Omeprazole co-crystals with 2,6-dihydroxybenzoic acid and uses thereof

Abstract

The present application discloses a co-crystal of omeprazole and 2,6-dihydroxybenzoic acid, wherein the molar ratio of omeprazole to 2,6-dihydroxybenzoic acid is 1:1, and the co-crystal has higher solubility, dissolution rate, bioavailability and stability 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 2,6-dihydroxybenzoic 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 H19N3O3S, and the structural formula is shown below. It specifically acts on the site of gastric wall 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 the 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 for duodenal ulcer is also high, and the recurrence rate is low [1] .

[0003] The molecular formula of 2,6-dihydroxybenzoic acid is C7H6O4, and the structural formula is shown below.

[0004]

[0005] Currently, six kinds of omeprazole co-crystals / 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] There is a need to improve the bioavailability and stability of omeprazole. SUMMARY

[0007] One or more embodiments of the present application provide a co-crystal of omeprazole and 2,6-dihydroxybenzoic acid, wherein the molar ratio of omeprazole to 2,6-dihydroxybenzoic acid is 1:1.

[0008] In one or more embodiments, the powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks using CuK α radiation and expressed in terms of 2θ angles: 7.16±0.2°, 7.78±0.2°, 12.72±0.2°, 13.92±0.2°, 15.42±0.2°, 17.62±0.2°, 17.96±0.2°, 19.72±0.2°, 20.02±0.2°.

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

[0010] 2 theta ± 0.2° Peak area % ± 5% 7.16 74.5 7.78 11.4 12.72 32.8 13.92 100.0 15.42 42.8 17.62 15.8 17.96 15.3 19.72 14.3 20.02 13.8 .

[0011] In one or more embodiments, the powder X-ray diffraction pattern of the co-crystal is determined using Cu K α radiation and expressed in terms of 2-theta angles, has the following characteristic peaks: 7.16±0.2°, 7.78±0.2°, 12.72±0.2°, 13.92±0.2°, 15.42±0.2°, 17.62±0.2°, 17.96±0.2°, 19.72±0.2°, 20.02±0.2°, 20.54±0.2°, 21.56±0.2°, 23.56±0.2°, 23.96±0.2°, 25.22±0.2°, 25.86±0.2°, 26.50±0.2°, 27.70±0.2°, 28.62±0.2°.

[0012] In one or more embodiments, the powder X-ray diffraction pattern of the co-crystal is determined using Cu K α radiation and expressed in terms of 2-theta angles, has the following characteristic peaks and percentage of peak area:

[0013]

[0014]

[0015] In one or more embodiments, the powder X-ray diffraction pattern of the co-crystal is determined using Cu K α radiation and expressed in terms of 2-theta angles, has the powder X-ray diffraction pattern 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, is in the range of 3063±2 cm -1 , 2997±2 cm -1 , 2936±2 cm -1 , 2835±2 cm -1 , 2722±2 cm -1 , 1631±2 cm -1 , 1577±2 cm -1 , 1471±2 cm -1 , 1444±2 cm -1 , 1386±2 cm -1, 1354 ± 2 cm -1 , 1308 ± 2 cm -1 , 1291 ± 2 cm -1 , 1267 ± 2 cm -1 , 1223 ± 2 cm -1 , 1206 ± 2 cm -1 , 1154 ± 2 cm -1 , 1113 ± 2 cm -1 , 1058 ± 2 cm -1 , 1026 ± 2 cm -1 , 971 ± 2 cm -1 , 817 ± 2 cm -1 , 801 ± 2 cm -1 , 769 ± 2 cm -1 , 705 ± 2 cm -1 , 646 ± 2 cm -1 , 601 ± 2 cm -1 , 529 ± 2 cm -1 , 484 ± 2 em -1 , 453 ± 2 em -1 , 428 ± 2 em -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 143℃ ± 3℃.

[0019] In one or more embodiments, in the differential scanning calorimetry spectrum of the co-crystal, the temperature range is 30-200℃, and the temperature rising rate is 10℃ / min.

[0020] One or more embodiments of the present application provide a preparation method of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application, which comprises mixing omeprazole and 2,6-dihydroxybenzoic 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 2,6-dihydroxybenzoic 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, the amount of the co-crystal being 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, or Zollinger-Ellison syndrome.

[0031] In one or more embodiments, there are provided a co-crystal of omeprazole and 2,6-dihydroxybenzoic acid formed by non-covalent bond, and a preparation method and use thereof. Specifically, a co-crystal of omeprazole and 2,6-dihydroxybenzoic acid is disclosed, and the molecular formula of the co-crystal is C 17 H 19 N3O3S·C7H6O4; a preparation method of a co-crystal of omeprazole and 2,6-dihydroxybenzoic acid; and an application of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid in treating duodenal ulcer, gastric ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.

[0032] In one or more embodiments, a new substance different from omeprazole, 2,6-dihydroxybenzoic acid, and a simple physical mixture of the two is formed by preparing a co-crystal solid substance of omeprazole (English name: Omeprazole) and 2,6-dihydroxybenzoic acid (English name: 2,6-Dihydroxybenzoic acid) with a specific non-covalent force.

[0033] In one or more embodiments, the co-crystal solid substance of the present application has unexpected technical advantages in preparing a drug for treating diseases such as duodenal ulcer, gastric ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.

[0034] In one or more embodiments, the existence state and characterization method of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid are determined.

[0035] In one or more embodiments, a preparation method of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid is provided.

[0036] In one or more embodiments, a mixed solid substance or a pharmaceutical composition containing any non-zero proportion of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid is provided.

[0037] In one or more embodiments, a pharmaceutical composition using the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid as a pharmaceutically active ingredient is provided, and the dosage of each administration is 10-1000 mg. The pharmaceutical composition can be prepared into tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.

[0038] In one or more embodiments, the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid of the present application has better solubility than omeprazole.

[0039] In one or more embodiments, the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid of the present application is beneficial to release during the treatment of diseases due to the formation of the co-crystal substance, and unexpected clinical effects are produced.

[0040] In one or more embodiments, there is provided use of the co-crystal of omeprazole and 2,6-dihydroxybenzoic 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.

[0041] Form feature of omeprazole and 2,6-dihydroxybenzoic acid co-crystal sample

[0042] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application is a co-crystal substance formed by omeprazole-2,6-dihydroxybenzoic acid combined in a 1:1 molar ratio by non-covalent bond.

[0043] The omeprazole and 2,6-dihydroxybenzoic 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 peak relative intensity: peak height value (Height %) or peak area value (Area %), see Table 1 and Figure 1 .

[0044] The powder X-ray diffraction patterns of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal and the physical mixture of omeprazole and 2,6-dihydroxybenzoic acid are obviously different in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, diffraction peak topological patterns, etc., indicating that omeprazole and 2,6-dihydroxybenzoic acid form a co-crystal, and the physical mixture of omeprazole and 2,6-dihydroxybenzoic acid is a different substance.

[0045] Table 1 Powder X-ray diffraction peak data of omeprazole and 2,6-dihydroxybenzoic acid co-crystal

[0046]

[0047] Table 2 Powder X-ray diffraction peak data of the physical mixture of omeprazole and 2,6-dihydroxybenzoic acid

[0048]

[0049] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application, when analyzed using attenuated total reflection Fourier infrared spectroscopy, exhibits peaks at 3063, 2997, 2936, 2835, 2722, 1631, 1577, 1471, 1444, 1386, 1354, 1308, 1291, 1267, 1223, 1206, 1154, 1113, 1058, 1026, 971, 817, 801, 769, 705, 646, 601, 529, 484, 453, 428 cm -1The infrared spectrum characteristic peak is present, wherein the allowable deviation of the infrared spectrum characteristic peak is ±2 cm -1 (see Figure 3 ).

[0050] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application has an endothermic peak at 143.1°C±10°C when analyzed by differential scanning calorimetry at a temperature rate of 10°C / min in the range of 30-200°C (see Figure 4 ), which is the melting point peak of the co-crystal. The DSC patterns of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal and omeprazole and 2,6-dihydroxybenzoic acid have obvious differences in the number and position of endothermic and exothermic peaks, indicating that the omeprazole and 2,6-dihydroxybenzoic acid form a new phase, i.e., the omeprazole and 2,6-dihydroxybenzoic acid co-crystal (see Figure 5 ).

[0051] Preparation method of omeprazole and 2,6-dihydroxybenzoic acid co-crystal

[0052] The preparation method of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application adopts liquid addition grinding method, omeprazole and 2,6-dihydroxybenzoic acid are mixed at a molar ratio of 1:1, an organic solvent is added, the grinding time is 0.1 hour-10 hours under room temperature conditions, and the drying time is 2-10 hours; the comprehensive filling rate of the pot body of the liquid addition grinding method is 10%-50%, and the reciprocating motion speed is 20-70 m / min, to obtain the omeprazole and 2,6-dihydroxybenzoic acid co-crystal. The organic solvent is selected from any one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, dioxane, n-hexane, and cyclohexane, or a mixed solvent prepared by different proportions of combinations thereof.

[0053] The mixed solid substance containing the omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application is obtained by mixing the omeprazole and 2,6-dihydroxybenzoic acid co-crystal prepared by the above method with other chemical substances in any non-zero proportion and by a conventional method.

[0054] Pharmaceutical preparation composition, administration dose characteristics, and pharmaceutical use containing omeprazole and 2,6-dihydroxybenzoic acid co-crystal

[0055] The pharmaceutical composition of the present application contains the omeprazole and 2,6-dihydroxybenzoic acid co-crystal and a pharmaceutically acceptable carrier.

[0056] The pharmaceutical composition of the present application contains the mixed solid substance of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal and a pharmaceutically acceptable carrier.

[0057] The pharmaceutical composition of the present application comprises omeprazole and 2,6-dihydroxybenzoic acid co-crystal in a daily dosage of 10-1000 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 omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application has an application in treating diseases such as duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.

[0060] The pharmaceutical composition of the present application using omeprazole and 2,6-dihydroxybenzoic acid co-crystal as the active ingredient can be prepared according to the methods known in the art. The omeprazole and 2,6-dihydroxybenzoic acid co-crystal 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 omeprazole and 2,6-dihydroxybenzoic acid co-crystal or the mixed solid substance containing omeprazole and 2,6-dihydroxybenzoic acid co-crystal in the pharmaceutical composition of the present application is 10-90% by weight.

[0061] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application can be administered in unit dosage form and the administration route can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

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

[0063] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application or the mixed solid substance containing omeprazole and 2,6-dihydroxybenzoic acid co-crystal can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0064] For the preparation of the tablet of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application, 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 acid 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 tablet can 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] For the preparation of the capsule of the administration unit, the effective ingredient omeprazole and 2,6-dihydroxybenzoic acid co-crystal can be mixed with diluents and glidants, and the mixture can be directly placed in a hard or soft capsule. The effective ingredient omeprazole and 2,6-dihydroxybenzoic acid co-crystal can also be first mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed in a hard or soft capsule. The various diluents, binders, wetting agents, disintegrants and glidants used for the preparation of the tablet of omeprazole and 2,6-dihydroxybenzoic acid co-crystal can also be used for the preparation of the capsule of omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application.

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

[0068] For the purpose of medication and enhancement of therapeutic effect, the pharmaceutical of the present application can be administered by any known administration method.

[0069] The administration dose of the pharmaceutical composition of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal 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 administration route and the dosage form, etc. The above-mentioned dose can be administered in one dosage unit or divided into several dosage units, which depends on the clinical experience of the doctor and the administration scheme including the use of other therapeutic means.

[0070] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal or composition of the present application can be taken alone or in combination with other therapeutic or symptomatic drugs. When the omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application has 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 omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application has advantages in safety, solubility, dissolution rate, stability, bioavailability and absorption;

[0073] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application does not contain any crystallization solvent and has the advantage of good safety of drug preparation;

[0074] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application shows higher concentration in gastric acid, specifically, in the simulated gastric fluid (pH 1.2) dissolution system, the drug dissolution increases by about 1.4 times after reaching equilibrium (see Figure 6 ) compared with the raw drug;

[0075] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application can exist stably under high temperature (60°C), high humidity (25°C, relative humidity 90%±5%), and light (4500lx±500lx) conditions, and has the advantage of good stability of drug preparation compared with omeprazole raw material which is unstable under high temperature and high humidity (see Figure 7 ).

[0076] In one or more embodiments, the pharmaceutical composition of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal of the present application has many factors affecting the dosage of the active ingredient, such as different daily dosages for different uses for prevention and treatment, different daily dosages for different disease natures and severity, different daily dosages for different patient genders, ages, body surface areas, different daily dosages for different administration routes, administration frequencies, and treatment purposes, in addition to different absorption and blood concentrations among different crystal samples, etc., which also cause the present application to have a suitable daily dosage range of 0.002-20 mg / kg body weight, for example, 0.01-10 mg / kg body weight, of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal composition. When used, different total dosage schemes of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal active ingredient should be formulated according to the actual needs of different prevention and treatment situations, and can be completed by multiple or single administration. BRIEF DESCRIPTION OF DRAWINGS

[0077] Figure 1The powder X-ray diffraction pattern of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid.

[0078] Figure 2 The powder X-ray diffraction pattern of the physical mixture of omeprazole and 2,6-dihydroxybenzoic acid.

[0079] Figure 3 The infrared absorption spectrum of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid.

[0080] Figure 4 The differential scanning calorimetry pattern of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid.

[0081] Figure 5 The differential scanning calorimetry superimposition pattern of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid and the raw materials of omeprazole and 2,6-dihydroxybenzoic acid.

[0082] Figure 6 The solubility curve of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid in simulated gastric juice (pH 1.2).

[0083] Figure 7 The stability pattern of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid. DETAILED DESCRIPTION

[0084] In order to better illustrate the technical solutions of the present application, the following examples are given, but the present application is not limited to them.

[0085] Example 1

[0086] Preparation method of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid

[0087] Take omeprazole and 2,6-dihydroxybenzoic acid in proper amounts, 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 a proper amount of organic solvent is added. The obtained powder or paste samples are naturally dried or dried under reduced pressure at room temperature for a proper time. The condition parameters of the preparation method are shown in Table 3. The powder X-ray diffraction analysis is performed on the samples, and the diffraction patterns are all consistent with the diffraction pattern of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid, indicating that the obtained samples are the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid. Figure 1

[0088] Table 3 Specific examples of the preparation method of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid

[0089]

[0090] Example 2

[0091] ​Dissolution characteristics of omeprazole and 2,6-dihydroxybenzoic acid co-crystal in vitro

[0092] The dissolution characteristics of omeprazole and 2,6-dihydroxybenzoic acid co-crystal and omeprazole in water were investigated. The experiment was carried out according to the Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations. The model-independent similarity factor f2 value was 68, with omeprazole as the reference. The content of omeprazole was determined by high performance liquid chromatography at a wavelength of 305 nm, and the dissolution amount was calculated by external standard method. The dissolution curves were plotted with time as the abscissa and the dissolution amount as the ordinate (see Figure 6 ).

[0093] Table 4 Dissolution curve data

[0094]

[0095] From the dissolution data, it can be seen that the dissolution behavior of omeprazole and 2,6-dihydroxybenzoic acid co-crystal in pH 1.2 is higher than that of omeprazole, which is reflected in that the dissolution amount and dissolution rate of omeprazole and 2,6-dihydroxybenzoic acid co-crystal are 1.4 times higher than those of omeprazole after about half an hour, and a higher blood concentration can be obtained during the treatment of the disease.

[0096] Example 3

[0097] Stability of omeprazole and 2,6-dihydroxybenzoic acid co-crystal

[0098] High temperature test: The omeprazole and 2,6-dihydroxybenzoic acid co-crystal sample was placed in an open clean surface dish, and was placed at 60℃ for 10 days. Samples were taken at 0th, 5th and 10th day. The samples obtained at the above sampling points were analyzed by powder X-ray diffraction, and the results showed that the omeprazole and 2,6-dihydroxybenzoic acid co-crystal was stable under the influence of high temperature.

[0099] High humidity test: The omeprazole and 2,6-dihydroxybenzoic acid co-crystal sample was placed in an open clean surface dish, and was placed at 25℃ under the condition of relative humidity 90%±5% for 10 days. Samples were taken at 0th, 5th and 10th day. The samples obtained at the above sampling points were analyzed by powder X-ray diffraction, and the results showed that the omeprazole and 2,6-dihydroxybenzoic acid co-crystal was stable under high humidity.

[0100] Light test: The sample of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal was placed in an open clean surface dish, in a light box equipped with a daylight lamp, under the condition of 4500 lx ± 500 lx for 10 days, and samples were taken on day 0, day 5 and day 10. The samples obtained at the above sampling points were subjected to powder X-ray diffraction analysis, and the results showed that the omeprazole and 2,6-dihydroxybenzoic acid co-crystal was stable under light conditions.

[0101] The stability study of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal proved that the co-crystal remained stable within 10 days under high temperature, high humidity and light conditions, which improved the defect of omeprazole raw material instability in high humidity environment, and had stable drug-making characteristics (see Figure 7 ).

[0102] Example 4

[0103] Preparation method 1 (tablets) of the co-crystal pharmaceutical preparation:

[0104] Preparation method: Using the pure omeprazole and 2,6-dihydroxybenzoic acid co-crystal as the raw material, using several excipients as the auxiliary components of the tablets, the tablets with drug content of 10-500 mg per tablet were prepared by mixing the raw material and the excipients in a certain proportion, and the tablet formulation ratio is shown in Table 6.

[0105] Table 6 Preparation formulation of omeprazole and 2,6-dihydroxybenzoic acid co-crystal tablets

[0106]

[0107] The method of preparing the omeprazole and 2,6-dihydroxybenzoic acid co-crystal into tablet preparation is: mixing several excipients and raw material uniformly, directly compressing the tablets; or mixing the excipients by dry granulation, then mixing the raw material uniformly and compressing the tablets.

[0108] Preparation method 2 (tablets) of the co-crystal pharmaceutical preparation:

[0109] Preparation method: Using the pure omeprazole and 2,6-dihydroxybenzoic acid co-crystal as the raw material, using several excipients as the auxiliary components of the tablets, the tablets with drug content of 10-500 mg per tablet were prepared by mixing the raw material and the excipients in a certain proportion, and the tablet formulation ratio is shown in Table 7.

[0110] Table 7 Preparation formulation of omeprazole and 2,6-dihydroxybenzoic acid co-crystal tablets

[0111]

[0112] The method for preparing the omeprazole and 2,6-dihydroxybenzoic acid co-crystal into a tablet formulation is as follows: several excipients are mixed with the raw material, an appropriate amount of 1% sodium methyl cellulose solution is added, soft material is prepared, sieving and granulation, the wet granules are dried, sieving and granulation, magnesium stearate and talc powder are added and mixed uniformly, and then the tablet is pressed to obtain the tablet.

[0113] Preparation method 3 of the co-crystal drug formulation (capsule):

[0114] Preparation method: the omeprazole and 2,6-dihydroxybenzoic acid co-crystal is used as the raw material of the combined drug, several excipients are used as the auxiliary components of the combined drug capsule, and the capsule samples containing 10-500 mg of drug per tablet are prepared according to a certain proportion, and the capsule formulation proportion is shown in Table 8.

[0115] Table 8 Raw material and auxiliary formulation of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal capsule formulation

[0116]

[0117] The method for preparing the omeprazole and 2,6-dihydroxybenzoic acid co-crystal into a tablet formulation is as follows: several excipients are mixed with the raw material, an appropriate amount of 1% sodium methyl cellulose solution is added, soft material is prepared, sieving and granulation, the wet granules are dried, sieving and granulation, magnesium stearate and talc powder are added and mixed uniformly, and then the tablet is pressed to obtain the tablet.

[0118] Example 5

[0119] Dose 1 of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal (tablet):

[0120] The omeprazole and 2,6-dihydroxybenzoic acid co-crystal sample is used as the active ingredient of the drug to prepare the developed drug composition, the omeprazole and 2,6-dihydroxybenzoic acid co-crystal is used as the active ingredient of the drug, the daily dose is 0.5-300 mg, and the common tablet type containing 10, 100, 200, 300, and 500 mg of active ingredient can be prepared into 1-6 tablets per time.

[0121] Dose 2 of the omeprazole and 2,6-dihydroxybenzoic acid co-crystal (capsule):

[0122] The developed pharmaceutical composition using the sample of the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid as the pharmaceutical active ingredient, using the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid as the active ingredient of the medicine, and the daily administration dose of 10-3000mg can be prepared into 1-6 capsules each time, containing 10, 100, 200, 300, 500mg of active ingredients.

[0123] REFERENCES

[0124] [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.

[0125] [2] Skieneh J, Khalili Najafabadi B, Horne S, et a1. Crystallization of Esomeprazole Magnesium Water / Butanol Solvate. [J] Molecules, 2016, 21(4): 544.

[0126] [3] Yan Yimin, Ge Jilong, Tu Yongrui. Omeprazole salt hydrate and its preparation method: China, CN1136564A[P]. 1996.11.27

[0127] [4] Deng Jingen, Tian Tian, Zhu Jin, et al. New S-omeprazole salt: China, CN102241668A[P]. 2011-11-16.

[0128] [5] Sakurai F, Khutia A, Kikuchi T, et a1. X-ray Structure Analysis of N-Containing Nucleophilic Compounds by the Crystalline Sponge Method. Chemistry. 2017 Oct 26;23(60):15035-15040.

[0129] [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 2,6-dihydroxybenzoic acid, wherein the molar ratio of omeprazole to 2,6-dihydroxybenzoic acid is 1 : 1, wherein the powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks: 7.16 ± 0.2°, 7.78 ± 0.2°, 12.72 ± 0.2°, 13.92 ± 0.2°, 15.42 ± 0.2°, 17.62 ± 0.2°, 17.96 ± 0.2°, 19.72 ± 0.2°, 20.02 ± 0.2° using Cu K α radiation and expressed in terms of 2 theta angles.

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 of claim 1, wherein the powder X-ray diffraction pattern of the co-crystal has the following characteristic peaks: 7.16 ± 0.2°, 7.78 ± 0.2°, 12.72 ± 0.2°, 13.92 ± 0.2°, 15.42 ± 0.2°, 17.62 ± 0.2°, 17.96 ± 0.2°, 19.72 ± 0.2°, 20.02 ± 0.2°, 20.54 ± 0.2°, 21.56 ± 0.2°, 23.56 ± 0.2°, 23.96 ± 0.2°, 25.22 ± 0.2°, 25.86 ± 0.2°, 26.50 ± 0.2°, 27.70 ± 0.2°, 28.62 ± 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 3063 ± 2 cm"1, 2997 ± 2 cm"1, 2936 ± 2 cm"1, 2835 ± 2 cm"1, 2722 ± 2 cm"1, 1631 ± 2 cm"1, 1577 ± 2 cm"1, 1471 ± 2 cm"1, 1444 ± 2 cm"1, 1386 ± 2 cm"1, 1354 ± 2 cm"1, 1308 ± 2 cm"1, 1291 ± 2 cm"1, 1267 ± 2 cm"1, 1223 ± 2 cm"1, 1206 ± 2 cm"1, 1154 ± 2 cm"1, 1113 ± 2 cm"1, 1058 ± 2 cm"1, 1026 ± 2 cm"1, 971 ± 2 cm"1, 817 ± 2 cm"1, 801 ± 2 cm"1, 769 ± 2 cm"1, 705 ± 2 cm"1, 646 ± 2 cm"1, 601 ± 2 cm"1, 529 ± 2 cm"1, 484 ± 2 cm"1, 453 ± 2 cm"1, 428 ± 2 cm"1, when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy. -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 7. The co-crystal of claim 6, wherein the infrared spectrum of the co-crystal is 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 143°C ± 3°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 for preparing the co-crystal of omeprazole and 2,6-dihydroxybenzoic acid according to any one of claims 1-9, comprising mixing omeprazole and 2,6-dihydroxybenzoic acid in a molar ratio of 1:1, and preparing the co-crystal by organic solvent liquid grinding method.

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 amount of the organic solvent added in the organic solvent liquid grinding method is 5-100 mL per gram of the mixture of omeprazole and 2,6-dihydroxybenzoic acid; the grinding 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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