CN110279865A - A kind of eutectic compound with collaboration bacteriostasis - Google Patents

A kind of eutectic compound with collaboration bacteriostasis Download PDF

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CN110279865A
CN110279865A CN201910737755.2A CN201910737755A CN110279865A CN 110279865 A CN110279865 A CN 110279865A CN 201910737755 A CN201910737755 A CN 201910737755A CN 110279865 A CN110279865 A CN 110279865A
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eutectic compound
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向飞
曹新欣
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Huang Yong Hua
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Huang Yong Hua
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Abstract

One aspect of the present invention provides a kind of eutectic compound being made of proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor, it is characterized in that, the proton pump inhibitor is selected from one of Omeprazole, Ai Simeila azoles, Pantoprazole, Rabeprazole and Lansoprazole, and the hydroxy-3-methylglutaryl CoA reductase inhibitor is selected from one of Atorvastatin, Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin or its pharmaceutically acceptable salt.Eutectic compound of the present invention can generate the bacteriostasis of collaboration.

Description

A kind of eutectic compound with collaboration bacteriostasis
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of eutectic that can generate collaboration bacteriostasis simultaneously is compound Object.
Background technique
Bacterial infection disease is a kind of disease for seriously threatening human health and life quality, and is resisted with having Bacterium drug resistance it is increasingly serious, develop new antimicrobial then and seem and is especially urgent.
It is clinical using Atorvastatin as hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor class drug of representative Upper common regulating plasma lipid medicine, the antibacterial activity of such drug appears in the newspapers announcement repeatly in recent years.JerwoodS et al. researches show that (JAntimicrobChemother.2008Feb；61 (2): 362-4), Simvastatin and Fluvastatin all have certain antibacterial Effect, wherein the former is respectively 29.2 and 74.9mg/L to the average MIC of MSSA and MRSA, and in contrast, Fluvastatin Antibacterial action is substantially less than Simvastatin.WelshAM et al. reports (Pathology.2009；41 (7): 689-91) claim atropic to cut down Statin and Rosuvastatin also have antibacterial action, but are all remarkably higher than it to the MIC value of MRSA and MSSA and are used to adjust blood lipid When typical blood concentration.MasadehM(AnnClinMicrobiolAntimicrob.2012May7；11:13) et al. also report The antibacterial action of road Atorvastatin, Simvastatin and Rosuvastatin, but its MIC value it is equal > 100mg/L, and antibacterial is made It is unrelated with hydroxyl first glutaryl coenzyme A with mechanism.
Equally there is certain bacteriostasis by the proton pump inhibitor class drug of representative of Omeprazole, than how benefit is magnificent Et al. report (disease surveillance, 2002 (12): 452-454.) Rabeprazole to the MIC of helicobacter pylori99For 2.25 μ g/ ML, the bacteriostasis need to be further increased with bacteriostatic activity of other proton pump inhibitors to other bacteriums.
Pharmaceutical co-crystals refer to active pharmaceutical ingredient (activepharmaceulicalingredient, API) and eutectic Formation (cocrystalformer, CCF) acts on, under Van der Waals force or other non-covalent bond effects in hydrogen bond, pi-pi accumulation, with The crystal that fixed stoichiometric ratio is combined into, the wherein pure state of API and CCF is solid at room temperature, API be molecule or Ionic.CCF is physiologically acceptable acid, alkali, non-ionic compound, can be auxiliary material, vitamin, minerals, amino Acid and food additives etc..Some API molecules can also make CCF, two kinds of general indications of API in this kind of eutectic it is similar or Person is that play the role of synergy, and the effective concentration relationship of the two is similar with the stoichiometric ratio of two components in eutectic, institute A kind of new paragon for preparing compound medicine is also provided with eutectic.In addition, eutectic can also improve the solubility and biology benefit of former API Multiple physical signs such as expenditure.
Temporarily eutectic is formed without proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor in currently available technology to produce The technical teaching of the bacteriostasis of raw collaboration.
Summary of the invention
The purpose of the present invention is to provide one kind by proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor structure At eutectic compound and contain the composition of the eutectic compound.The eutectic compound can generate the antibacterial work of collaboration With.
To achieve the goals above, present invention firstly provides one kind by proton pump inhibitor and hydroxyl first glutaryl coenzyme A The eutectic compound that reductase inhibitor is constituted, which is characterized in that the proton pump inhibitor is selected from Omeprazole, Ai Simei One of azoles, Pantoprazole, Rabeprazole and Lansoprazole are drawn, the hydroxy-3-methylglutaryl CoA reductase inhibitor is One in Atorvastatin, Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin Kind or its pharmaceutically acceptable salt.
On the one hand preferred, proton pump inhibitor and hydroxyl first glutaryl coenzyme A reductase in eutectic compound of the present invention The molar ratio of enzyme inhibitor is between 0.318:1~3.149:1.
It is furthermore preferred that eutectic compound of the present invention is selected from one of eutectic compound as described below:
The eutectic compound that Omeprazole and Atorvastatin are constituted with the molar ratio of 0.503:1,
The eutectic compound that Omeprazole and Atorvastatin are constituted with the molar ratio of 2.089:1,
The eutectic compound that Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 0.973:1,
The eutectic compound that Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 3.137:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.340:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.494:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 1.947:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 2.952:1,
The eutectic compound that Rabeprazole and Atorvastatin are constituted with the molar ratio of 0.349:1,
The eutectic compound that Rabeprazole and Atorvastatin are constituted with the molar ratio of 2.100:1,
The eutectic compound that Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.318:1,
The eutectic compound that Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.505:1,
The eutectic compound that Lansoprazole and Atorvastatin are constituted with the molar ratio of 1.997:1,
The eutectic compound that Omeprazole and Rosuvastatin are constituted with the molar ratio of 0.321:1,
The eutectic compound that Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 0.499:1,
The eutectic compound that Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 1.954:1,
The eutectic compound that Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.342:1,
The eutectic compound that Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.498:1,
The eutectic compound that Pantoprazole and Rosuvastatin are constituted with the molar ratio of 3.131:1,
The eutectic compound that Rabeprazole and Rosuvastatin are constituted with the molar ratio of 2.937:1,
The eutectic compound that Lansoprazole and Rosuvastatin are constituted with the molar ratio of 0.510:1,
The eutectic compound that Lansoprazole and Rosuvastatin are constituted with the molar ratio of 2.912:1,
The eutectic compound that Omeprazole and Simvastatin are constituted with the molar ratio of 1.991:1,
The eutectic compound that Ai Simeila azoles and Simvastatin are constituted with the molar ratio of 1.904:1,
The eutectic compound that Rabeprazole and Simvastatin are constituted with the molar ratio of 0.478:1,
The eutectic compound that Rabeprazole and Simvastatin are constituted with the molar ratio of 0.957:1,
The eutectic compound that Lansoprazole and Simvastatin are constituted with the molar ratio of 0.521:1,
The eutectic compound that Omeprazole and Pitavastatin are constituted with the molar ratio of 3.128:1,
The eutectic compound that Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 0.499:1,
The eutectic compound that Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 2.033:1,
The eutectic compound that Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 3.149:1,
The eutectic compound that Pantoprazole and Pitavastatin are constituted with the molar ratio of 0.964:1,
The eutectic compound that Rabeprazole and Pitavastatin are constituted with the molar ratio of 1.047:1,
The eutectic compound that Rabeprazole and Pitavastatin are constituted with the molar ratio of 3.006:1,
The eutectic compound that Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.325:1,
The eutectic compound that Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.486:1,
The eutectic compound that Lansoprazole and Pitavastatin are constituted with the molar ratio of 2.920:1,
The eutectic compound that Omeprazole and Lovastatin are constituted with the molar ratio of 0.494:1,
The eutectic compound that Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.330:1,
The eutectic compound that Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.520:1,
The eutectic compound that Rabeprazole and Lovastatin are constituted with the molar ratio of 0.332:1,
The eutectic compound that Lansoprazole and Lovastatin are constituted with the molar ratio of 1.946:1,
The eutectic compound that Omeprazole and Fluvastatin are constituted with the molar ratio of 0.344:1,
The eutectic compound that Omeprazole and Fluvastatin are constituted with the molar ratio of 0.504:1,
The eutectic compound that Omeprazole and Fluvastatin are constituted with the molar ratio of 0.976:1,
The eutectic compound that Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 1.022:1,
The eutectic compound that Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 2.966:1,
The eutectic compound that Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.345:1,
The eutectic compound that Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.503:1,
The eutectic compound that Lansoprazole and Fluvastatin are constituted with the molar ratio of 0.328:1,
The eutectic compound that Lansoprazole and Fluvastatin are constituted with the molar ratio of 1.900:1,
The eutectic compound that Omeprazole and Pravastatin are constituted with the molar ratio of 0.323:1,
The eutectic compound that Omeprazole and Pravastatin are constituted with the molar ratio of 0.952:1,
The eutectic compound that Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 0.341:1,
The eutectic compound that Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 3.063:1,
The eutectic compound that Rabeprazole and Pravastatin are constituted with the molar ratio of 0.489:1,
The eutectic compound that Rabeprazole and Pravastatin are constituted with the molar ratio of 1.985:1,
The eutectic compound that Rabeprazole and Pravastatin are constituted with the molar ratio of 2.863:1,
The eutectic compound that Lansoprazole and Pravastatin are constituted with the molar ratio of 0.332:1,
The eutectic compound that Lansoprazole and Pravastatin are constituted with the molar ratio of 0.501:1,
The eutectic compound that Lansoprazole and Pravastatin are constituted with the molar ratio of 3.079:1,
It is further preferred that eutectic compound of the present invention is selected from one of eutectic compound as described below:
Omeprazole and Atorvastatin are constituted with the molar ratio of 0.503:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 22.6 °,
Omeprazole and Atorvastatin are constituted with the molar ratio of 2.089:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 10.6 °,
Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 0.973:1, and are indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure have the eutectic compound of maximum characteristic absorption peak at 5.3 °,
Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 3.137:1, and are indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure have the eutectic compound of maximum characteristic absorption peak at 31.9 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.340:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 41.3 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.494:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 28.8 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 1.947:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 3.6 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 2.952:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 28.9 °,
Rabeprazole and Atorvastatin are constituted with the molar ratio of 0.349:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 40.0 °,
Rabeprazole and Atorvastatin are constituted with the molar ratio of 2.100:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 16.0 °,
Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.318:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 9.4 °,
Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.505:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 37.2 °,
Lansoprazole and Atorvastatin are constituted with the molar ratio of 1.997:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 41.5 °,
Omeprazole and Rosuvastatin are constituted with the molar ratio of 0.321:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 46.3 °,
Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 0.499:1, and are indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure have the eutectic compound of maximum characteristic absorption peak at 1.3 °,
Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 1.954:1, and are indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure have the eutectic compound of maximum characteristic absorption peak at 15.6 °,
Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.342:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 15.7 °,
Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.498:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 37.9 °,
Pantoprazole and Rosuvastatin are constituted with the molar ratio of 3.131:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 14.9 °,
Rabeprazole and Rosuvastatin are constituted with the molar ratio of 2.937:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 3.8 °,
Lansoprazole and Rosuvastatin are constituted with the molar ratio of 0.510:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 23.4 °,
Lansoprazole and Rosuvastatin are constituted with the molar ratio of 2.912:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 27.9 °,
Omeprazole and Simvastatin are constituted with the molar ratio of 1.991:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 3.1 °,
Ai Simeila azoles and Simvastatin are constituted with the molar ratio of 1.904:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 25.6 °,
Rabeprazole and Simvastatin are constituted with the molar ratio of 0.478:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 23.2 °,
Rabeprazole and Simvastatin are constituted with the molar ratio of 0.957:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 6.7 °,
Lansoprazole and Simvastatin are constituted with the molar ratio of 0.521:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 36.2 °,
Omeprazole and Pitavastatin are constituted with the molar ratio of 3.128:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 15.8 °,
Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 0.499:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 37.6 °,
Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 2.033:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 34.5 °,
Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 3.149:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 37.2 °,
Pantoprazole and Pitavastatin are constituted with the molar ratio of 0.964:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 35.9 °,
Rabeprazole and Pitavastatin are constituted with the molar ratio of 1.047:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 15.0 °,
Rabeprazole and Pitavastatin are constituted with the molar ratio of 3.006:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 22.6 °,
Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.325:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 11.5 °,
Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.486:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 10.6 °,
Lansoprazole and Pitavastatin are constituted with the molar ratio of 2.920:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 5.3 °,
Omeprazole and Lovastatin are constituted with the molar ratio of 0.494:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 4.1 °,
Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.330:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 13.4 °,
Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.520:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 17.3 °,
Rabeprazole and Lovastatin are constituted with the molar ratio of 0.332:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 1.3 °,
Lansoprazole and Lovastatin are constituted with the molar ratio of 1.946:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 13.4 °,
Omeprazole and Fluvastatin are constituted with the molar ratio of 0.344:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 44.1 °,
Omeprazole and Fluvastatin are constituted with the molar ratio of 0.504:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 44.9 °,
Omeprazole and Fluvastatin are constituted with the molar ratio of 0.976:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 32.6 °,
Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 1.022:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 8.3 °,
Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 2.966:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 1.6 °,
Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.345:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 7.0 °,
Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.503:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 8.8 °,
Lansoprazole and Fluvastatin are constituted with the molar ratio of 0.328:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 4.8 °,
Lansoprazole and Fluvastatin are constituted with the molar ratio of 1.900:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 23.9 °,
Omeprazole and Pravastatin are constituted with the molar ratio of 0.323:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 42.9 °,
Omeprazole and Pravastatin are constituted with the molar ratio of 0.952:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 32.1 °,
Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 0.341:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 24.7 °,
Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 3.063:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction X-ray powder diffraction figure has the eutectic compound of maximum characteristic absorption peak at 1.5 °,
Rabeprazole and Pravastatin are constituted with the molar ratio of 0.489:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 7.8 °,
Rabeprazole and Pravastatin are constituted with the molar ratio of 1.985:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 21.3 °,
Rabeprazole and Pravastatin are constituted with the molar ratio of 2.863:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 24.6 °,
Lansoprazole and Pravastatin are constituted with the molar ratio of 0.332:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 38.6 °,
Lansoprazole and Pravastatin are constituted with the molar ratio of 0.501:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 10.7 °,
Lansoprazole and Pravastatin are constituted with the molar ratio of 3.079:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 27.6 °.
Most preferably, eutectic compound of the present invention can be prepared by the following method:
Proton pump inhibitor of the molar ratio between 0.333:1~3:1 and HMG-CoA reductase is taken to inhibit Agent is sufficiently mixed and is placed in planetary ball mill, and 30~60min is ground under the revolving speed of 200~400r/min, collects product, It is recrystallized again with selected from one of ethyl alcohol, acetone, methanol, acetonitrile, ethyl acetate and isopropanol organic solvent.
Another aspect of the present invention provides the composition containing eutectic compound as previously described.
Preferably, composition of the present invention can be made into the pharmaceutical preparation of oral or injection administration.
It is further preferred that oral drug preparation of the present invention is selected from one of capsule, tablet and granule.
Another aspect of the present invention provide foregoing eutectic compound preparation for treat bacterial infection and/or Purposes in the drug of anaphylactia.
Preferably, bacterial infection of the present invention be by selected from actinomyces viscosus, bacteroides fragilis, brevibacterium epidermidis, Infection caused by one of clostridium difficile, clostridium tetani, paratyphosus A bacillus and streptococcus pneumonia.
Eutectic compound of the present invention can generate the antibacterial action of collaboration simultaneously.
Specific embodiment
Below with reference to the embodiment of the present invention, clear, complete description is carried out to technical solution of the present invention, it is clear that retouched The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair The range of bright protection.
The present invention indicates being total to for the two with hydroxy-3-methylglutaryl CoA reductase inhibitor with " " connection proton pump inhibitor Brilliant compound.
Molar ratio of the present invention is proton pump inhibitor and HMG-CoA reductase in eutectic compound The molar ratio of inhibitor.
The preparation of 1 eutectic compound
Present invention polishing with reference to disclosed by ScottC.McKellar et al. (CrystalGrowth&Design2014, 14,5,2422~2430) eutectic compound of the present invention has been prepared.
Specifically, the proton pump inhibitor of certain mol proportion and hydroxy-3-methylglutaryl CoA reductase inhibitor is taken to be placed in ball In grinding machine, ground 15~60 minutes with the frequency of 30~60Hz at room temperature.It is melted away from≤2 DEG C using product as standard, to ball milling Unit frequency is optimized and is screened with milling time.
The structural identification and characterization of 2 eutectic compounds
The Preliminary detection of determination and purity that 2.1 eutectics are formed
If the product melting range of grinding is lower than 2 DEG C, then it is assumed that have formed single eutectic compound.
The measurement of proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor molar ratio in 2.2 eutectic compounds
The present invention uses1H-NMR (500Hz, CD3Cl proton pump inhibitor and hydroxyl first glutaryl in eutectic compound) are measured The molar ratio of CoA-reductase inhibitors, specifically, by calculating various eutectic compounds1Specific absorption in H-NMR map The ratio (r) that peak corresponding peak area (X) accounts for total peak area (Y) calculates molar ratio (R), and the peak area disregards- OH、-NH2,-NH- isoreactivity hydrogen peak area.
The corresponding δ value of X and ownership for calculating the R value of various eutectics is as shown in table 1.
Table 1
Eutectic compound δ value (ppm) Ownership
Eutectic compound containing Atorvastatin ~1.35 Two methyl of isopropyl on Atorvastatin pyrrole ring
Eutectic compound containing Rosuvastatin ~1.35 Two methyl of isopropyl on Rosuvastatin pyrimidine ring
Eutectic compound containing Simvastatin 0.8~0.9 Three methyl in Simvastatin
Eutectic compound containing Lovastatin 0.8~0.95 Three methyl in Lovastatin
Eutectic compound containing Fluvastatin ~1.35 Two methyl of isopropyl on Fluvastatin indole ring
Eutectic compound containing Pravastatin 0.8~0.95 Two methyl in Pravastatin
Eutectic compound containing Pitavastatin 0.95~1.25 Two methylene of cyclopropyl in Pitavastatin
1.3X- ray powder diffraction
Use Rigaku Co., Ltd. X-ray powder diffraction instrument MiniFlex II, concrete operations parameter such as table 2.
2 X-ray powder diffraction instrument operating parameter of table
Instrument model RigakuMinfiFlexⅡ Emit target CuKα(1.5405A)
Scanning speed 8°/min Scanning step 0.02°
The preparation of 1. Omeprazole Atorvastatin eutectic compound of embodiment
Omeprazole 46.056g and Atorvastatin 148.971g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 350r/min, collects product, obtains 183.363g micro white powder, and fusing point is 82.8~84.8 DEG C.With 182.740g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 155.1~156.0 DEG C, and R value is 0.503.
The preparation of 2. Omeprazole Atorvastatin eutectic compound of embodiment
Omeprazole 92.112g and Atorvastatin 74.485g are taken, is sufficiently mixed and is placed in planetary ball mill, 30min is ground under the revolving speed of 300r/min, collects product, obtains 161.854g micro white powder, and fusing point is 109.2~111.1 DEG C. With 161.362g white crystals type powder is obtained after acetone recrystallization, fusing point is 110.6~111.5 DEG C, and R value is 2.089.
The preparation of 3. Ai Simeila azoles Atorvastatin eutectic compound of embodiment
Ai Simeila azoles 69.084g and Atorvastatin 111.728g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 200r/min, collects product, obtains 173.986g micro white powder, and fusing point is 101.2~103.0 DEG C. With 173.644g white crystals type powder is obtained after recrystallizing methanol, fusing point is 103.1~104.1 DEG C, and R value is 0.973.
The preparation of 4. Ai Simeila azoles Atorvastatin eutectic compound of embodiment
Ai Simeila azoles 103.626g and Atorvastatin 55.864g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 400r/min, collects product, obtains 155.509g micro white powder, and fusing point is 66.6~68.6 DEG C.With 155.139g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 67.1~68.0 DEG C, and R value is 3.137.
The preparation of 5. Pantoprazole Atorvastatin eutectic compound of embodiment
Pantoprazole 38.308g and Atorvastatin 167.634g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 400r/min, collects product, obtains 199.357g micro white powder, and fusing point is 98.2~100.2 DEG C. With 198.601g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 99.9~100.9 DEG C, and R value is 0.340.
The preparation of 6. Pantoprazole Atorvastatin eutectic compound of embodiment
Pantoprazole 51.116g and Atorvastatin 148.971g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 350r/min, collects product, obtains 197.465g micro white powder, and fusing point is 72.3~74.3 DEG C.With 197.298g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 72.0~73.0 DEG C, and R value is 0.494.
The preparation of 7. Pantoprazole Atorvastatin eutectic compound of embodiment
Pantoprazole 102.232g and Atorvastatin 74.485g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 200r/min, collects product, obtains 161.419g micro white powder, and fusing point is 129.4~131.3 DEG C. With 160.771g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 129.0~130.0 DEG C, and R value is 1.947.
The preparation of 8. Pantoprazole Atorvastatin eutectic compound of embodiment
Pantoprazole 115.011g and Atorvastatin 55.864g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 300r/min, collects product, obtains 155.028g micro white powder, and fusing point is 108.0~109.8 DEG C. With 154.261g white crystals type powder is obtained after acetone recrystallization, fusing point is 108.4~109.3 DEG C, and R value is 2.952.
The preparation of 9. Rabeprazole Atorvastatin eutectic compound of embodiment
Rabeprazole 35.917g and Atorvastatin 167.634g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 350r/min, collects product, obtains 189.586g micro white powder, and fusing point is 110.7~112.7 DEG C. With 189.453g white crystals type powder is obtained after recrystallizing methanol, fusing point is 112.5~113.5 DEG C, and R value is 0.349.
The preparation of 10. Rabeprazole Atorvastatin eutectic compound of embodiment
Rabeprazole 95.851g and Atorvastatin 74.485g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 300r/min, collects product, obtains 163.011g micro white powder, and fusing point is 96.1~98.1 DEG C.With 162.669g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 172.8~173.8 DEG C, and R value is 2.100.
The preparation of 11. Lansoprazole Atorvastatin eutectic compound of embodiment
Lansoprazole 36.908g and Atorvastatin 167.634g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 400r/min, collects product, obtains 201.217g micro white powder, and fusing point is 97.8~99.7 DEG C.With 201.146g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 98.2~99.2 DEG C, and R value is 0.318.
The preparation of 12. Lansoprazole Atorvastatin eutectic compound of embodiment
Lansoprazole 49.248g and Atorvastatin 148.971g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 350r/min, collects product, obtains 195.903g micro white powder, and fusing point is 56.9~58.9 DEG C.With 195.194g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 56.7~57.7 DEG C, and R value is 0.505.
The preparation of 13. Lansoprazole Atorvastatin eutectic compound of embodiment
Lansoprazole 98.496g and Atorvastatin 74.485g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 200r/min, collects product, obtains 159.718g micro white powder, and fusing point is 119.5~121.4 DEG C. With 159.467g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 114.2~115.2 DEG C, and R value is 1.997.
The preparation of 14. Omeprazole Rosuvastatin eutectic compound of embodiment
Omeprazole 34.516g and Rosuvastatin 144.498g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 200r/min, collects product, obtains 161.976g micro white powder, and fusing point is 110.7~112.5 DEG C. With 161.268g white crystals type powder is obtained after acetone recrystallization, fusing point is 111.8~112.8 DEG C, and R value is 0.321.
The preparation of 15. Ai Simeila azoles Rosuvastatin eutectic compound of embodiment
Ai Simeila azoles 46.056g and Rosuvastatin 128.411g are taken, is sufficiently mixed and is placed in planetary ball mill, 30min is ground under the revolving speed of 350r/min, collects product, obtains 174.042g micro white powder, and fusing point is 115.4~117.3 DEG C. With 173.633g white crystals type powder is obtained after recrystallizing methanol, fusing point is 114.0~115.0 DEG C, and R value is 0.499.
The preparation of 16. Ai Simeila azoles Rosuvastatin eutectic compound of embodiment
Ai Simeila azoles 92.112g and Rosuvastatin 64.205g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 200r/min, collects product, obtains 148.739g micro white powder, and fusing point is 93.5~95.4 DEG C.With 148.001g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 92.1~93.1 DEG C, and R value is 1.954.
The preparation of 17. Pantoprazole Rosuvastatin eutectic compound of embodiment
Pantoprazole 38.308g and Rosuvastatin 144.498g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 350r/min, collects product, obtains 164.847g micro white powder, and fusing point is 109.8~111.7 DEG C. With 164.031g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 104.6~105.5 DEG C, and R value is 0.342.
The preparation of 18. Pantoprazole Rosuvastatin eutectic compound of embodiment
Pantoprazole 51.116g and Rosuvastatin 128.411g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 350r/min, collects product, obtains 162.899g micro white powder, and fusing point is 98.5~100.4 DEG C. With 162.878g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 96.9~97.8 DEG C, and R value is 0.498.
The preparation of 19. Pantoprazole Rosuvastatin eutectic compound of embodiment
Pantoprazole 115.011g and Rosuvastatin 48.154g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 350r/min, collects product, obtains 156.275g micro white powder, and fusing point is 116.8~118.8 DEG C. With 155.872g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 115.6~116.5 DEG C, and R value is 3.131.
The preparation of 20. Rabeprazole Rosuvastatin eutectic compound of embodiment
Rabeprazole 107.832g and Rosuvastatin 48.154g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 300r/min, collects product, obtains 154.264g micro white powder, and fusing point is 105.7~107.7 DEG C. With 153.981g white crystals type powder is obtained after acetone recrystallization, fusing point is 106.3~107.3 DEG C, and R value is 2.937.
The preparation of 21. Lansoprazole Rosuvastatin eutectic compound of embodiment
Lansoprazole 49.248g and Rosuvastatin 128.411g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 400r/min, collects product, obtains 174.952g micro white powder, and fusing point is 88.5~90.3 DEG C.With 174.574g white crystals type powder is obtained after recrystallizing methanol, fusing point is 88.0~88.9 DEG C, and R value is 0.510.
The preparation of 22. Lansoprazole Rosuvastatin eutectic compound of embodiment
Lansoprazole 110.808g and Rosuvastatin 48.154g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 250r/min, collects product, obtains 148.070g micro white powder, and fusing point is 167.4~169.3 DEG C. With 147.338g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 164.6~165.5 DEG C, and R value is 2.912.
The preparation of 23. Omeprazole Simvastatin eutectic compound of embodiment
Omeprazole 92.112g and Simvastatin 55.809g are taken, is sufficiently mixed and is placed in planetary ball mill, in 250r/ 55min is ground under the revolving speed of min, collects product, obtains 147.172g micro white powder, and fusing point is 66.1~68.0 DEG C.Use acetic acid 146.883g white crystals type powder is obtained after ethyl ester recrystallization, fusing point is 65.7~66.7 DEG C, and R value is 1.991.
The preparation of 24. Ai Simeila azoles Simvastatin eutectic compound of embodiment
Ai Simeila azoles 92.112g and Simvastatin 55.809g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 300r/min, collects product, obtains 140.665g micro white powder, and fusing point is 142.1~144.0 DEG C. With 140.618g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 139.8~140.7 DEG C, and R value is 1.904.
The preparation of 25. Rabeprazole Simvastatin eutectic compound of embodiment
Rabeprazole 47.925g and Simvastatin 111.619g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 300r/min, collects product, obtains 147.903g micro white powder, and fusing point is 103.4~105.2 DEG C. With 147.880g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 104.0~105.0 DEG C, and R value is 0.478.
The preparation of 26. Rabeprazole Simvastatin eutectic compound of embodiment
Rabeprazole 71.888g and Simvastatin 83.714g are taken, is sufficiently mixed and is placed in planetary ball mill, in 300r/ 50min is ground under the revolving speed of min, collects product, obtains 148.660g micro white powder, and fusing point is 104.3~106.2 DEG C.With third 148.459g white crystals type powder is obtained after ketone recrystallization, fusing point is 105.4~106.3 DEG C, and R value is 0.957.
The preparation of 27. Lansoprazole Simvastatin eutectic compound of embodiment
Lansoprazole 49.248g and Simvastatin 111.619g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 400r/min, collects product, obtains 146.551g micro white powder, and fusing point is 124.4~126.3 DEG C. With 146.302g white crystals type powder is obtained after recrystallizing methanol, fusing point is 122.8~123.8 DEG C, and R value is 0.521.
The preparation of 28. Omeprazole Pitavastatin eutectic compound of embodiment
Omeprazole 103.626g and Pitavastatin 42.146g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 350r/min, collects product, obtains 131.672g micro white powder, and fusing point is 82.6~84.5 DEG C.With 131.522g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 82.7~83.7 DEG C, and R value is 3.128.
The preparation of 29. Ai Simeila azoles Pitavastatin eutectic compound of embodiment
Ai Simeila azoles 46.056g and Pitavastatin 112.389g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 400r/min, collects product, obtains 153.289g micro white powder, and fusing point is 103.2~105.1 DEG C. With 153.210g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 101.2~102.1 DEG C, and R value is 0.499.
The preparation of 30. Ai Simeila azoles Pitavastatin eutectic compound of embodiment
Ai Simeila azoles 92.112g and Pitavastatin 56.195g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 300r/min, collects product, obtains 136.986g micro white powder, and fusing point is 62.6~64.6 DEG C.With 136.822g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 63.7~64.7 DEG C, and R value is 2.033.
The preparation of 31. Ai Simeila azoles Pitavastatin eutectic compound of embodiment
Ai Simeila azoles 103.626g and Pitavastatin 42.146g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 300r/min, collects product, obtains 133.482g micro white powder, and fusing point is 136.6~138.4 DEG C. With 133.471g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 137.6~138.6 DEG C, and R value is 3.149.
The preparation of 32. Pantoprazole Pitavastatin eutectic compound of embodiment
Pantoprazole 76.674g and Pitavastatin 84.292g are taken, is sufficiently mixed and is placed in planetary ball mill, in 400r/ 50min is ground under the revolving speed of min, collects product, obtains 159.500g micro white powder, and fusing point is 98.1~99.9 DEG C.Use acetone 158.727g white crystals type powder is obtained after recrystallization, fusing point is 96.2~97.1 DEG C, and R value is 0.964.
The preparation of 33. Rabeprazole Pitavastatin eutectic compound of embodiment
Rabeprazole 71.888g and Pitavastatin 84.292g are taken, is sufficiently mixed and is placed in planetary ball mill, in 200r/ 55min is ground under the revolving speed of min, collects product, obtains 143.320g micro white powder, and fusing point is 105.3~107.2 DEG C.Use first 143.148g white crystals type powder is obtained after alcohol recrystallization, fusing point is 106.5~107.5 DEG C, and R value is 1.047.
The preparation of 34. Rabeprazole Pitavastatin eutectic compound of embodiment
Rabeprazole 107.832g and Pitavastatin 42.146g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 350r/min, collects product, obtains 144.152g micro white powder, and fusing point is 145.7~147.6 DEG C. With 143.756g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 143.7~144.6 DEG C, and R value is 3.006.
The preparation of 35. Lansoprazole Pitavastatin eutectic compound of embodiment
Lansoprazole 36.908g and Pitavastatin 126.470g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 250r/min, collects product, obtains 150.573g micro white powder, and fusing point is 107.3~109.2 DEG C. With 150.032g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 106.8~107.7 DEG C, and R value is 0.325.
The preparation of 36. Lansoprazole Pitavastatin eutectic compound of embodiment
Lansoprazole 49.248g and Pitavastatin 112.389g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 350r/min, collects product, obtains 155.443g micro white powder, and fusing point is 82.8~84.6 DEG C.With 154.918g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 82.1~83.1 DEG C, and R value is 0.486.
The preparation of 37. Lansoprazole Pitavastatin eutectic compound of embodiment
Lansoprazole 110.808g and Pitavastatin 42.146g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 200r/min, collects product, obtains 138.930g micro white powder, and fusing point is 103.9~105.8 DEG C. With 138.441g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 105.1~106.0 DEG C, and R value is 2.920.
The preparation of 38. Omeprazole Lovastatin eutectic compound of embodiment
Omeprazole 46.056g and Lovastatin 107.877g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 250r/min, collects product, obtains 141.472g micro white powder, and fusing point is 91.5~93.5 DEG C.With 140.805g white crystals type powder is obtained after acetone recrystallization, fusing point is 92.2~93.2 DEG C, and R value is 0.494.
The preparation of 39. Ai Simeila azoles Lovastatin eutectic compound of embodiment
Ai Simeila azoles 34.516g and Lovastatin 121.392g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 250r/min, collects product, obtains 153.946g micro white powder, and fusing point is 114.8~116.8 DEG C. With 153.851g white crystals type powder is obtained after recrystallizing methanol, fusing point is 115.8~116.8 DEG C, and R value is 0.330.
The preparation of 40. Ai Simeila azoles Lovastatin eutectic compound of embodiment
Ai Simeila azoles 46.056g and Lovastatin 107.877g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 250r/min, collects product, obtains 143.321g micro white powder, and fusing point is 72.1~74.0 DEG C.With 142.823g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 71.5~72.5 DEG C, and R value is 0.520.
The preparation of 41. Rabeprazole Lovastatin eutectic compound of embodiment
Rabeprazole 35.917g and Lovastatin 121.392g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 400r/min, collects product, obtains 143.323g micro white powder, and fusing point is 101.1~103.1 DEG C. With 142.791g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 100.9~101.8 DEG C, and R value is 0.332.
The preparation of 42. Lansoprazole Lovastatin eutectic compound of embodiment
Lansoprazole 98.496g and Lovastatin 53.939g are taken, is sufficiently mixed and is placed in planetary ball mill, in 300r/ 40min is ground under the revolving speed of min, collects product, obtains 149.445g micro white powder, and fusing point is 130.7~132.6 DEG C.With different 149.379g white crystals type powder is obtained after propyl alcohol recrystallization, fusing point is 129.7~130.7 DEG C, and R value is 1.946.
The preparation of 43. Omeprazole Fluvastatin eutectic compound of embodiment
Omeprazole 34.516g and Fluvastatin 123.472g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 350r/min, collects product, obtains 152.219g micro white powder, and fusing point is 142.2~144.0 DEG C. With 152.012g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 144.6~145.5 DEG C, and R value is 0.344.
The preparation of 44. Omeprazole Fluvastatin eutectic compound of embodiment
Omeprazole 46.056g and Fluvastatin 109.725g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 300r/min, collects product, obtains 149.663g micro white powder, and fusing point is 104.0~105.8 DEG C. With 149.162g white crystals type powder is obtained after acetone recrystallization, fusing point is 103.3~104.3 DEG C, and R value is 0.504.
The preparation of 45. Omeprazole Fluvastatin eutectic compound of embodiment
Omeprazole 69.084g and Fluvastatin 82.294g are taken, is sufficiently mixed and is placed in planetary ball mill, in 250r/ 40min is ground under the revolving speed of min, collects product, obtains 150.001g micro white powder, and fusing point is 101.1~103.0 DEG C.Use first 149.788g white crystals type powder is obtained after alcohol recrystallization, fusing point is 100.3~101.2 DEG C, and R value is 0.976.
The preparation of 46. Ai Simeila azoles Fluvastatin eutectic compound of embodiment
Ai Simeila azoles 69.084g and Fluvastatin 82.294g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 350r/min, collects product, obtains 144.823g micro white powder, and fusing point is 110.5~112.4 DEG C. With 144.191g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 110.5~111.5 DEG C, and R value is 1.022.
The preparation of 47. Ai Simeila azoles Fluvastatin eutectic compound of embodiment
Ai Simeila azoles 103.626g and Fluvastatin 41.147g are taken, is sufficiently mixed and is placed in planetary ball mill, 40min is ground under the revolving speed of 250r/min, collects product, obtains 142.830g micro white powder, and fusing point is 100.0~101.9 DEG C. With 142.599g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 98.8~99.8 DEG C, and R value is 2.966.
The preparation of 48. Pantoprazole Fluvastatin eutectic compound of embodiment
Pantoprazole 38.308g and Fluvastatin 123.472g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 300r/min, collects product, obtains 150.110g micro white powder, and fusing point is 130.5~132.4 DEG C. With 149.569g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 128.8~129.8 DEG C, and R value is 0.345.
The preparation of 49. Pantoprazole Fluvastatin eutectic compound of embodiment
Pantoprazole 51.116g and Fluvastatin 109.725g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 250r/min, collects product, obtains 155.977g micro white powder, and fusing point is 115.3~117.2 DEG C. With 155.266g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 116.5~117.4 DEG C, and R value is 0.503.
The preparation of 50. Lansoprazole Fluvastatin eutectic compound of embodiment
Lansoprazole 36.908g and Fluvastatin 123.472g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 250r/min, collects product, obtains 155.249g micro white powder, and fusing point is 123.0~125.0 DEG C. With 154.701g white crystals type powder is obtained after acetone recrystallization, fusing point is 120.9~121.9 DEG C, and R value is 0.328.
The preparation of 51. Lansoprazole Fluvastatin eutectic compound of embodiment
Lansoprazole 98.496g and Fluvastatin 54.863g are taken, is sufficiently mixed and is placed in planetary ball mill, in 350r/ 55min is ground under the revolving speed of min, collects product, obtains 153.203g micro white powder, and fusing point is 109.8~111.6 DEG C.Use first 153.194g white crystals type powder is obtained after alcohol recrystallization, fusing point is 111.4~112.3 DEG C, and R value is 1.900.
The preparation of 52. Omeprazole Pravastatin eutectic compound of embodiment
Omeprazole 34.516g and Pravastatin 133.986g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 350r/min, collects product, obtains 167.359g micro white powder, and fusing point is 128.9~130.9 DEG C. With 167.119g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 127.0~128.0 DEG C, and R value is 0.323.
The preparation of 53. Omeprazole Pravastatin eutectic compound of embodiment
Omeprazole 69.084g and Pravastatin 89.302g are taken, is sufficiently mixed and is placed in planetary ball mill, in 300r/ 40min is ground under the revolving speed of min, collects product, obtains 153.809g micro white powder, and fusing point is 72.3~74.2 DEG C.Use acetic acid 153.797g white crystals type powder is obtained after ethyl ester recrystallization, fusing point is 71.8~72.7 DEG C, and R value is 0.952.
The preparation of 54. Ai Simeila azoles Pravastatin eutectic compound of embodiment
Ai Simeila azoles 34.516g and Pravastatin 133.986g are taken, is sufficiently mixed and is placed in planetary ball mill, 50min is ground under the revolving speed of 200r/min, collects product, obtains 163.510g micro white powder, and fusing point is 139.3~141.2 DEG C. With 163.358g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 139.5~140.4 DEG C, and R value is 0.341.
The preparation of 55. Ai Simeila azoles Pravastatin eutectic compound of embodiment
Ai Simeila azoles 103.626g and Pravastatin 44.651g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 350r/min, collects product, obtains 147.021g micro white powder, and fusing point is 174.3~176.2 DEG C. With 146.601g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 171.5~172.4 DEG C, and R value is 3.063.
The preparation of 56. Rabeprazole Pravastatin eutectic compound of embodiment
Rabeprazole 47.925g and Pravastatin 119.069g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 250r/min, collects product, obtains 156.909g micro white powder, and fusing point is 60.9~62.8 DEG C.With 156.334g white crystals type powder is obtained after acetone recrystallization, fusing point is 61.8~62.7 DEG C, and R value is 0.489.
The preparation of 57. Rabeprazole Pravastatin eutectic compound of embodiment
Rabeprazole 95.851g and Pravastatin 59.535g are taken, is sufficiently mixed and is placed in planetary ball mill, in 350r/ 60min is ground under the revolving speed of min, collects product, obtains 141.283g micro white powder, and fusing point is 153.7~155.5 DEG C.Use first 140.957g white crystals type powder is obtained after alcohol recrystallization, fusing point is 154.9~155.8 DEG C, and R value is 1.985.
The preparation of 58. Rabeprazole Pravastatin eutectic compound of embodiment
Rabeprazole 107.832g and Pravastatin 44.651g are taken, is sufficiently mixed and is placed in planetary ball mill, 45min is ground under the revolving speed of 300r/min, collects product, obtains 143.094g micro white powder, and fusing point is 157.1~158.9 DEG C. With 142.966g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 159.4~160.4 DEG C, and R value is 2.863.
The preparation of 59. Lansoprazole Pravastatin eutectic compound of embodiment
Lansoprazole 36.908g and Pravastatin 133.986g are taken, is sufficiently mixed and is placed in planetary ball mill, 60min is ground under the revolving speed of 250r/min, collects product, obtains 161.492g micro white powder, and fusing point is 122.3~124.3 DEG C. With 160.936g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 121.4~122.4 DEG C, and R value is 0.332.
The preparation of 60. Lansoprazole Pravastatin eutectic compound of embodiment
Lansoprazole 49.248g and Pravastatin 119.069g are taken, is sufficiently mixed and is placed in planetary ball mill, 35min is ground under the revolving speed of 300r/min, collects product, obtains 154.643g micro white powder, and fusing point is 131.1~132.9 DEG C. With 153.922g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 128.9~129.8 DEG C, and R value is 0.501.
The preparation of 61. Lansoprazole Pravastatin eutectic compound of embodiment
Lansoprazole 110.808g and Pravastatin 44.651g are taken, is sufficiently mixed and is placed in planetary ball mill, 55min is ground under the revolving speed of 300r/min, collects product, obtains 154.711g micro white powder, and fusing point is 140.1~142.1 DEG C. With 153.989g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 141.7~142.6 DEG C, and R value is 3.079.
The X-ray powder diffraction of 62 Examples 1 to 6 of embodiment, 1 gained eutectic compound characterizes
Structural characterization is carried out to gained eutectic compound in Examples 1 to 61 using foregoing condition, as a result such as table 3 It is shown.
The X-ray powder diffraction characterization result of 3 eutectic compound of table
1 proton pump inhibitor of test example, hydroxy-3-methylglutaryl CoA reductase inhibitor and proton pump inhibitor hydroxyl first penta The antibacterial action of two acyl coenzyme A reductase inhibitor eutectic compounds
Measure proton pump inhibitor, hydroxy-3-methylglutaryl CoA reductase inhibitor and proton respectively using filter paper enzyme Bacteriostatic activity of the pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor eutectic compound to various bacteria.Specifically, with Liquid-transfering gun draws prepared bacterial suspension (1 × 105/ mL, preparation method: will be for examination strain in slant tube culture It is activated on base [37 ± 1 DEG C, 3 days], recycles oese to beat easily a small amount of lawn from inclined-plane, be respectively added to be contained with In the conical flask of 50mL sterile saline), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.It takes and goes out Bacterium filter paper is let off in the tested material methanol solution of 6 kinds of concentration gradients (2 times are incremented by) respectively and impregnates 1h, by the 6mm impregnated circle Shape filter paper is attached on the above-mentioned plate containing bacterium made, and it is dense that each culture dish (diameter 90mm) sticks 3 dipped same quality The filter paper (filter paper is spaced identical as far as possible) for spending tested material methanol solution, using 50% methanol solution as blank control.Place The plate containing bacterium managed, which is placed in 37 DEG C of insulating boxs, to be cultivated for 24 hours, measures colony diameter using crossing method, and according to following public affairs Formula calculates inhibiting rate (IR).
It is mapped with logarithm of the inhibiting rate (IR) to free drug concentration (μM), and carries out linear regression with Excel, according to Regression equation extrapolates the concentration for generating proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor when fa inhibits, point It Wei not ICfa(A)With ICfa(B)Value.For eutectic compound, then with inhibiting rate (IR) to the dense of eutectic compound proton pump inhibitor Logarithm (log (the c)) mapping of (μM) is spent, and carries out linear regression with Excel, is extrapolated according to regression equation total when fa inhibits The concentration of proton pump inhibitor in brilliant compound, i.e. ICfa(mixA), further according to R value, extrapolate eutectic compound when fa inhibits The concentration of interior hydroxy-3-methylglutaryl CoA reductase inhibitor, i.e. ICfa(mixB)。
The eutectic compound index (CI) generated when fa inhibits is calculated according to the following formula
It when CI < 1, as acts synergistically, CI value is smaller, acts synergistically stronger.
As a result as shown in table 4~10.
Collaboration bacteriostasis of the 4. proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table to actinomyces viscosus
Note:
aMaximum concentration refers to the minimum concentration of tested material when inhibiting rate enters plateau, for eutectic compound, institute State the maximum concentration that maximum concentration refers to proton pump inhibitor in eutectic compound.
bThe slope and intercept represent the slope and intercept of IR-log (c) equation of linear regression, the r of each regression equation2≥ 0.997
cFor eutectic compound, ICfaRepresent ICfa(mixA).
The definition of 5~table of table, 12 gauge outfit is identical as table 4.
5 proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of bacteroides fragilis With
6 proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of brevibacterium epidermidis With
Collaboration bacteriostasis of the 7 proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table to clostridium difficile
8 proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of clostridium tetani With
Collaboration of the 9 proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table to paratyphosus A bacillus Bacteriostasis
10 proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of streptococcus pneumonia With
It is compound that embodiment 8 contains the eutectic being made of proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor The preparation of the oral solid formulation of object
Prescription (1000 unit dose)
Preparation method
50g eutectic compound and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take eutectic compound, lactose, microcrystalline cellulose, Crospovidone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to be according to hydroxypropyl methylcellulose meter concentration The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in 10% solution, is pelletized with 16 meshes, and 80 DEG C dry 3~4h.With 16 mesh sieves, be added the superfine silica gel powder of recipe quantity and magnesium stearate mix mixing, filling capsule to get Capsule；
50g eutectic compound and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take eutectic compound, lactose, microcrystalline cellulose, Crospovidone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to be according to hydroxypropyl methylcellulose meter concentration The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in 10% solution, is pelletized with 16 meshes, and 80 DEG C dry 3~4h.With 16 mesh sieves, the superfine silica gel powder of recipe quantity is added and magnesium stearate mixes mixing, dispenses to get particle Agent；
50g eutectic compound and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take eutectic compound, lactose, microcrystalline cellulose, Crospovidone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to be according to hydroxypropyl methylcellulose meter concentration The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in 10% solution, is pelletized with 16 meshes, and 80 DEG C dry 3~4h.With 16 mesh sieves, the superfine silica gel powder of recipe quantity is added and magnesium stearate mixes mixing, tabletting both obtains piece Agent.
Injection of the embodiment 9 containing proton pump inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor eutectic compound The preparation of liquid
Prescription (100)
Preparation method
1.5g eutectic compound, recipe quantity sodium citrate are taken, with 0.5mol/L citric acid after adding water for injection 100mL to dissolve Adjust pH to 5.0 or so.Sterilizing, filtering, packing to get.

Claims (10)

1. the eutectic compound being made of proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor, which is characterized in that The proton pump inhibitor is one in Omeprazole, Ai Simeila azoles, Pantoprazole, Rabeprazole and Lansoprazole Kind, the hydroxy-3-methylglutaryl CoA reductase inhibitor is cut down selected from Atorvastatin, Rosuvastatin, Simvastatin, fluorine One of statin, Pravastatin, Lovastatin and Pitavastatin or its pharmaceutically acceptable salt.
2. eutectic compound according to claim 1, which is characterized in that proton pump inhibitor and hydroxyl first penta 2 in eutectic compound The molar ratio of acyl coenzyme A reductase inhibitor is between 0.318:1~3.149:1.
3. eutectic compound according to claim 2, which is characterized in that the eutectic compound is selected from eutectic as described below One of compound:
The eutectic compound that Omeprazole and Atorvastatin are constituted with the molar ratio of 0.503:1,
The eutectic compound that Omeprazole and Atorvastatin are constituted with the molar ratio of 2.089:1,
The eutectic compound that Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 0.973:1,
The eutectic compound that Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 3.137:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.340:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.494:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 1.947:1,
The eutectic compound that Pantoprazole and Atorvastatin are constituted with the molar ratio of 2.952:1,
The eutectic compound that Rabeprazole and Atorvastatin are constituted with the molar ratio of 0.349:1,
The eutectic compound that Rabeprazole and Atorvastatin are constituted with the molar ratio of 2.100:1,
The eutectic compound that Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.318:1,
The eutectic compound that Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.505:1,
The eutectic compound that Lansoprazole and Atorvastatin are constituted with the molar ratio of 1.997:1,
The eutectic compound that Omeprazole and Rosuvastatin are constituted with the molar ratio of 0.321:1,
The eutectic compound that Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 0.499:1,
The eutectic compound that Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 1.954:1,
The eutectic compound that Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.342:1,
The eutectic compound that Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.498:1,
The eutectic compound that Pantoprazole and Rosuvastatin are constituted with the molar ratio of 3.131:1,
The eutectic compound that Rabeprazole and Rosuvastatin are constituted with the molar ratio of 2.937:1,
The eutectic compound that Lansoprazole and Rosuvastatin are constituted with the molar ratio of 0.510:1,
The eutectic compound that Lansoprazole and Rosuvastatin are constituted with the molar ratio of 2.912:1,
The eutectic compound that Omeprazole and Simvastatin are constituted with the molar ratio of 1.991:1,
The eutectic compound that Ai Simeila azoles and Simvastatin are constituted with the molar ratio of 1.904:1,
The eutectic compound that Rabeprazole and Simvastatin are constituted with the molar ratio of 0.478:1,
The eutectic compound that Rabeprazole and Simvastatin are constituted with the molar ratio of 0.957:1,
The eutectic compound that Lansoprazole and Simvastatin are constituted with the molar ratio of 0.521:1,
The eutectic compound that Omeprazole and Pitavastatin are constituted with the molar ratio of 3.128:1,
The eutectic compound that Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 0.499:1,
The eutectic compound that Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 2.033:1,
The eutectic compound that Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 3.149:1,
The eutectic compound that Pantoprazole and Pitavastatin are constituted with the molar ratio of 0.964:1,
The eutectic compound that Rabeprazole and Pitavastatin are constituted with the molar ratio of 1.047:1,
The eutectic compound that Rabeprazole and Pitavastatin are constituted with the molar ratio of 3.006:1,
The eutectic compound that Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.325:1,
The eutectic compound that Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.486:1,
The eutectic compound that Lansoprazole and Pitavastatin are constituted with the molar ratio of 2.920:1,
The eutectic compound that Omeprazole and Lovastatin are constituted with the molar ratio of 0.494:1,
The eutectic compound that Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.330:1,
The eutectic compound that Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.520:1,
The eutectic compound that Rabeprazole and Lovastatin are constituted with the molar ratio of 0.332:1,
The eutectic compound that Lansoprazole and Lovastatin are constituted with the molar ratio of 1.946:1,
The eutectic compound that Omeprazole and Fluvastatin are constituted with the molar ratio of 0.344:1,
The eutectic compound that Omeprazole and Fluvastatin are constituted with the molar ratio of 0.504:1,
The eutectic compound that Omeprazole and Fluvastatin are constituted with the molar ratio of 0.976:1,
The eutectic compound that Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 1.022:1,
The eutectic compound that Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 2.966:1,
The eutectic compound that Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.345:1,
The eutectic compound that Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.503:1,
The eutectic compound that Lansoprazole and Fluvastatin are constituted with the molar ratio of 0.328:1,
The eutectic compound that Lansoprazole and Fluvastatin are constituted with the molar ratio of 1.900:1,
The eutectic compound that Omeprazole and Pravastatin are constituted with the molar ratio of 0.323:1,
The eutectic compound that Omeprazole and Pravastatin are constituted with the molar ratio of 0.952:1,
The eutectic compound that Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 0.341:1,
The eutectic compound that Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 3.063:1,
The eutectic compound that Rabeprazole and Pravastatin are constituted with the molar ratio of 0.489:1,
The eutectic compound that Rabeprazole and Pravastatin are constituted with the molar ratio of 1.985:1,
The eutectic compound that Rabeprazole and Pravastatin are constituted with the molar ratio of 2.863:1,
The eutectic compound that Lansoprazole and Pravastatin are constituted with the molar ratio of 0.332:1,
The eutectic compound that Lansoprazole and Pravastatin are constituted with the molar ratio of 0.501:1,
The eutectic compound that Lansoprazole and Pravastatin are constituted with the molar ratio of 3.079:1.
4. eutectic compound according to claim 3, which is characterized in that the eutectic compound is selected from eutectic as described below One of compound:
Omeprazole and Atorvastatin are constituted with the molar ratio of 0.503:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 22.6 °,
Omeprazole and Atorvastatin are constituted with the molar ratio of 2.089:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 10.6 °,
Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 0.973:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 5.3 °,
Ai Simeila azoles and Atorvastatin are constituted with the molar ratio of 3.137:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 31.9 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.340:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 41.3 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 0.494:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 28.8 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 1.947:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 3.6 °,
Pantoprazole and Atorvastatin are constituted with the molar ratio of 2.952:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 28.9 °,
Rabeprazole and Atorvastatin are constituted with the molar ratio of 0.349:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 40.0 °,
Rabeprazole and Atorvastatin are constituted with the molar ratio of 2.100:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 16.0 °,
Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.318:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 9.4 °,
Lansoprazole and Atorvastatin are constituted with the molar ratio of 0.505:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 37.2 °,
Lansoprazole and Atorvastatin are constituted with the molar ratio of 1.997:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 41.5 °,
Omeprazole and Rosuvastatin are constituted with the molar ratio of 0.321:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 46.3 °,
Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 0.499:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 1.3 °,
Ai Simeila azoles and Rosuvastatin are constituted with the molar ratio of 1.954:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction Ray powder diffraction pattern has the eutectic compound of maximum characteristic absorption peak at 15.6 °,
Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.342:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 15.7 °,
Pantoprazole and Rosuvastatin are constituted with the molar ratio of 0.498:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 37.9 °,
Pantoprazole and Rosuvastatin are constituted with the molar ratio of 3.131:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 14.9 °,
Rabeprazole and Rosuvastatin are constituted with the molar ratio of 2.937:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 3.8 °,
Lansoprazole and Rosuvastatin are constituted with the molar ratio of 0.510:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 23.4 °,
Lansoprazole and Rosuvastatin are constituted with the molar ratio of 2.912:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 27.9 °,
Omeprazole and Simvastatin are constituted with the molar ratio of 1.991:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 3.1 °,
Ai Simeila azoles and Simvastatin are constituted with the molar ratio of 1.904:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 25.6 °,
Rabeprazole and Simvastatin are constituted with the molar ratio of 0.478:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 23.2 °,
Rabeprazole and Simvastatin are constituted with the molar ratio of 0.957:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 6.7 °,
Lansoprazole and Simvastatin are constituted with the molar ratio of 0.521:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 36.2 °,
Omeprazole and Pitavastatin are constituted with the molar ratio of 3.128:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 15.8 °,
Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 0.499:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 37.6 °,
Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 2.033:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 34.5 °,
Ai Simeila azoles and Pitavastatin are constituted with the molar ratio of 3.149:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 37.2 °,
Pantoprazole and Pitavastatin are constituted with the molar ratio of 0.964:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 35.9 °,
Rabeprazole and Pitavastatin are constituted with the molar ratio of 1.047:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 15.0 °,
Rabeprazole and Pitavastatin are constituted with the molar ratio of 3.006:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 22.6 °,
Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.325:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 11.5 °,
Lansoprazole and Pitavastatin are constituted with the molar ratio of 0.486:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 10.6 °,
Lansoprazole and Pitavastatin are constituted with the molar ratio of 2.920:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 5.3 °,
Omeprazole and Lovastatin are constituted with the molar ratio of 0.494:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 4.1 °,
Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.330:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 13.4 °,
Ai Simeila azoles and Lovastatin are constituted with the molar ratio of 0.520:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 17.3 °,
Rabeprazole and Lovastatin are constituted with the molar ratio of 0.332:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 1.3 °,
Lansoprazole and Lovastatin are constituted with the molar ratio of 1.946:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 13.4 °,
Omeprazole and Fluvastatin are constituted with the molar ratio of 0.344:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 44.1 °,
Omeprazole and Fluvastatin are constituted with the molar ratio of 0.504:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 44.9 °,
Omeprazole and Fluvastatin are constituted with the molar ratio of 0.976:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 32.6 °,
Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 1.022:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 8.3 °,
Ai Simeila azoles and Fluvastatin are constituted with the molar ratio of 2.966:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 1.6 °,
Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.345:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 7.0 °,
Pantoprazole and Fluvastatin are constituted with the molar ratio of 0.503:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 8.8 °,
Lansoprazole and Fluvastatin are constituted with the molar ratio of 0.328:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 4.8 °,
Lansoprazole and Fluvastatin are constituted with the molar ratio of 1.900:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 23.9 °,
Omeprazole and Pravastatin are constituted with the molar ratio of 0.323:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 42.9 °,
Omeprazole and Pravastatin are constituted with the molar ratio of 0.952:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 32.1 °,
Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 0.341:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 24.7 °,
Ai Simeila azoles and Pravastatin are constituted with the molar ratio of 3.063:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate Line powder diagram has the eutectic compound of maximum characteristic absorption peak at 1.5 °,
Rabeprazole and Pravastatin are constituted with the molar ratio of 0.489:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 7.8 °,
Rabeprazole and Pravastatin are constituted with the molar ratio of 1.985:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 21.3 °,
Rabeprazole and Pravastatin are constituted with the molar ratio of 2.863:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 24.6 °,
Lansoprazole and Pravastatin are constituted with the molar ratio of 0.332:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 38.6 °,
Lansoprazole and Pravastatin are constituted with the molar ratio of 0.501:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 10.7 °,
Lansoprazole and Pravastatin are constituted with the molar ratio of 3.079:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction Powder diagram has the eutectic compound of maximum characteristic absorption peak at 27.6 °.
5. eutectic compound according to claim 4, which is characterized in that the eutectic compound can carry out by the following method Preparation:
Proton pump inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor of the molar ratio between 0.333:1~3:1 are taken, is filled Point mixing be placed in planetary ball mill, under the revolving speed of 200~400r/min grind 30~60min, collect product, then with select It is recrystallized from one of ethyl alcohol, acetone, methanol, acetonitrile, ethyl acetate and isopropanol organic solvent.
6. the composition containing eutectic compound according to claim 1~any one of 5.
7. composition according to claim 6, which is characterized in that the composition can be made into the drug of oral or injection administration Preparation.
8. composition according to claim 7, which is characterized in that the oral drug preparation be selected from capsule, tablet with One of granula.
9. eutectic compound according to claim 1~any one of 5 or the group according to any one of claim 6~8 Close purposes of the object in bacterial infection and/or the drug of anaphylactia.
10. purposes according to claim 9, which is characterized in that the bacterial infection is by quasi- selected from actinomyces viscosus, fragility Caused by one of bacillus, brevibacterium epidermidis, clostridium difficile, clostridium tetani, paratyphosus A bacillus and streptococcus pneumonia Infection.
CN201910737755.2A 2019-08-12 2019-08-12 A kind of eutectic compound with collaboration bacteriostasis Pending CN110279865A (en)

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Application publication date: 20190927