CN109053685B - Pharmaceutical composition containing ilaprazole sodium and preparation method thereof - Google Patents
Pharmaceutical composition containing ilaprazole sodium and preparation method thereof Download PDFInfo
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- 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
- C07D401/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Abstract
The invention relates to a pharmaceutical composition containing ilaprazole sodium and a preparation method thereof, wherein the pharmaceutical composition consists of ilaprazole sodium and derivatives of ilaprazole, wherein the ilaprazole derivatives are ilaprazole sulfone, ilaprazole thioether, ilaprazole carboxyl onium inner salt, ilaprazole hydroxyl onium inner salt, ilaprazole mercaptomethyl onium inner salt, ilaprazole methyl onium inner salt, ilaprazole thiocyanomethylium inner salt, ilaprazole disulfide dimer, ilaprazole trithione dimer and ilaprazole nitrogen oxide. The pharmaceutical composition can be used for treating peptic ulcer bleeding and stress ulcer and preventing upper gastrointestinal bleeding caused by severe diseases.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a pharmaceutical composition containing ilaprazole sodium and a preparation method thereof.
Background
Ilaprazole (Ilaprazole Sodium) with the chemical name: 5- (1H-pyrrol-1-yl) -2- [ [ (4-methoxy-3-methyl) -2-pyridyl ] -methyl ] -sulfinyl-1H-benzimidazole sodium salt. Ilaprazole is the latest generation Proton Pump Inhibitor (PPI) on the market developed by the beauty pearl group and widely used for digestive tract diseases associated with various acids, such as duodenal ulcer, gastric ulcer, reflux esophagitis and the like. Compared with other PPIs, the ilaprazole has the advantages of strongest acid resistance activity, no individual difference in treatment, stronger acid control capacity at night and the like, and is expected to become a core product in the PPI market.
Chinese patents CN1184970C and CN1225240C disclose ilaprazole oral tablets and its particulate preparation, respectively. However, such enteric tablets and pellets are only suitable for oral administration in the treatment of peptic ulcers with benign ulcerative lesions of the gastric and duodenal mucosa due to the action of gastric acid and pepsin. CN102038648B and CN105769778A both disclose ilaprazole sodium powder injection and a preparation method thereof, which are applied to severe patients who cannot take orally, such as hemorrhage due to peptic ulcer, hemorrhage due to acute gastric mucosa pathological changes under reactive ulcer, severe stress reaction due to acute gastric mucosa damage such as multiple trauma, and the like, and the prevention of severe diseases (such as cerebral hemorrhage, severe trauma, and the like) and upper gastrointestinal hemorrhage caused after gastric surgery.
However, at present, no further research work is available on how to effectively control bleeding due to acute gastric mucosal lesions, severe stress reactions due to acute gastric mucosal lesions such as multiple trauma and the like, and the formula of the ilaprazole powder injection with more stable quality.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing ilaprazole sodium, which has less adverse reaction and stable property and meets clinical requirements, and a preparation method thereof.
The above object of the present invention is achieved by the following means.
In one aspect, the present invention provides a pharmaceutical composition comprising ilaprazole sodium and a derivative of ilaprazole, wherein the ilaprazole derivative is ilaprazole sulfone, ilaprazole sulfide, ilaprazole carboxyl-onium inner salt, ilaprazole hydroxyl-onium inner salt, ilaprazole mercaptomethyl-onium inner salt, ilaprazole methyl-onium inner salt, ilaprazole thiocyanomethylium inner salt, ilaprazole disulfide dimer, ilaprazole trithione dimer, and ilaprazole nitroxide.
Preferably, the amount of the ilaprazole derivative is not more than 2.3 wt.% (≦ 2.3 wt.%);
preferably, the amount of the ilaprazole derivative is not more than 2.2 wt%, preferably not more than 2.1 wt%, more preferably not more than 2.0 wt%, further preferably not more than 1.9 wt%, most preferably not more than 1.8 wt%, for example not more than 1.7 wt%, not more than 1.6 wt%, not more than 1.5 wt%, not more than 1.4 wt%, not more than 1.3 wt%, not more than 1.2 wt%, not more than 1.1 wt%, not more than 1.0 wt%, not more than 0.9 wt%, not more than 0.8 wt%, not more than 0.7 wt%, not more than 0.6 wt%, not more than 0.5 wt%, not more than 0.4 wt%, not more than 0.3 wt%, or not more than 0.2 wt%.
Preferably, the purity of the ilaprazole sodium is not less than 99.9%;
preferably, the amount of the onium inner salt of ilaprazole (including the carboxy onium inner salt of ilaprazole, the hydroxy onium inner salt of ilaprazole, the mercaptomethyl onium inner salt of ilaprazole, the methyl onium inner salt of ilaprazole, and the thiocyanomethylium inner salt of ilaprazole) in the composition is not higher than 1.3 wt%, not higher than 1.2 wt%, not higher than 1.1 wt%, not higher than 1.0 wt%, not higher than 0.9 wt%, preferably not higher than 0.8 wt%, preferably not higher than 0.7 wt%, preferably not higher than 0.6 wt%, preferably not higher than 0.5 wt%, preferably not higher than 0.4 wt%, preferably not higher than 0.3 wt%, preferably not higher than 0.2 wt%;
preferably, the amount of the ilaprazole carboxyl onium inner salt in the composition is not higher than 0.3 wt%,
preferably, the amount of the mercaptopolyium salt of ilaprazole in the composition is not higher than 0.3 wt%,
preferably, the amount of ilaprazole polysulfur dimer (including ilaprazole dithiol dimer and ilaprazole trithiol dimer) in the composition is not higher than 0.4 wt%, preferably not higher than 0.3 wt%;
preferably, the amount of ilaprazole nitroxide in the composition is not higher than 0.3 wt%, preferably not higher than 0.2 wt%;
preferably, the mass ratio of ilaprazole sulfone to ilaprazole thioether is 1: 0.5-2, preferably 1: 0.5-1 or 1: 1-2, more preferably 1: 1;
preferably, the weight ratio of the ilaprazole disulfide dimer to the ilaprazole trithione dimer is 1: 0.5-2, preferably 1: 0.5-1 or 1: 1-2, more preferably 1: 1.
in a preferred embodiment, the pharmaceutical composition comprises the following materials in parts by weight:
in a more preferred embodiment, the pharmaceutical composition comprises the following materials in parts by weight:
on the other hand, the invention also provides a powder injection, which comprises the pharmaceutical composition and a pharmaceutically acceptable carrier;
preferably, the pharmaceutically acceptable carrier is mannitol and EDTA-2 Na;
preferably, the weight ratio of the mannitol to the EDTA-2Na is 10-50: 1, preferably 30: 1;
preferably, the weight ratio of the sum of the weight of the ilaprazole sodium and the ilaprazole derivative (namely the pharmaceutical composition), the mannitol and the EDTA-2Na in the powder injection is 1: 3-5: 0.1 to 0.3, preferably 1: 3: 0.1.
preferably, the pH value of the powder injection is 10.5-11.5, and preferably 11.
In another aspect, the invention also provides a method for preparing the powder injection, which comprises the following steps:
(1) weighing ilaprazole sodium, ilaprazole derivatives and pharmaceutically acceptable carriers according to the prescription amount;
(2) dissolving a pharmaceutically acceptable carrier with water for injection, adjusting the pH value to 10.5-11.5, preferably 10.5 by using 2mol/L sodium hydroxide solution, adding a prescription amount of ilaprazole sodium and derivatives of ilaprazole, adjusting the pH value to 10.5-11.5, preferably 11 by using 2mol/L sodium hydroxide solution after full dissolution, and finally supplementing 4 ℃ water for injection to 1500 mg;
(3) filtering with 0.2 μm filter membrane for 2 times to remove bacteria, lyophilizing to obtain lyophilized powder for injection, vacuum pressing, taking out, and rolling aluminum cover.
The chemical name and the preparation method of the ilaprazole derivative are as follows:
ilaprazole thioether: 2- [ [ (4-methoxy-3-methyl) -2-pyridinyl ] -methylsulfanyl ] -5- (1H-pyrrol-1-yl) -1H-benzimidazole;
the preparation method comprises the following steps:
5- (1H-pyrrol-1-yl) -2-mercaptobenzimidazole 10.0g (46.4mmol) and NaHOH 3.71g (92.8mmol) were dissolved in 100mL of methanol, heated to 50 ℃ to dissolve, 4-methoxy-2-chloromethyl-3-methylpyridine hydrochloride 9.65g (46.4mmol) was dissolved in 100mL of methanol, added to the reaction mixture, refluxed for 1.5H, a large amount of yellow solid precipitated, and TLC monitored for completion of the reaction. Adding 200mL of water into the reaction solution, stirring for 30min, performing suction filtration, washing the filter cake with water, and drying. To give 16.1g of 2- [ [ (4-methoxy-3-methyl) -2-pyridinyl ] -methylsulfanyl ] -5- (1H-pyrrol-1-yl) -1H-benzimidazole, and the resulting solid was purified with dichloromethane/ethyl acetate to give 13.2g of an off-white solid, yield: 81.2 percent
Ilaprazole sulfone: 5- (1H-pyrrol-1-yl) -2- [ [ (4-methoxy-3-methyl) -2-pyridinyl ] -methyl ] -sulfonyl-1H-benzimidazole;
the preparation method comprises the following steps:
ilaprazole thioether (7.0g,20.0mmol) was dissolved in 70ml chloroform, and 50ml of a chloroform solution of CPBA (13.8g, 80.0mol) was added at room temperature, and the reaction spot was controlled in the plate until no starting material remained. Quenching the reaction with 70ml saturated sodium carbonate solution, collecting the organic layer, washing the organic layer with 70ml water, removing water with 7.0g magnesium sulfate, concentrating to dryness, purifying with silica gel column to obtain 3.48g ilaprazole sulfone with a yield of 45.5%
Ilaprazole carboxyl onium inner salt: 1- [5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl ] -4-methoxy-3-methylpyridine-2-carboxylic acid-1-ium inner salt;
the preparation method comprises the following steps:
preparation of a destructive sample, namely placing 5g of ilaprazole in 200ml of a destructive solution [0.02mol/L potassium dihydrogen phosphate-methanol (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20 hours, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destructive sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The collected fractions were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 75mg of a solid as a target.
Ilaprazole hydroxyl onium inner salt: 1- [5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl ] -4-hydroxy-2, 3-dimethylpyridin-1-ium inner salt;
the preparation method comprises the following steps:
preparation of a destructive sample, namely placing 5g of ilaprazole in 200ml of a destructive solution [0.02mol/L potassium dihydrogen phosphate-methanol (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20 hours, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destructive sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The collected fractions were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25mg of a solid as a target.
Ilaprazole mercaptomethylium inner salt: 1- [5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl ] -2-mercaptomethyl-4-methoxy-3-methylpyridin-1-ium inner salt;
the preparation method comprises the following steps:
preparation of a destructive sample, namely placing 5g of ilaprazole in 200ml of a destructive solution [0.02mol/L potassium dihydrogen phosphate-methanol (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20 hours, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destructive sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The collected fractions were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 75mg of a solid as a target.
Ilaprazole disulfide dimer: 2- (2- ((((1- (5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4-methoxy-3-methylpyridin-1-ium inner salt-2-yl) -methyl) -disulfide) -methyl) -4-methoxy-3-methylpyridin-1-ium inner salt) -5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazole;
the preparation method comprises the following steps:
preparation of a destructive sample, namely placing 5g of ilaprazole in 200ml of a destructive solution [0.02mol/L potassium dihydrogen phosphate-methanol (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20 hours, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destructive sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The fractions obtained by separation were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25mg of a solid as a target.
Ilaprazole trithione dimer: 2- (2- ((((1- (5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4-methoxy-3-methylpyridin-1-ium inner salt-2-yl) -methyl) -trithio) -methyl) -4-methoxy-3-methylpyridin-1-ium inner salt) -5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazole;
the preparation method comprises the following steps:
preparation of a destructive sample, namely placing 5g of ilaprazole in 200ml of a destructive solution [0.02mol/L potassium dihydrogen phosphate-methanol (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20 hours, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destructive sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The fractions obtained by separation were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25mg of a solid as a target.
Ilaprazole methyl onium inner salt: 1- [5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl ] -4-methoxy-2, 3-methylpyridin-1-ium inner salt;
the preparation method comprises the following steps:
preparation of a destructive sample, namely placing 5g of ilaprazole in 200ml of a destructive solution [0.02mol/L potassium dihydrogen phosphate-methanol (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20 hours, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destructive sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The fractions obtained by separation were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 75mg of a solid as an object.
Ilaprazole thiocyanomethylium inner salt: 1- [5- (1H-pyrrol-1-yl) -1H-benzo [ d ] imidazol-2-yl ] -4-methoxy-3-methyl-2-thiocyanomethylpyridin-1-ium inner salt;
the preparation method comprises the following steps:
preparation of a destroyed sample, namely, putting 5g of ilaprazole into 200ml of a destroyed solution [0.02mol/L potassium dihydrogen phosphate-acetonitrile (55: 45), adjusting the pH to 10.0 by using 1mol/L sodium hydroxide solution, stirring and dissolving under the heating condition of 50-60 ℃, keeping the temperature, stirring and reacting for 20h, distilling under reduced pressure at 30-50 ℃ to remove the solvent to obtain a viscous substance, and drying in vacuum to obtain the target destroyed sample.
And (3) purification and separation: the target sample is dissolved in DMSO and the concentration is controlled to be about 100 mg/ml. The target fraction was collected by semi-preparative HPLC (high performance liquid chromatography) using 0.3ml per needle and 5mM ammonium bicarbonate/methanol (20: 60) as a mobile phase. The collected fractions obtained by separation were subjected to rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25mg of a solid as a target.
Ilaprazole nitroxide: 5- (1H-pyrrol-1-yl) -2- [ [ (4-methoxy-3-methyl) -2-pyridinyl-1-oxide ] -methyl ] -sulfinyl-1H-benzimidazole.
The preparation method comprises the following steps:
dissolving ilaprazole thioether (7.0g, 0.02mol) with 20ml of acetic acid, adding 7.2g of 50% hydrogen peroxide and 0.06g of copper hydroxyphosphate, heating to 45 ℃, detecting the starting materials by TLC to completely react, pouring the reaction solution into 50ml of water, adjusting the pH to be neutral by using 10% sodium hydroxide solution, extracting the water layer with 25ml of dichloromethane for 3 times each time, combining the organic layers, and concentrating to be dry. The residue was dissolved in 35ml of dichloromethane, added to 70ml of ethyl acetate and stirred for 1h to give 5.5g of a pale yellow solid with a yield of 72.4%. Recrystallization from dichloromethane/ethyl acetate twice gave 3.58g of an off-white solid in 65.0% yield
Detailed Description
The invention is further illustrated below with reference to specific examples. It should be understood that the examples given herein are for illustrative purposes only and are not intended to limit the scope of the present invention.
The experimental procedures, in which specific conditions are not specified, in the following examples are generally carried out under conventional conditions or under conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Material sources are as follows:
sodium ilaprazole: lizhu pharmaceutical factory
Ilaprazole sulfone: prepared by the method as described in the specification of the application
Ilaprazole thioether: prepared by the method as described in the specification of the application
Ilaprazole carboxyl onium inner salt: prepared by the method as described in the specification of the application
Ilaprazole hydroxyl onium inner salt: prepared by the method as described in the specification of the application
Ilaprazole mercaptomethylium inner salt: prepared by the method as described in the specification of the application
Ilaprazole disulfide dimer: prepared by the method as described in the specification of the application
Ilaprazole trithione dimer: prepared by the method as described in the specification of the application
Ilaprazole methyl onium inner salt: prepared by the method as described in the specification of the application
Ilaprazole thiocyanomethylium inner salt: prepared by the method as described in the specification of the application
Ilaprazole nitroxide: prepared by the method as described in the specification of the application
The purity of the medicines is 99.9 percent
Example 1 preparation of ilaprazole sodium powder injection
(1) Taking materials according to the prescription: 97.7mg of ilaprazole sodium (purity 99.9%), 0.2mg of ilaprazole sulfone, 0.2mg of ilaprazole sulfide, 0.3mg of ilaprazole carboxyl onium inner salt, 0.3mg of ilaprazole hydroxyl onium inner salt, 0.3mg of ilaprazole mercaptomethyl onium inner salt, 0.2mg of ilaprazole methyl onium inner salt, 0.2mg of ilaprazole thiocyanomethylium inner salt, 0.2mg of ilaprazole disulfide dimer, 0.2mg of ilaprazole trithione dimer, 0.2mg of ilaprazole nitroxide, 300mg of mannitol, and EDTA-2Na10 mg.
(2) Dissolving mannitol and disodium edetate with water for injection, adjusting the pH value to 10.5 by using 2mol/L sodium hydroxide solution, adding the sodium ilaprazole (purity is 99.9%) weighed in the step (1), ilaprazole sulfone, ilaprazole thioether, ilaprazole carboxyl onium inner salt, ilaprazole hydroxyl onium inner salt, ilaprazole mercaptomethyl onium inner salt, ilaprazole methyl onium inner salt, ilaprazole thiocyanomethylium inner salt, ilaprazole disulfide dimer, ilaprazole trithione dimer and ilaprazole nitrogen oxide, fully dissolving, adjusting the pH value to 11 by using 2mol/L sodium hydroxide solution, and finally supplementing 4 ℃ water for injection to 1500 mg;
(3) filtering with a filter membrane with the aperture of 0.2 μm for 2 times for sterilization and freeze-drying to obtain ilaprazole sodium freeze-dried powder injection, performing vacuum tamponade, taking out of a box, and rolling an aluminum cover.
Example 2-9 preparation of sodium ilaprazole powder injection
The formulations of examples 2-9 are shown in Table 1, and the preparation method is the same as example 1.
TABLE 1
Experimental example 10
1. Clarity detection
30mg of ilaprazole sodium powder injection prepared in example 1 and the following A, B, C groups of ilaprazole sodium powder injection are taken, water for injection is added to 1g, the bottle mouth is opened, the mixture is respectively placed at 4 ℃, 16 ℃, 25 ℃ and 40 ℃, and the change of the color and the clarity of the solution is observed. A blank group was prepared by dissolving 30mg of mannitol and 1mg of EDTA2Na in an appropriate amount of water for injection, and adding 1g of water for injection. The results are shown in Table 2.
Group a ilaprazole composition: according to the preparation method of CN102038648A embodiment 2, the ilaprazole sodium powder injection (A for short) is obtained;
group B ilaprazole compositions: according to the preparation method of CN105769778A embodiment 1, the ilaprazole sodium powder injection (abbreviated as B) is obtained;
group C ilaprazole compositions: according to the preparation method of CN105055342A example 1, the ilaprazole sodium powder injection (abbreviated as C) is obtained.
TABLE 2
From the above results, the clarity of the composition of example 1 was better than that of groups A, B and C under the conditions of 4 ℃, 16 ℃, 25 ℃ and 40 ℃.
2. Stability test
The samples of examples 1-9 and group C were placed at 60 ℃ and 95% relative humidity for 30 days, and the specific test results are shown in Table 3 below:
TABLE 3
As shown in the above table, the decrease rate of the ilaprazole sodium content in examples 1 to 4 and 6 was slow under the high-temperature and high-humidity conditions of 60 ℃ and 95% relative humidity, and the decrease rate of the ilaprazole sodium content in example 1 was the slowest and the effect was the best. The sodium ilaprazole content of examples 5, 7-9 decreased more rapidly.
3. Pharmacodynamic test
(1) Test model:
selecting a rat acute gastric ulcer hemorrhage model (simulating the hemostasis effect of the injection ilaprazole sodium composition under the condition of direct gastric ulcer hemorrhage)
(2) Selecting the dosage: according to the clinical effective dose of the ilaprazole sodium for injection and non-clinical research data, the ilaprazole sodium for injection is converted into a dose which is 1-10 mg/kg effective to a rat gastric ulcer model caused in a laboratory.
(3) Administration dose:
in rodent studies, the dose range is 0.5-10 mg/kg (0.5,1,2,5,10mg/kg), and the blank control group is injected with 1ml/kg of intravenous solvent.
(4) Establishing an acute gastric ulcer bleeding model of a rat
SD rats weighing 180-250 g are divided into 5 groups at random, 5 rats in each group are anesthetized by 25g/L sodium pentobarbital (1ml/kg) in an abdominal cavity, and then are fixed on a rat board, and test drugs or blank auxiliary materials are injected into femoral veins.
After a certain time of administration (reference value of 30min, adjusted according to preliminary experiments), the abdomen is exposed, the abdomen is cut along the midline, the stomach is cut open, a small biopsy forceps is used for simultaneously grasping one gastric antrum and one gastric body mucosa to form an acute bleeding focus, an ulcer bleeding model is established, the bleeding time of the Gastric Mucosa (GMBT) of each rat is recorded, and the average value, the median and the standard deviation are calculated and statistically tested.
(5) Grouping tests: each set of test was set with a blank, example 1, group a, group B, and group C, wherein the preparation methods of group a, group B, and group C were the same as those in the clarity test, and the test results are shown in table 4:
TABLE 4
As shown in the table, the composition described in example 1 can stop bleeding of acute gastric ulcer in rats more effectively and effectively.
It is to be understood that the invention described herein is not limited to particular methodologies, protocols, or reagents, as these may vary. The discussion and examples provided herein are presented solely for the purpose of describing particular embodiments and are not intended to limit the scope of the present invention, which is limited only by the claims.
Claims (12)
1. The pharmaceutical composition is characterized by comprising the following substances in parts by weight:
2. the pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the following materials in parts by weight:
3. a powder injection comprising the pharmaceutical composition of claim 1 or 2 and a pharmaceutically acceptable carrier.
4. The powder injection according to claim 3, wherein the pharmaceutically acceptable carrier is mannitol and EDTA-2 Na.
5. The powder injection according to claim 4, wherein the weight ratio of mannitol to EDTA-2Na is 10-50: 1.
6. the powder injection according to claim 5, wherein the weight ratio of mannitol to EDTA-2Na is 30: 1.
7. the powder injection according to any one of claims 3 to 6, wherein the weight ratio of the pharmaceutical composition according to claim 1 or 2, mannitol, EDTA-2Na contained in the powder injection is 1: 3-5: 0.1-0.3.
8. The powder injection according to any one of claims 3 to 6, wherein the weight ratio of the pharmaceutical composition according to claim 1 or 2, mannitol, EDTA-2Na contained in the powder injection is 1: 3: 0.1.
9. the powder injection according to any one of claims 3 to 6, wherein the pH value of the powder injection is 10.5-11.5.
10. The powder injection according to any one of claims 3 to 6, wherein the pH value of the powder injection is 11.
11. A method of preparing a powder for injection according to any one of claims 3 to 9, the method comprising the steps of:
(1) weighing ilaprazole sodium, ilaprazole derivatives and pharmaceutically acceptable carriers according to the prescription amount;
(2) dissolving a pharmaceutically acceptable carrier with water for injection, adjusting the pH value to 10.5-11.5 by using 2mol/L sodium hydroxide solution, adding a prescription amount of ilaprazole sodium and derivatives of ilaprazole, adjusting the pH value to 10.5-11.5 by using 2mol/L sodium hydroxide solution after full dissolution, and finally supplementing 4 ℃ water for injection to 1500 mg;
(3) filtering with 0.2 μm filter membrane for 2 times to remove bacteria, lyophilizing to obtain lyophilized powder for injection, vacuum pressing, taking out, and rolling aluminum cover.
12. A method of preparing the powder injection of claim 10, the method comprising the steps of:
(1) weighing ilaprazole sodium, ilaprazole derivatives and pharmaceutically acceptable carriers according to the prescription amount;
(2) dissolving a pharmaceutically acceptable carrier with water for injection, adjusting the pH value to 10.5 by using 2mol/L sodium hydroxide solution, adding a prescription amount of ilaprazole sodium and derivatives of ilaprazole, adjusting the pH value to 11 by using 2mol/L sodium hydroxide solution after full dissolution, and finally supplementing 4 ℃ water for injection to 1500 mg;
(3) filtering with 0.2 μm filter membrane for 2 times to remove bacteria, lyophilizing to obtain lyophilized powder for injection, vacuum pressing, taking out, and rolling aluminum cover.
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| CN1121714A (en) * | 1994-02-28 | 1996-05-01 | 一洋药品株式会社 | Novel 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole derivatives |
| CN102038648A (en) * | 2009-10-23 | 2011-05-04 | 丽珠医药集团股份有限公司 | Powder injection for treating peptic ulcers and preparation method thereof |
| CN105055342A (en) * | 2015-08-13 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer |
| CN105769778A (en) * | 2016-04-02 | 2016-07-20 | 丽珠医药集团股份有限公司 | Sodium ilaprazole powder injection and preparation method thereof |
| WO2017216789A1 (en) * | 2016-06-16 | 2017-12-21 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
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| CN1121714A (en) * | 1994-02-28 | 1996-05-01 | 一洋药品株式会社 | Novel 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole derivatives |
| CN102038648A (en) * | 2009-10-23 | 2011-05-04 | 丽珠医药集团股份有限公司 | Powder injection for treating peptic ulcers and preparation method thereof |
| CN105055342A (en) * | 2015-08-13 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer |
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