Eutectic of omeprazole and 3, 5-dinitrobenzoic acid and application thereof

Abstract

The invention discloses a eutectic of omeprazole and 3, 5-dinitrobenzoic acid, the molar ratio of omeprazole to 3, 5-dinitrobenzoic acid is 1: 1, and compared with omeprazole, the eutectic has higher stability, in-vivo absorption speed and onset speed.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a cocrystal of omeprazole and 3,5-dinitrobenzoic acid, a preparation method, a composition and a use thereof. Background Art

[0002] Omeprazole is a proton pump inhibitor and a fat-soluble weakly alkaline drug. Its chemical name is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole. The molecular formula is C 17 H 19 N3O3S, with the structural formula shown below, specifically acts on the proton pump (H + , K + -ATPase) and irreversibly binds to the proton pump, thereby inhibiting H + , K + -ATPase activity, blocking the final step of gastric acid secretion, allowing H + It cannot be transported to the stomach cavity, which greatly reduces the acid content in gastric juice. It has a strong inhibitory effect on the basic gastric acid and gastric acid secretion caused by stimulation. The cure rate of duodenal ulcer is also high, and the recurrence rate is low. [1] .

[0003] The molecular formula of 3,5-dinitrobenzoic acid is C7H4N2O6 and its structural formula is shown below.

[0004]

[0005] At present, six omeprazole cocrystals / salts have been found, including omeprazole sodium hydrate, S-omeprazole magnesium salt trihydrate, omeprazole sodium salt hemihydrate, omeprazole zinc salt, omeprazole-piperazine-0.5 toluene solvate [2-6] .

[0006] Currently, there is a need to improve the stability, in vivo absorption rate and onset speed of oguanprazole. Summary of the invention

[0007] One or more embodiments of the present application provide a co-crystal of oxazolazole and 3,5-dinitrobenzoic acid, wherein the molar ratio of oxazolazole to 3,5-dinitrobenzoic acid is 1:1.

[0008] In one or more embodiments, CuK αThe powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks when irradiated and expressed in 2θ angles: 5.94±0.2°, 10.42±0.2°, 11.86±0.2°, 12.90±0.2°, 14.62±0.2°, 15.38±0.2°, 17.90±0.2°, 18.88±0.2°, 19.12±0.2°, 19.98±0.2°, 20.32±0.2°, and 26.52±0.2°.

[0009] In one or more embodiments, CuK α The powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and peak area percentages:

[0010] 2θ±0.2° Peak area %±5% 5.94 41.3 10.42 3.3 11.86 24.0 12.90 4.3 14.62 33.9 15.38 35.2 17.90 12.6 18.88 28.8 19.12 21.0 19.98 14.8 20.32 14.7 26.52 100.0 .

[0011] In one or more embodiments, CuK α The powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks: 5.94±0.2°, 10.42±0.2°, 11.86±0.2°, 12.90±0.2°, 14.62±0.2°, 15.38±0.2°, 17.90±0.2°, 18.88±0.2°, 19.12±0.2°, 19.98±0.2°, 20.32±0.2°, 21.10±0.2°, 21.54±0.2°, 26.52±0.2°, 21.88±0.2°, 23.04±0.2°, 23.50±0.2°, and 23.68±0.2°.

[0012] In one or more embodiments, CuK α The powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and peak area percentages:

[0013]

[0014]

[0015] In one or more embodiments, CuK α The powder X-ray diffraction pattern of the co-crystal is as follows: Figure 1 shown.

[0016] In one or more embodiments, when analyzed using attenuated total reflection Fourier transform infrared spectroscopy, the infrared spectrum of the co-crystal is at 3212 cm -1 、3102cm -1 、2980cm-1 、2835cm -1 、1728cm -1 、1623cm -1 、1588cm -1 、1540cm -1 、1506cm -1 、1470cm -1 、1435cm -1 、1393cm -1 、1341cm -1 、1269cm -1 、1204cm -1 、1177cm -1 、1153cm -1 、1085cm -1 、1050cm -1 、1028cm -1 、964cm -1 、946cm -1 、910cm -1 、886cm -1 、811cm -1 、780cm -1 、722cm -1 、662cm -1 、620cm -1 、602cm -1 、512cm -1 、439cm -1 There are characteristic peaks in the infrared spectrum.

[0017] In one or more embodiments, the infrared spectrum of the co-crystal is as follows Figure 3 shown.

[0018] In one or more embodiments, in the differential scanning calorimetry spectrum of the co-crystal, there is an endothermic peak at 123°C±10°C.

[0019] In one or more embodiments, within the range of 30-200° C., the heating rate is 10° C. / min.

[0020] One or more embodiments of the present application provide a method for preparing the co-crystal of oxazolidinone and 3,5-dinitrobenzoic acid of the present application, which comprises mixing oxazolidinone and 3,5-dinitrobenzoic acid in a molar ratio of 1:1, and preparing the co-crystal by an organic solvent liquid grinding method;

[0021] In one or more embodiments, the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane.

[0022] In one or more embodiments, the volume ratio between any two of the organic solvents is 1:10 to 10:1 (e.g., 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1).

[0023] In one or more embodiments, the amount of liquid added in the organic solvent liquid grinding method is 5 to 100 mL of organic solvent per gram of the mixed sample of oxaloprazole and 3,5-dinitrobenzoic acid; the grinding time is 0.1 hour to 10 hours (for example, 5 hours), the drying temperature is 25-60° C. (for example, 40° C.), and the drying time is 2 to 10 hours (for example, 6 hours); the comprehensive filling rate of the bowl is 10% to 50% (for example, 30%), and the reciprocating speed is 20 to 70 m / min (meters per minute) (for example, 45 m / min).

[0024] One or more embodiments of the present application provide a solid mixture, which contains the eutectic of the present application, and the amount of the eutectic is 1-99.9 weight % (for example, 10 weight %, 20 weight %, 30 weight %, 40 weight %, 50 weight %, 60 weight %, 70 weight %, 80 weight %, 90 weight %) based on the weight of the solid mixture.

[0025] In one or more embodiments, the amount of the eutectic is 10-99.9 wt %, 50-99.9 wt %, or 85-99.9 wt % based on the weight of the solid mixture.

[0026] One or more embodiments of the present application provide a pharmaceutical composition comprising a therapeutically effective amount of the co-crystal of the present application or the solid mixture of the present application and a pharmaceutically acceptable carrier.

[0027] In one or more embodiments, the daily dosage of the pharmaceutical composition is 10 to 1000 mg (eg, 100 mg, 500 mg, 900 mg).

[0028] In one or more embodiments, the pharmaceutical composition is prepared as tablets, capsules, pills, or powder injections.

[0029] In one or more embodiments, the pharmaceutical composition is prepared as a sustained-release formulation or a controlled-release formulation.

[0030] One or more embodiments of the present application provide use of the co-crystal, solid mixture, or pharmaceutical composition of the present application in the preparation of a drug for treating duodenal ulcer, gastric ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.

[0031] In one or more embodiments, a cocrystal formed by non-covalent bonding of omeprazole and 3,5-dinitrobenzoic acid and a preparation method and use thereof are provided. Specifically, a cocrystal formed by omeprazole and 3,5-dinitrobenzoic acid is disclosed, and the molecular formula of the cocrystal is C 17 H 19 N3O3S·C7H4N2O6; preparation method of omeprazole and 3,5-dinitrobenzoic acid eutectic; application of omeprazole and 3,5-dinitrobenzoic acid eutectic in the treatment of duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.

[0032] In one or more embodiments, omeprazole (English name: Omeprazole) and 3,5-dinitrobenzoic acid (English name: 3,5-Dinitrobenzoic acid) are prepared into a eutectic solid material with specific non-covalent interaction forces, thereby forming a new substance different from omeprazole, 3,5-dinitrobenzoic acid and a simple physical mixture of the two.

[0033] In one or more embodiments, the eutectic solid material of the present application has achieved unexpected technical advantages in the preparation of drugs for treating diseases such as duodenal ulcer, gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome, etc.

[0034] In one or more embodiments, the existence state and characterization method of the co-crystal of oxaloprazole and 3,5-dinitrobenzoic acid are determined.

[0035] In one or more embodiments, a method for preparing a co-crystal of omeprazole and 3,5-dinitrobenzoic acid is provided.

[0036] In one or more embodiments, a mixed solid material or pharmaceutical composition is provided comprising any non-zero ratio of oxaprazole to 3,5-dinitrobenzoic acid co-crystal.

[0037] In one or more embodiments, a pharmaceutical composition using a cocrystal of omeprazole and 3,5-dinitrobenzoic acid as a pharmaceutically active ingredient is provided, wherein the dosage per administration is 10 to 1000 mg. The pharmaceutical composition can be prepared as tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.

[0038] In one or more embodiments, the co-crystal of oxaloprazole and 3,5-dinitrobenzoic acid of the present application has good solubility.

[0039] In one or more embodiments, provided is the use of a cocrystal of omeprazole and 3,5-dinitrobenzoic acid and a mixed crystal solid material thereof as a pharmaceutical active ingredient in the preparation of a drug for treating duodenal ulcer, gastric ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.

[0040] Morphological characteristics of omeprazole and 3,5-dinitrobenzoic acid cocrystal samples

[0041] The omeprazole and 3,5-dinitrobenzoic acid cocrystal of the present application is a cocrystal material formed by non-covalent bonding of omeprazole and 3,5-dinitrobenzoic acid in a molar ratio of 1:1.

[0042] The cocrystal of oguanprazole and 3,5-dinitrobenzoic acid of the present application is analyzed by powder X-ray diffraction using CuK α Under radiation experimental conditions, it is manifested as the diffraction peak position: 2-Theta (°) or Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%), see Table 1 and Figure 1 .

[0043] The powder X-ray diffraction patterns of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid and the physical mixture of omeprazole and 3,5-dinitrobenzoic acid are significantly different in terms of the number of diffraction peaks, the positions of the diffraction peaks, the intensities of the diffraction peaks, the topological patterns of the diffraction peaks, etc., indicating that omeprazole and 3,5-dinitrobenzoic acid form a cocrystal and are different substances from the physical mixture of omeprazole and 3,5-dinitrobenzoic acid.

[0044] Table 1 Powder X-ray diffraction peak data of omeprazole and 3,5-dinitrobenzoic acid cocrystal

[0045]

[0046]

[0047] Table 2 Powder X-ray diffraction peak data of physical mixture of omeprazole and 3,5-dinitrobenzoic acid

[0048]

[0049] The cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application is analyzed by attenuated total reflection Fourier transform infrared spectroscopy at 3212, 3102, 2980, 2835, 1728, 1623, 1588, 1540, 1506, 1470, 1435, 1393, 1341, 1269, 1204, 1177, 1153, 1085, 1050, 1028, 964, 946, 910, 886, 811, 780, 722, 662, 620, 602, 512, 439cm -1 There is a characteristic peak of infrared spectrum at the position, and the allowable deviation of the characteristic peak of infrared spectrum is ±2cm -1 (See Figure 3 ).

[0050] When the omeprazole and 3,5-dinitrobenzoic acid cocrystal of the present application is analyzed by differential scanning calorimetry, the DSC spectrum has an exothermic peak at 123.49°C±10°C when the heating rate is 10°C / min in the range of 30-200°C (see Figure 4 ), which is the decomposition peak of the cocrystal. The DSC spectra of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid are significantly different from those of omeprazole and 3,5-dinitrobenzoic acid in terms of the number and position of endothermic / exothermic peaks, indicating that omeprazole and 3,5-dinitrobenzoic acid have formed a new phase, namely, the cocrystal of omeprazole and 3,5-dinitrobenzoic acid (see Figure 5 ).

[0051] Preparation method of omeprazole and 3,5-dinitrobenzoic acid eutectic and mixed solid material

[0052] The preparation method of the eutectic of omeprazole and 3,5-dinitrobenzoic acid of the present application adopts the liquid grinding method, omeprazole and 3,5-dinitrobenzoic acid are mixed in a molar ratio of 1:1, an organic solvent is added, and the grinding time is 0.1 hour to 10 hours under room temperature, and the drying time is 2 to 10 hours; the comprehensive filling rate of the bowl of the liquid grinding method is 10% to 50%, and the reciprocating speed is 20 to 70m / min. The eutectic of omeprazole and 3,5-dinitrobenzoic acid is obtained. The organic solvent can be selected from any one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, dioxane, n-hexane, cyclohexane, and a mixed solvent prepared by combining them in different proportions.

[0053] The mixed solid material containing the cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application is prepared by mixing the cocrystal of omeprazole and 3,5-dinitrobenzoic acid obtained by the above method with other chemical substances in any non-zero ratio and in a conventional manner.

[0054] Pharmaceutical preparation composition containing cocrystal of omeprazole and 3,5-dinitrobenzoic acid, dosage characteristics and pharmaceutical use

[0055] The pharmaceutical composition of the present application comprises a cocrystal of oxaloprazole and 3,5-dinitrobenzoic acid and a pharmaceutically acceptable carrier.

[0056] The pharmaceutical composition of the present application comprises a mixed solid of a cocrystal of oxaloprazole and 3,5-dinitrobenzoic acid and a pharmaceutically acceptable carrier.

[0057] The pharmaceutical composition of the present application comprises a cocrystal of oxaprazole and 3,5-dinitrobenzoic acid, and the daily dosage thereof is within the range of 10 to 1000 mg.

[0058] The dosage form of the pharmaceutical composition of the present application can be various tablets, capsules, pills, injection preparations, sustained-release preparations or controlled-release preparations.

[0059] The cocrystal of oxaloprazole and 3,5-dinitrobenzoic acid of the present application has application in treating diseases such as duodenal ulcer, gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome and the like.

[0060] The pharmaceutical composition with the cocrystal of omeprazole and 3,5-dinitrobenzoic acid as the active ingredient of the present application can be prepared according to methods known in the art. The cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use. The cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application, and the mixed solid containing the cocrystal of omeprazole and 3,5-dinitrobenzoic acid in the pharmaceutical composition contain 10% to 90% by weight.

[0061] The co-crystal of oxaloprazole and 3,5-dinitrobenzoic acid of the present application can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0062] The dosage form of the present application may be a solid dosage form. The solid dosage form may be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols (powders), sprays, etc.

[0063] The cocrystal of oxazolidinone and 3,5-dinitrobenzoic acid and the mixed solid material containing the cocrystal of oxazolidinone and 3,5-dinitrobenzoic acid of the present application can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0064] In order to form the co-crystal of oxaloprazole and 3,5-dinitrobenzoic acid of the present application into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0065] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0066] In order to prepare the dosing unit into a capsule, the active ingredient omeprazole and 3,5-dinitrobenzoic acid eutectic can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient omeprazole and 3,5-dinitrobenzoic acid eutectic can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare omeprazole and 3,5-dinitrobenzoic acid eutectic tablets can also be used to prepare the capsules of the omeprazole and 3,5-dinitrobenzoic acid eutectic of the present invention.

[0067] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0068] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug of the present invention can be administered by any known administration method.

[0069] The dosage of the pharmaceutical composition of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application can vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form, etc. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other treatment means.

[0070] The cocrystal or composition of omeprazole and 3,5-dinitrobenzoic acid of the present application can be taken alone or used in combination with other therapeutic drugs or symptomatic drugs. When the cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0071] Beneficial technical effects of the present invention:

[0072] The cocrystal of oxaprozole and 3,5-dinitrobenzoic acid of the present application has advantages in safety, solubility, dissolution rate, stability, bioavailability and absorbability;

[0073] The cocrystal of oguanprazole and 3,5-dinitrobenzoic acid of the present application does not contain any crystallization solvent and has good safety and drugability advantages:

[0074] The cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application shows a dissolution effect comparable to that of the omeprazole raw material in terms of solubility, and shows a dissolution rate substantially consistent with that of the omeprazole raw material in a simulated gastric fluid (pH 1.2) dissolution system ( Figure 6 );

[0075] The omeprazole and 3,5-dinitrobenzoic acid cocrystal of the present application can be stably present under high humidity (25°C, relative humidity 90%±5%) and light (45001x±5001x) conditions, and has certain stability advantages in drug formulation ( Figure 7 ).

[0076] The omeprazole and 3,5-dinitrobenzoic acid cocrystal of the present application is used as the active ingredient of the drug and the pharmaceutical composition thereof. The drug is rapidly and massively released through the gastrointestinal tract or blood after oral administration, and the maximum blood drug concentration (Cmax) is increased by 3.4 times, the peak time (Tmax) is shortened by 35 times, and the half-life (t 1 / 2 shortened by half), and played a dominant role in preventing and treating diseases ( Figure 8 ).

[0077] In one or more embodiments, there are many factors affecting the dosage of the active ingredient in the pharmaceutical composition of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid of the present application, such as: different daily dosages due to different uses for prevention and treatment; different daily dosages due to different nature and severity of the disease; different daily dosages due to different genders, ages, body surface areas of patients, different routes of administration, number of administrations, and different therapeutic purposes; in addition, the different absorption and blood drug concentrations between crystal samples also cause the daily suitable dosage range of the cocrystal component of omeprazole and 3,5-dinitrobenzoic acid in the present invention to be 0.002-20 mg / kg body weight, such as 0.01-10 mg / kg body weight. When used, different total dosage plans of the active ingredient of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid should be formulated according to the actual prevention and treatment requirements, and can be completed in multiple or one administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 The figure is the powder X-ray diffraction pattern of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid.

[0079] Figure 2 The X-ray powder diffraction pattern of the physical mixture of omeprazole and 3,5-dinitrobenzoic acid.

[0080] Figure 3 This is the infrared absorption spectrum of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid.

[0081] Figure 4 This is the differential scanning calorimetry spectrum of the cocrystal of oxaloprazole and 3,5-dinitrobenzoic acid.

[0082] Figure 5 The differential scanning calorimetry spectra of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid and the raw materials of omeprazole and 3,5-dinitrobenzoic acid are shown.

[0083] Figure 6 The solubility curve of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid in simulated gastric fluid (pH 1.2).

[0084] Figure 7 This is the stability spectrum of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid.

[0085] Figure 8 The blood concentration-time curve (0-24h) of omeprazole in the cocrystal of omeprazole and 3,5-dinitrobenzoic acid and its physical mixture. DETAILED DESCRIPTION

[0086] In order to better illustrate the technical solution of the present invention, the following embodiments are given, but the present invention is not limited thereto.

[0087] Example 1

[0088] Preparation method of omeprazole and 3,5-dinitrobenzoic acid eutectic

[0089] Take appropriate amounts of omeprazole and 3,5-dinitrobenzoic acid in a molar ratio of 1:1, add the sample to a mortar of appropriate capacity at room temperature by liquid grinding method, add an appropriate amount of organic solvent, grind at room temperature at an appropriate speed for an appropriate time, and dry the obtained powder or paste sample naturally or under reduced pressure. The condition parameters of the preparation method are shown in Table 3. Powder X-ray diffraction analysis was performed on it, and the diffraction patterns were consistent with Figure 1 The results are consistent, indicating that the obtained sample is a cocrystal of omeprazole and 3,5-dinitrobenzoic acid.

[0090] Table 3 Specific examples of the preparation method of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid

[0091]

[0092] Example 2

[0093] In vitro solubility characteristics of omeprazole and 3,5-dinitrobenzoic acid cocrystal

[0094] The solubility characteristics of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid and omeprazole API in water were investigated. The experiment was conducted in accordance with the "Technical Guidelines for Dissolution Tests of Ordinary Oral Solid Preparations". The omeprazole API was used as a reference, and the calculation model independent similarity factor f2 value was 93. The omeprazole content was determined at a wavelength of 305nm by high performance liquid chromatography, and its dissolved amount was calculated by the external standard method. Dissolution curves were drawn with time as the horizontal axis and the dissolved amount as the vertical axis ( Figure 6 ). The specific data are shown in Table 4:

[0095] Table 4 Dissolution curve data

[0096]

[0097] It can be seen from the solubility data that the dissolution behavior of the omeprazole and 3,5-dinitrobenzoic acid cocrystal at pH 1.2 is not significantly different from that of the omeprazole raw material. The dissolution amount and dissolution rate of the omeprazole-3,5-dinitrobenzoic acid cocrystal are consistent with those of the omeprazole raw material, and the solubility curves have a stable release platform.

[0098] Example 3

[0099] Stability of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid

[0100] High humidity test: Place the cocrystal sample of omeprazole and 3,5-dinitrobenzoic acid in an open clean surface dish, place at 25°C and relative humidity of 90%±5% for 10 days, and take samples on the 0th day, the 5th day and the 10th day. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis, and the results showed that the cocrystal of omeprazole and 3,5-dinitrobenzoic acid was stable under high humidity conditions.

[0101] Light test: Place the sample of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid in an open clean surface dish, place it in a light box equipped with a fluorescent lamp, and place it for 10 days under the condition of illumination of 45001x±5001x, and take samples on the 0th day, the 5th day and the 10th day. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis, and the results showed that the cocrystal of omeprazole and 3,5-dinitrobenzoic acid was stable under light conditions.

[0102] The stability study of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid proved that the cocrystal remained stable in a high humidity and light environment for 10 days, improving the defect of the omeprazole raw material being unstable in a high humidity environment and having certain drug-forming characteristics ( Figure 7 ).

[0103] Example 4

[0104] In vivo bioabsorption advantage of the cocrystal of omeprazole and 3,5-dinitrobenzoic acid

[0105] Standard solution: Accurately weigh 1.00 mg of omeprazole standard, add 1 mL of methanol to fully dissolve and mix, prepare 1.00 mg / mL omeprazole stock solution, store at -20°C, and dilute with methanol to make standard solutions of different concentrations before use. Internal standard solution: Accurately weigh 1.00 mg of carbamazepine, add 1 mL of methanol to fully dissolve and mix, prepare 1.00 mg / mL carbamazepine stock solution, store at -20°C, and dilute with methanol to make 500 ng / mL internal standard working solution before use.

[0106] SD rats were randomly divided into 2 groups, 6 in each group, and raised under conventional feeding conditions, with free access to water. After fasting for 12 hours, omeprazole and omeprazole-3,5-dinitrobenzoic acid cocrystal samples were given by solid gavage at a dose of 100 mg / kg. At 2 minutes, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration, about 0.3 mL of blood was collected from the posterior ocular venous plexus into a heparinized anticoagulation tube, centrifuged at 4°C and 5000 rpm for 10 minutes, and 100 μl of the supernatant was frozen in a -80°C refrigerator for testing.

[0107] During the determination, 100 μL of plasma was precisely drawn, 10 μL of internal standard carbamazepine working solution was added, and then 890 μL of protein extractant methyl tert-butyl ether: ethyl acetate (v:v 80:20) was added, fully shaken for 3 minutes, centrifuged (13000 rpm, 10 minutes), the upper layer solution was nitrogen blown until dry, and then 100 μL of 50% methanol was added to re-dissolve, fully shaken for 3 minutes, centrifuged (13000 rpm, 3 minutes), 90 μL of the upper layer solution was taken into the inner liner tube, and 3 μL was injected. The standard curve was detected by the same method, and the blood concentration of omeprazole and 3,5-dinitrobenzoic acid was calculated by substituting the ratio of the peak area of ​​the drug to the internal standard into the standard curve, and the blood concentration-time curve was drawn.

[0108] Detection conditions: Chromatographic column: ACQUITY BEH C 18 (2.1×50mm, 1.7μm); mobile phase A is 0.1% formic acid, mobile phase B is acetonitrile. Column temperature is 40℃; injection volume: 3μL; running time: 6min. Gradient elution conditions are as follows:

[0109]

[0110] Mass spectrometry conditions: positive ion mode, mass-to-charge ratio of omeprazole was 346.1, and mass-to-charge ratio of carbamazepine was 237.1.

[0111] The pharmacokinetic parameters of the measured oguanprazole blood concentration data of the cocrystal of oguanprazole and oguanprazole-3,5-dinitrobenzoic acid were calculated. The main pharmacokinetic parameter results are shown in Table 5. The blood concentration-time change curves at 0-24 h are shown in Figure 8 shown.

[0112] Table 5 Main pharmacokinetic parameters of omeprazole in omeprazole bulk drug and cocrystal of omeprazole and 3,5-dinitrobenzoic acid

[0113]

[0114] (mean ± standard error)

[0115] From the above experimental research data, it can be seen that compared with omeprazole, the maximum blood concentration (Cmax) of omeprazole in the cocrystal of omeprazole and 3,5-dinitrobenzoic acid increased by 3.4 times, its peak time (Tmax) was shortened by 35 times, and the half-life (t 1 / 2 ) is also shortened by half, allowing it to reach a higher therapeutic concentration faster than the omeprazole raw material, making it more suitable for diseases that require rapid release and faster onset of action, such as gastric ulcers.

[0116] Example 5

[0117] Preparation method 1 of co-crystal pharmaceutical preparation (tablets):

[0118] Preparation method: Use the pure cocrystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material of the combination drug, use several excipients as the auxiliary material components of the tablet, and prepare tablet samples with a drug content of 10 to 500 mg per tablet according to a certain ratio. Table 6 gives the tablet formula ratio:

[0119] Table 6 Preparation formula of omeprazole and 3,5-dinitrobenzoic acid cocrystal tablets

[0120]

[0121] The method of preparing a tablet preparation using the pure product of omeprazole and 3,5-dinitrobenzoic acid cocrystal as a raw material is as follows: several excipients are mixed evenly with the raw material and directly tableted; or the auxiliary materials are mixed and dry granulated, and then mixed evenly with the raw material and then tableted.

[0122] Preparation method 2 of combined pharmaceutical preparation (tablets):

[0123] Preparation method: The pure cocrystal of omeprazole and 3,5-dinitrobenzoic acid is used as the raw material, and several excipients are used as the auxiliary ingredients of the tablets. Tablet samples with a drug content of 10 to 500 mg per tablet are prepared in a certain proportion. Table 7 gives the tablet formula ratio.

[0124] Table 7 Preparation formula of omeprazole and 3,5-dinitrobenzoic acid cocrystal tablets

[0125]

[0126] The method for preparing a tablet preparation using a pure cocrystal of omeprazole and 3,5-dinitrobenzoic acid as a raw material is as follows: uniformly mixing several excipients with the raw material, adding an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare a soft material, sieving granules, drying the wet granules, sieving whole granules, adding magnesium stearate and talcum powder, mixing uniformly, and tableting to obtain the tablet preparation.

[0127] Preparation method 3 of combined pharmaceutical preparation (capsules):

[0128] Preparation method: Use the pure cocrystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material of the combination drug, use several excipients as auxiliary ingredients for preparing the combination drug capsules, and prepare capsule samples with a drug content of 10 to 500 mg per tablet according to a certain ratio. Table 8 gives the capsule formula ratio.

[0129] Table 8 API and excipient formula of omeprazole and 3,5-dinitrobenzoic acid cocrystal capsule preparation

[0130]

[0131] The method for preparing a tablet preparation from a cocrystal drug substance of omeprazole and 3,5-dinitrobenzoic acid is as follows: uniformly mixing several excipients with the drug substance, adding an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare wet granules, drying and sieving the whole granules, adding magnesium stearate and mixing uniformly, and inserting the granules into capsules; or without using a granulation step, directly mixing the cocrystal drug substance of omeprazole and 3,5-dinitrobenzoic acid with several excipients and auxiliary materials, sieving, and directly filling the granules into capsules.

[0132] Example 6

[0133] Dosage of cocrystal of omeprazole and 3,5-dinitrobenzoic acid 1 (tablet):

[0134] The pharmaceutical composition is developed using a sample of a cocrystal of omeprazole and 3,5-dinitrobenzoic acid as a pharmaceutical active ingredient. The pharmaceutical composition is characterized in that a sample of a cocrystal of omeprazole and 3,5-dinitrobenzoic acid is used as a pharmaceutical active ingredient. The daily dosage is 0.5-300 mg and the composition can be prepared into ordinary tablet types of 1-6 tablets each time, containing 10, 100, 200, 300, and 500 mg of active ingredient.

[0135] Dosage of cocrystal of omeprazole and 3,5-dinitrobenzoic acid 2 (capsules):

[0136] The pharmaceutical composition is developed by using a sample of a cocrystal of omeprazole and 3,5-dinitrobenzoic acid as the active ingredient of the drug. The pharmaceutical composition is characterized in that the cocrystal of omeprazole and 3,5-dinitrobenzoic acid is used as the active ingredient of the drug, the daily dosage is 10-3000 mg, and the drug can be prepared into capsules of 1-6 capsules each time, containing 10, 100, 200, 300, and 500 mg of the active ingredient.

[0137] References

[0138] [1] Langtry HD, Wilde M I. Omeprazole. A review of its use in Helicobacter pylori infection, gastro-oesophageal reflux disease and pepticulcers induced by nonsteroidal anti-inflammatory drugs. [J] Drugs, 1998, 56(3): 447-486.

[0139] [2] Skieneh J, Khalili Najafabadi B, Horne S, et al. Crystallization of Esomeprazole Magnesium Water / Butanol Solvate. [J] Molecules, 2016, 21(4): 544.

[0140] [3] Yan Yimin, Ge Jilong, Tu Yongrui. Oguanprazole salt hydrate and its preparation method: China, CN1136564A[P]. 1996.11.27

[0141] [4] Deng Jingen, Tian Tian, ​​Zhu Jin, et al. New S-oguanoprazole salts: China, CN102241668A[P]. 2011-11-16.

[0142] [5] Sakurai F, Khutia A, Kikuchi T, et al.

[0143] [6] Brüning J, Bolte M. & Schmidt MU New Toluene Hemi Solvate of the Proton Pump Inhibitor Piperazinium Esomeprazolate[J]. Chem Crystallogr, 2009, 39(4): 256-260.

Claims

1. A eutectic of oxazolidinone and 3,5-dinitrobenzoic acid, wherein the molar ratio of oxazolidinone to 3,5-dinitrobenzoic acid is 1:

1.

2. The eutectic of claim 1, wherein CuK α The powder X-ray diffraction pattern of the cocrystal has the following characteristic peaks: 5.94±0.2°, 10.42±0.2°, 11.86±0.2°, 12.90±0.2°, 14.62±0.2°, 15.38±0.2°, 17.90±0.2°, 18.88±0.2°, 19.12±0.2°, 19.98±0.2°, 20.32±0.2°, 26.52±0.2°; Preferably, CuK is used α The powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and peak area percentages: Preferably, CuK is used α The powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks: 5.94±0.2°, 10.42±0.2°, 11.86±0.2°, 12.90±0.2°, 14.62±0.2°, 15.38±0.2°, 17.90±0.2°, 18.88±0.2°, 19.12±0.2°, 19.98±0.2°, 20.32±0.2°, 21.10±0.2°, 21.54±0.2°, 26.52±0.2°, 21.88±0.2°, 23.04±0.2°, 23.50±0.2°, 23.68±0.2°; Preferably, CuK is used α The powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and peak area percentages: Preferably, CuK is used α The powder X-ray diffraction pattern of the co-crystal is shown in FIG1 .

3. The eutectic material according to claim 1, wherein when analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the infrared spectrum of the eutectic material is at 3212 cm -1 、3102cm -1 、2980cm -1 、2835cm -1 、1728cm -1 、1623cm -1 、1588cm -1 、1540cm -1 、1506cm -1 、1470cm -1 、1435cm -1 、1393cm -1 、1341cm -1 、1269cm -1 、1204cm -1 、1177cm -1 、1153cm -1 、1085cm -1 、1050cm -1 、1028cm -1 、964cm -1 、946cm -1 、910cm -1 、886cm -1 、811cm -1 、780cm -1 、722cm -1 、662cm -1 、620cm -1 、602cm -1 、512cm -1 、439cm -1 There is a characteristic peak of infrared spectrum at; preferably, the infrared spectrum of the eutectic is as shown in Figure 3.

4. The eutectic according to claim 1, wherein in the differential scanning calorimetry spectrum of the eutectic, there is an endothermic peak at 123°C±10°C; preferably, in the range of 30 to 200°C, the heating rate is 10°C / min.

5. A method for preparing the cocrystal of omeprazole and 3,5-dinitrobenzoic acid according to any one of claims 1 to 4, comprising mixing omeprazole and 3,5-dinitrobenzoic acid in a molar ratio of 1:1, and preparing the cocrystal by an organic solvent liquid grinding method; Preferably, the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane; preferably, the volume ratio between any two of the organic solvents is 1:10 to 10:1; Preferably, the amount of liquid added in the organic solvent liquid grinding method is 5 to 100 mL of organic solvent per gram of the mixed sample of omeprazole and 3,5-dinitrobenzoic acid; the grinding time is 0.1 hour to 10 hours, the drying temperature is 25-60°C, and the drying time is 2 to 10 hours; the comprehensive filling rate of the bowl is 10% to 50%, and the reciprocating motion speed is 20 to 70 m / min.

6. A solid mixture comprising the eutectic of any one of claims 1 to 4, wherein the amount of the eutectic is 1-99.9 wt %, preferably 10-99.9 wt %, more preferably 50-99.9 wt %, and most preferably 85-99.9 wt %, based on the weight of the solid mixture.

7. A pharmaceutical composition comprising a therapeutically effective amount of the cocrystal according to any one of claims 1 to 4 or the solid mixture according to claim 6 and a pharmaceutically acceptable carrier; preferably, the single-day dosage of the pharmaceutical composition is 10 to 1000 mg; preferably, the pharmaceutical composition is prepared as a tablet, capsule, pill, powder injection; preferably, the pharmaceutical composition is prepared as a sustained-release preparation or a controlled-release preparation.

8. Use of the cocrystal according to any one of claims 1 to 4, the solid mixture according to claim 6, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating duodenal ulcer, gastric ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.

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