WO2019223799A1 - Esomeprazole strontium new compound, and pharmaceutical composition and use thereof - Google Patents

Abstract

The α type, β type, κ type, ν type, and ω type compounds of the esomeprazole strontium new molecular structure of the present invention have the features of faster and lower energy-consuming production, less hygroscopicity, better storage stability and accessibility, and being suitable for the preparation of drugs and pharmaceutical compositions thereof for the treatment or prevention of diseases such as human or animal gastro-oesophageal reflux disease, erosive reflux oesophagitis, upper gastrointestinal bleeding, stress ulcers, duodenal ulcers, and Zollinger-Ellison syndrome, for eradicating Helicobacter pylori, preventing recurrence of peptic ulcers associated with Helicobacter pylori, and long-term maintenance treatment for cured patients with oesophagitis to prevent recurrence, and for reducing adverse reactions during treatment.

Description

New compound strontium esomeprazole and its pharmaceutical composition and use Technical field

The invention relates to the technical field of medicine, in particular to providing a new compound of proton pump inhibitor esomeprazole and strontium and a pharmaceutical composition thereof.

Background technique

Esomeprazole is an optical isomer proton pump inhibitor of omeprazole, mainly in the form of sodium and magnesium salts. It can inhibit the H + / K + -ATPase near the gastric secretion tube of gastric parietal cells, and has a good acid suppression effect. Due to its metabolic advantages, esomeprazole has higher bioavailability and more consistent pharmacokinetics. Increases the amount of drugs that reach the proton pump, and is now widely used in clinical treatment of gastroesophageal reflux disease, erosive reflux esophagitis, upper gastrointestinal bleeding, stress ulcers, duodenal ulcers, eradication of pyloric screw Relevant diseases such as bacteria, Zhuo-Ellison syndrome, prevention of recurrence of peptic ulcer related to Helicobacter pylori, long-term maintenance treatment to prevent recurrence of patients with esophagitis that have been cured.

The combination of esomeprazole and non-steroidal anti-inflammatory drugs is beneficial to prevent patients with risk of gastric ulcer. The literature discloses esomeprazole compound, for example: (document 1, aspirin-esomeprazole compound enteric pellets, Chinese patent, CN 103479653A); document 2, containing proton pump inhibitors, NSAID and antacid Drug formulation (Chinese patent, 102294031A); Literature 3, naproxen and esomeprazole magnesium compound enteric-coated tablets and preparation method thereof, Chinese patent, 106606496A); the literature also discloses more acid resistant Esso Meprazole pharmaceutical composition and its preparation (Document 4, Esomeprazole pharmaceutical composition and its preparation, Chinese patent, CN 103845734A); Document 5, Chinese patent CN 102078616A discloses an esomeprazole hydrogen carbonate Sodium composition. Reference 6, Xu Pingru, Huang Jian, Zhou Feng.Efficacy of Esomeprazole, Levofloxacin, Furazolidone Triad Therapy for Helicobacter Pylori Eradication [J] .Chinese Journal of Nosocomiology, 2010,20 (6): 857-859; Literature 7. Chen Yuanhong, Wang Wanmei, Wang Hao, et al. Comparative study of esomeprazole triple and omeprazole triple therapy in the treatment of Hp-positive duodenal ulcer [J] .Journal of the First Military Medical University, 2005 (8): 1045- 1047; Literature 8, Zhu Hong, Liao Jiangtao, Li Qinqin, et al. Observation on the curative effect of quadruple therapy on Helicobacter pylori positive gastric ulcer [J] .Progress in Modern Biomedicine, 2011,11 (7): 1330-1332 + 1335; Literature 9, Teng Chunyuan, Zhao Qingxi.Efficacy of esomeprazole, levofloxacin and ornidazole in the treatment of chronic gastritis [J]. Qilu Medical Journal, 2010,25 (2): 165-166 + 168; Literature 10, Wang Tao, Liao Zhongli, Yang Li, et al. Efficacy of 10-day and 14-day treatment with bismuth-containing quadruple therapy for Helicobacter pylori eradication [J] .Journal of Regional Anatomy and Operative Surgery, 2017,26 (11): 831-833 ..

On May 5, 2010, the U.S. FDA approved a compound tablet (trade name Vimovo) containing enteric naproxen and esomeprazole magnesiumnesium (trade name Vimovo) for the treatment of osteoarthritis Symptoms in patients with rheumatoid arthritis and spinal stiffness. Vimovo is a combination of non-steroidal anti-inflammatory drugs (NSAID) / proton pump inhibitors. It is suitable for patients who need long-term treatment with non-steroidal anti-inflammatory drugs and are at risk of associated gastric ulcers. Compared with giving 500 mg of enteric naproxen twice daily, the use of naproxen / exomeprazole magnesium enteric tablets twice daily reduced the incidence of gastric ulcers under endoscopy (4.1% vs. 23.1%, respectively) , And 7.1% vs. 24.3%; P values for both studies were less than 0.001).

Esomeprazole magnesium trihydrate and dihydrate are reported in the literature [Ref. 11, NOVELFORM OFS-OMEPRAZOLE WO9854171; Ref. 12, a method for preparing esomeprazole magnesium dihydrate, CN201210017761.9; Reference 13: Ye Jiang, Cao Qing, Wang Liyun, et al. Process improvement of esomeprazole magnesium [J] .Strait Pharmaceutical, 2015,27 (01): 222-224.], But the reaction time is as long as 3 -12 hours.

Strontium is a Group IIA alkaline earth metal. The literature reports that strontium has not shown safety issues in rats even at a dose of 633 mg / kg / day (see PJMarie et al., Mineral & Electrolyte Metabolism, 11, 5-13 (1985 )). It is reported that in daily life, people consume strontium in an average amount of about 3.3 mg / day (per 70 kg body weight) (see Report of Toxicological Profile for Strontium, U.S. Department of Health and Human Services, 2004). It was further found that strontium is beneficial for calcium metabolism in bone tissue to promote bone formation and inhibit bone tissue reabsorption (see reference 14: S.P. Nielsen, Bone, 35, 583-588 (2004)). An example of a known, pharmaceutically acceptable strontium salt is strontium ranelate. The literature reported crystalline S-omeprazole strontium tetrahydrate, S-omeprazole strontium anhydrous (Document 15: Chinese patent, CN101296921A), the US FDA approved the listing of esomeprazole strontium tetrahydrate; however From the current actual situation, there are some problems in the stability or preparation of esomeprazole strontium 4 hydrate. From a pharmacological point of view, continuous innovation is still needed.

So far, no published literature at home and abroad has reported that the new esomeprazole strontium compounds of the present invention are more stable or easier to prepare, such as esomeprazole strontium α, β, and κ new Crystal compound of molecular formula, and esomeprazole strontium v type crystal compound, esomeprazole strontium ω type new molecular formula crystal compound, that is, new esomeprazole strontium crystal hydrate with different molecular formula or different crystal form and its Preparation method and use.

Polymorphs of chemical drugs play an important role in drug research, not only for building drug compound libraries, etc., but also for better pharmaceutical needs. Thermal analysis methods have important value and status in materials science, chemical or pharmaceutical analysis, and can be used to detect the polymorphism of a compound or the change in the crystal form alone (Li Zengyu, Thermal Analysis, Tsinghua University Press, (First edition, August 1987). Differential thermal analysis (DTA) is a more commonly used analytical method. It can be used for both identification or characterization of materials and quantitative analysis. It was used by Barta et al. At the 2nd International Thermal Analysis Conference in 1968. Identify unknown compounds. Pharmacopoeias in many foreign countries have already included differential thermal analysis methods. Ten years ago, differential thermal analysis methods have been widely used in chemical and pharmaceutical systems.

Summary of the Invention

The invention relates to a new molecular formula and molecular weight of a proton pump inhibitor drug, Esomeprazole Strontium, a new molecular structure compound, and a preparation method and application thereof (C ₁₇ H ₁₈ N ₃ O ₃ S ) ₂ Sr · nH ₂ O, n = 1.5, ₂ , 2.5, ₃ , 3.5. That is, esomeprazole strontium α-type, β-type, κ-type, ν-type, and ω-type compounds, and a preparation method and application thereof.

Advantageous discovery of the present invention: In the process of completing the present invention, it was unexpectedly found that, although the current literature reports that the crystal of esomeprazole strontium 4 hydrate is the best choice for pharmacology, esomeprazole strontium 4 hydrates It has also been approved for marketing, but this study also found that the thermal stability of esomeprazole strontium 4 hydrate is not as good as that of esomeprazole strontium 3 hydrate, and it is not the best choice in pharmacy. Similar to the preparation of the solvent, even in the process of preparing the esomeprazole strontium crystalline hydrate, it was found that it is easier to prepare and obtain the more stable esomeprazole strontium 3 hydrate or esomeprazole strontium of the present invention. 3.5 Hydrate and so on.

Not only that, the present invention has also found that the reaction time to obtain the preparation of esomeprazole strontium 3.5 hydrate or esomeprazole strontium 3 hydrate or esomeprazole strontium strontium 2 hydrate is much lower than the preparation of esomeprazole What is required for strontium tetrazolium hydrate (Examples 1 to 6 of Patent Document 15 require a stirring reaction for 3 hours, and most of the examples of the present invention are unexpected and only need to stir the reaction for about 10-30 minutes to complete Reaction; and the drying time is much shorter than the drying time of the example of Comparative Document 15, which is beneficial to the preparation of the product and reduces energy consumption), while the esomeprazole strontium 3.5 hydrate or esomeprazole strontium 3 hydrate Stability completion can meet the requirements of pharmacy. This reflects better stability of esomeprazole strontium 3.5 hydrate or esomeprazole strontium 3 hydrate or esomeprazole strontium 2 hydrate, etc., which have better availability in the production process, and It also shows that the substance of the present invention is more convenient for production.

More importantly, we repeatedly found through multiple experiments that the strontium hydroxides in Examples 1 to 3 of Comparative Document 15 (Document 15: Chinese Patent, CN101296921A) for the preparation of estrometrazole strontium 4-hydrate The octahydrate cannot be dissolved in the methanol solution described in this example, even if 4.6 g of strontium hydroxide octahydrate in a hard powder state passed through a 60-mesh sieve (Chinese Pharmacopoeia 2010 edition standard) is added to 50 ml of methanol or 100 ml Methanol or even 120ml of methanol (chemical reagent grade methanol, analytical grade, produced by Sinopharm Group), equipped with a reflux condenser, whether at room temperature or 15 ° C or 25 ° C or 30 ° C or 40 ° C or under normal pressure reflux in methanol After stirring for 2-3 hours, the hard powder of strontium hydroxide octahydrate and methanol remained a turbid white substance in the reaction flask, and no dissolution was observed. 13.8 g of the strontium hydroxide octahydrate passed through a 40 mesh sieve mentioned in Example 1 was added to 100 ml of methanol or even 120 ml of methanol, whether it was refluxed in methanol for 1 hour, and then cooled to about 30 ° C ± 1.5 ° C. The liquid was mixed with a methanol solution of esomeprazole and stirred at room temperature of about 25 ° C ± 1.5 ° C for 3 hours. The pure esomeprazole strontium tetrahydrate mentioned in the literature could not be effectively prepared. The precipitate obtained by filtration was mostly mixed with A large amount of solids of strontium hydroxide octahydrate; according to the operations of Examples 1-3, the precipitates obtained after filtration are mostly solids precipitated and mixed with a large amount of strontium hydroxide octahydrate after washing with methanol (while Example 1 of the present invention) In -6, add a strontium chloride or strontium acetate methanol solution to the reaction bottle to form a uniform solid from the solution state within 15-30 minutes).

The new molecular formula and new molecular structure of the esomeprazole strontium compound obtained by the present invention are surprisingly that the esomeprazole strontium containing crystal water has a lower hygroscopicity than the esomeprazole strontium that does not contain crystal water. The deliquescent of anhydrous substances makes it necessary to isolate the air to prevent blocking during processing. The hydrate of the present invention has good sliding properties, thereby improving the operability of the preparation. The substance of the present invention containing relatively low crystal water is free of crystals. Water esomeprazole strontium is more stable. It is unexpectedly easier to prepare than esomeprazole strontium 4 hydrate, and it is easy to store and transport. It is beneficial to reduce manufacturing costs and costs, and it is also conducive to the manufacture of formulations. The different new molecular formula and new molecular structure of the esomeprazole strontium crystalline hydrate of the present invention have different advantages in terms of stability or manufacturability. It can be seen that the esomeprazole strontium 3.5 hydrate, esomeprazole strontium sulphate 3 hydrate, esomeprazole strontium strontium 2.5 hydrate and the like of the present invention have better industrialization value or medicinal value.

Surprisingly, characteristically, the thermal analysis (TG-DSC or TG-DTA) pattern of the hydrate of the present invention has a corresponding endothermic peak under the weightlessness platform (under the weightlessness curve before about 160 ° C), Thermal analysis shows a new structure of esomeprazole strontium compound, esomeprazole strontium 1.5 hydrate [(C ₁₇ H ₁₈ N ₃ O ₃ S) ₂ Sr · 1.5H ₂ O] (α-type compound) , Esomeprazole Strontium 2 Hydrate [(C ₁₇ H ₁₈ N ₃ O ₃ S) ₂ Sr · 2H ₂ O] (β-type), Esomeprazole Strontium 2.5 Hydrate [(C ₁₇ H ₁₈ N ₃ O ₃ S) ₂ Sr · 2.5H ₂ O) (κ type), esomeprazole strontium esomeprazole strontium 3 hydrate (ν type) [(C ₁₇ H ₁₈ N ₃ O ₃ S) ₂ Sr · 3H ₂ O], esomeprazole strontium esomeprazole strontium 3.5 hydrate (ω type) [(C ₁₇ H ₁₈ N ₃ O ₃ S) ₂ Sr · 3.5H ₂ O]. In terms of pharmacy, even if different crystal forms of the same compound are prepared or obtained, they have practical or potential or future significance or value in pharmacology, not to mention the acquisition of crystalline hydrates of different molecular formulas of the same drug. They all have real or potential or future meanings or values.

The preparation of new esomeprazole strontium compounds includes the following methods:

Method A. In a reaction vessel, add esomeprazole or one or more of esomeprazole sodium or esomeprazole potassium salt, add water and / or low-molecular organic solvents C ₁ -C ₆ Alcohol (selected from, but not limited to, methanol, ethanol, isopropanol, 1-propanol, n-butanol, etc.), C ₂ -C ₈ low molecular ether (selected from, but not limited to, ether, tetrahydrofuran, isopropyl ether, etc.) One or more of C ₂ -C ₆ low-molecular-weight nitriles, stir, and add strontium oxide, strontium nitrate, strontium acetate, strontium acetate hemihydrate, strontium chloride, and strontium chloride at 10-50 ° C. One or more of hydrate, strontium bromide, strontium nitrate, strontium perchlorate, strontium carbonate, strontium oxalate, strontium sulfate, strontium phosphate, etc., and water, C ₁ -C ₆ low molecular alcohols, C ₂ -C ₈ low molecular ethers, C ₃ -C ₈ low molecular ketones and other organic solvents in one or several solutions, stirred at 15-50 ° C, the solids were analyzed, filtered, water or C ₁ -C ₆ low One or more of molecular alcohols, C ₂ -C ₈ low molecular ethers, C ₃ -C ₈ low molecular ketones, C ₂ -C ₆ low molecular nitriles, C ₁ -C ₆ low molecular halogenated hydrocarbons Wash once or several times, and filter. The obtained solid can be reused. And C ₁ -C ₆ lower alcohol is, C ₂ -C ₈ ether of a low molecular weight, C ₃ -C ₈ low molecular weight ketones, C ₁ -C ₆ halogenated hydrocarbons of low molecular weight of one or more of The crystallization solvent is recrystallized one or more times, and it is placed below 40 ° C to allow the crystals to be fully analyzed, filtered, and water or a C1-C6 low-molecular alcohol, a C2-C8 lower ether, a C3-C8 low-molecular ketone, and C1-C6. One or more of the lower halogenated hydrocarbons, washed, filtered, and dried to obtain a new esomeprazole strontium compound;

Or Method B. In a reaction vessel Jia Aisuo esomeprazole, add water and / or organic solvent is a lower alcohol C ₁ -C ₆ (taken from but not limited to, methanol, ethanol, isopropanol, 1-propanol, n Butanol, etc.), C ₂ -C ₈ low molecular ethers (selected from but not limited to ether, tetrahydrofuran, isopropyl ether, etc.), C ₂ -C ₆ low molecular nitriles, C ₁ -C ₆ low molecular halogenated One or more of the hydrocarbons, stir, then add one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, etc., stir to dissolve, adjust the pH of the solution to 9.0 to 14.0 (preferably adjust the pH To 10.0-13.0), add strontium nitrate, strontium acetate, strontium acetate hemihydrate, strontium chloride, strontium chloride hexahydrate, strontium bromide, strontium nitrate, strontium perchlorate, strontium carbonate at 10-50 ° C One or more of strontium oxalate, strontium sulfate, strontium phosphate, etc. with water, C ₁ -C ₆ low molecular alcohol, C ₂ -C ₈ low molecular ether, C ₃ -C ₈ low molecular ketone and other organic A solution of one or several kinds of solvents, stirred at 10-50 ° C, so that the solids are fully eluted, filtered, water or low molecular alcohols of C ₁ -C ₆ , low molecular ethers of C ₂ -C ₈ , C ₃ -C ₈ low molecular ketone, C ₂ -C ₆ low molecular nitriles, C ₁ -C ₆ low molecular halogenated hydrocarbons, one or more kinds of washing 1 to several times, filtration, the resulting solid water and C ₁ -C ₆ low molecular alcohols, C _{One or more of 2-} C ₈ low-molecular-weight ether, C ₃ -C ₈ -low-molecular-weight ketone, and C ₁ -C ₆ -low-molecular halogenated hydrocarbon are crystallization solvents for one or more recrystallizations, 40 ° C Place it as follows to crystallize it out, filter, and use one or more of water or C1-C6 low-molecular alcohol, C2-C8 lower ether, C3-C8 low-molecular ketone, and C1-C6 lower halogenated hydrocarbon. Wash, filter and dry to obtain new strontium esomeprazole compounds;

In method A or method B, wherein esomeprazole or sodium or potassium esomeprazole used in the reaction: strontium nitrate, strontium acetate, strontium acetate hemihydrate, strontium chloride, strontium chloride The equivalent ratio of one of hydrate, strontium bromide, strontium nitrate, strontium perchlorate, strontium carbonate, strontium oxalate, strontium sulfate, and strontium phosphate is about 1: 1 to 1.2; more preferred is strontium chloride, Strontium chloride hexahydrate, strontium bromide, strontium nitrate and strontium acetate or hydrates thereof.

In method A or method B, the esomeprazole sodium or potassium or esomeprazole (weight g) and water, or a low molecular alcohol of C1-C6, or a lower ether of C2-C8 used in the reaction (Selected from, but not limited to, diethyl ether, tetrahydrofuran, isopropyl ether, etc.), or C2-C6 lower nitriles (selected from, but not limited to, acetonitrile, propionitrile, etc.), C _1- C ₆ low molecular halogenated hydrocarbons and other organic solvents One or more of the weight-volume ratios are generally: 1 (g): 3.0 to 15 (ml), and the more preferred ratio is: 1 (g): 4 to 9 (ml); used in crystallization or recrystallization The volume ratio of water to organic solvents is generally 0.01 to 1: 0.1 to 98, and a more preferred ratio is 0.01 to 1: 4 to 60.

The organic solvent in the reaction is selected from one or more of, but not limited to, water, acetonitrile, methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, isopropyl ether, dichloromethane, chloroform, and the like. Water, tetrahydrofuran, One or more of methanol, ethanol, isopropyl alcohol, isopropyl ether, and the like.

The crystallization or recrystallization solvent of the new compound of esomeprazole and strontium is selected from, but not limited to, one of water, acetonitrile, methanol, ethanol, isopropanol, ether, tetrahydrofuran, isopropyl ether, dichloromethane, chloroform, or the like Several; esomeprazole strontium crystal crystallization or recrystallization solvent, more preferably one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether, dichloromethane, chloroform. In the preparation method of the present invention, during recrystallization, one or more of water or formamide, methanol, or ethanol is used to dissolve the esomeprazole strontium crystal hydrate. After dissolution, it can be decolorized with activated carbon or the like. It is crystallized with the organic solvent mentioned in the present invention.

In the present invention, the carbon number of the organic solvent lower alcohol or low molecular alcohol is defined as C1-C6 (that is, alcohol having 1-6 carbon atoms), such as methanol, ethanol, isopropyl alcohol, etc .; lower ether or low molecular ether The number of carbon atoms is defined as C2-C8, such as diethyl ether, butyl ether, tetrahydrofuran, etc .; the number of carbon atoms of lower halogenated hydrocarbons is defined as C1-C6, including dichloromethane, dichloroethane, chloroform, etc .; C3-C8 Low-molecular-weight ketones are defined as ketones of 3 to 8 carbon atoms, including acetone, methyl ethyl ketone, isohexone, etc .; the method of marking the number of carbon atoms for any type of compound described as "lower or lower molecular" only needs to appear once in the text The carbon number of any other unidentified compound of the same kind described as "lower or lower molecule" is the same as the number already marked in this text.

The product of the present invention can be dried at different temperatures (such as 20-80 ° C), drying time (such as 0.5 hours to several hours), or attached with other desiccants (including silica gel, phosphorus pentoxide, hydrogen) Sodium oxide, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous sodium sulfate, etc.), or the final product is dried under normal or reduced pressure.

Preparation of esomeprazole strontium anhydrate can be obtained from esomeprazole strontium crystalline hydrate through different drying methods, and its preparation can be performed at different temperatures (such as 25-100 ° C) and drying time (up to several days) , Or with other desiccants (including silica gel, molecular sieves, phosphorus pentoxide, sodium hydroxide, soda lime, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.) The final product is dried under normal pressure or reduced pressure. It can also be mixed with anhydrous benzene for several days or treated with distilled water, and combined with other drying methods described in this article to obtain .

Preparation of esomeprazole strontium anhydrate mentioned in the examples of the present invention: The method of Example 1 of the present invention is used to prepare the esomeprazole strontium hydrate sample, the method of Example 9 of reference 15, at 100 ° C It was dried under vacuum for 5 hours and then at room temperature for 2 hours to obtain an anhydrous strontium esomeprazole. Its moisture content was determined by Karl Fischer method to be about 0.9%.

Determination of content of new compounds of esomeprazole and strontium or determination of related substances by reference method (References: Zheng Jingzhe, Mu Lingli, RP-HPLC method for determination of esomeprazole magnesium content and related substances [J] .Hunan Normal University Journal of Medical Science, 2014,11 (1): 90-92 + 96; Dong Qixin, Zhu Jiajun, Yu Yunqiu, et al. Determination of esomeprazole in drug substances by HPLC [J] .Fudan Journal (Medical Edition) , 2014,41 (1): 118-120; Li Tingting, Zheng Zidong, Determination of related substances in esomeprazole sodium by RP-HPLC method [J] .Journal of Pharmaceutical Analysis, 2013,33 (4): 656-660.) .

Esomeprazole content in the strontium compound of esomeprazole of the present invention (including the examples) HPLC method conditions: Chromatographic column: WatersXTerra MS C8 reversed-phase column (150mm × 4.6mm, 3.5μm), mobile phase : V (acetonitrile): V (20mmol / L ammonium acetate buffer, pH7.6) = 28: 72, detection wavelength 280nm, column temperature 25 ° C, flow rate 1mL / min. Esomeprazole was used as a reference substance and determined by external standard method.

The conditions for the determination of esomeprazole strontium-related substances in the present invention (including the examples): Venusil XBP C18 (L) chromatography column (250mm × 4.6mm, 5μm), and mobile phase using acetonitrile-phosphate buffer solution (pH 7.6) -Water gradient elution with a flow rate of 0.8 mL / min, a column temperature of 30 ° C, and a detection wavelength of 302 nm.

The qualitative analysis of strontium in the new strontium compound of esomeprazole according to the present invention is determined by atomic absorption spectrometry. All preparation examples of the present invention have been found to produce strontium-containing compounds by atomic absorption spectrometry. The reference method for content determination is EDTA volumetric method. Determination, in addition to atomic absorption spectrometry to determine the review (Reference: Lai Qingying. Analysis of Strontium in Strontium Alloys-EDTA Volumetric Method [J] .Iron Alloys, 1988 (6): 33-34; Jiang Ying, Peng Qiang.Flame Atoms Determination of strontium in geological samples by absorption spectrometry [J] .Inner Mongolia Petrochemical Industry, 2009,35 (23): 25-26; and reference 15).

For the determination of the water content of the strontium compound of esomeprazole in the present invention, refer to the method for determining the water content of sodium esomeprazole sodium in the second part of the Chinese Pharmacopoeia of the 2015 edition (Appendix ⅧM, first method A), and determine it by Karl Fischer method. However, when the moisture of the compounds mentioned in the present invention is measured by the Karl Fischer method, anhydrous methanol and formamide (1: 2) are used as a mixed solvent.

Powder X-ray diffraction can often be used to characterize and / or identify polymorphs, and for powder X-ray diffraction to characterize and / or identify, use the modifier "about" before reporting a peak. This is a common practice in the field of solid state chemistry given the inherent variation in peak values. The general accuracy of the 2θx-axis values of the powder pattern peaks is on the order of ± 0.2 ° 2θ. Therefore, the powder X-ray diffraction peaks appearing at "about 8.0 ° 2θ" mean that the peaks when measured on most X-ray diffractometers May be between 7.8 ° 2θ and 8.2 ° 2θ. The change in peak intensity is a result of how the crystals are oriented in the sample container relative to the external X-ray source. The orientation effect does not provide structural information about the crystals.

In one aspect, the invention provides different specific crystalline hydrates or polymorphs of esomeprazole strontium.

In another aspect, the present invention provides different crystalline hydrates and methods for their preparation.

The present invention in another aspect provides a pharmaceutical composition comprising any one or more strontium esomeprazole prepared by the method of the present invention, and one or more pharmaceutically acceptable excipients.

The present invention further provides a method of preparing a pharmaceutical formulation comprising any one or more of the esomeprazole strontium preparation prepared by the method of the present invention or a combination with at least one or a pharmaceutically acceptable excipient.

The invention provides that esomeprazole strontium 3.5 hydrate or esomeprazole strontium 3 hydrate can shorten the preparation time compared with esomeprazole strontium 4 hydrate, which is conducive to greatly reducing energy consumption and reducing the cost of preparing the drug. Conducive to environmental protection.

At the same time, the new crystal drug expands the library of materials obtained by the formulation scientist to design, for example, the drug dosage form of the drug with a target release curve or other desired characteristics. The construction of a library of drug compounds is very important, not only for comparative research, etc., in this field A new crystalline strontium hydrate of esomeprazole is needed.

The present invention provides esomeprazole strontium trihydrate is basically a loose crystalline substance, which is not only convenient for filtration and drying, but also has a relatively short preparation time. The stability of the drug is higher than that of esomeprazole strontium. Not lower than esomeprazole strontium 4-hydrate.

In addition, compared with the example of reference 15, the esomeprazole strontium hydrate of the present invention includes esomeprazole strontium 3 hydrate or esomeprazole strontium 3.5 hydrate and the like are all better than esomeprazole strontium 4-hydrate is easier to prepare. When preparing esomeprazole strontium 4-hydrate, it is prone to dehydration to form esomeprazole strontium 3-hydrate or esomeprazole strontium 3.5 hydrate, which causes the original target product to qualified.

New compounds of esomeprazole and strontium, also used to prepare new compounds of esomeprazole and strontium and non-steroidal anti-inflammatory drugs or with antacids and other antiulcer drugs (including H ₂ receptor antagonists) or pharmacy A pharmaceutical composition of an acceptable gastric mucosa protective agent and one or more of the above components, a pharmaceutical composition of a new compound of esomeprazole and strontium and a non-steroidal anti-inflammatory drug comprises an effective dose of a non-steroidal anti-inflammatory drug And an effective dose of a new compound of esomeprazole or strontium or with an effective dose of an antacid and other pharmaceutically acceptable excipients.

The new esomeprazole strontium novel compound is used for preparing a pharmaceutical composition with a non-steroidal anti-inflammatory drug. The pharmaceutical composition comprises an effective dose of a non-steroidal anti-inflammatory drug and an effective dose of esomeprazole strontium new Compounds and other pharmaceutically acceptable excipients.

Further, the pharmaceutical composition of the non-steroidal anti-inflammatory drug and the new compound strontium esomeprazole provided by the present invention is more preferably parts by weight or parts by weight of the non-steroidal anti-inflammatory drug and esomeprazole. The ratio is from 0.05 to 60: 0.2 to 1.2, wherein the strontium hydrate of esomeprazole is contained based on the weight of esomeprazole; the non-steroidal anti-inflammatory drug is selected from, but not limited to, aspirin, naproxen, ( s)-(-)-naproxen, ibuprofen, dextro- ibuprofen, ketoprofen, dexketoprofen, etodolac, S-etodolac, loxoprofen, fenofrol , Diclofenac, potassium diclofenac, asimicin, indomethacin, piroxicam, meloxicam, lornoxicam, celecoxib, rofecoxib, etc. or their chiral isomers or their pharmaceutical use A salt or a solvent compound thereof. The above-mentioned components of the composition of the present invention can be individually prepared into a preparation, and then prepared into a composition package, as one package.

Specifically, the present invention provides a pharmaceutical composition of a novel compound of aspirin and esomeprazole strontium, which is composed of the active pharmaceutical ingredients aspirin and strontium esomeprazole and other pharmaceutically acceptable excipients, more preferably aspirin and esome The parts by weight or the ratio of parts by weight of meprazole strontium hydrate is from 3 to 16: 0.2 to 1.2. The strontium hydrate containing esomeprazole is based on the weight of esomeprazole.

More specifically, for aspirin-essomeprazole new compound strontium compound enteric-coated pellets, it may consist of aspirin enteric-coated pellets and esomeprazole strontium-new compound enteric-coated pellets, aspirin and esomeprazole The parts by weight or the ratio of parts by weight may be selected from 3 to 16: 1. Among them, the unit dose of the non-steroidal anti-inflammatory drug aspirin is more preferably 50 mg to 500 mg; the esomeprazole-containing strontium hydrate is based on the unit dose and weight of the esomeprazole and the esomeprazole strontium hydrate More preferably, it is 10 to 60 mg, and more preferably 20 to 30 mg. For example, the unit dose of aspirin is more than 50 mg: 20 mg / esomeprazole, or the unit dose of aspirin is more than 50 mg: 30 mg / esomeprazole, or aspirin. Unit dose 75mg: 20mg / esomeprazole, or aspirin Unit dose 75mg: 30mg / esomeprazole, or aspirin unit dose 250mg: 20mg / esomeprazole, or aspirin unit dose Less than 500mg: 20mg / Esomeprazole, or aspirin unit dose less than 500mg: 30mg / Esomeprazole.

The present invention also provides pharmaceutical compositions of naproxen or its chiral isomer or (s)-(-)-naproxen or its pharmaceutically acceptable salt and a new compound of esomeprazole and strontium, and others Pharmaceutically acceptable excipients are used to prepare pharmaceutically acceptable formulations. Among them, the main medicine is more preferably parts by weight or the ratio of parts by weight is: 200 to 750: 10 to 60. Among them, esomeprazole strontium hydrate is included. Based on the weight of esomeprazole. The unit dose of the nonsteroidal anti-inflammatory drug naproxen is more preferably 200 mg to 750 mg; the unit dose of esomeprazole-containing strontium hydrate is more preferably 10 to 40 mg, and more preferably 20 to 30mg.

Among them, naproxen and esomeprazole new compound strontium compound enteric-coated tablets can be made of (1) naproxen enteric-coated pellets and (2) esomeprazole new compound strontium immediate-release particles. Film-coated tablets; each tablet contains naproxen from 375mg to 500mg, and the new compound containing esomeprazole and strontium is 20mg in terms of esomeprazole; more preferably, a single dose contains 375mg of naproxen per tablet, The new compound containing esomeprazole and strontium is 20 mg as esomeprazole; or more preferably, a single dose contains 500 mg of naproxen per tablet, and the new compound containing esomeprazole and strontium as esomeprazole as 20mg.

Naproxen or dexketoprofen or etodolac or a pharmaceutically acceptable salt of a non-steroidal anti-inflammatory drug is selected from, but is not limited to, sodium, potassium, calcium, lysine, arginine, tromethamine Triolates, etc.

The non-steroidal anti-inflammatory drug ibuprofen, the ibuprofen pharmaceutical salt is selected from, but not limited to, ibuprofen, ibuprofen arginine, ibuprofen L-arginine, ibuprofen DL-arginine Acid salt, ibuprofen lysine, ibuprofen L-lysine, ibuprofen histidine, d-ibuprofen potassium, ibuprofen sodium, ibuprofen calcium, ibuprofen ammonia One or more of butanetriol or its solvent compound or its crystalline or amorphous form or its inclusion compound. The above-mentioned components of the composition of the present invention can be individually prepared into a preparation, and then prepared into a composition package, as one package.

Non-steroidal anti-inflammatory drug d-ibuprofen, d-ibuprofen medicinal salt selected from, but not limited to, d-ibuprofen arginine, d-ibuprofen L-arginine, d-ibuprofen Ibuprofen DL-arginine, dextro-ibuprofen lysine, dextro-ibuprofen L-lysine, dextro-ibuprofen histidine, dextro-ibuprofen potassium, dextro-ibuprofen One or more of ibuprofen sodium, dextro-ibuprofen calcium, d-ibuprofen tromethamine or a solvent compound thereof or a crystalline or amorphous form thereof.

New compounds of esomeprazole and strontium with effective doses of anti-ulcer drugs (including H ₂ receptor antagonists) or gastric mucosal protective agents or pharmaceutical compositions composed of one or more of the above components or effective doses of antibacterial drugs , Its weight or weight ratio is selected from 0.2 to 3: 0.01 to 2 (weight unit: gram or milligram, or g or mg; the above is not limited to the actual weight of the various components, but can also be used as the anhydrous component of various components Calculate the corresponding ratio of each component by weight, and calculate the corresponding ratio or weight ratio of each component by the weight of the parent compound of each component, which is also the same in the present invention). Wherein, the anti-ulcer drug (including H ₂ receptor antagonist) or gastric mucosal protective agent is selected from, but not limited to, famotidine, cimetidine, ranitidine, ranitidine hydrochloride, nizatidine, Nizatidine hydrochloride, lafuridine, rebamipide, bismuth aluminate, bismuth citrate, pectin bismuth, bismuth glycyrrhizinate, medicinal bismuth or its pharmaceutically acceptable salt or its solvent compound or its optics One or more of the isomers. Antibacterials are selected from, but are not limited to, tetracycline, doxycycline, minocycline, amoxicillin, amoxicillin trihydrate, erythromycin, clarithromycin, roxithromycin, azithromycin, metronidazole, One or more of nitrazole, ornidazole, seconidazole, ofloxacin, levofloxacin, furazolidone or a pharmaceutically acceptable salt thereof, or a solvent compound or hydrate thereof. The above-mentioned components of the composition of the present invention can be individually prepared into a preparation, and then prepared into a composition package, as one package.

A pharmaceutical composition may contain 20mg of esomeprazole strontium neohydrate and 0.15g of ranitidine hydrochloride, a pharmaceutical composition may contain 30mg of esomeprazole strontium neohydrate and cimetidine 0.2g, in a pharmaceutical composition may contain 30mg esomeprazole strontium neohydrate and famotidine 20mg, in a pharmaceutical composition may contain 30mg esomeprazole strontium neohydrate and famotidine 10mg; 30mg esomeprazole strontium neohydrate and 75mg nizatidine in a pharmaceutical composition; 30mg esomeprazole strontium neohydrate and lafuridine in a pharmaceutical composition Butan 10mg or containing 30mg of esomeprazole strontium neohydrate and 5mg of lafuridine but 5mg of esomeprazole strontium neohydrate and 5mg of lafuridine (the above is not limited to the actual weight calculation of various components (You can also calculate the corresponding proportion of each component by the weight of the anhydrous component of each component, and also calculate the corresponding proportion or weight of each component by the weight of the parent compound of each component); the above pharmaceutical composition can Pharmaceutically acceptable excipients Preparations. The above-mentioned components of the composition of the present invention can be individually prepared into a preparation, and then prepared into a composition package, as one package.

The invention provides a pharmaceutical composition of a new compound of esomeprazole and strontium. The parts by weight of the main medicine or the ratio of parts by weight: 10 to 60 parts by weight of esomeprazole strontium hydrate and 100 to 1700 weight of antacid. And other pharmaceutical excipients; the antacid is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, aluminum carbonate, magnesium carbonate, magnesium hydroxide, magnesium oxide, light magnesium oxide, hydrogen One or more of alumina, magnesium aluminum carbonate, aluminum magnesium carbonate, or hydrates thereof, and esomeprazole-containing strontium hydrate is based on the weight of esomeprazole. The above-mentioned components of the composition of the present invention can be individually prepared into a preparation, and then prepared into a composition package, as one package.

The pharmaceutical composition provided by the present invention preferably has an esomeprazole strontium neohydrate content of 20 to 40 parts by weight (the above is not limited to the actual weight of the component, but can also be calculated based on the weight of the anhydrous component. It can be calculated based on the mass of esomeprazole), and the antacid content is 300-1200 parts by weight, preferably 400-650 parts by weight.

In yet another preferred embodiment, 20 parts by weight of esomeprazole strontium neohydrate (calculated based on the mass of esomeprazole, the same applies hereinafter), 250-300 parts by weight of potassium bicarbonate, and 160-180 magnesium oxide Parts by weight

Or in another preferred embodiment, 40 parts by weight of esomeprazole strontium neohydrate, 300-330 parts by weight of potassium bicarbonate, and 200-220 parts by weight of magnesium oxide.

In another preferred embodiment, 20 parts by weight of esomeprazole strontium neohydrate (calculated based on the mass of esomeprazole, the same applies hereinafter), and 1100 parts by weight of sodium bicarbonate;

In still another preferred embodiment, 20 parts by weight of esomeprazole strontium neohydrate (calculated based on the mass of esomeprazole, the same applies hereinafter), 260-280 parts by weight of sodium bicarbonate, and 300-300 mg of aluminum magnesium carbonate 320 parts by weight;

Or in another preferred embodiment, 40 parts by weight of esomeprazole strontium neohydrate (calculated based on the mass of esomeprazole, hereinafter the same), 280-320 parts by weight of sodium bicarbonate, and 320- parts by weight of aluminum magnesium carbonate 330 parts by weight.

In another embodiment, 20 parts by weight of esomeprazole strontium neohydrate, 500-700 parts by weight of sodium bicarbonate, and 200 parts by weight of magnesium hydroxide.

The new strontium esomeprazole compound is used for preparing a pharmaceutical composition of the new esomeprazole strontium compound and an effective dose of an antibacterial drug. 10 to 60 parts by weight of meprazole, 300 to 1,200 parts by weight of an antibacterial drug or other pharmaceutically acceptable excipients are used in combination with antibiotics to prepare a pharmaceutical composition for eradicating H. pylori infection. Antibacterials are selected from, but are not limited to, tetracycline, doxycycline, minocycline, amoxicillin, amoxicillin trihydrate, erythromycin, clarithromycin, roxithromycin, azithromycin, metronidazole, One or more of nitrazole, ornidazole, secconidazole, ofloxacin, levofloxacin, furazolidone or its pharmaceutically acceptable salt or its solvent compound or hydrate (the above is not limited to the actual weight of the various components For calculation, the corresponding proportion of each component can also be calculated by the weight of the anhydrous substance of each component, and the corresponding proportion of each component can also be calculated by the weight of the parent compound of each component). The above-mentioned components of the composition of the present invention can be individually prepared into a preparation, and then prepared into a composition package and placed in one package.

The parts by weight or the ratio of parts by weight (in weight units) in the above pharmaceutical composition may be: esomeprazole strontium new compound 20-60 mg, amoxicillin 0.5-1 g, clarithromycin 500 mg; main The parts by weight or the ratio of parts by weight may also be: 20-40 mg of esomeprazole strontium new compound, 400 mg of clarithromycin, and 900 mg of amoxicillin; the above-mentioned components of the composition of the present invention may be separated Prepared into a formulation, then packaged into a composition, and placed in a separate package.

For mammals, including humans, the usual daily dose range of the new compound esomeprazole strontium is usually about 0.2 to 30 mg / kg body weight, more preferably 0.4 to 10 mg / kg body weight, and can be given in a single Sub-dose administration.

The advantages of the novel esomeprazole strontium compound of the present invention are as follows: The new esomeprazole strontium compound of the present invention can be stably stored. Samples of the esomeprazole strontium crystalline hydrate or its composition and the anhydrous substance or its composition of the present invention were subjected to a comparative study of the hygroscopicity test.

1.Humidity test

The novel strontium esomeprazole compound of the present invention is more favorable for stable storage. Samples of the new strontium esomeprazole compound and anhydrous samples were subjected to a hygroscopicity test: taking the strontium esomeprazole anhydrous (the water content of the method was about 0.9% by Karl Fischer method) and about 5 g of the new compound of the present invention , Placed in a dry and constant-weight surface dish, accurately weighed, placed in an experiment box at about 25 ± 2 ° C and relative humidity of about 56 ± 5%, taking samples at 0h and 8h respectively to calculate the moisture gain As a percentage, the results show that the hygroscopicity of the anhydrous substance is significantly different from that of the corresponding new esomeprazole strontium novel compound of the present invention, and the compound of the present invention can be stably stored better. The results are shown in Table 1.

Table 1. Humidity test results

The results of the hygroscopic test show that the dehydration of esomeprazole strontium anhydrate is more serious. The new esomeprazole strontium novel compound of the present invention is different from the deliquescent of an anhydrous substance so that it must be isolated from the air to prevent adhesion during processing. Crystalline hydrate has good sliding properties, thereby improving the operability of the preparation during dispensing or flow; making it prevent the occurrence of blockage during dispensing or processing due to moisture absorption during dispensing As a result of the difference in content uniformity, the dosage is insufficient or exceeds the standard, which leads to product failure.

The experiment also found that the speed and solubility of the new compound of the present invention in water are not significantly different from those of esomeprazole strontium 4-hydrate. If it is made into a solid preparation, the prepared solid preparation can have good dissolution performance. , And help to play its role quickly.

Stability experiments show that the storage stability of estromethrazole strontium anhydrate is not as good as the new compound of the present invention, and the compound of the present invention is more suitable for use as a medicament.

2. Stability experiment

Under the conditions of RH65 ± 5% and 25 ± 2 ° C, samples of the esomeprazole strontium crystalline hydrate of the present invention (respectively prepared according to the method of Example 1, the method of Example 1, the method of Example 3, and the method of Example 6) Samples) and the reference substances esomeprazole strontium strontium tetrahydrate and esomeprazole strontium strontium anhydrous (prepared by the method of reference 15) were sealed and protected from light for a 12-month stability test, and the appearance and color were observed. Changes and determination of related substances before and after the experiment. Relevant substances are determined by HPLC to determine the strontium-related substances in esomeprazole.

The experimental results show that the appearance and color change is not obvious, the increase of related substances in the samples of each group in the examples is small, the color of esomeprazole strontium anhydrous changes, and the increase of related substances is large. The experimental results show that the esomeprazole strontium crystal hydrate of the present invention has good room-temperature storage stability (see Table 2 for the results).

Table 2. Results of experimental stability studies

Application of the novel esomeprazole strontium compound of the present invention: for preparing a pharmaceutical composition or a solid preparation, a suppository, an injection and a pharmaceutically acceptable preparation containing the compound, wherein the injection is selected from, but not limited to, a lyophilized powder for injection Needle preparations, sterile powder injection preparations, and large infusion preparations, wherein the large infusion preparations are selected from, but not limited to, two-chamber instant infusion, non-PVC solid-liquid two-chamber instant infusion, non-PVC multilayer co-infusion A large infusion made of squeezed film.

The pharmaceutical composition of the present invention can be administered by a variety of routes including oral, rectal and injection administration, preferably the oral route.

The esomeprazole strontium neohydrate pharmaceutical composition according to the present invention can be used to prepare solid preparations for gastrointestinal administration, and is selected from but not limited to tablets (including enteric tablets, fast disintegrating tablets, sustained release or controlled release) Release tablets, etc.), capsules (including enteric capsules, slow-release or controlled-release capsules), granules or pellets or enteric pellets, etc., the pharmaceutical excipients used may also contain pharmaceutically acceptable fillers, lubricants , A binder, a disintegrant, an antioxidant, an emulsifier or a surfactant, a preservative or a stabilizer, and the like. The filler is selected from, but not limited to, starch, corn starch, modified starch, compressible starch, lactose, lactose monohydrate, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, amino acids, and the like. The binder is selected from, but is not limited to, starch syrup, gelatinized starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl Cellulose, polyvinylpyrrolidone, gelatin, alginate, etc. The disintegrant is selected from, but not limited to, dry starch, modified starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, microcrystalline cellulose, effervescent Disintegrants, cross-linked polyvinyl pyrrolidone, surfactants (sodium lauryl sulfate, etc.), and the like. Lubricants selected from, but not limited to: talc, stearic acid, magnesium or calcium stearate, micronized silica gel, hydrogenated castor oil and solid polyethylene glycol, polyethylene glycol 4000-20,000, magnesium dodecyl sulfate, etc. ; Surfactant is selected from, but not limited to: polysorbate, polyethylene glycol, sodium lauryl sulfate, povidone, glycerol fatty acid ester, glycerol organic acid fatty acid ester, polyglycerol fatty acid ester, poly Glycerin condensation ricinoleate, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, propylene glycol fatty acid ester, polyglycerol oleate, spanner 20, division Pan 60, Span 80, Polyglycerol-6-dioleate, Polyoxyethylene sorbitan monooleate, Tween-60, Tween-80, Vitamin E succinate polyethylene glycol ester (vitamin E TPGS), glycerol-polyethylene glycol oxystearate, PEG-32 palmityl stearate, sodium lauryl sulfate, sodium octadecyl sulfate, sorbitan monolaurate, poly Oxyethylene ether (35) castor oil, polyoxyethylene ether (40) hydrogenated castor oil, lauric acid polyethylene glycol glyceride, polyethylene glycol caprylic acid / Capric acid glyceride, polyethylene glycol, polyethylene glycol series, polyethylene glycol 200-20000, polyethylene glycol-1000, polyethylene glycol-15-stearate, polyethylene glycol- 12-hydroxystearate, polyethylene glycol-7-stearate, polyethylene glycol octylphenyl ether (OP), polyvinylpyrrolidone, polyvinyl alcohol, monoglyceride, triglyceride Acid esters, triacetin, amino acids or their pharmaceutically acceptable salts, poloxamers, poloxamers 407, poloxamers 188, azatones, lauryl azelastone, cetyl alcohol and glyceryl monostearate Etc .; and pharmaceutically acceptable gastric or enteric coating materials; pharmaceutically acceptable sweeteners and flavors, such as aspartame, cyclamate, sodium saccharin, sucralose, food flavors, etc. . (Medicinal excipients can be found in the literature: Shanghai Pharmaceutical Industry Research Institute, etc., Pharmaceutical Excipient Application Technology (Second Edition), China Medical Science and Technology Press, Beijing, 2002; Remington's Pharmaceutical Science, Mack Publishing Company, Easton., Pa 19th Edition, 1995; Manuals 1 to 3 for comparison of standards for pharmaceutical excipients in various countries, edited by the National Pharmacopoeia Committee, China Medical Science and Technology Press, Beijing, 2016; Manual for Pharmaceutical Excipients, Raymond Rowrow, PJ House Paul Jheskey, edited by PJ Weller, translated by Zheng Junmin, Beijing: Chemical Industry Press, 2005).

Esomeprazole strontium crystalline hydrate injection, its preparation includes:

Preparation of aseptically packed powder needles: Aseptically use aseptic raw materials for dispensing.

Large infusion preparations, including dual-chamber instant infusions, non-PVC solid-liquid dual-chamber instant infusions, and non-PVC multi-layer co-extruded films, are ready for large infusions, which can be prepared according to conventional methods.

The preparation method of the lyophilized powder injection preparation is: taking esomeprazole strontium crystal hydrate, and adding pharmaceutically acceptable lyophilized support or auxiliary agent, co-solvent, stabilizer, water for injection, stirring to dissolve, can be used The pharmaceutically acceptable pH is adjusted to 9.0 to 14.0, filtered, replenished, filtered, divided into 10 to 80 mg / bottle of strontium esomeprazole, freeze-dried, and pressed to obtain a finished product.

The pharmaceutically acceptable pH adjusting agent may be a pharmaceutically acceptable inorganic or organic acid, an inorganic base or an organic base, or a broad-based Lewis acid or base, which may contain one or more kinds, and may be hydrochloric acid, Phosphoric acid, propionic acid, acetic acid and acetate, such as sodium acetate, lactic acid and lactic acid medicinal salt, citric acid medicinal salt, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, phosphoric acid Salt, tartaric acid and its pharmaceutically acceptable salts, borax, boric acid, succinic acid, hexanoic acid, adipic acid, fumaric acid, maleic acid, polyhydroxycarboxylic acids and pharmaceutically acceptable salts such as glucuronic acid, One or more of gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptanoic acid and the like.

Its pharmaceutically acceptable antioxidants and stabilizers can be sulfurous acid, sulfite, bisulfite, pyrosulfite, dithionite, thiosulfate, organic sulfur compound thiourea, glutathione Glycine, dimercaptopropanol, thioglycolic acid and salts, thiolactic acid and salts, thiodipropionic acid and salts, phenol compounds such as gallic acid and salts, caffeic acid and its salts, ferulic acid and its salts, Di-tert-butyl p-phenol, 2,5-dihydroxybenzoic acid and its salt, salicylic acid or its salt; ascorbic acid and its salt, erythorbic acid and its salt, nicotinamide, tartaric acid, nitrate, phosphate, acetate One or more of salt, citrate, EDTA and EDTA salts, such as disodium EDTA, tetrasodium EDTA, calcium EDTA sodium, N-bis (2-hydroxyethyl) glycine, etc. are used.

The novel esomeprazole strontium crystalline compound or its pharmaceutical composition is suitable for use in the preparation of the following disorders of humans or animals: gastroesophageal reflux disease, treatment of erosive reflux esophagitis, upper gastrointestinal tract Bleeding, stress ulcers, duodenal ulcers, eradication of Helicobacter pylori, Zoe-Ellison syndrome, prevention of recurrence of peptic ulcers associated with Helicobacter pylori, long-term maintenance treatment to prevent recurrence in patients with esophagitis who have been cured, etc. Application in the treatment or prevention of related diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a thermal analysis spectrum of esomeprazole strontium trihydrate (Example 1)

Fig. 2 is a powder X-ray diffraction pattern of esomeprazole strontium trihydrate (Example 1)

Fig. 3 is a thermal analysis spectrum of esomeprazole strontium trihydrate (Example 3)

Fig. 4 is a powder X-ray diffraction pattern of esomeprazole strontium 3.5 hydrate (Example 3)

Figure 5 is a thermal analysis spectrum of strontium 1.5 hydrate of esomeprazole (Example 4)

FIG. 6 is a thermal analysis spectrum of esomeprazole strontium dihydrate (Example 5)

FIG. 7 is a thermal analysis spectrum of esomeprazole strontium 2.5 hydrate (Example 6)

Detailed ways

Except in the examples and when otherwise indicated, all numerical values used in the specification and claims are to be understood as modified in all instances by the term "about," so unless stated to the contrary, the specification and The numerical parameters given in the appended claims are approximate values that can be changed according to the required properties sought through this disclosure, at least, and are not intended to limit the scope of applications of the claims of the principle of equivalence, each Numerical parameters should be interpreted taking into account the number of significant digits and conventional rounding methods.

Although a wide range of numerical values and parameters that set the disclosure are approximate. However, the values given in the specific examples are reported as accurately as possible, and any values essentially include certain errors necessarily resulting from the standard deviation found in their respective tests.

It should be noted that the singular forms "a", "an" and "the" used in this specification and the appended claims include the plural forms of referents unless the context clearly dictates otherwise, for example. If reference to a composition containing "a compound" includes a mixture of two or more compounds, it is further noted that the term "or" generally includes "and / or" unless expressly stated otherwise herein.

As used herein, the term "obtained," or "obtained," refers to compounds that are isolated at a valuable content or purity level that includes, but is not limited to, greater than 90%, 95%, 96%, 97% And 98%, and 99% levels and purity levels. The content or purity level can be determined by the high performance liquid chromatography method referred to in the present invention with respect to esomeprazole. Fourier transform infrared spectrometer is used to measure the infrared spectrum data of the sample. The instruments used include Nexus intelligent Fourier transform infrared spectrometer (Thermo Nicolet) and so on.

The term "solvate" herein refers to a crystalline form of molecules, atoms and / or ions that also include solvent molecules infiltrated into the crystal structure. The solvent molecules of the solvate may be in a regular and / or disordered arrangement, The solvate of the present invention is a solvent hydrate.

Polymorphs here refer to crystals that have the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystals.

Pharmaceutical composition: As used herein, a "pharmaceutical composition" refers to a composition of a drug, which may contain at least one pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable excipient or carrier" refers to a pharmaceutically acceptable carrier or vehicle suitable for the administration of a compound provided herein, and includes any such method known to those skilled in the art to be suitable for a particular mode of administration. Carrier.

In the present invention, unless otherwise stated, "its" in a pharmaceutically acceptable salt or solvate thereof or an inclusion complex thereof represents one of them or their or any of them.

In the present invention, unless otherwise stated, the "appropriate amount" represents a better or optimal amount or a minimum required amount or mass or weight or volume required to complete the present invention.

In the present invention, unless stated otherwise, "the combination or a combination thereof" means a multi-component mixture of said elements, such as two, three, four and up to the maximum possible multi-component mixture.

In the present invention, unless otherwise stated, all "parts" and percentages (%) may refer to parts by weight or weight percent or weight volume percent.

All aseptic raw materials are prepared in a sterile environment or a clean environment with GMP specifications. The clean environment in accordance with the GMP specifications in the pharmaceutical industry is selected from, but not limited to, a 100-grade clean zone environment or a 10,000-grade clean environment. In such cases, use solvents such as sterile water for injection or sterile solvents or raw materials or packaging materials or facilities, and clean or sterilize equipment, facilities and the environment.

In the embodiments of the present invention, the abbreviation may be used for expression. For example, after the appearance of esomeprazole strontium 3.5 hydrate in the prescription of the embodiment, the subsequent preparation process may be further referred to as esomeprazole strontium, and the rest are similar.

In order to further understand the present invention, the preferred embodiments of the present invention are described below with reference to the examples, but it should be understood that these descriptions are merely to further illustrate the features and advantages of the present invention, rather than to limit the claims of the present invention.

Infrared spectroscopy: potassium bromide tableting, measuring the infrared spectral data of the sample, the instruments used include the NICOLT 5700 FTIR Spectrometer, the Nexus Intelligent Fourier Transform Infrared Spectrometer (Thermo Nicolet), etc. Infrared spectrometer company name: American thermoelectric company NICOLET 5700 FTIR Spectrometer, use function: mid-infrared 4000-400cm-1, resolution 4cm-1. Up to 0.09cm-1. Infrared microscope model attached to NICOLET 5700 FTIR Spectrometer, American Thermoelectric Company: Continu IR Microscope (Continu IR infrared microscope, ten times magnification); reflection accessories: Ge crystal-ATR, diamond-ATR.

Thermal analysis method

Test conditions: Setsys 16 from Setaram, sample volume is about 3-10mg, heating rate: 10K / min, N2 flow rate: 50ml / min, temperature: generally room temperature ~ 400 ℃.

Surprisingly, the characteristic, thermal analysis (TG-DTA or TG-DSC) pattern of the hydrate of the present invention has a corresponding endothermic peak under a weightless platform, and the thermal analysis pattern shows esomeprazole strontium New molecular formula compounds, such as its 3.5 hydrate, trihydrate, etc.

Powder X-ray diffraction

Using D / MX-ⅢA X-ray diffractometer, voltage: about 30-60kv, current: about 30-100mA, scanning speed: 10 ° / min, copper target, wavelength wavelength (A): 1.54, diffraction angle 2θ, scanning range The powder X-ray diffraction pattern of strontium crystal hydrate of esomeprazole was measured at 3-60 °, and all peak positions were within ± 0.2 ° 2θ; or using the D8 Advance X-ray diffractometer of Bruker, Germany, wavelength

: 1.54, diffraction angle 2θ, scanning range 3-60 °, others (voltage, current and other indicators) are about the same as before, and the sample is measured. The drawings and data in this specification are evidence of each other.

Specific embodiment

Example 1 Preparation of esomeprazole strontium trihydrate (type v)

At room temperature, add 6.824 g of esomeprazole sodium and 40 ml of methanol in a 250 ml flask, stir to dissolve, heat to about 40 ° C, and then add about 16 ml of a 2.37 g solution of strontium chloride hexahydrate dropwise, stir, about 10 A large amount of precipitate precipitated in about 15 minutes, continued stirring for about 12 minutes, took out the suction filtration, washed a small amount of water and ethanol to remove the residual sodium chloride in the solid, and filtered it. The resulting solid was diluted and dried at about 40 ° C for 1 hour, and then blasted at about 43 ° C. Air-drying for about 4h yielded 6.3g of off-white solid; HPLC: measured by two methods, content and related substances, the main peak retention time of HPLC of the product of this example and the main peak of esomeprazole or sodium esomeprazole reference substance The HPLC retention time is the same; the moisture content is 6.65% measured by the Karst method, thermal analysis: the platform loses about 6.61% (see Figure 1), and there is a corresponding endothermic peak (DTA) under the weightless platform before about 158 ° C, which The result with the sample containing 3 crystal waters (theoretical value 6.51%) is within the error range; X powder diffraction: measured at a diffraction angle of 2θ in the range of 3-60 °, there are multiple obvious characteristic peaks (powder X-ray diffraction, (See attached picture 2) About: 5.52, 8.71, 11.02, 12.27, 13.07 , 13.51, 14.14, 14.73, 16.20, 17.47, 18.01, 20.0, 20.42, 21.17, 22.17, 24.49, 25.18, 25.41, 25.82, 26.33, 27.01, 28.61, 29.77, 30.32, 31.03, 32.77, 33.32, 34.17, 34.72, 35.72 , 36.48, 37.37, 37.97, 38.65, 39.94, 40.13, 40.74, 41.52, 43.10, 45.18, 46.93; Infrared spectrum (ν ^KBr _max cm ^-1 ): 3387.6, 3066.3, 2993.0, 2940.5, 2830.8, 1610.4, 1591.0, 1568.0, 1475.7, 1449.9, 1393.2, 1360.4, 1270.1, 1198.4, 1151.3, 1075.3, 1027.5, 1000.0, 951.0, 837.8, 805.8, 760.2, 630.3; Strontium content: 11.3% (theoretical value is calculated based on anhydrous substances, the theoretical value is 11.3%) ; Esomeprazole content (HPLC): 88.6% (theoretical value is calculated as anhydrous, 88.7%);

Example 2 Preparation of esomeprazole strontium trihydrate (type v)

At room temperature, add 6.91g of esomeprazole sodium and 40ml of methanol in a 250ml flask and stir to dissolve. Add about 20ml of a 2.38g methanol solution of strontium chloride hexahydrate at about 40 ° C. Stir to dissolve and stir. After a large amount of white precipitate precipitated in about 10 minutes, continue to stir for 20 minutes, add about 2ml of water, continue to stir for 8 minutes, suction filter the objects in the reaction bottle, wash with a small amount of water and ethanol five times, and suction filter. The resulting solids are diluted at about 46 ° C. Air drying for 5h, 6.2g of off-white solid was obtained; HPLC: measured by two methods, content and related substances, the main peak retention time of HPLC was the same as the main peak retention time of esomeprazole sodium reference; The water is divided into 6.77%, thermal analysis: the platform loses about 6.72%, and there is a corresponding endothermic peak (DTA) under the weightless platform before about 158 ° C. This is the result of the sample containing 3 crystal water (theoretical value 6.51%). Within the error range. X powder diffraction: measured at a diffraction angle of 2θ in the range of 3-60 ° (powder X-ray diffraction); strontium content: 11.3% (theoretical value is calculated as anhydrous, 11.3%), Esomeprazole content (HPLC): 88.5% (theoretical value is calculated as anhydrous, 88.7%)

Example 3 Preparation of Esomeprazole Strontium 3.5 Hydrate (ω Type)

In a 500 ml flask, add 13.8 g of esomeprazole sodium (purity 99.9%), add 85 ml of methanol, stir at 40 ° C to dissolve, add about 40 ml of 4.75 g of methanol solution of strontium chloride hexahydrate, stir to dissolve, stir A large amount of white precipitated out in about 10 minutes. Continue stirring for about 20 minutes, add about 10ml of water, continue stirring for about 10 minutes, suction filter the objects in the reaction flask, and wash the solid with a small amount of water and ethanol to remove the residual sodium chloride in the solid. After suction filtration, the obtained solid was diluted in a blast drying oven at about 30 ° C for 1 hour, and then dried at 45 ° C for about 2 hours to obtain 12.4 g of a white-like solid. HPLC: measured by two methods of content and related substances. The main peak of HPLC was retained. The time is consistent with the main peak retention time of esomeprazole or sodium esomeprazole control sample; the moisture content of the cardiostat method is 7.53%; the thermal analysis: the platform weight loss is about 7.60% (see Figure 3), about 158 ° C There is a corresponding endothermic peak (DTA) under the weightless platform, which is within the error range from the result of the sample containing 3.5 crystal water (theoretical value 7.51%); X powder diffraction: at a diffraction angle of 2θ, in the range of 3-60 ° There are several obvious characteristic peaks in the internal measurement (powder X-ray Diffraction pattern, see Figure 4) Approximately: 5.53, 8.74, 11.04, 13.07, 13.53, 14.73, 16.22, 17.49, 17.99, 20.05, 20.38, 21.21, 22.19, 24.52, 25.22, 25.40, 26.32, 28.62, 29.81, 31.03, 32.75, 33.38, 34.17, 34.69, 35.63, 36.57, 37.43, 38.04, 40.0, 45.26, 46.95; Infrared spectrum: (ν ^KBr _max cm ^-1 ): 3390.6, 3066.3, 2995.9, 2937.8, 2830.7, 1610.9, 1595.9, 1567.5, 1475.6, 1446.9, 1391.1, 1362.5, 1270.1, 1225.7, 1200.4, 1152.7, 1076.0, 1027.4, 1000.0, 952.1, 840.4, 800.4, 762.7, 632.4; Strontium content: 11.3% (theoretical value is calculated as anhydrous, 11.3%) ; Esomeprazole content (HPLC): 88.6% (theoretical value is calculated as anhydrous, 88.7%)

Example 4 Preparation of Esomeprazole Strontium 1.5 Hydrate (α Form)

At room temperature, add 6.83 g of esomeprazole sodium (99.9% purity) and 40 ml of methanol in a 250 ml flask, stir to dissolve, add about 18 ml of 2.37 g of methanol solution of strontium chloride hexahydrate at about 40 ° C, stir, about A large amount of precipitate was precipitated in about 10 minutes, about 6 ml of isopropanol was added, and the stirring was continued for 10 minutes. The solid was removed by suction filtration, the solid was washed with a small amount of water and ethanol to remove chloride ions from the solid, and the solid was diluted and dried at 45 ° C for 1 h Then, it was blow-dried at about 60 ° C for about 3.5 hours to obtain 5.2 g of off-white solid. HPLC: Measured by two methods: content and related substances. The main peak retention time of HPLC and esomeprazole sodium or angstrom The HPLC retention time of the main peak of the strontium strontium 4 hydrate reference substance is the same; the moisture content measured by the Karst method is 3.57%, and the thermal analysis: the platform weight loss is about 3.59% (see Figure 5). The corresponding endothermic peak (DTA), which is within the error range from the result of the sample containing 1.5 crystal water (theoretical value is 3.36%); X powder diffraction: measured at a diffraction angle of 2θ in the range of 3-60 °. Obvious characteristic peak (powder X-ray diffraction) approx .; strontium content: 11.3 (Theoretical value calculated on an anhydrous, 11.3%), esomeprazole content (HPLC): 88.5% (theoretical value calculated on an anhydrous, 88.7%)

Example 5 Preparation of Esomeprazole Strontium Dihydrate (β-form)

At room temperature, add 6.85g of esomeprazole sodium and 40ml of methanol in a 250ml flask, stir at 40 ° C to dissolve, add about 16ml of 1.99g of strontium acetate hemihydrate solution, stir to dissolve, stir, about 12 A large amount of precipitated out in minutes, continued stirring for 10 minutes, cooled to 30 ° C, suction-filtered the contents of the reaction flask, washed five times with a small amount of water and ethanol, and filtered, the resulting solid was diluted and dried at about 45 ° C for 2h, and then about 78 ° C. After drying for about 2 hours, 5.4 g of off-white solid was obtained. HPLC: measured by two methods, content and related substances. The main peak retention time of HPLC was the same as the main peak retention time of esomeprazole or sodium esomeprazole reference. ; The moisture content measured by Karst method is 4.53%; thermal analysis: platform weight loss is about 4.35% (see Figure 6), there is a corresponding endothermic peak (DTA) under the weightless platform before 158 ℃, which contains 2 crystals The result of water (theoretical value 4.43%) is within the error range; X powder diffraction: measured at a diffraction angle of 2θ in the range of 3-60 °, and there are multiple obvious characteristic peaks measured in the range of 3-60 ° (powder X-rays) Diffraction); Strontium content: 11.3% (theoretical value is calculated as anhydrous, 11 .3%), esomeprazole content (HPLC): 88.6% (theoretical value is calculated as anhydrous, 88.7%)

Example 6 Preparation of esomeprazole strontium 2.5 hydrate (type κ)

At room temperature, add 6.83 g of esomeprazole sodium (purity 99.9%) and 40 ml of methanol in a 250 ml flask, stir and dissolve at about 40 ° C, add about 18 ml of 2.37 g of methanol solution of strontium chloride hexahydrate, and stir to dissolve Stirring, a large amount of precipitates precipitated in about 12 minutes, continued stirring for 20 minutes, cooled to 20 ° C, filtered with suction, washed with a small amount of water and ethanol to remove the residual sodium chloride in the solid, filtered with suction, and the resulting solid was thinned and blown to dry at about 45 ° C. 1h, and then dried at about 60 ° C for about 2h to obtain 5.1g of off-white solid; HPLC: measured by two methods of content and related substances, the main peak retention time of HPLC is compared with esomeprazole or esomeprazole sodium The HPLC retention time of the main peak of the product is consistent; the moisture content measured by the Karst method is 5.56%, thermal analysis: the platform weight loss is about 5.44% (see Figure 7), and there is a corresponding endothermic peak (DTA) under the weightless platform before 155 ° C, This is within the error range with the result that the sample contains 2.5 crystal water (theoretical value 5.48%); X powder diffraction: measured at a diffraction angle of 2θ in the range of 3-60 ° (powder X-ray diffraction) ); Infrared spectrum (ν ^KBr _max cm ^-1 ): 3406.9, 3067.3, 2995.9, 2939. 6,2831.0,1610.6,1592.9,1568.2,1475.6,1393.3,1360.4,1270.1,1198.5,1151.3,1075.4,1027.6,1000.0,951.0,837.9,805.6,760.0,630.4; Strontium content: 11.3% (theoretical value is anhydrous Calculation, 11.3%), esomeprazole content (HPLC): 88.6% (theoretical value is calculated as anhydrous, 88.7%)

Example 7: Preparation of esomeprazole strontium hydrate enteric-coated capsules (prescription: 1000 capsules)

Prescription: Esomeprazole Strontium 3.5 Hydrate (based on esomeprazole weight) 20g

Microcrystalline Cellulose: 60g

Magnesium Stearate: 1g

Esomeprazole strontium 3.5 hydrate (prepared according to the method of Example 3), microcrystalline cellulose, and magnesium stearate were sieved through an 80-mesh sieve, mixed and filled in No. 2 enteric hard capsule.

Example 8 Esomeprazole Strontium Capsules (Prescription: 1000 Capsules)

The raw and auxiliary materials were crushed separately and passed through a 100-mesh sieve; the main compound esomeprazole strontium new compound was uniformly mixed with magnesium oxide and microcrystalline cellulose in the same amount increasing method, granulated, and then mixed with magnesium stearate uniformly. It is made into large pieces, and then the pieces are ground into 18-24 mesh sieve granules and filled into enteric capsules.

Example 9 Preparation of Esomeprazole Strontium Enteric Coated Pellets

1. Preparation of drug-loaded pellets

(1) Preparation of the drug-containing layer coating liquid: According to the prescription in the table, each solid component of the drug-containing layer composition is taken through a 100-mesh sieve, and a portion of hot 55% ethanol pure water is added to the hydroxypropene while stirring. Methylcellulose is fully dispersed, and then cooled to room temperature to obtain a clear solution. Another appropriate amount of 55% ethanol pure water is used to completely dissolve the prescribed amount of Tween-80. The two solutions are mixed, and sodium hydroxide and sieved Low-substituted hydroxypropyl cellulose. After being fully dispersed, add esomeprazole strontium to the above solution under electric stirring while avoiding light, stir until a homogeneous suspension is formed, and protect the suspension from light. spare.

(2) Encapsulated drug layer: install fluidized bed equipment, and slowly pour the sugar pills taken according to the prescription in the table into the hopper. Turn on the air compression pump, turn on the power, enter the fluidized bed operation interface, start the program and fan, and heating device. When the material temperature rises to the required temperature, start the spray, adjust the air volume and spray pressure, and the coating process parameters are the inlet air temperature. 50 ℃ ～ 65 ℃, material temperature 40 ℃ ～ 42 ℃, spray pressure of 0.16MPa ～ 0.20MPa, spraying speed 20r / min ～ 80r / min. Make more pellets in the hopper blow out from the mouth of the deflector, and stabilize the state. Start the peristaltic pump, start spraying the coating liquid while stirring, and observe whether the pellets are sticking or agglomerating through a window, and adjust the parameters of the fluidized bed according to the phenomenon. After the coating is finished, it is dried at 40 ° C. to 50 ° C., so as to obtain drug-loaded layer pellets.

2. Preparation of barrier pellets

(1) Preparation of the coating for the isolation layer: Slowly add the prescribed amount of hypromellose to the hot purified water while magnetically stirring, and allow it to cool to room temperature to obtain a clear solution for use.

(2) Isolation coating: Adjust the coating process parameters, inlet air temperature 50 ℃ ～ 60 ℃, material temperature 40 ℃ ～ 45 ℃, spray pressure 0.16MPa ～ 0.20MPa, spray speed 20 ～ 80r / min. The isolation layer coating liquid is spray-coated on the drug-loaded layer pellets and dried at 40 ° C-50 ° C to obtain the isolation layer pellets.

3. Preparation of enteric-coated pellets

(1) Preparation of enteric layer coating solution: According to the formula in the table, weigh methacrylic acid-ethyl acrylate aqueous dispersion, Tween-80, glyceryl monostearate, triethyl citrate and add to boiling water. And immediately use a shear emulsification mixer to stir at a speed of 600 r / min, let it cool to room temperature, pass through a 120 mesh sieve, add the prescribed amount of enteric material to the table, and stir until needed.

(2) Enteric-coated layer: adjust the coating process parameters, inlet air temperature 40 ℃ ～ 45 ℃, material temperature 30 ℃ ～ 32 ℃, spray pressure 0.16MPa ～ 0.20MPa, spray speed 20r / min ～ 80r / min. The enteric layer coating solution is spray-coated on the isolation layer pellets, and dried at 40 ° C-50 ° C to obtain the enteric layer pellets.

4. Preparation of protective layer pellets

(1) Preparation of the protective layer coating liquid: add hypromellose according to the direction of ethanol water in the table, and after it swells sufficiently, add the prescribed amount of talc powder in the table and stir until needed.

(2) Coating protective layer: adjust the coating process parameters, the inlet air temperature is 50 ℃ ～ 60 ℃, the material temperature is 40 ℃ ～ 45 ℃, the spray pressure is 0.16MPa ～ 0.20MPa, and the spraying speed is 20r / min ～ 80r / min. The protective layer coating solution is sprayed on the enteric layer pellets to obtain the protective layer pellets.

(3) Curing: The above-mentioned protective layer pellets are dried in an oven at 40 ° C. ± 2 ° C. for 2 hours to obtain esomeprazole strontium enteric-coated pellets.

5.Capsule filling

According to the content of esomeprazole and strontium enteric pellets, calculate the required filling amount (specification: 20mg, 40mg). Use a hard capsule filling machine, select the No. 1 capsule shell mold, adjust the capsule filling equipment, and fill the capsule. .

Example 10 Preparation of Compound Esomeprazole Strontium Aspirin Enteric-coated Pellets

Preparation of aspirin-containing pills:

Aspirin and excipients were sieved through a 100-mesh sieve and mixed uniformly, and a soft material was prepared by using 95% alcohol as a binder. The prepared soft material is placed in an extrusion spheronization machine, the extrusion speed is 18 Hz, the spheronization speed is 21 Hz, and the spheronization time is 3-6 min. The prepared pellets were dried at about 45-50 ° C for 3h.

Packet isolation layer I:

Prescription: HPMC E5 50g

Talc powder 0.6g

50% ethanol pure water 1000mL

Hydroxypropyl methylcellulose (HPMC) E5 is slowly added to hot 50% ethanol pure water under agitation, and after cooling and dissolving, talc is added, and it is set aside. The prepared aspirin-containing pill core was placed in a fluidized bed, and the isolation layer was fluidized and coated. The control temperature is about 40 ° C; the atomizing pressure is 0.08 to 0.12 MPa; the blowing frequency is 25 to 35 Hz; the spraying speed is 1.0 to 2.0 mL / min; and the coating is dried in a fluidized bed for 30 minutes.

Esomeprazole-containing strontium drug-containing layer

The prescribed amounts of sodium bicarbonate, esomeprazole strontium, and poloxamer were slowly added to the 3% HPMC / E5 solution in a stirred state in order, and evenly dispersed, then fluidized bed coating and drug application were performed. Control temperature is 37 ～ 40 ℃; atomizing pressure is 0.15 ～ 0.2MPa; air blowing frequency is 25 ～ 35Hz; spray liquid flow rate is 0.5 ～ 1mL / min. The pharmaceutical pills were fluidized and dried at 40 ° C for 30 minutes.

Packet isolation layer Ⅱ:

HPMC E5 is slowly added to a hot 50% ethanol aqueous solution under stirring. After cooling and dissolving, talc and titanium dioxide are added, and it is set aside. The prepared esomeprazole-coated strontium-containing pellets were placed in a fluidized bed, and the isolation layer was fluidized and coated. The control temperature is about 40 ° C; the atomizing pressure is 0.08 to 0.12 MPa; the blowing frequency is 25 to 35 Hz; the spraying speed is 1.0 to 2.0 mL / min; and the coating is dried in a fluidized bed for 30 minutes.

Enteric layer

Add the prescribed amount of Eudragit L30D-55 (aqueous methacrylic acid-ethyl acrylate copolymer dispersion) to the stirred water, and continue to add the prescribed amount of PEG 6000 and talc while stirring, until completely dispersed. The first type of pelleted enteric coating is to place aspirin pellets and esomeprazole strontium pellets in a fluidized bed with isolation layer Ⅰ and isolation layer Ⅱ, respectively, and to enter the enteric layer with the same prescription. The control temperature is about 30-35 ° C; the atomizing pressure is 0.08-0.11 MPa; the blowing frequency is 25-35 Hz; the spraying speed is 1.0-2.0 mL / min; and the coating is dried in a fluidized bed for about 30 minutes. The aspirin enteric-coated pellets and esomeprazole strontium enteric-coated pellets are obtained, and then the capsules are combined and filled in a predetermined dose. The second type of pellets is the aspirin-esomeprazole strontium pellets coated with isolation layer II in a fluidized bed, the enteric layer is coated, and the coating parameters are the same as before. The obtained pellets are the compound aspirin-esomeprazole strontium enteric-coated pellets.

Example 11: Preparation of compound naproxen esomeprazole strontium enteric-coated tablets (prescription 10,000 tablets)

Preparation:

(1) Take 650 g of hypromellose (E5) dissolved in about 13600 g of purified water, slowly add 3750 g of naproxen raw materials (D90 <10 microns) micronized with a jet mill under stirring, and continue to stir to make a drug mixture Suspension

(2) Take 900g of microcrystalline cellulose pellet core (0.1-0.2mm) in a fluidized bed, preheat to the product temperature of 35 ° C ± 5 ° C, spray into the drug suspension in step (1), adjust the flow Inlet air temperature (45-60 ℃), inlet air volume (300-800m ³ / h), spray speed (5-100g / min) and atomizing pressure (1-3bar), the product temperature is 35 ± 5 ° C, and keep the pellets in a fluidized state, without sticking or spray drying, until the spraying of the drug suspension is completed, maintaining the product temperature, and continuing to dry for 30 minutes, so that the pellet moisture is less than 2.0%, and the drug-containing pellets are obtained. ;

(3) Formulating a coating solution for the isolation layer 1: Dissolve 50 g of hypromellose (E5) in 1250 g of purified water, add 160 g of mannitol under stirring, and continue stirring to prepare a coating solution for the isolation layer 1;

(4) Place the medicine-containing pellets in step (2) in a fluidized bed, preheat to the product temperature of 35 ° C ± 5 ° C, spray into the coating liquid of step 3 in the isolation layer, and adjust the inlet temperature of the fluidized bed (45-55 ℃), inlet air volume (300-800m ³ / h), liquid injection speed (5-100g / min), and atomizing pressure (1-3bar), so that the product temperature is 35 ± 5 ℃, and The pellets are in a fluidized state, non-adhesive and spray-drying, until the spray solution or suspension of the barrier layer is sprayed out, maintaining the product temperature, and continuing to dry for 30 minutes, so that the moisture of the pellets is <2.0%, and the barrier layer 1 pellets are obtained;

(5) Preparation of enteric coating solution: take 400g of purified water, heat to 70 ° C, add 40g of triethyl citrate and 10g of Tween-80, disperse with a disperser, add 20g of glyceryl monostearate, disperser Disperse for 20 minutes, add 500g of purified water, continue stirring with a mixer, cool to 30 ° C, mix with Utech L30D-55, and stir slowly to prepare an enteric coating solution;

(6) Place the pellets of the isolation layer 1 in step (4) in a fluidized bed, preheat to the product temperature of 25-30 ° C, spray the enteric coating solution in step (5), and adjust the inlet air temperature of the fluidized bed ( 35-45 ℃), inlet air volume (300-800m ³ / h), spraying speed (5-100g / min) and atomizing pressure (1-3bar), make product temperature 25-30 ℃, and make micro The pill is in a fluidized state without sticking or spray drying until the enteric coating solution is sprayed, maintaining the product temperature, and continuing to dry for 30 minutes, so that the pellet moisture is <2.0%, and the enteric layer pellets are obtained;

(7) Preparation of a coating solution for the isolation layer 2: Dissolve 50 g of hypromellose (E5) in 1250 g of purified water, add 100 g of mannitol under stirring, and continue to stir to prepare a coating solution for the isolation layer 2;

(8) Place the enteric layer pellets in a fluidized bed, preheat to the product temperature of 35 ° C, and spray into the coating liquid of step 2 (7), adjust the inlet temperature of the fluidized bed (45-55 ° C) , Inlet air volume (300-800m ³ / h), spray speed (5-100g / min) and atomizing pressure (1-3bar), make the product temperature 35 ± 2 ℃, and keep the pellets in a fluidized state , Non-adhesion, not spray-drying, until the insulation layer solution or suspension is sprayed, maintaining the product temperature, and continuing to dry for 30 minutes (specific temperature), so that the pellet moisture <2.0%, to obtain the naproxen intestine with insulation layer 2 Dissolve pellets

(9) Pass 260 g of esomeprazole strontium, 1500 g of microcrystalline cellulose (101), 300 g of croscarmellose sodium, and 40 g of sodium glycine through 80-mesh sieves, and mix in a mixer.

(10) Put the material in step (9) into a dry granulator and dry granulate, with a screen diameter of 0.8 mm;

(11) Mix the granules obtained in step (10) with 10 g of magnesium stearate and place in a mixer for 3-5 minutes;

(12) mixing the naproxen enteric-coated pellets obtained in step (8) and the esomeprazole strontium immediate-release granules prepared in step (11) to mix well;

(13) Place the material in step (12) in a tablet press, adjust the tablet weight and pressure, control the tablet hardness to 80-120N during tableting, and obtain naproxen and esomeprazole strontium compound tablets;

(14) Formulating a tablet coating solution: 315 g of hypromellose (E5) was dissolved in 6400 g of 40% ethanol, 190 g of titanium dioxide and 50 g of triethyl citrate were slowly added under stirring, and the coating suspension was continuously stirred to prepare a coating suspension.

(15) The naproxen and esomeprazole strontium compound tablets prepared in step (13) are placed in a coating pan, and the speed of the coating pan (4-15 rpm), the inlet air temperature (35-50 ° C), Inlet air volume (250-500m ³ / h) parameters, preheating to make the product temperature 25-35 ℃, spray (14) step coating liquid to start coating, until the coating liquid is sprayed, maintain the product temperature, and continue drying In 30 minutes, naproxen and esomeprazole strontium compound enteric-coated tablets were obtained.

Example 12: Preparation of esomeprazole strontium hydrate enteric-coated capsules (prescription: 1000 capsules)

The esomeprazole strontium trihydrate (prepared according to the method of Example 1), lafuridine, microcrystalline cellulose, and magnesium stearate were sieved through an 80-mesh sieve, and filled into No. 1 enteric hard capsule in.

Industrial applicability, etc. and its description:

The present invention has been described in detail through specific implementations and examples, but it should be understood that these descriptions do not constitute any limitation on the scope of the present invention, and those skilled in the art can obviously do without departing from the spirit and scope of the present invention. A variety of modifications, improvements, substitutions, and combinations can be made to the technical solution of the present invention and its embodiments to implement the technology of the present invention, which all fall into the protection scope of the present invention. It should be particularly pointed out that it can be understood that many changes in details are possible, and all similar replacements and modifications will be apparent to those skilled in the art, and they are all considered to be included in the spirit, scope and content of the present invention. However, the present invention is not limited to the above embodiments.

Claims (13)

1. The new esomeprazole strontium compound is characterized in that the molecular formula of the new esomeprazole strontium compound is (C ₁₇ H ₁₈ N ₃ O ₃ S) ₂ Sr · nH ₂ O, where n = 1.5, 2, 2.5, 3, 3.5.
2. The new strontium esomeprazole compound according to claim 1, wherein the new strontium esomeprazole compound is strontium esomeprazole trihydrate.
3. The new strontium esomeprazole compound according to claim 3, characterized in that: measured by powder X-ray diffraction method, within the measurement range of the diffraction angle 2θ, 3-60 °, there is a corresponding position at the following 2θ value Characteristic values: 5.52, 8.71, 11.02, 12.27, 13.07, 13.51, 14.14, 14.73, 16.20, 17.47, 18.01, 20.0, 20.42, 21.17, 22.17, 24.49, 25.18, 25.41, 25.82, 26.33, 27.01, 27.50, 28.61, 29.77, 30.32, 31.03, 32.77, 33.32, 34.17, 34.72, 35.60, 36.48, 37.37, 37.97, 38.65, 39.94, 40.13, 40.74, 41.52, 43.10, 45.18, 46.93.
4. The new strontium esomeprazole compound according to claim 1, wherein the new strontium esomeprazole compound is strontium 3.5 hydrate.
5. The new strontium esomeprazole compound according to claim 5, characterized in that: measured by powder X-ray diffraction method, within the measurement range of the diffraction angle 2θ, 3-60 °, there is a corresponding position at the following 2θ value Characteristic values: 5.53, 8.74, 11.04, 13.07, 13.53, 14.73, 16.22, 17.49, 17.99, 20.05, 20.38, 21.21, 22.19, 24.52, 25.22, 25.40, 26.32, 27.50, 28.62, 29.81, 31.03, 32.75, 33.38, 34.17, 34.69, 35.63, 36.57, 37.43, 38.04, 40.0, 45.26, 46.95.
6. The new strontium esomeprazole compound according to claim 1, characterized in that the new strontium esomeprazole compound is esomeprazole strontium 1.5 hydrate, esomeprazole strontium 2 hydrate, Someprazole Strontium 2.5 Hydrate.
7. The new strontium esomeprazole strontium compound according to any one of claims 1-6, characterized in that it is used for preparing a pharmaceutical composition containing the new strontium esomeprazole compound, and for preparing a solid preparation, a suppository, Injections and pharmaceutically acceptable preparations, where the injections are selected from, but not limited to, lyophilized powder injection preparations for injection, sterile powder injection preparations, and solid preparations are selected from, but not limited to, tablets, capsules, granules, and pellets.
8. The new strontium esomeprazole compound according to any one of claims 1-7, characterized in that it is used for preparing the new strontium esomeprazole compound and a non-steroidal anti-inflammatory drug or an antacid or and H ₂ receptor antagonist or gastric mucosa protective agent or the above-mentioned pharmaceutical composition with one or more of the above components, the esomeprazole strontium new compound and the non-steroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs and effective doses of new strontium esomeprazole or compounds with effective doses of antacids and other pharmaceutically acceptable excipients; among them, H ₂ receptor antagonists or gastric mucosal protective agents are selected From but not limited to famotidine, cimetidine, ranitidine, nizatidine, lafuridine, bismuth aluminate, bismuth citrate, bismuth pectin, bismuth glycyrrhizinate or a pharmaceutically acceptable salt thereof One or more.
9. The pharmaceutical composition of a non-steroidal anti-inflammatory drug and a new compound of esomeprazole and strontium according to any one of claims 8, characterized in that parts by weight of the non-steroidal anti-inflammatory drug and esomeprazole Or the ratio of parts by weight is from 3 to 50: 0.8 to 1.2; the non-steroidal anti-inflammatory drug is selected from, but not limited to, aspirin, naproxen, ibuprofen, dextro- ibuprofen, ketoprofen, and dexketoprox Fen, Etodol, S-Etodol, Loxoprofen, Fenoprofen, Diclofenac, Asimicin, Indomethacin, Piroxicam, Meloxicam, Lornoxicam, Celecoxib Cloth, rofecoxib and the like or a pharmaceutically acceptable salt thereof or a solvent compound thereof.
10. The new strontium esomeprazole compound according to any one of claims 1 to 7, characterized in that it is used for preparing the new strontium esomeprazole compound with an antacid or an effective dose of a non-steroidal anti-inflammatory Drug composition, the weight fraction or ratio of weight fraction of its main medicine: 10-60 parts by weight of esomeprazole, 100-1200 parts by weight of antacid, or an effective dose of a non-steroidal anti-inflammatory drug And other pharmaceutically acceptable excipients.
11. The antacid according to claim 10, wherein the antacid is selected from, but not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, aluminum carbonate, magnesium carbonate, hydroxide One or more of magnesium, magnesium oxide, light magnesium oxide, aluminum hydroxide, magnesium aluminum carbonate, or a hydrate thereof.
12. The new strontium esomeprazole strontium compound according to any one of claims 1 to 7, characterized in that the main composition is a pharmaceutical composition for preparing a new strontium esomeprazole strontium compound and an effective dose of an antibacterial drug. Parts by weight or ratio of parts by weight: 10-60 parts by weight of esomeprazole, 300-1200 parts by weight of antibacterial drugs, or other pharmaceutically acceptable excipients, the antibacterial drugs are selected from, but not limited to, tetracycline, doxycycline Minocycline, minocycline, amoxicillin, amoxicillin trihydrate, erythromycin, clarithromycin, roxithromycin, azithromycin, metronidazole, tinidazole, ornidazole, seconidazole, One or more of ofloxacin, levofloxacin, furazolidone or a pharmaceutically acceptable salt thereof or a solvent compound or hydrate thereof.
13. The method for preparing a new strontium esomeprazole compound according to any one of claims 1 to 7, wherein the preparation method comprises:

    In the reaction vessel, add esomeprazole or esomeprazole sodium or potassium, add water, organic solvent C ₁ -C ₆ low molecular alcohol, C ₂ -C ₈ low molecular ether, C ₂ -C ₆ One or more of the low-molecular-weight nitriles, stir, and add strontium oxide, strontium nitrate, strontium acetate, strontium acetate hemihydrate, strontium chloride, strontium chloride hexahydrate, and strontium bromide at 10-50 ° C while stirring. , One or more of strontium nitrate, strontium perchlorate, strontium carbonate, strontium oxalate, strontium phosphate or hydrates thereof with water, C ₁ -C ₆ low molecular alcohols, C ₂ -C ₈ low molecular ethers, A solution of one or more of the low molecular ketones of C ₃ -C ₈ , stirred at 10-50 ° C to precipitate solids, filtered, water for solids, C ₁ -C ₆ low molecular alcohols, C ₂ -C ₈ low molecular weight ethers, C ₃ -C ₈ low molecular weight ketones, C ₂ -C ₆ of a low molecular weight nitrile, C ₁ -C ₆ halogenated low molecular weight in one or more washing once or several times, filtered, and dried to give esomeprazole strontium new compounds; the resulting solid was washed with water and a lower alcohol C ₁ -C ₆ is, C ₂ -C ₈ ether of a low molecular weight, C ₃ -C ₈ low molecular weight ketones, C ₁ -C One or more of low molecular halogenated hydrocarbons of ₆ and low molecular esters of C ₂ -C ₈ Performing one or more recrystallizations for a crystallization solvent, filtering, washing, and drying to obtain a new compound of esomeprazole and strontium;

    The low-molecular-weight alcohols of the organic solvents C ₁ -C ₆ are selected from, but not limited to, methanol, ethanol, isopropanol, and butanol; the low-molecular-weight nitriles of the C ₂ -C ₆ are selected from, but not limited to, acetonitrile; C ₂ -C The low molecular ether or low molecular ether of ₈ is selected from, but not limited to, diethyl ether, isopropyl ether, tetrahydrofuran, methyltetrahydrofuran; C ₁ -C ₆ lower halogenated hydrocarbons are selected from, but not limited to, dichloromethane and chloroform; C ₂ -C ₈ low molecular esters are selected from, but not limited to, butyl acetate, ethyl acetate, ethyl formate; C ₃ -C ₈ low molecular ketones are selected from, but not limited to, acetone, methyl ethyl ketone, and isohexanone.

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