并混合均匀；3) Sizing and mixing: sizing and mixing the first granule and the second granule;
4)压片：混合颗粒与处方量硬脂酸镁混合，采用压片机进行压片；4) Tablet compression: the mixed granules are mixed with the prescribed amount of magnesium stearate, and a tablet press is used for tablet compression;
5)包衣：配置薄膜包衣溶液，于包衣机中进行包衣。5) Coating: Prepare a film coating solution and perform coating in a coating machine.
实施例4加入葡甲胺未分开制粒Embodiment 4 adds meglumine without separate granulation
处方组成prescription composition
制备方法Preparation
1)将处方量利格列汀、盐酸二甲双胍和葡甲胺混合均匀，再与聚乙烯吡咯烷酮加入水制得包含粘合剂的混合溶液，采用流化床制粒，设定进风温度50℃～60℃，物料温度37℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的甘露醇和玉米淀粉加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥颗粒的干燥失重(LOD)至2.0％～3％；1) Mix the prescribed amount of linagliptin, metformin hydrochloride and meglumine evenly, and then add water with polyvinylpyrrolidone to prepare a mixed solution containing a binder, use fluidized bed granulation, and set the inlet air temperature to 50°C ~60°C, material temperature 37°C, fan air volume adjusted according to the fluidization state of the material; after the inlet air temperature reaches the set value, add the pre-mixed mannitol and cornstarch into it and preheat for 5-10 minutes, start spraying and bonding agent solution, the loss on drying (LOD) of the dried particles after spraying is 2.0% to 3%;
2)将利格列汀+盐酸二甲双胍颗粒整粒并干燥；2) Sizing and drying the linagliptin+metformin hydrochloride granules;
3)颗粒与处方量硬脂酸镁混合，采用压片机进行压片；3) the granule is mixed with the prescribed amount of magnesium stearate, and tableted by a tablet press;
4)配置薄膜包衣溶液，于包衣机中进行包衣。4) Prepare a film coating solution and perform coating in a coating machine.
实施例5对比实施例：未加入葡甲胺且未采用分开制粒Example 5 Comparative Example: Meglumine was not added and separate granulation was not adopted
处方组成prescription composition
制备方法Preparation
1)将处方量利格列汀和盐酸二甲双胍混合均匀，再与聚乙烯吡咯烷酮加入水制得包含粘合剂的混合溶液，采用流化床制粒，设定进风温度50℃～60℃，物料温度37℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的甘露醇和玉米淀粉加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥颗粒的干燥失重(LOD)至2.0％～3％；1) Mix the prescribed amount of linagliptin and metformin hydrochloride evenly, then add water with polyvinylpyrrolidone to prepare a mixed solution containing the binder, use fluidized bed granulation, set the inlet air temperature at 50°C to 60°C, The temperature of the material is 37°C, and the air volume of the fan is adjusted according to the fluidization state of the material; after the inlet air temperature reaches the set value, add the pre-mixed mannitol and corn starch and preheat for 5-10 minutes, start spraying the binder solution, spray The loss on drying (LOD) of the dried granules after the solution is completed is 2.0% to 3%;
2)将利格列汀+盐酸二甲双胍颗粒整粒并干燥；2) Sizing and drying the linagliptin+metformin hydrochloride granules;
3)颗粒与处方量硬脂酸镁混合，采用压片机进行压片；3) the granule is mixed with the prescribed amount of magnesium stearate, and tableted by a tablet press;
4)配置薄膜包衣溶液，于包衣机中进行包衣。4) Prepare a film coating solution and perform coating in a coating machine.
实施例6对比实施例：未加入葡甲胺分开制粒Example 6 Comparative Example: Separate granulation without adding meglumine
处方组成prescription composition
制备方法：Preparation:
1)制备第一颗粒：将处方量利格列汀和聚乙烯吡咯烷酮加入水制得包含粘合剂的混合溶液，采用流化床制粒，设定进风温度50℃～60℃，物料温度37℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将预先混合好的甘露醇和玉米淀粉加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥颗粒的干燥失重(LOD)至2.0％～3％；1) Preparation of the first granule: add the prescribed amount of linagliptin and polyvinylpyrrolidone to water to prepare a mixed solution containing the binder, and use a fluidized bed to granulate, set the inlet air temperature to 50°C to 60°C, and 37°C, the air volume of the fan is adjusted according to the fluidization state of the material; after the inlet air temperature reaches the set value, add the pre-mixed mannitol and cornstarch into it and preheat for 5-10 minutes, start spraying the binder solution, and the spraying is completed The loss on drying (LOD) of post-dried particles is 2.0% to 3%;
2)制备第二颗粒：将处方量聚乙烯吡咯烷酮加入水中制得粘合剂溶液，采用流化床制粒，设定进风温度45℃～55℃，物料温度34℃，风机风量根据物料流化状态调节；待进风温度达到设定值后，将盐酸二甲双胍加入其中并预热5～10min，开始喷粘合剂溶液，喷液完毕后干燥LOD至1.0％～1.5％；2) Prepare the second granule: Add the prescribed amount of polyvinylpyrrolidone into water to prepare a binder solution, use a fluidized bed to granulate, set the inlet air temperature at 45°C to 55°C, and the material temperature at 34°C. The air volume of the fan depends on the material flow Adjust the chemical state; after the inlet air temperature reaches the set value, add metformin hydrochloride and preheat it for 5-10 minutes, start spraying the binder solution, and dry the LOD to 1.0%-1.5% after the spraying is completed;
3)整粒及混合：将第一颗粒和第二颗粒整粒并混合均匀；3) Sizing and mixing: sizing and mixing the first granule and the second granule;
4)压片：混合颗粒与处方量硬脂酸镁混合，采用压片机进行压片；4) Tablet compression: the mixed granules are mixed with the prescribed amount of magnesium stearate, and a tablet press is used for tablet compression;
5)包衣：配置薄膜包衣溶液，于包衣机中进行包衣。5) Coating: Prepare a film coating solution and perform coating in a coating machine.
实施例7稳定性对比试验Embodiment 7 stability comparative test
分别将含有葡甲胺的组合物(实施例1)和不含有葡甲胺的组合物(实施例4)置于60℃的玻璃瓶内，分别于初始时间0个月、1个月、2个月、3个月和6个月时测定稳定性数据，对比其稳定性差异，结果见表1。The composition containing meglumine (Example 1) and the composition (Example 4) not containing meglumine were placed in glass bottles at 60°C respectively, at the initial time of 0 months, 1 month, and 2 months respectively. Stability data were measured at 1 month, 3 months and 6 months, and their stability differences were compared. The results are shown in Table 1.
表1.稳定性对比试验结果Table 1. Stability comparison test results
稳定性测试结果显示，经60℃的玻璃瓶内放置6个月，添加葡甲胺的组合物中利格列汀降解含量仍小于0.1％，而未加入葡甲胺且未采用分开制粒方法制备所得的组合物(实施例5)以及未加入葡甲胺的组合物(实施例6)，内利格列汀降解含量分别高达35.7％和29.6％。由实施例4可知，组合物中加入葡甲胺时，可以大大提高组合物的稳定性，由实施例1可知，本发明在加入葡甲胺的基础上进一步采用的分开制粒方法可以进一步稳定产品性质。因此，葡甲胺加入和分开制粒法可显著抑制利格列汀降解，提高组合物的稳定性。The results of the stability test showed that after being placed in a glass bottle at 60°C for 6 months, the degradation content of linagliptin in the composition added with meglumine was still less than 0.1%, while no meglumine was added and no separate granulation method was adopted In the prepared composition (Example 5) and the composition without adding meglumine (Example 6), the degradation content of nelinagliptin was as high as 35.7% and 29.6%, respectively. As can be seen from Example 4, when meglumine is added in the composition, the stability of the composition can be greatly improved, as can be seen from Example 1, the separate granulation method further adopted by the present invention on the basis of adding meglumine can further stabilize product nature. Therefore, the addition of meglumine and separate granulation can significantly inhibit the degradation of linagliptin and improve the stability of the composition.
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410826967.5ACN104840960A (en) | 2014-02-14 | 2014-12-26 | Antidiabetic pharmaceutical composition and preparation method thereof |
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| CN2014100519418 | 2014-02-14 | ||
| CN201410051941 | 2014-02-14 | ||
| CN201410826967.5ACN104840960A (en) | 2014-02-14 | 2014-12-26 | Antidiabetic pharmaceutical composition and preparation method thereof |
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| CN201410826967.5APendingCN104840960A (en) | 2014-02-14 | 2014-12-26 | Antidiabetic pharmaceutical composition and preparation method thereof |
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| RJ01 | Rejection of invention patent application after publication | Application publication date:20150819 |