Omeprazole co-crystal with 3,5-dinitrobenzoic acid and uses thereof

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine. Specifically, it relates to a co-crystal of omeprazole and 3,5-dinitrobenzoic acid, a preparation method, a composition and a use thereof. BACKGROUND

[0002] Omeprazole is a proton pump inhibitor, which is a weakly basic, fat-soluble 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, and the structural formula is shown below. It specifically acts on the site of gastric parietal cell proton pump (H + , K + -ATPase), irreversibly binds to the proton pump, thereby inhibiting the activity of H + , K + -ATPase, blocking the last step of gastric acid secretion, and making H + in the parietal cell unable to transport into the stomach cavity, thereby greatly reducing the acid content in the gastric juice. It has a strong inhibitory effect on both basal gastric acid and stimulated gastric acid secretion. 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 the structural formula is shown below.

[0004]

[0005] Currently, six kinds of co-crystals / salts of omeprazole 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] There is a need to improve the stability, in vivo absorption rate and onset speed of omeprazole. SUMMARY

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

[0008] In one or more embodiments, CuK αradiated and expressed in terms of 2-theta angles, 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°, 26.52 ± 0.2°.

[0009] In one or more embodiments, Cu K α radiated and expressed in terms of 2-theta angles, the powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and peak area percentages:

[0010] 2 theta ± 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, Cu K α radiated and expressed in terms of 2-theta angles, 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°.

[0012] In one or more embodiments, Cu K α radiated and expressed in terms of 2-theta angles, 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, Cu K α radiated and expressed in terms of 2-theta angles, the powder X-ray diffraction pattern of the co-crystal is as shown in Figure 1 .

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

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

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

[0019] In one or more embodiments, the temperature is raised at a rate of 10℃ / min in the range of 30-200℃.

[0020] One or more embodiments of the present application provide a preparation method of the omeprazole and 3,5-dinitrobenzoic acid co-crystal of the present application, which comprises mixing omeprazole and 3,5-dinitrobenzoic acid in a molar ratio of 1:1, and using organic solvent liquid grinding method to prepare the co-crystal;

[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 1:10-10:1 (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 the organic solvent added in the liquid-adding grinding method is 5-100 mL of the organic solvent per gram of the mixture of omeprazole and 3,5-dinitrobenzoic acid; the grinding time is 0.1 hour-10 hours (e.g., 5 hours), the drying temperature is 25-60°C (e.g., 40°C), the drying time is 2-10 hours (e.g., 6 hours); the comprehensive filling rate of the mortar body is 10%-50% (e.g., 30%), and the reciprocating speed is 20-70 m / min (e.g., 45 m / min).

[0024] One or more embodiments of the present application provide a solid mixture comprising the co-crystal of the present application, wherein the amount of the co-crystal is 1-99.9% by weight (e.g., 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight) based on the weight of the solid mixture.

[0025] In one or more embodiments, the amount of the co-crystal is 10-99.9% by weight, 50-99.9% by weight, or 85-99.9% by weight 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 single daily dose of the pharmaceutical composition is 10-1000 mg (e.g., 100 mg, 500 mg, 900 mg).

[0028] In one or more embodiments, the pharmaceutical composition is prepared as a tablet, a capsule, a pill, a powder injection.

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

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

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

[0032] In one or more embodiments, by preparing omeprazole (English name: Omeprazole) and 3,5-dinitrobenzoic acid (English name: 3,5-Dinitrobenzoic acid) into co-crystals solid substances with specific non-covalent forces, a new substance different from omeprazole, 3,5-dinitrobenzoic acid and their simple physical mixture is formed.

[0033] In one or more embodiments, the co-crystals solid substances of the present application have 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 omeprazole and 3,5-dinitrobenzoic acid co-crystals are determined.

[0035] In one or more embodiments, there are provided preparation methods of omeprazole and 3,5-dinitrobenzoic acid co-crystals.

[0036] In one or more embodiments, there are provided mixed solid substances or pharmaceutical compositions containing any non-zero proportion of omeprazole and 3,5-dinitrobenzoic acid co-crystals.

[0037] In one or more embodiments, there are provided pharmaceutical compositions using omeprazole and 3,5-dinitrobenzoic acid co-crystals as the active pharmaceutical ingredient, with a dosage of 10-1000 mg per administration. The pharmaceutical compositions can be prepared into tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.

[0038] In one or more embodiments, the omeprazole and 3,5-dinitrobenzoic acid co-crystals of the present application have good solubility.

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

[0040] Omeprazole and 3,5-dinitrobenzoic acid co-crystal sample morphological characteristics

[0041] The omeprazole and 3,5-dinitrobenzoic acid co-crystal of the present application is a co-crystal substance formed by omeprazole-3,5-dinitrobenzoic acid combined in a 1:1 molar ratio by non-covalent bonds.

[0042] The omeprazole and 3,5-dinitrobenzoic acid co-crystal of the present application, when analyzed using powder X-ray diffraction, exhibits diffraction peak positions: 2-Theta (°) or α when the experimental conditions of Cu K 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 omeprazole and 3,5-dinitrobenzoic acid co-crystal and the physical mixture of omeprazole and 3,5-dinitrobenzoic acid differ significantly in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, diffraction peak topological patterns, etc., indicating that omeprazole and 3,5-dinitrobenzoic acid form a co-crystal, and that the co-crystal is different 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 co-crystal

[0045]

[0046]

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

[0048]

[0049] The omeprazole-3,5-dinitrobenzic acid cocrystal of this application, when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, showed the following parameters 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, and 439 cm⁻¹. -1 There is an infrared spectral characteristic peak at this location, with an allowable deviation of ±2cm for the infrared spectral characteristic peak. -1 (see Figure 3 ).

[0050] When the omeprazole-3,5-dinitrobenzoic acid cocrystal of this application was analyzed using differential scanning calorimetry (DSC), an exothermic peak was observed at 123.49℃±10℃ in the DSC spectrum within the temperature range of 30–200℃ at a heating rate of 10℃ / min (see [link to DSC]). Figure 4 The peak at which the omeprazole-3,5-dinitrobenzoic acid cocrystal decomposes is observed. The DSC spectra of the omeprazole-3,5-dinitrobenzoic acid cocrystal show significant differences from those of the omeprazole-3,5-dinitrobenzoic acid cocrystal 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 omeprazole-3,5-dinitrobenzoic acid cocrystal (see [link to DSC]). Figure 5 ).

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

[0052] The method for preparing the eutectic of omeprazole and 3,5-dinitrobenzoic acid disclosed in this application employs a liquid-addition 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 to 10 hours at room temperature, followed by a drying time of 2 to 10 hours. The overall filling rate of the grinding bowl in the liquid-addition grinding method is 10% to 50%, and the reciprocating speed is 20 to 70 m / 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, and cyclohexane, combined in different proportions to form a mixed solvent.

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

[0054] Pharmaceutical composition, dosage form, and pharmaceutical use comprising a co-crystal of omeprazole and 3,5-dinitrosalicylic acid

[0055] The pharmaceutical composition of the present application comprises a co-crystal of omeprazole and 3,5-dinitrosalicylic acid and a pharmaceutically acceptable carrier.

[0056] The pharmaceutical composition of the present application comprises a co-crystal of omeprazole and 3,5-dinitrosalicylic acid and a pharmaceutically acceptable carrier.

[0057] The pharmaceutical composition of the present application comprises a co-crystal of omeprazole and 3,5-dinitrosalicylic acid and a pharmaceutically acceptable carrier.

[0058] The pharmaceutical composition of the present application can be in various tablet, capsule, pill, injection, sustained release, or controlled release forms.

[0059] The co-crystal of omeprazole and 3,5-dinitrosalicylic acid of the present application has an application in treating duodenal ulcer, gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome, and the like.

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

[0061] The co-crystal of omeprazole and 3,5-dinitrosalicylic acid of the present application can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, and the like.

[0062] The dosage form of the present application can be a solid dosage form. The solid dosage form can be a tablet (including ordinary tablets, enteric-coated tablets, chewable tablets, dispersible tablets, effervescent tablets, oral disintegrating tablets), a capsule (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosol (powder) sprays, sprays, and the like.

[0063] The omeprazole and 3,5-dinitrobenzoic acid co-crystal of the present application, the mixed solid substance comprising the omeprazole and 3,5-dinitrobenzoic acid co-crystal can be prepared into common formulations, and also into sustained-release formulations, controlled-release formulations, targeted formulations and various microparticle drug delivery systems.

[0064] In order to prepare the omeprazole and 3,5-dinitrobenzoic acid co-crystal of the present application into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrants can 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 sorbitol fatty acid ester, sodium dodecylsulfate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0065] The tablets can also be further prepared 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 administration units into capsules, the effective ingredient omeprazole and 3,5-dinitrobenzoic acid co-crystal can be mixed with diluents and glidants, and the mixture can be directly placed into hard capsules or soft capsules. The effective ingredient omeprazole and 3,5-dinitrobenzoic acid co-crystal can also be first mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing the omeprazole and 3,5-dinitrobenzoic acid co-crystal tablets can also be used for preparing the omeprazole and 3,5-dinitrobenzoic acid co-crystal capsules of the present application.

[0067] In addition, if necessary, coloring agents, preservatives, flavors, taste correctors or other additives can also be added into the pharmaceutical formulations.

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

[0069] The dosage of the pharmaceutical composition of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid of the present application can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. The above-mentioned dosage can be administered as one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the administration schedule including the use of other therapeutic agents.

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

[0071] The beneficial technical effects of the present application are:

[0072] The co-crystal of omeprazole and 3,5-dinitrobenzoic acid of the present application has advantages in safety, solubility, dissolution rate, stability, bioavailability and absorbability.

[0073] The co-crystal of omeprazole and 3,5-dinitrobenzoic acid of the present application does not contain any crystallization solvent and has the advantage of good safety of drug preparation:

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

[0075] The co-crystal of omeprazole and 3,5-dinitrobenzoic acid of the present application can stably exist under high humidity (25℃, relative humidity 90%±5%) and light (45001x±5001x) conditions, and has the advantage of certain stability of drug preparation. Figure 7

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

[0077] ​​​In one or more embodiments, the pharmaceutical composition of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid of the present application has a number of factors affecting the dosage of the active ingredient, such as: different uses for prevention and treatment resulting in different daily dosages; different disease natures and severities resulting in different daily dosages; different patient genders, ages, body surface areas, administration routes, administration frequencies, and treatment purposes resulting in different daily dosages; in addition, different absorption and blood concentrations among different crystal samples also result in different daily suitable dosage ranges of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid of the present application, for example, 0.002-20 mg / kg of body weight, such as 0.01-10 mg / kg of body weight. In use, different total dosage schemes of the active ingredient of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid should be formulated according to actual different needs of prevention and treatment, and can be completed by multiple or single administration. BRIEF DESCRIPTION OF DRAWINGS DETAILED DESCRIPTION BRIEF DESCRIPTION OF DRAWINGS

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

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

[0080] Figure 3 The infrared absorption spectrum of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid.

[0081] Figure 4 The differential scanning calorimetry pattern of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid.

[0082] Figure 5 The differential scanning calorimetry patterns of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid and the raw materials of omeprazole and 3,5-dinitrobenzoic acid.

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

[0084] Figure 7 The stability pattern of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid.

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

[0086] The following examples are given to better illustrate the technical solutions of the present application, but the present application is not limited to them.

[0087] Example 1

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

[0089] Take omeprazole and 3,5-dinitrobenzoic acid in proper amount, and the molar ratio of the two is 1:1. The samples are added into a mortar of proper volume at room temperature by liquid addition grinding method, and proper amount of organic solvent is added. The obtained powder or paste samples are naturally dried or dried under reduced pressure after grinding at room temperature for proper time. The condition parameters of the preparation method are shown in Table 3. The powder X-ray diffraction analysis is performed, and the diffraction patterns are consistent with Figure 1 , which indicates that the obtained samples are co-crystals of omeprazole and 3,5-dinitrobenzoic acid.

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

[0091]

[0092] Example 2

[0093] In-vitro dissolution characteristics of co-crystal of omeprazole and 3,5-dinitrobenzoic acid

[0094] The dissolution characteristics of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid and omeprazole raw material in water are investigated. The experiment is performed according to the Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations. The omeprazole raw material is taken as a reference, and the model-independent similarity factor f2 value is 93. The high performance liquid chromatography is adopted to determine the omeprazole content at a wavelength of 305 nm, and the external standard method is adopted to calculate the dissolution amount. The dissolution curves are drawn respectively with time as the abscissa and the dissolution amount as the ordinate Figure 6 . The specific data are shown in Table 4.

[0095] Table 4 Dissolution curve data

[0096]

[0097] It can be seen from the dissolution data that the dissolution behavior of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid in pH 1.2 medium has no obvious change compared with the omeprazole raw material. The dissolution amount and dissolution rate of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid are consistent with those of the omeprazole raw material, and the dissolution curves have a smooth release platform.

[0098] Example 3

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

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

[0101] Light test: the sample of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid was placed in an open clean surface dish, and was placed in a light box equipped with a daylight lamp under the condition of illumination of 4500 lx±500 lx for 10 days, and was sampled at the 0th day, the 5th day and the 10th day. The obtained sample at the above sampling points was subjected to powder X-ray diffraction analysis, and the results showed that the co-crystal of omeprazole and 3,5-dinitrobenzoic acid was stable under the condition of light.

[0102] The stability study of the co-crystal of omeprazole and 3,5-dinitrobenzoic acid proved that the co-crystal was stable within 10 days under the conditions of high humidity and light, and the defect of instability of omeprazole raw material in a high humidity environment was improved, and the co-crystal had certain drug-making characteristics. Figure 7

[0103] Example 4

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

[0105] Standard solution: 1.00 mg of omeprazole standard was accurately weighed, and was dissolved and mixed in 1 mL of methanol to prepare a 1.00 mg / mL omeprazole stock solution, which was stored at -20°C. Before use, the omeprazole stock solution was diluted with methanol to prepare standard solutions of different concentrations. Internal standard solution: 1.00 mg of carbamazepine was accurately weighed, and was dissolved and mixed in 1 mL of methanol to prepare a 1.00 mg / mL carbamazepine stock solution, which was stored at -20°C. Before use, the carbamazepine stock solution was diluted with methanol to prepare an internal standard working solution of 500 ng / mL.

[0106] SD rats were randomly divided into 2 groups, 6 rats in each group, and were raised under conventional feeding conditions, and were allowed to drink water freely. After fasting for 12 h, the rats were respectively given omeprazole and the co-crystal of omeprazole and 3,5-dinitrobenzoic acid by solid gavage at a dose of 100 mg / kg. At 2 min, 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration, about 0.3 mL of blood was taken from the retro-orbital plexus into a heparinized anticoagulant tube, and was centrifuged at 4°C and 5000 rpm for 10 min. 100 μl of supernatant was frozen in a -80°C refrigerator for testing.​

[0107] At the time of determination, 100 μL of plasma was precisely pipetted, 10 μL of internal standard carbamazepine working solution was added, 890 μL of protein extraction agent methyl tert-butyl ether: ethyl acetate (v:v 80:20) was added, and the mixture was shaken thoroughly for 3 min, centrifuged (13000 rpm, 10 min), and the supernatant was blown to dryness with nitrogen, 100 μL of 50% methanol was added to dissolve the residue, the mixture was shaken thoroughly for 3 min, centrifuged (13000 rpm, 3 min), and 90 μL of the supernatant was taken into an inner tube and 3 μL was injected. The standard curve was determined by the same method, and the blood drug concentration of omeprazole and 3,5-dinitrobenzoic acid was calculated by substituting the peak area ratio of the drug and the internal standard into the standard curve to draw the blood drug concentration-time curve.

[0108] Detection conditions: column: ACQUITY BEH C 18 (2.1 x 50 mm, 1.7 μm); mobile phase A was 0.1% formic acid, and mobile phase B was acetonitrile. The column temperature was 40°C; the injection amount was 3 μL; and the running time was 6 min. The gradient elution conditions were as follows:

[0109]

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

[0111] The blood drug concentration data of omeprazole in the omeprazole-3,5-dinitrobenzoic acid co-crystal were subjected to pharmacokinetic parameter calculation, and the main pharmacokinetic parameter results are shown in Table 5, and the 0-24 h blood drug concentration-time curve is shown in Figure 8 .

[0112] Table 5 Main pharmacokinetic parameters of omeprazole in omeprazole raw material and omeprazole-3,5-dinitrobenzoic acid co-crystal

[0113]

[0114] (mean ± standard error)

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

[0116] Example 5

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

[0118] Preparation method: using the co-crystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material of the combination drug, using several excipients as the auxiliary components of the tablet, and preparing the tablet samples with the drug content of 10-500 mg per tablet according to a certain proportion, the tablet formulation proportion is shown in Table 6:

[0119] Table 6 Preparation formulation of the co-crystal tablet of omeprazole and 3,5-dinitrobenzoic acid

[0120]

[0121] The preparation method of the tablet preparation using the co-crystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material is as follows: mixing several excipients and the raw material uniformly, directly compressing the tablet, or granulating the auxiliary materials by dry method, then mixing the granules and the raw material uniformly, and compressing the tablet.

[0122] Preparation method 2 (tablets) of the combination drug preparation:

[0123] Preparation method: using the co-crystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material, using several excipients as the auxiliary components of the tablet, and preparing the tablet samples with the drug content of 10-500 mg per tablet according to a certain proportion, the tablet formulation proportion is shown in Table 7.

[0124] Table 7 Preparation formulation of the co-crystal tablet of omeprazole and 3,5-dinitrobenzoic acid

[0125]

[0126] The preparation method of the tablet preparation using the co-crystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material is as follows: mixing several excipients and the raw material uniformly, adding an appropriate amount of 1% sodium methylol cellulose solution to prepare soft material, sieving and granulating, drying the wet granules, sieving and granulating, mixing magnesium stearate and talc uniformly, and compressing the tablet.

[0127] Preparation method 3 (capsules) of the combination drug preparation:

[0128] Preparation method: using the co-crystal of omeprazole and 3,5-dinitrobenzoic acid as the raw material of the combination drug, using several excipients as the auxiliary components of the capsule, and preparing the capsule samples with the drug content of 10-500 mg per tablet according to a certain proportion, the capsule formulation proportion is shown in Table 8.

[0129] Table 8 Raw material and auxiliary formulation of the co-crystal capsule preparation of omeprazole and 3,5-dinitrobenzoic acid

[0130]

[0131] The method for preparing the omeprazole and 3,5-dinitrobenzoic acid co-crystal drug substance into tablet formulation is as follows: several excipients are mixed with the drug substance, an appropriate amount of 1% sodium hydroxymethyl cellulose solution is added, wet granules are prepared, dried, sieved, and granulated, magnesium stearate is added and mixed uniformly, inserted into a capsule to obtain; or without using the granulation step, the omeprazole and 3,5-dinitrobenzoic acid co-crystal drug substance is directly mixed with several excipients, sieved, and directly filled into a capsule to obtain.

[0132] Example 6

[0133] The administration dose 1 (tablets) of the omeprazole and 3,5-dinitrobenzoic acid co-crystal is as follows:

[0134] The developed pharmaceutical composition prepared using the omeprazole and 3,5-dinitrobenzoic acid co-crystal sample as the pharmaceutical active ingredient is characterized in that the omeprazole and 3,5-dinitrobenzoic acid co-crystal is used as the active ingredient of the drug, the daily administration dose is 0.5-300 mg, and the common tablet type containing 10, 100, 200, 300, 500 mg of the active ingredient can be prepared into 1-6 tablets each time.

[0135] The administration dose 2 (capsules) of the omeprazole and 3,5-dinitrobenzoic acid co-crystal is as follows:

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

[0137] Reference

[0138] [1] Langtry H D, Wilde M I. Omeprazole. A review of its use in Helicobacter pylori infection, gastro-oesophageal reflux disease and peptic ulcers 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. Omeprazole salt hydrate and method for preparing the same: China, CN1136564A[P]. 1996.11.27

[0141] [4] Deng JG, Tian T, Zhu J, et al. New S-omeprazole salt: China, CN102241668A[P]. 2011-11-16.

[0142] [5] Sakurai F, Khutia A, Kikuchi T, et al. X-ray Structure Analysis of N-Containing Nucleophilic Compounds by the Crystalline Sponge Method. Chemistry. 2017 Oct 26;23(60):15035-15040.

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

Claims

1. A co-crystal of omeprazole and 3,5-dinitrobenzoic acid, wherein the molar ratio of omeprazole to 3,5-dinitrobenzoic acid is 1 : 1, using Cu Ka radiation and expressed in terms of 2 theta angles, having 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°. α A co-crystal of omeprazole and 3,5-dinitrobenzoic acid, wherein the molar ratio of omeprazole to 3,5-dinitrobenzoic acid is 1 : 1, using Cu Ka radiation and expressed in terms of 2 theta angles, having 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 2. The co-crystal of claim 1, wherein the powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and percent area of peak using Cu K α Radiated and expressed in terms of 2-theta angle: 。 3. The co-crystal as claimed in claim 1, wherein 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° using Cu K α Radiation and expressed in terms of 2 theta angles.

4. The co-crystal of claim 3, wherein the powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks and percent area of peak using Cu K α Radiated and expressed in terms of 2-theta angle:

5. The co-crystal of claim 1, wherein Cu K α The powder X-ray diffraction pattern of the co-crystal is shown in Figure 1, using Cu K radiation and expressed in terms of 2 theta angles.

6. The co-crystal of claim 1, wherein the infrared spectrum of the co-crystal has infrared spectral features at 3212 cm -1 , 3102 cm -1 , 2980 cm -1 , 2835 cm -1 , 1728 cm -1 , 1623 cm -1 , 1588 cm -1 , 1540 cm -1 , 1506 cm -1 , 1470 cm -1 , 1435 cm -1 , 1393 cm -1 , 1341 cm -1 , 1269 cm -1 , 1204 cm -1 , 1177 cm -1 , 1153 cm -1 , 1085 cm -1 , 1050 cm -1 , 1028 cm -1 , 964 cm -1 , 946 cm -1 , 910 cm -1 , 886 cm -1 , 811 cm -1 , 780 cm -1 , 722 cm -1 , 662 cm -1 , 620 cm -1 , 602 cm -1 , 512 cm -1 , 439 cm -1 when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy.

7. The co-crystal of claim 6, wherein the infrared spectrum of the co-crystal is as shown in Figure 3.

8. The co-crystal of claim 1, wherein the differential scanning calorimetry of the co-crystal has one endothermic peak at 123 °C ± 10 °C.

9. The co-crystal of claim 8, wherein the temperature rate is 10 °C / min in the range of 30-200 °C.

10. A method of preparing the co-crystal of omeprazole and 3,5-dinitrobenzoic acid of any one of claims 1-9, comprising mixing omeprazole and 3,5-dinitrobenzoic acid in a molar ratio of 1:1, and preparing the co-crystal by liquid-adding and trituration method using an organic solvent.

11. The method of claim 10, wherein the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane.

12. The method of claim 11, wherein the volume ratio between any two of the organic solvents is 1:10-10:

1.

13. The method of claim 10, wherein the liquid-adding amount in the liquid-adding and trituration method is 5-100 mL of the organic solvent per gram of the mixture of omeprazole and 3,5-dinitrobenzoic acid; the trituration time is 0.1 hour-10 hours, the drying temperature is 25-60 °C, the drying time is 2-10 hours; the comprehensive filling rate of the mortar body is 10%-50%, and the reciprocating speed is 20-70 m / min.

14. A solid mixture comprising the co-crystal of any one of claims 1-9, wherein the amount of the co-crystal is 1-99.9% by weight based on the weight of the solid mixture.

15. The solid mixture of claim 14, wherein the amount of the co-crystal is 10-99.9% by weight based on the weight of the solid mixture.

16. The solid mixture of claim 14, wherein the amount of the co-crystal is 50-99.9% by weight based on the weight of the solid mixture.

17. The solid mixture of claim 14, wherein the amount of the co-crystal is 85-99.9% by weight based on the weight of the solid mixture.

18. A pharmaceutical composition comprising a therapeutically effective amount of the co-crystal of any one of claims 1-9 or the solid mixture of any one of claims 14-17 and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, wherein the single daily dose of the pharmaceutical composition is 10-1000 mg.

20. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is prepared as a tablet, a capsule, a pill, or a powder injection.

21. The pharmaceutical composition of claim 18, wherein, The pharmaceutical composition is prepared as a sustained-release preparation or a controlled-release preparation.

22. Use of the co-crystal of any one of claims 1-9, the solid mixture of any one of claims 14-17, or the pharmaceutical composition of any one of claims 18-21 in the preparation of a medicament for treating duodenal ulcer, gastric ulcer, reflux esophagitis, or Zollinger-Ellison syndrome.

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