Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to S-omeprazole strontium or a hydrate thereof having improved optical purity, thermal stability, solubility and non-hygroscopicity, a method for preparing same, and a pharmaceutical composition comprising same.
• Patent No. 0 005 129 Patent No. 0 005 129
• Losec ® Commercial formulations
• Prilosec ® (AstraZeneca AB), are marketed as medicaments for prevention and treatment of gastric acid-related disorders.
• This omeprazole should be formulated as enteric coated form because it has a structurally neutral molecule and thus it is thermally and chemically unstable under a condition below neutral pH value.
• omeprazole salts and hydrates thereof e.g., lithium, sodium, potassium, magnesium, calcium, titanium, ammonium, and guanidine salts.
• Such omeprazole salts are much more stable than omeprazole in the neutral form.
• Omeprazole is a racemic mixture composed of equal amounts of R- and S-enantiomers.
• S-omeprazole of formula (III) is much more preferred over the R-isomer in the treatment of gastric or duodenal ulcer, gastroesophageal reflux disease, etc., because the R-isomer tends to be metabolized as inactive metabolites in the irregular variations. Accordingly, there have been many attempts to develop a method for preparing pure S-omeprazole which is substantially free of R-omeprazole.
• racemic omerprazole has been resolved to isolate the S-isomer by a high performance liquid chromatography (see Erlandsson et al., Journal of Chromatography, 535, 305-319 (1990)), and a process for preparing each of the omeprazole enantiomers is disclosed in PCT Publication No. WO 1992/08716.
• the separated S-omeprazole products have not been regarded as a stable solid of the pharmaceutically required purity.
• US patent No. 6,162,816 discloses a crystalline S-omeprazole, but even this crystalline form of S-omeprazole is not sufficiently stable.
• US Patent Nos. 5,714,504 and 5,693,818 disclose S-omeprazole salts and hydrates thereof, e.g., lithium, sodium, potassium, magnesium, calcium, and ammonium salts.
• US Patent Nos. 6,369,085 and 6,511,996 disclose the crystalline potassium salt as well as magnesium salt dihydrate and trihydrate of S-omeprazole, together with their polymorphs. These S-omeprazole salts have stability superior to S-omeprazole itself.
• S-omeprazole salts with sodium, potassium and magnesium, or hydrates thereof are commercially marketed with the trade name Nexium ® (AstraZeneca AB) as a medicament for prevention and treatment of ulcer.
• the sodium and potassium salts are preferred for injectable administration because of their good solubility, but they are unsuitable for oral administration due to their hygroscopicity.
• non-hygroscopic S-omeprazole magnesium trihydate is preferred in terms of oral administration of a solid form of omeprazole, but it is not easy to achieve the optical purity required pharmaceutically.
• S-omeprazole magnesium trihydate has been subjected to the salt exchange with the optically pure sodium or potassium salt prepared in advance to achieve satisfactory therapeutic effects ⁇ see Cotton et al., Tetrahedron Asymmetry, 11, 3819-3825 (2000)).
• Strontium is an alkaline earth metal of IIA group and it exists in nature in the form of 4 isotopes, 88 Sr (82.58%), 87 Sr (7.00%), 86 Sr (9.86%) and 84 Sr (0.56%). It is also known that strontium exerts no safety problems even at a dose of 633 mg/kg/day in rats ⁇ see P. J. Marie et al., Mineral & Electrolyte Metabolism, 11, 5-13 (1985)). Strontium is reported to be ingested by people in an average amount of about 3.3mg/day per 70 kg body weight during the course of everyday life ⁇ see Report of Toxicological Profile for Strontium, U.S. Department of Health and Human Services, 2004).
• strontium supports calcium metabolism in bone tissues to promote the bone formation and inhibit the resorption of bone tissues ⁇ see S. P. Nielsen, Bone, 35, 583-588 (2004)).
• strontium salts which have been pharmaceutically used, strontium ranelate, the salt of strontium with ranelic acid is known.
• the present inventors have endeavored to develop a novel salt of S-omeprazole and found that S-omeprazole strontium or a hydrate thereof has much improved optical purity, thermo-stability, non-hygroscopicity and solubility over conventional salts.
• a method for preparing S-omeprazole strontium of formula (I) or a hydrate thereof which comprises the step of adding strontium hydroxide or another strontium salt to a neutral or basic solution containing S-omeprazole and stirring the resulting mixture.
• a pharmaceutical composition comprising S-omeprazole strontium of formula (I) or a hydrate thereof as an active ingredient and a pharmaceutical acceptable carrier for preventing or treating a gastric acid-related disorder.
• FIG. 1 an X-ray powder diffraction (XPRD) spectrum of the crystalline S-omeprazole strontium tetrahydrate (Crystalline Form A) obtained according to a preferred embodiment of the present invention in Example 1 ;
• XPRD X-ray powder diffraction
• FIG. 2 a differential scanning calorimeter (DSC) curve of the crystalline S-omeprazole strontium tetrahydrate (Crystalline Form A) obtained according to a preferred embodiment of the present invention in Example 1;
• FIG. 3 an XPRD spectrum of the crystalline S-omeprazole strontium anhydrate (Crystalline Form B) obtained according to another preferred embodiment of the present invention in Example 9;
• FIG. 4 a DSC curve of the crystalline S-omeprazole strontium anhydrate (Crystalline Form B) obtained according to another preferred embodiment of the present invention in Example 9;
• FIG. 5 an XPRD spectrum of the crystalline S-omeprazole strontium hydrate (Crystalline Form C) obtained according to still another preferred embodiment of the present invention in Example 10;
• FIG. 6 a DSC curve of the crystalline S-omeprazole strontium hydrate (Crystalline Form C) obtained according to still another preferred embodiment of the present invention in Example 10;
• FIG. 7 an XPRD spectrum of the amorphous S-omeprazole strontium obtained according to yet another preferred embodiment of the present invention in Example 11 ;
• FIG. 8 a DSC curve of the amorphous S-omeprazole strontium obtained according to yet another preferred embodiment of the present invention in Example 11.
• the inventive S-omeprazole strontium of formula (I) or a hydrate thereof is a novel salt of S-omeprazole, which is optically purer, thermally more stable, less hygroscopic and more soluble than any of the corresponding magnesium salts.
• the S-omeprazole strontium according to the present invention has two S-omeprazole molecules coordinated to strontium ion (II), to which at least one H 2 O molecule may be coordinated.
• strontium ion II
• Such S-omeprazole strontium or a hydrate thereof can be produced in an amorphous form or crystalline form, preferably a crystalline form, which may be confirmed by X-ray powder diffraction (XRD) or differential scanning calorimeter (DSC) analysis.
• a preferred embodiment of the present invention is the crystalline tetrahydrate of S-omeprazole strontium, represented by formula (IV):
• the XRD spectrum of the crystalline S-omeprazole strontium tetrahydrate shows major peaks having 1/I 0 values of at least 3% (I is the 5 intensity of each peak; I 0 is the intensity of the highest peak) at 2 ⁇ 0.2 of 5.6, 11.1, 13.5, 14.8, 16.2, 17.5, 18.0, 20.1, 20.4, 21.2, 22.2, 24.5, 25.2, 26.3, 27.5, 29.8, 31.1, 32.8 and 36.5 (FIG. 1).
• a DSC scan of the crystalline tetrahydrate obtained at 5 ° C/min shows an endothermic peak of about 179 J/g which starts at about 100 0 C and reaches its maximum at about 118 ° C , as l o well as an exothermic peak of about 451 J/g which starts at about 203 ° C and reaches its maximum at about 211 ° C (FIG. 2).
• the actually observed melting point of the crystalline tetrahydrate is around 202 ° C, and the moisture content thereof determined by loss-on-drying test is 8.0 to 9.5% which is within the experimental error range of 8.49% of the theoretical
• the present invention also covers a partial or heterogenic crystalline form of S-omeprazole strontium or a hydrate thereof.
• Another preferred embodiment of the present invention provides a partial or heterogenic crystalline anhydrate of S-omeprazole
• Still another preferred embodiment of the present invention provides a partial or heterogenic crystalline hydrate of S-omeprazole strontium whose XRD spectrum shows a major peak having an 1/I 0 value of 100% at 2 ⁇ 0.2 of 25.2 (FIG. 5).
• S-omeprazole strontium of formula (I) is also provided in an amorphous form, and its XRD spectrum shows no distinctively characteristic peak (FIG. 7).
• a DSC scan of the amorphous form obtained at 5 °C/min shows an endothermic peak which starts at about 29 °C and reaches its maximum at about 56 ° C, as well as an exothermic peak which starts at about 183 ° C and reaches its maximum at about 208 0 C (FIG. 8). This suggests that a phase transition occurs at about 196 " C .
• the amorphous form is observed to decompose at a temperature of about 180 ° C or higher.
• the inventive S-omeprazole strontium of formula (I) or a hydrate thereof satisfies the pharmaceutically required stability since it can maintain the initial moisture content, purity and crystallinity under a long-term storage condition (25 °C under 60% relative humidity), an accelerated aging condition (40 ° C under 75% relative humidity) or an stressed condition (60 ° C and 75% relative humidity) conducted for 4 weeks or more in a closed state.
• the crystalline S-omeprazole strontium tetrahydrate (crystalline form A) is non-hygroscopic and it is capable of maintaining its initial moisture content under an exposed condition at 25 to 40 °C and 40 to 90% relative humidity for 2 weeks or more.
• inventive S-omeprazole strontium of formula (I) or a hydrate thereof may be pharmaceutically preferred in terms of water solubility over other salts of S-omeprazole.
• it has a water solubility of about 17.6 mg/ml, which is at least 10 times higher than that of
• S-omeprazole strontium of formula (I) or a hydrate thereof may be prepared by adding strontium hydroxide or another strontium salt to a neutral or basic solution containing
• the crystalline S-omeprazole strontium tetrahydrate of formula (IV) may be prepared by adding strontium hydroxide to a neutral solution containing S-omeprazole of formula (III), stirring the resulting mixture until precipitates form, and filtering and drying the resulting precipitates by a conventional method:
• the neutral solution used herein means a solution prepared by dissolving or suspending S-omeprazole in an organic solvent selected from methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran and acetone, preferably, methanol and acetone, or in a mixture of one of said organic solvents and water, preferably, having a mix ratio having a mix ratio of 99:1 to 50:50 (v/v).
• strontium hydroxide is preferably used in an amount of 0.5 to 0.75 molar equivalent based on S-omeprazole of formula (III).
• the stirring procedure may be carried out at a temperature ranging from 0 °C to the boiling point of the solvent used for 30 minutes to 24 hours.
• the crystalline S-omeprazole strontium tetrahydrate may be prepared by adding a reactive strontium salt to a basic solution of S-omeprazole of formula (III) containing a base, stirring the resulting mixture until precipitates form, and filtering and drying the resulting precipitates by a conventional method.
• the reactive strontium salt may be selected from strontium chloride, strontium bromide, strontium sulfate, strontium nitrate, strontium perchlorate, strontium acetate, strontium carbonate and strontium oxalate, preferably strontium chloride and strontium acetate.
• the basic solution means a solution prepared by dissolving or suspending S-omeprazole and a base in an organic solvent selected from methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran and acetone, preferably, methanol and acetone or in a mixture of one of said organic solvents and water, preferably, having a mix ratio of 99:1 to 50:50 (v/v).
• the base may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine and triethylamine, preferably sodium hydroxide and potassium hydroxide.
• the base is preferably used in an amount ranging from 1 to 3 molar equivalents based on 1 mole of S-omeprazole of formula (III) and the amount of the reactive strontium salt is preferably in the range of 0.5 to 0.75 molar equivalent based on the base.
• the stirring may be conducted at a temperature ranging from 0 ° C to the boiling point of the solvent used for 30 minutes to 24 hours.
• the neutral or basic solution contains Ig of S-omeprazole of formula (III) in a volume of 1 to 20m£, preferably 3 to lOm-C.
• S-omeprazole salts having high optical purity can be obtained even when an optically impure S-omeprazole is used as a starting material.
• the partial or heterogenic crystalline anhydrate of S-omeprazole strontium may be prepared by drying the crystalline S-omeprazole strontium tetrahydrate at 80 to 130 ° C for 30 minutes to 24 hours to dehydrate, if necessary, under a reduced pressure.
• the partial or heterogenic crystalline hydrate of S-omeprazole strontium may be prepared by suspending such crystalline anhydrate in water, stirring the suspension at room temperature for 1 to 24 hours, and filtering and drying the resultant by a conventional method.
• the amorphous form of S-omeprazole strontium may be prepared by dissolving the crystalline S-omeprazole strontium tetrahydrate in an organic solvent such as acetone and removing the organic solvent from the resulting solution by evaporation under a reduced pressure or spray drying.
• the inventive S-omeprazole strontium of formula (I) or a hydrate thereof as mentioned above has a high optical purity of at least 99.0% enantiomeric excess (ee), non-hygroscopicity and good stability against moisture and heat, so that it can be pharmaceutically used for the prevention or treatment of gastric acid-related disorders such as gastroesophageal reflux disease, gastroenteritis and gastric ulcer due to hyperacidity. Accordingly, the present invention provides a pharmaceutical composition comprising the inventive S-omeprazole strontium of formula (I) or a hydrate thereof as an active ingredient.
• the pharmaceutical composition according to the present invention may be administered via various routes including oral, rectal and injectable application, preferably the oral route.
• the pharmaceutical composition of the present invention may be in the form of tablets, capsules, pills, and the like, and may be formulated with pharmaceutically acceptable carriers, diluents or excipients.
• suitable carriers, diluents and excipients are excipients such as starches, sugar and mannitol; filling agents or increasing agents such as calcium phosphate and silica derivatives; binding agents such as cellulose derivatives of carboxymethylcellulose or hydroxypropylcellulose, gelatin, arginic acid salt, and polyvinylpyrrolidone; lubricating agents such as talc, magnesium or calcium stearate, hydrogenated castor oil and solid polyethylene glycol; disintegrants such as povidone, croscarmellose sodium, and crospovidone; and surfactants such as polysorbate, cetyl alcohol and glycerol monostearate.
• compositions comprising a specific amount of active ingredient, together with or without additives such as said excipients, diluents or additives, may be prepared in accordance with any of the conventional procedures ⁇ see Remington's Pharmaceutical Science, Mack Publishing Company, Easton, Pa., 19 th Edition, 1995).
• the pharmaceutical composition of the present invention may be prepared by directly filling the inventive S-omeprazole strontium or a hydrate thereof and a pharmaceutically acceptable carrier in vials under a sterile condition, or by filling the amorphous powder obtained by dissolving the inventive S-omeprazole strontium or a hydrate thereof and a pharmaceutically acceptable carrier in sterile water and then freeze-drying in vials, which is dissolved in sterile water to be administered.
• the pharmaceutical composition for oral administration of the present invention may contain S-omeprazole strontium of formula (I) or a hydrate thereof in an amount ranging from 0.1 to 95% by weight, preferably 1 to 70% by weight based on the total weight of the composition.
• a typical daily dose of S-omeprazole strontium of formula (I) or a hydrate thereof for a mammalian including human may range from about 0.5 to 500 mg/kg body weight, preferably 5 to 100 mg/kg body weight, and can be administered in a single dose or in divided doses.
• Example 1 S-Omeprazole (30.Og 5 86.9mmol) having an optical purity of 95% ee was dissolved in 200m£ of methanol, and strontium hydroxide octahydrate (13.8g, 51.9mmol) dissolved in lOOm ⁇ of methanol was slowly added thereto, followed by stirring the mixture at room temperature for 3 hours. The precipitate formed was filtered, washed with lOOm- ⁇ of methanol and dried at 45 " C for 12 hours, to obtain 33.8 g of the title compound (yield: 92%) as an white crystalline powder.
• the differential scanning calorimeter (DSC) curve obtained at 5 ° C /min of the crystalline S-omeprazole strontium tetrahydrate showed an endothermic peak of 178.9 J/g which starts at
• Moisture content (Loss-on-Drying Test): 8.7% (calculated for tetrahydrate,
• Moisture content (Loss-on-Drying Test): 8.9% (calculated for tetrahydrate, 8.49%)
• Strontium content (EDTA titration): 11.35% (calculated for anhydrate, 11.3%)
• Potassium hydroxide (5.3g, 94.5mmol) was dissolved in 150m# of water, and S-omeprazole (27.5g, 79.6mmol) having an optical purity of 95% o ee was dissolved therein.
• strontium chloride hexahydrate (12.7g, 47.8mmol) dissolved in 150m# of methanol was slowly added, and the resulting mixture was stirred at room temperature for 3 hours.
• the precipitate formed was filtered, washed with a mixture of water (20M) and methanol (8(M) and dried at 45 ° C for 12 hours, to obtain 28.7 g of the title 5 compound (yield: 85%) as an white crystalline powder.
• Moisture content (Loss-on-Drying Test): 9.0% (calculated for tetrahydrate,
• Potassium hydroxide (5.3g, 94.5mmol) was dissolved in 15OmU. of water, and S-omeprazole (27.5g, 79.6mmol) having an optical purity of 95% ee was dissolved therein.
• 150m£ of methanol and strontium acetate (12.7g, 47.8mmol) dissolved in 50m£ of water were slowly added thereto, and the 0 resulting mixture was stirred at room temperature for 3 hours.
• the precipitate formed was filtered, washed with a mixture of water (2Om-C) and methanol (8Om-E) and dried at 45 ° C for 12 hours, to obtain 28.0 g of the title compound (yield: 83%) as an white crystalline powder.
• Moisture content (Loss-on-Drying Test): 9.0% (calculated for tetrahydrate,
• Omerprazole content (HPLC, condition A): 88.5% (calculated for anhydrate, 0 88.7%)
• Example 7 50g of the inclusion complex of (S)-(-)-binol and S-omeprazole 5 (optical purity: 97.0% ee) obtained in Example 7 was dissolved in 50Om-S of isopropyl acetate, and sodium hydroxide (3.8g, 95.0mmol) dissolved in 150 mi of water was thereto, followed by stirring the resulting mixture at room temperature for 3 hours. After separating isopropyl acetate, the aqueous layer was washed with 20(M of isopropyl acetate. To the basic aqueous 5 layer including S-omeprazole, a strontium chloride hexahydrate (12.6g, 47.5 mmol) dissolved in 150M of methanol was slowly added.
• Moisture content (Loss-on-Drying Test): 8.8% (calculated for tetrahydrate, 8.49%) 5 Strontium content (EDTA titration): 11.3% (calculated for anhydrate, 11.3%) Omerprazole content (HPLC, condition A): 88.6% (calculated for anhydrate, 88.7%) Optical purity (HPLC, condition B): 99.7% ee
• Example 2 30.Og of crystalline S-omeprazole strontium tetrahydrate (Crystalline Form A) obtained in Example 1 was dried at 100 ° C for 5 hours, to obtain 27.0 g of the title compound. 5
• Example 9 obtained in Example 9 was suspended in 150 mi of water and stirred at room temperature for 12 hours. The precipitate formed was filtered and dried at 45 °C for 12 hours, to obtain 16.5 g of the title compound.
• the result of XRD analysis for the S-omerprazole strontium obtained 5 showed a major peak having an 1/I 0 value of 100% at 2 ⁇ 0.2 of 25.2 (FIG. 5), and DSC curve obtained at 5 °C/min showed an endothermic peak which starts at 37.11 °C and reaches its maximum at 68.09 °C , as well as an exothermic peak which starts at 161.3 ° C and reaches its maximum at 188.81 °C (FIG. 6), which was a partial and heterogenic crystalline hydrate 0 form.
• Example 2 25.Og of crystalline S-omeprazole strontium tetrahydrate (Crystalline Form A) obtained in Example 1 was dissolved in 250 mi of acetone, and the 5 resulting solution was subjected to solvent-evaporation under a reduced pressure, to obtain 21.O g of the title compound.
• the result of XRD analysis for the S-omerprazole strontium obtained showed an amorphous form having no distinctively characteristic peak as shown in FIG. 7. 5 Also, as can be seen from FIG. 8, DSC curve of the amorphous form obtained at 5 ° C/min showed an endothermic peak which starts at 29.16°C reaching maximum heat absorption point at 55.88 °C, as well as an exothermic peak which starts at 182.85 ° C reaching its peak at 207.78 ° C in which phase transition occurred at 195.13 °C .
• Comparative Example 1 The procedure of Comparative Example 1 was repeated except for using S-omeprazole having an optical purity of 90% ee and 80% ee, respectively.
• the S-omeprazole strontium or a hydrate thereof prepared according to the present invention and the S-omeprazole magnesium trihydrate were each dissolved in deionized water to saturation.
• the water-solubility of each of the saturated solutions was analyzed by HPLC under the previously described condition A and the amount of each salt hydrate dissolved was measured. The results are shown in Table 3.
• the solubility of the inventive S-omeprazole strontium and hydrates thereof are at least 10 times higher than that of the known S-omeprazole magnesium trihydrate, which suggests that the inventive strontium salt and hydrates thereof are more suitable for injectable application.
• the S-omeprazole strontium tetrahydrate prepared according to the present invention was exposed in the naked state at 25 to 40 °C and 40 to 90% relative humidity for a period of over 15 days.
• the moisture contents of the inventive salt measured by loss-on-drying test at storage time O 5 3, 7 and 15 days are shown in Table 4.
• the inventive S-omeprazole strontium tetrahydrate was less hygroscopic under a highly humid condition, and its initial moisture content was maintained under a low humidity condition.
• the S-omeprazole strontium tetrahydrate prepared according to the present invention was stored in the sealed state under a stressed condition of
• the inventive S-omeprazole strontium tetrahydrate is highly stable as witnessed by the result obtained under the accelerated aging condition.

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