WO2019242181A1 - 一种含艾普拉唑或其盐的药物组合物及其制备方法 - Google Patents

一种含艾普拉唑或其盐的药物组合物及其制备方法 Download PDF

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WO2019242181A1
WO2019242181A1 PCT/CN2018/111611 CN2018111611W WO2019242181A1 WO 2019242181 A1 WO2019242181 A1 WO 2019242181A1 CN 2018111611 W CN2018111611 W CN 2018111611W WO 2019242181 A1 WO2019242181 A1 WO 2019242181A1
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ilaprazole
weight
salt
pharmaceutical composition
derivative
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PCT/CN2018/111611
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English (en)
French (fr)
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王涛
侯雪梅
成彩华
陆文岐
孔祥生
张象娜
涂增清
张裕容
吴小红
李菁
谌红丹
陈嘉璐
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丽珠医药集团股份有限公司
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Priority to EP18923679.7A priority Critical patent/EP3811941B1/en
Priority to PL18923679.7T priority patent/PL3811941T3/pl
Priority to ES18923679T priority patent/ES2969740T3/es
Priority to US17/254,830 priority patent/US20210260046A1/en
Priority to MX2020014028A priority patent/MX2020014028A/es
Priority to BR112020026264-1A priority patent/BR112020026264A2/pt
Priority to JP2021520259A priority patent/JP7250920B2/ja
Publication of WO2019242181A1 publication Critical patent/WO2019242181A1/zh
Priority to PH12020552230A priority patent/PH12020552230A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • 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 invention relates to the technical field of medicine, in particular to a pharmaceutical composition containing ilaprazole or a salt thereof and a preparation method thereof.
  • Ilaprazole Sodium chemical name: 5- (1hydro-pyrrole-1-yl) -2-[[(4-methoxy-3-methyl) -2-pyridyl] -formaldehyde []] Sulfinyl-1 hydrogen-benzimidazole sodium salt.
  • Ipraprazole is the latest generation of proton pump inhibitors (PPIs) developed and marketed by Livzon Group. It is widely used in various acid-related gastrointestinal diseases such as duodenal ulcers, gastric ulcers, and reflux esophagitis. Wait. Compared with other PPIs, ilaprazole has the advantages of strongest antacid activity, no individual difference in treatment, and stronger acid control at night, etc., and is expected to become a core product in the PPI market.
  • PPIs proton pump inhibitors
  • Chinese patents CN1184970C and CN1225240C respectively disclose ilaprazole oral tablets and microparticle preparations thereof.
  • enteric-coated tablets and enteric-coated pellets are only suitable for the treatment of peptic ulcers of benign ulcerative damage of the stomach and duodenal mucosa caused by the effects of gastric acid and pepsin.
  • CN102038648B and CN105769778A both disclose ilaprazole sodium powder injection and its preparation method, and its application to severe patients that cannot be taken orally, such as peptic ulcer bleeding, acute gastric mucosal lesion bleeding under reactive ulcer, and acute gastric mucosal damage Such as severe trauma and other serious stress reactions and prevention of severe diseases (such as cerebral hemorrhage, severe trauma, etc.) and upper gastrointestinal bleeding caused by gastric surgery.
  • the object of the present invention is to provide a pharmaceutical composition containing ilaprazole or a salt thereof with few adverse reactions, stable properties, and adapting to clinical needs, and a preparation method thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising ilaprazole or a salt thereof and a derivative of ilaprazole, wherein the amount of the ilaprazole derivative in the composition is not Higher than 1.3wt% ( ⁇ 1.3wt%);
  • the amount of ilaprazole derivative in the composition is not higher than 1.2 wt%, preferably not higher than 1.1 wt%, more preferably not higher than 1.0 wt%, further preferably not higher than 0.9 wt%, and most preferably It is preferably not higher than 0.8% by weight, for example, the amount of ilaprazole derivative in the composition is not higher than 0.7% by weight, not higher than 0.6% by weight, not higher than 0.5% by weight, and not higher than 0.4% by weight, Not higher than 0.3 wt%, or not higher than 0.2 wt%.
  • the salt of ilaprazole is ilaprazole sodium
  • the purity of the ilaprazole or a salt thereof is not less than 99.9%;
  • the ilaprazole derivative is selected from one or more of ilaprazole sulfone, ilaprazole sulfide, and an onium salt of ilaprazole;
  • the onium internal salt of ilaprazole is selected from one or more of ilaprazole carboxylium internal salt, ilaprazole hydroxynium internal salt, and ilaprazole mercaptomethyl internal salt. .
  • the amount of onium salt of ilaprazole in the composition is not higher than 0.9% by weight, preferably not higher than 0.8% by weight, more preferably not higher than 0.7% by weight, and still more preferably not higher than 0.6% by weight , Most preferably not higher than 0.5 wt%, such as not higher than 0.4 wt%, not higher than 0.3 wt%, or not higher than 0.2 wt%;
  • the ilaprazole derivative is ilaprazole sulfone, ilaprazole sulfide, ilaprazole carboxylium internal salt, ilaprazole hydroxylium internal salt, and ilaprazole mercaptomethyl Onium internal salt, preferably, the amount of the ilaprazole carboxylium internal salt in the composition is not higher than 0.3% by weight,
  • the mass ratio of ilaprazole sulfone to ilaprazole sulfide is 1: 0.5-2, preferably 1: 0.5-1 or 1: 1-2, and more preferably 1: 1;
  • the pharmaceutical composition includes the following substances by weight:
  • the pharmaceutical composition includes the following substances by weight:
  • the present invention also provides a powder injection comprising the pharmaceutical composition as described above and a pharmaceutically acceptable carrier;
  • the pharmaceutically acceptable carriers are mannitol and EDTA-2Na;
  • the weight ratio of the mannitol and EDTA-2Na is 10-50: 1, preferably 30: 1;
  • the weight ratio of the total weight of ilaprazole or its salt and ilaprazole derivative (that is, the pharmaceutical composition as described above), mannitol, and EDTA-2Na in the powder injection is: 1: 3-5: 0.1-0.3, preferably 1: 3: 0.1.
  • the pH value of the powder injection is 10.5-11.5, preferably 11.
  • the present invention also provides a method for preparing the powder injection, which includes the following steps:
  • the present invention also provides other technical solutions to achieve the objectives of the present invention.
  • the present invention provides another pharmaceutical composition, which comprises ilaprazole sodium and a derivative of ilaprazole, wherein the ilaprazole derivative is ilaprazole A polysulfide dimer, and / or one or more selected from the group consisting of ilaprazole sulfone, ilaprazole sulfide, and an onium salt of ilaprazole;
  • the amount of the ilaprazole derivative is not higher than 1.7% by weight ( ⁇ 1.7% by weight), preferably not higher than 1.6% by weight, more preferably not higher than 1.5% by weight, and further preferably not higher than 1.4% by weight.
  • the purity of the ilaprazole sodium is not less than 99.9%;
  • the ilaprazole polysulfide dimer is an ilaprazole disulfide dimer and / or an ilaprazole trisulfide dimer.
  • the onium internal salt of ilaprazole is selected from one or more of ilaprazole carboxylium internal salt, ilaprazole hydroxynium internal salt, and ilaprazole mercaptomethyl internal salt. .
  • the ilaprazole derivative is ilaprazole polysulfide dimer, ilaprazole sulfone, ilaprazole sulfide, ilaprazole carboxylium internal salt, ilaprazole hydroxynium Internal salt, ilaprazole mercaptomethyl internal salt;
  • the amount of the onium internal salt of ilaprazole is not higher than 0.9 wt%, preferably not higher than 0.8 wt%, more preferably not higher than 0.7 wt%, preferably not higher than 0.6 wt%, preferably not higher Less than 0.5% by weight, preferably not more than 0.4% by weight, preferably not more than 0.3% by weight, preferably not more than 0.2% by weight;
  • the amount of the ilaprazole carboxynium internal salt in the composition is not higher than 0.3% by weight
  • the mass ratio of ilaprazole sulfone to ilaprazole sulfide is 1: 0.5-2, preferably 1: 0.5-1 or 1: 1-2, and more preferably 1: 1;
  • the amount of the ilaprazole polysulfide dimer is not higher than 0.4% by weight, preferably not higher than 0.3% by weight.
  • the ilaprazole polysulfide dimer is ilaprazole disulfide dimer and ilaprazole trisulfide dimer;
  • the weight ratio of the ilaprazole disulfide dimer and the ilaprazole trisulfide dimer is 1: 0.5-2, preferably 1: 0.5-1 or 1: 1-2, and more preferably Is 1: 1.
  • the pharmaceutical composition comprises or consists of the following parts by weight:
  • the composition comprises or consists of the following parts by weight:
  • the present invention also provides a powder injection comprising the pharmaceutical composition as described above (the pharmaceutical composition includes ilaprazole sodium and a derivative of ilaprazole, wherein the ilaprazole
  • the derivative is an ilaprazole polysulfide dimer, and / or one or more selected from the group consisting of ilaprazole sulfone, ilaprazole sulfide, and an onium internal salt of ilaprazole) and pharmaceutically Acceptable carrier
  • the pharmaceutically acceptable carriers are mannitol and EDTA-2Na;
  • the weight ratio of the mannitol and EDTA-2Na is 10-50: 1, preferably 30: 1;
  • the weight ratio of the sum of the weight of ilaprazole or its salt and the derivative of ilaprazole that is, the pharmaceutical composition as described above, mannitol, and EDTA-2Na in the powder injection. It is 1: 3-5: 0.1-0.3, preferably 1: 3: 0.1.
  • the pH value of the powder injection is 10.5-11.5, preferably 11.
  • the present invention also provides a method for preparing the powder injection, which includes the following steps:
  • the present invention also provides a method for treating a gastrointestinal disease, the method comprising administering a therapeutically effective amount of the aforementioned pharmaceutical composition to a patient in need, wherein, preferably, the gastrointestinal disease is selected from twelve fingers Intestinal ulcer, gastric ulcer and reflux esophagitis.
  • Ipraprazole sulfide 2-[[(4-methoxy-3-methyl) -2-pyridyl] -methylthio] -5- (1H-pyrrole-1-yl) -1H- Benzimidazole
  • Iprazolone 5- (1H-pyrrole-1-yl) -2-[[(4-methoxy-3-methyl) -2-pyridyl] -methyl] -sulfonyl-1H- Benzimidazole
  • Ilaprazole sulfide (7.0 g, 20.0 mmol) was dissolved in 70 ml of chloroform, and 50 ml of m-CPBA (13.8 g, 80.0 mol) in chloroform was added at room temperature, and the reaction point was controlled in a plate until no raw material remained. The reaction was quenched with 70 ml of saturated sodium carbonate solution, and the organic layer was collected. The organic layer was was washed with 70 ml of water, 7.0 g of magnesium sulfate was removed from the water, concentrated to dryness, and purified with a silica gel column to obtain 3.48 g of ilaprazole sulfone. .
  • Ilaprazole carboxylium internal salt 1- [5- (1H-pyrrole-1-yl) -1H-benzo [d] imidazol-2-yl] -4-methoxy-3methylpyridine-2 -Carboxylic acid-1-onium salt
  • the target sample is dissolved with DMSO, and the concentration is controlled at about 100 mg / ml.
  • concentration is controlled at about 100 mg / ml.
  • the collected components were removed by rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 75 mg of a target solid.
  • Ipraprazole hydroxylium internal salt 1- [5- (1H-pyrrole-1-yl) -1H-benzo [d] imidazol-2-yl] -4-hydroxy-2,3-dimethylpyridine -1-onium salt
  • the target sample is dissolved with DMSO, and the concentration is controlled at about 100 mg / ml.
  • concentration is controlled at about 100 mg / ml.
  • the collected components were removed by rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25 mg of a target solid.
  • Ipraprazole mercaptomethyl internal salt 1- [5- (1H-pyrrole-1-yl) -1H-benzo [d] imidazol-2-yl] -2-mercaptomethyl-4-methoxy 3-methylpyridin-1-ium internal salt
  • the target sample is dissolved with DMSO, and the concentration is controlled at about 100 mg / ml.
  • concentration is controlled at about 100 mg / ml.
  • the collected components were removed by rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 75 mg of a target solid.
  • Ilaprazole disulfide dimer 2- (2-(((((1- (5- (1H-pyrrole-1-yl) -1H-benzene [d] imidazol-2-yl) -4-methyl Oxy-3-methylpyridin-1-ium internal salt-2-yl) -methyl) -dithio) -methyl) -4-methoxy-3-methylpyridin-1-ium internal salt ) -5- (1H-pyrrole-1-yl) -1H-benzo [d] imidazole
  • the target sample is dissolved with DMSO, and the concentration is controlled at about 100 mg / ml.
  • concentration is controlled at about 100 mg / ml.
  • the separated component was separated by rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25 mg of a target solid.
  • Ilaprazole trisulfide dimer 2- (2-(((((((1- (5- (1H-pyrrole-1-yl) -1H-benzene [d] imidazol-2-yl) -4-methyl Oxy-3-methylpyridin-1-ium internal salt-2-yl) -methyl) -trithio) -methyl) -4-methoxy-3-methylpyridin-1-ium internal salt ) -5- (1H-pyrrole-1-yl) -1H-benzo [d] imidazole
  • the target sample is dissolved with DMSO, and the concentration is controlled at about 100 mg / ml.
  • concentration is controlled at about 100 mg / ml.
  • the separated component was separated by rotary evaporation to remove the organic solvent, and the residue was freeze-dried to obtain 25 mg of a target solid.
  • the ilaprazole powder injection composition provided by the invention has more stable quality, can more effectively control the symptoms of gastric mucosal bleeding, and has more clinical significance.
  • Ipraprazole sulfide prepared as described in the specification of this application
  • Ipraprazole carboxynium internal salt prepared as described in the specification of this application
  • Ilaprazole hydroxynium internal salt prepared as described in the specification of this application
  • Ipraprazole mercaptomethyl internal salt prepared as described in the specification of this application
  • Ilaprazole disulfide dimer prepared as described in the specification of this application
  • Ipraprazole trisulfide dimer prepared as described in the specification of this application
  • step (1) Dissolve mannitol and disodium edetate with water for injection, adjust the pH value to 10.5 with 2mol / L sodium hydroxide solution, and add the ilaprazole sodium (purity 99.9%) weighed in step (1).
  • Ilaprazole sulfone, ilaprazole sulfide, ilaprazole carboxylium internal salt, ilaprazole hydroxynium internal salt, ilaprazole mercaptomethyl internal salt, and 2mol / L sodium hydroxide solution adjusted the pH value to 11, and finally added 4 ° C water for injection to 1500mg;
  • Group A ilaprazole composition According to the preparation method of CN102038648A Example 2, an ilaprazole sodium powder injection (referred to as A) is obtained;
  • Iraprazole composition of group B According to the preparation method of CN 105769778A Example 1, ilaprazole sodium powder injection (abbreviation B) is obtained;
  • Ilaprazole composition in group C According to the preparation method of CN105055342A Example 2, an ilaprazole sodium powder injection (referred to as C) is obtained.
  • Example 1 has better clarity than the powder injection of Group A, Group B, and Group C under the conditions of 4 ° C, 16 ° C, 25 ° C, and 40 ° C.
  • Examples 1-8 were placed at a temperature of 60 ° C and a relative humidity of 95% for 30 days, and samples were taken.
  • the specific test results are shown in Table 3 below:
  • Example 1 The slowest rate of ilaprazole sodium decline and the best effect.
  • Example 5 the content of ilaprazole sodium decreased rapidly.
  • ilaprazole sodium for injection should be effective in the laboratory-induced gastric ulcer model in rats in the range of 1-10 mg / kg. .
  • the dosage range was 0.5 to 10 mg / kg (0.5, 1, 2, 5, 10 mg / kg), and the blank control group was injected intravenously with 1 ml / kg of solvent.
  • SD rats weighing 180-250g, were randomly divided into 5 groups, 5 in each group. After intraperitoneal anesthesia with 25g / L sodium pentobarbital (1ml / kg), they were fixed on a rat plate, and the test drug was injected into the femoral vein. Or blank excipients.
  • Test grouping Each group is set with blank control, Example 1, Group A, Group B, and Group C.
  • the preparation methods of Group A, Group B, and Group C are the same as those in the clarification test.
  • Table 4 shows:
  • Example 1 can more effectively stop bleeding and has a better effect on acute gastric ulcer bleeding in rats.
  • ilaprazole sodium purity 99.9%
  • ilaprazole sulfone 0.2mg ilaprazole sulfide 0.2mg
  • ilaprazole carboxynium internal salt 0.3mg Ipraprazole hydroxynium internal salt 0.3mg
  • ilaprazole mercaptomethyl internal salt 0.3mg ilaprazole disulfide dimer 0.2mg
  • ilaprazole trisulfide dimer 0.2mg mannitol 300mg, EDTA-2Na 10mg.
  • step (1) Dissolve mannitol and disodium edetate with water for injection, adjust the pH value to 10.5 with 2mol / L sodium hydroxide solution, and add the ilaprazole sodium (purity 99.9%) weighed in step (1).
  • Polymer ilaprazole trisulfide dimer, fully dissolved, then adjust the pH value to 11 with 2mol / L sodium hydroxide solution, and finally add 4 °C water for injection to 1500mg;
  • Group A ilaprazole composition According to the preparation method of CN102038648A Example 2, an ilaprazole sodium powder injection (referred to as A) is obtained;
  • Iraprazole composition of group B According to the preparation method of CN 105769778A Example 1, ilaprazole sodium powder injection (abbreviation B) is obtained;
  • Ilaprazole composition in group C According to the preparation method of CN105055342A Example 1, ilaprazole sodium powder injection (abbreviated as C) is obtained.
  • Example 10 has better clarity under the conditions of 4 ° C, 16 ° C, 25 ° C, and 40 ° C than that of Group A, Group B, and Group C.
  • ilaprazole sodium for injection should be effective in the laboratory-induced gastric ulcer model in rats in the range of 1-10 mg / kg. .
  • the dosage range was 0.5 to 10 mg / kg (0.5, 1, 2, 5, 10 mg / kg), and the blank control group was injected intravenously with 1 ml / kg of solvent.
  • SD rats weighing 180-250g, were randomly divided into 5 groups, 5 in each group. After intraperitoneal anesthesia with 25g / L sodium pentobarbital (1ml / kg), they were fixed on a rat plate, and the test drug was injected into the femoral vein. Or blank excipients.
  • Test grouping Each group is set up with blank control, Example 10, group A, group B, and group C.
  • the preparation method of group A, group B, and group C is the same as that in the clarification test.
  • the test results are as follows: Table 8 shows:
  • Example 10 can more effectively stop bleeding and has a better effect on acute gastric ulcer bleeding in rats.

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Abstract

本发明涉及一种含艾普拉唑或其盐的药物组合物及其制备方法，所述药物组合物包含或由艾普拉唑或其盐和艾普拉唑的衍生物组成，其中，所述组合物中艾普拉唑衍生物的量不高于1.3wt％(≤1.3wt％)。所述组合物可用于治疗消化性溃疡出血和应激性溃疡以及预防重症疾病引起的上消化道出血。

Description

一种含艾普拉唑或其盐的药物组合物及其制备方法
相关申请的交叉引用
本申请要求于2018年6月22日递交的中国专利申请CN201810652046.X的优先权，并在此将其全部内容以引用方式并入本文。
技术领域
本发明涉及医药技术领域，具体涉及一种含艾普拉唑或其盐的药物组合物及其制备方法。
背景技术
艾普拉唑(Ilaprazole Sodium)，化学名称为：5-(1氢-吡咯-1-基)-2-[[(4-甲氧基-3-甲基)-2-吡啶基]-甲基]-亚磺酰基-1氢-苯并咪唑钠盐。艾普拉唑是丽珠集团开发上市的最新一代质子泵抑制剂(PPI)，广泛地用于与各种酸相关的消化道疾病，如十二指肠溃疡、胃溃疡、反流性食管炎等。与其它PPI相比，艾普拉唑具有抗酸活性最强、治疗无个体差异、夜间控酸能力更强等优点，有望成为PPI市场中的核心产品。
中国专利CN1184970C和CN1225240C分别公开了艾普拉唑口服片剂及其微粒制剂。但此类肠溶片和肠溶微丸口服只适用于治疗由于胃酸和胃蛋白酶的作用而造成的胃和十二指肠黏膜的良性溃疡性损害的消化性溃疡。
CN102038648B和CN105769778A都公开了艾普拉唑钠粉针剂及其制备方法，针对不能口服的重症患者的应用，如消化性溃疡出血、反应激性溃疡下发生的急性胃粘膜病变出血、急性胃粘膜损害如多发性外伤等严重应激反应以及预防重症疾病(如脑出血、严重创伤等)和胃手术后引起的上消化道出血等情况。
然而，目前对于如何更有效地控制急性胃粘膜病变出血、急性胃粘膜损害如多发性外伤等严重应激反应、质量更稳定的艾普拉唑粉针剂处方，缺乏更进一步的研究工作。
发明内容
本发明的目的在于，提供一种不良反应少、性质稳定、适应临床需求的含艾普拉唑或其盐的药物组合物及其制备方法。
本发明的上述目的是通过以下技术方案来实现的。
一方面，本发明提供一种药物组合物，所述药物组合物包含艾普拉唑或其盐和艾普拉唑的衍生物，其中，所述组合物中艾普拉唑衍生物的量不高于1.3wt％(≤1.3wt％)；
优选地，所述组合物中艾普拉唑衍生物的量不高于1.2wt％，优选不高于1.1wt％，更优选不高于1.0wt％，进一步优选不高于0.9wt％，最优选不高于0.8wt％，例如所述组合物中艾普拉唑衍生物的量不高于0.7wt％，不高于0.6wt％，不高于0.5wt％，不高于0.4wt％，不高于0.3wt％，或者不高于0.2wt％。
优选地，所述艾普拉唑的盐为艾普拉唑钠；
优选地，所述艾普拉唑或其盐的纯度不低于99.9％；
优选地，所述艾普拉唑衍生物选自艾普拉唑砜、艾普拉唑硫醚和艾普拉唑的鎓内盐中的一种或多种；
优选地，所述艾普拉唑的鎓内盐选自艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐和艾普拉唑巯甲基鎓内盐中的一种或多种。
优选地，所述组合物中艾普拉唑的鎓内盐的量不高于0.9wt％，优选不高于0.8wt％，更优选不高于0.7wt％，进一步优选不高于0.6wt％，最优选不高于0.5wt％，例如不高于0.4wt％，不高于0.3wt％，或者不高于0.2wt％；
优选地，所述艾普拉唑衍生物为艾普拉唑砜、艾普拉唑硫醚、艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐和艾普拉唑巯甲基鎓内盐，优选地，所述组合物中所述艾普拉唑羧基鎓内盐的量不高于0.3wt％，
优选地，所述艾普拉唑砜与艾普拉唑硫醚的质量比为1：0.5-2，优选为1：0.5-1或1：1-2，更优选为1：1；
在一个优选的技术方案中，所述药物组合物包含以下重量份的物质：
Figure PCTCN2018111611-appb-000001
Figure PCTCN2018111611-appb-000002
在一个更优选的技术方案中，所述药物组合物包含以下重量份的物质：
Figure PCTCN2018111611-appb-000003
另一方面，本发明还提供一种粉针剂，所述粉针剂包含如上所述的药物组合物和药学上可接受的载体；
优选地，所述药学上可接受的载体为甘露醇和EDTA-2Na；
优选地，所述甘露醇和EDTA-2Na的重量比为10-50：1，优选为30：1；
优选地，所述粉针剂中艾普拉唑或其盐和艾普拉唑的衍生物的重量之和(即如上所述的药物组合物)、甘露醇、EDTA-2Na三者的重量比为1：3-5：0.1-0.3，优选为1：3：0.1。
优选地，所述粉针剂的pH值为10.5-11.5，优选为11。
再一方面，本发明还提供一种制备上述粉针剂的方法，所述方法包括以下步骤：
(1)按处方量称取艾普拉唑或其盐、艾普拉唑的衍生物、以及药学上可接受的载体；
(2)将药学上可接受的载体用注射用水溶解，用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为10.5，加入处方量的艾普拉唑或其盐、艾普拉唑的衍生物，充分溶解后再用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为11，最后补加4℃注射用水至1500mg；
(3)用孔径为0.2μm的滤膜过滤2次除菌、冻干，得到冻干粉针剂， 真空压塞，出箱，轧铝盖。
本发明还提供了实现本发明的目的的其他技术方案。具体而言，本发明提供了另外一种药物组合物，所述药物组合物包括艾普拉唑钠和艾普拉唑的衍生物，其中，所述艾普拉唑衍生物为艾普拉唑多硫二聚体，和/或选自艾普拉唑砜、艾普拉唑硫醚和艾普拉唑的鎓内盐中的一种或多种；
优选地，所述艾普拉唑衍生物的量不高于1.7wt％(≤1.7wt％)优选不高于1.6wt％，更优选不高于1.5wt％，进一步优选不高于1.4wt％，最优选不高于1.3wt％，例如不高于1.2wt％，不高于1.1wt％，不高于1.0wt％，不高于0.9wt％，不高于0.8wt％，不高于0.7wt％，不高于0.6wt％，不高于0.5wt％，不高于0.4wt％，或者不高于0.3wt％。
优选地，所述艾普拉唑钠的纯度不低于99.9％；
优选地，所述艾普拉唑多硫二聚体为艾普拉唑二硫二聚体和/或艾普拉唑三硫二聚体。
优选地，所述艾普拉唑的鎓内盐选自艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐中的一种或多种。
优选地，所述艾普拉唑衍生物为艾普拉唑多硫二聚体、艾普拉唑砜、艾普拉唑硫醚、艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐；
优选地，所述艾普拉唑的鎓内盐的量不高于0.9wt％，优选不高于0.8wt％，更优选不高于0.7wt％，优选不高于0.6wt％，优选不高于0.5wt％，优选不高于0.4wt％，优选不高于0.3wt％，优选不高于0.2wt％；
优选地，所述组合物中所述艾普拉唑羧基鎓内盐的量不高于0.3wt％，
优选地，所述艾普拉唑砜与艾普拉唑硫醚的质量比为1：0.5-2，优选为1：0.5-1或1：1-2，更优选为1：1；
优选地，所述艾普拉唑多硫二聚体的量不高于0.4wt％，优选不高于0.3wt％。
优选地，所述艾普拉唑多硫二聚体为艾普拉唑二硫二聚体和艾普拉唑三硫二聚体；
优选地，所述艾普拉唑二硫二聚体和艾普拉唑三硫二聚体的重量比为1：0.5-2，优选为1：0.5-1或1：1-2，更优选为1：1。
优选地，所述药物组合物包含或由以下重量份的物质组成：
Figure PCTCN2018111611-appb-000004
优选地，所述组合物包含或由以下重量份的物质组成：
Figure PCTCN2018111611-appb-000005
本发明还提供一种粉针剂，所述粉针剂包含如上所述的药物组合物(所述药物组合物包括艾普拉唑钠和艾普拉唑的衍生物，其中，所述艾普拉唑衍生物为艾普拉唑多硫二聚体，和/或选自艾普拉唑砜、艾普拉唑硫醚和艾普拉唑的鎓内盐中的一种或多种)和药学上可接受的载体；
优选地，所述药学上可接受的载体为甘露醇和EDTA-2Na；
优选地，所述甘露醇和EDTA-2Na的重量比为10-50：1，优选为30：1；
优选地，所述粉针剂中艾普拉唑或其盐和艾普拉唑的衍生物的重量之和(即如上所述的药物组合物)、甘露醇、EDTA-2Na三者的的重量比为1：3-5： 0.1-0.3，优选为1：3：0.1。
优选地，所述粉针剂的pH值为10.5-11.5，优选为11。
此外，本发明还提供了一种制备上述粉针剂的方法，所述方法包括以下步骤：
(1)按处方量称取艾普拉唑钠、艾普拉唑的衍生物、以及药学上可接受的载体；
(2)将药学上可接受的载体用注射用水溶解，用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为10.5，加入处方量的艾普拉唑钠、艾普拉唑的衍生物，充分溶解后再用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为11，最后补加4℃注射用水至1500mg；
(3)用孔径为0.2μm的滤膜过滤2次除菌、冻干，得到冻干粉针剂，真空压塞，出箱，轧铝盖。
本发明还提供一种用于治疗消化道疾病的方法，该方法包括将治疗有效量的前述的药物组合物施用于有需要的患者，其中，优选地，所述消化道疾病选自十二指肠溃疡、胃溃疡和反流性食管炎。
本发明所述的艾普拉唑衍生物的化学名称及制备方法如下：
艾普拉唑硫醚：2-[[(4-甲氧基-3－-甲基)-2-吡啶基]-甲硫基]-5-(1H-吡咯-1-基)-1H-苯并咪唑
制备方法：
5-(1H-吡咯-1-基)-2-巯基苯并咪唑10.0g(46.4mmol)和NaOH3.71g(92.8mmol)溶于100mL的甲醇中，加热至50℃使之溶解，4-甲氧基-2-氯甲基-3-甲基吡啶盐酸盐9.65g(46.4mmol)溶于100mL的甲醇中，加入到反应液中，回流1.5h，有大量黄色固体析出，TLC监测反应完全。向反应液中加入200mL的水，搅拌30min，抽滤，水洗滤饼，干燥。得到2-[[(4－甲氧基－3－甲基)－2－吡啶基]－甲硫基]－5－(1H－吡咯－1－基)－1H－苯并咪唑16.1g，所得固体经二氯甲烷/乙酸乙酯精制，得类白色固体13.2g，收率：81.2％
艾普拉唑砜：5-(1H-吡咯-1-基)-2-[[(4-甲氧基-3-甲基)-2-吡啶基]-甲基]-磺酰基-1H-苯并咪唑
制备方法：
将艾普拉唑硫醚(7.0g,20.0mmol)用70ml氯仿溶解，室温下加入50ml m-CPBA(13.8g，80.0mol)的氯仿溶液，反应点板中控，至无原料剩余。用70ml饱和碳酸钠溶液猝灭反应，收集有机层，有机层用70ml水洗，7.0g硫酸镁除水，浓缩至干，用硅胶色谱柱纯化，得到艾普拉唑砜3.48g，收率45.5％。
艾普拉唑羧基鎓内盐：1-[5-(1H-吡咯-1-基)-1H-苯并[d]咪唑-2-基]-4-甲氧基-3甲基吡啶-2-羧酸-1-鎓内盐
制备方法：
破坏样品准备:将艾普拉唑5g置于200ml破坏液[0.02mol/L磷酸二氢钾—甲醇(55：45)，用1mol/L氢氧化钠溶液调pH至10.0]中，50-60℃加热条件下搅拌溶解，保温搅拌反应20h，30-50℃减压蒸馏除去溶剂，得粘稠物，真空干燥，得目标破坏样品。
纯化分离：将目标样品用DMSO溶解，并控制浓度在100mg/ml左右。用半制备高效液相色谱仪，每针0.3ml，以5mM碳酸氢铵/甲醇(20：60)为流动相，收集目标组分。将收集的组分以旋转蒸发除去有机溶剂，剩余物经冷冻干燥获得目标物固体75mg。
艾普拉唑羟基鎓内盐：1-[5-(1H-吡咯-1-基)-1H-苯并[d]咪唑-2-基]-4-羟基-2,3-二甲基吡啶-1-鎓内盐
制备方法：
破坏样品准备:将艾普拉唑5g置于200ml破坏液[0.02mol/L磷酸二氢钾—甲醇(55：45)，用1mol/L氢氧化钠溶液调pH至10.0]中，50-60℃加热条件下搅拌溶解，保温搅拌反应20h，30-50℃减压蒸馏除去溶剂，得粘稠物，真空干燥，得目标破坏样品。
纯化分离：将目标样品用DMSO溶解，并控制浓度在100mg/ml左右。 用半制备高效液相色谱仪，每针0.3ml，以5mM碳酸氢铵/甲醇(20：60)为流动相，收集目标组分。将收集的组分以旋转蒸发除去有机溶剂，剩余物经冷冻干燥获得目标物固体25mg。
艾普拉唑巯甲基鎓内盐：1-[5-(1H-吡咯-1-基)-1H-苯并[d]咪唑-2-基]-2-巯甲基-4-甲氧基-3-甲基吡啶-1-鎓内盐
制备方法：
破坏样品准备:将艾普拉唑5g置于200ml破坏液[0.02mol/L磷酸二氢钾—甲醇(55：45)，用1mol/L氢氧化钠溶液调pH至10.0]中，50-60℃加热条件下搅拌溶解，保温搅拌反应20h，30-50℃减压蒸馏除去溶剂，得粘稠物，真空干燥，得目标破坏样品。
纯化分离：将目标样品用DMSO溶解，并控制浓度在100mg/ml左右。用半制备高效液相色谱仪，每针0.3ml，以5mM碳酸氢铵/甲醇(20：60)为流动相，收集目标组分。将收集的组分以旋转蒸发除去有机溶剂，剩余物经冷冻干燥获得目标物固体75mg。
艾普拉唑二硫二聚体：2-(2-((((1-(5-(1H-吡咯-1-基)-1H-苯[d]咪唑-2-基)-4-甲氧基-3-甲基吡啶-1-鎓内盐-2-基)-甲基)-二硫基)-甲基)-4-甲氧基-3-甲基吡啶-1-鎓内盐)-5-(1H-吡咯-1-基)-1H-苯并[d]咪唑
制备方法：
破坏样品准备:将艾普拉唑5g置于200ml破坏液[0.02mol/L磷酸二氢钾—甲醇(55：45)，用1mol/L氢氧化钠溶液调pH至10.0]中，50-60℃加热条件下搅拌溶解，保温搅拌反应20h，30-50℃减压蒸馏除去溶剂，得粘稠物，真空干燥，得目标破坏样品。
纯化分离：将目标样品用DMSO溶解，并控制浓度在100mg/ml左右。用半制备高效液相色谱仪，每针0.3ml，以5mM碳酸氢铵/甲醇(20：60)为流动相，收集目标组分。将分离所得组分以旋转蒸发除去有机溶剂，剩余物经冷冻干燥获得目标物固体25mg。
艾普拉唑三硫二聚体：2-(2-((((1-(5-(1H-吡咯-1-基)-1H-苯[d]咪唑-2-基)-4-甲氧基-3-甲基吡啶-1-鎓内盐-2-基)-甲基)-三硫基)-甲基)-4-甲氧基-3-甲基吡啶-1-鎓内盐)-5-(1H-吡咯-1-基)-1H-苯并[d]咪唑
制备方法：
破坏样品准备:将艾普拉唑5g置于200ml破坏液[0.02mol/L磷酸二氢钾—甲醇(55：45)，用1mol/L氢氧化钠溶液调pH至10.0]中，50-60℃加热条件下搅拌溶解，保温搅拌反应20h，30-50℃减压蒸馏除去溶剂，得粘稠物，真空干燥，得目标破坏样品。
纯化分离：将目标样品用DMSO溶解，并控制浓度在100mg/ml左右。用半制备高效液相色谱仪，每针0.3ml，以5mM碳酸氢铵/甲醇(20：60)为流动相，收集目标组分。将分离所得组分以旋转蒸发除去有机溶剂，剩余物经冷冻干燥获得目标物固体25mg。
本发明提供的艾普拉唑粉针剂组合物质量更为稳定，能够更有效的控制胃粘膜出血症状，更具有临床使用意义。
具体实施方式
下面结合具体实施例对本发明进行进一步阐述。应当理解，本发明给出的实施例仅用于说明本发明，并不用于限制本发明的范围。
下述实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。
此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
材料来源：
艾普拉唑钠：丽珠制药厂
艾普拉唑砜：如本申请的说明书所述的方法制备
艾普拉唑硫醚：如本申请的说明书所述的方法制备
艾普拉唑羧基鎓内盐：如本申请的说明书所述的方法制备
艾普拉唑羟基鎓内盐：如本申请的说明书所述的方法制备
艾普拉唑巯甲基鎓内盐：如本申请的说明书所述的方法制备
艾普拉唑二硫二聚体：如本申请的说明书所述的方法制备
艾普拉唑三硫二聚体：如本申请的说明书所述的方法制备
以上药物纯度均为99.9％。
实施例1艾普拉唑钠粉针剂制备
(1)按处方量取料：艾普拉唑钠98.7mg、艾普拉唑砜0.2mg、艾普拉唑硫醚0.2mg、艾普拉唑羧基鎓内盐0.3mg、艾普拉唑羟基鎓内盐0.3mg、艾普拉唑巯甲基鎓内盐0.3mg，甘露醇300mg，EDTA-2Na 10mg。
(2)将甘露醇、依地酸二钠用注射用水溶解，用2mol/L氢氧化钠溶液调pH值至10.5，加入步骤(1)中称取的艾普拉唑钠(纯度99.9％)、艾普拉唑砜、艾普拉唑硫醚、艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐，充分溶解后再用2mol/L氢氧化钠溶液调pH值至11，最后补加4℃注射用水至1500mg；
(3)用孔径为0.2μm的滤膜过滤2次除菌、冻干，得到艾普拉唑钠冻干粉针剂，真空压塞，出箱，轧铝盖。
实施例2-8
实施例2-8的处方如表1所示，制备方法同实施例1。
表1实施例1-8的处方
Figure PCTCN2018111611-appb-000006
Figure PCTCN2018111611-appb-000007
实验例9
1、澄清度检测
取30mg实施例1中制备得到的艾普拉唑钠粉针剂与如下A、B、C三组中制备得到的艾普拉唑钠粉针剂，加注射用水至1g，敞开瓶口，分别于4℃、16℃、25℃、40℃放置，观察溶液颜色及溶液澄清度变化。另取30mg甘露醇和1mg EDTA2Na加注射用水适量溶解，继续加注射用水至1g，作为空白组，同时进行试验。结果如表2所示。
A组艾普拉唑组合物：按照CN102038648A实施例2的制备方法，得到艾普拉唑钠粉针剂(简称A)；
B组艾普拉唑组合物：按照CN 105769778A实施例1的制备方法，得到艾普拉唑钠粉针剂(简称B)；
C组艾普拉唑组合物：按照CN105055342A实施例2的制备方法，得到艾普拉唑钠粉针剂(简称C)。
表2
Figure PCTCN2018111611-appb-000008
Figure PCTCN2018111611-appb-000009
从以上结果可以看出，实施例1的粉针剂相比于组A、组B、组C的粉针剂，在4℃、16℃、25℃、40℃的条件下澄清度更优。
2、稳定性实验
将实施例1-8在温度60℃，相对湿度95％放置30天，取样，具体检测结果如下表3所示：
表3
Figure PCTCN2018111611-appb-000010
Figure PCTCN2018111611-appb-000011
结果如上表所示，在实施例1-4、6-8的艾普拉唑钠含量在温度60℃，相对湿度95％的高温高湿条件下艾普拉唑钠含量下降速度较慢，实施例1艾普拉唑钠含量下降速度最慢，效果最优。实施例5艾普拉唑钠含量下降较快。
3、药效学试验
(1)试验模型：
选择大鼠急性胃溃疡出血模型(模拟直接胃溃疡出血条件下注射用艾普拉唑钠组合物的止血作用)
(2)剂量选择：根据注射用艾普拉唑钠临床有效剂量和非临床研究资料，折算可知注射用艾普拉唑钠应在1～10mg/kg范围对实验室致大鼠胃溃疡模型有效。
(3)给药剂量：
啮齿动物研究中，给药剂量范围为0.5～10mg/kg(0.5,1,2,5,10mg/kg)，空白对照组静脉注射溶剂1ml/kg。
(4)建立大鼠急性胃溃疡出血模型
SD大鼠，体重180～250g，随机分5组，每组5只，用25g/L的戊巴比妥钠(1ml/kg)腹腔内麻醉后，固定于鼠板上，股静脉注射试验药物或者空白辅料。
给药一定时间后(参考值为30min，根据预实验调整)，暴露腹部，沿中线剖开腹部，再剖开其胃，用小号活检钳同时钳取胃窦和胃体粘膜各一块，形成急性出血病灶，建成溃疡出血模型，记录每只大鼠胃粘膜出血时间(GMBT)，计算平均值、中位数、标准差并进行统计学检验。
(5)试验分组：每组试验均设空白对照、实施例1、组A、组B、组C，其中组A、组B、组C的制备方法与澄清度检测试验中相同，试验结果如表4所示：
表4
Figure PCTCN2018111611-appb-000012
从上表所示，实施例1所的粉针剂针对大鼠急性胃溃疡出血能够更有效地止血，效果更好。
实施例10艾普拉唑钠粉针剂制备
(1)按处方量取料：艾普拉唑钠(纯度99.9％)98.7mg、艾普拉唑砜0.2mg、艾普拉唑硫醚0.2mg、艾普拉唑羧基鎓内盐0.3mg、艾普拉唑羟基鎓内盐0.3mg、艾普拉唑巯甲基鎓内盐0.3mg，艾普拉唑二硫二聚体0.2mg，艾普拉唑三硫二聚体0.2mg，甘露醇300mg，EDTA-2Na 10mg。
(2)将甘露醇、依地酸二钠用注射用水溶解，用2mol/L氢氧化钠溶液调pH值至10.5，加入步骤(1)中称取的艾普拉唑钠(纯度99.9％)、艾普拉唑砜、艾普拉唑硫醚、艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐、艾普拉唑二硫二聚体、艾普拉唑三硫二聚体，充分溶解 后再用2mol/L氢氧化钠溶液调pH值至11，最后补加4℃注射用水至1500mg；
(3)用孔径为0.2μm的滤膜过滤2次除菌、冻干，得到艾普拉唑钠冻干粉针剂，真空压塞，出箱，轧铝盖。
实施例11-19艾普拉唑钠粉针剂制备
实施例11-19的处方见表5，制备方法同实施例10。
表5实施例10-19的处方
Figure PCTCN2018111611-appb-000013
实验例20
1、澄清度检测
取30mg实施例10中制备得到的艾普拉唑钠粉针剂与如下A、B、C三组中制备得到的艾普拉唑钠粉针剂，加注射用水至1g，敞开瓶口，分别于4℃、16℃、25℃、40℃放置，观察溶液颜色及溶液澄清度变化。另取30mg甘露 醇和1mg EDTA2Na加注射用水适量溶解，继续加注射用水至1g，作为空白组，同时进行试验。结果如表6所示。
A组艾普拉唑组合物：按照CN102038648A实施例2的制备方法，得到艾普拉唑钠粉针剂(简称A)；
B组艾普拉唑组合物：按照CN 105769778A实施例1的制备方法，得到艾普拉唑钠粉针剂(简称B)；
C组艾普拉唑组合物：按照CN105055342A实施例1的制备方法，得到艾普拉唑钠粉针剂(简称C)。
表6
Figure PCTCN2018111611-appb-000014
Figure PCTCN2018111611-appb-000015
从以上结果可以看出，实施例10的粉针剂相比于组A、组B、组C，在4℃、16℃、25℃、40℃的条件下澄清度更优。
2、稳定性实验
将实施例10-19在温度60℃，相对湿度95％放置30天，取样，具体检测结果如下表7所示：
表7
Figure PCTCN2018111611-appb-000016
结果如上表所示，在实施例10-13、15-17、19的艾普拉唑钠含量在温度60℃，相对湿度95％的高温高湿条件下艾普拉唑钠含量下降速度较慢，实施例10艾普拉唑钠含量下降速度最慢，效果最优。实施例艾14、18艾普拉唑钠含量下降较快。
3、药效学试验
(1)试验模型：
选择大鼠急性胃溃疡出血模型(模拟直接胃溃疡出血条件下注射用艾普拉唑钠组合物的止血作用)
(2)剂量选择：根据注射用艾普拉唑钠临床有效剂量和非临床研究资料，折算可知注射用艾普拉唑钠应在1～10mg/kg范围对实验室致大鼠胃溃疡模型有效。
(3)给药剂量：
啮齿动物研究中，给药剂量范围为0.5～10mg/kg(0.5,1,2,5,10mg/kg)，空白对照组静脉注射溶剂1ml/kg。
(4)建立大鼠急性胃溃疡出血模型
SD大鼠，体重180～250g，随机分5组，每组5只，用25g/L的戊巴比妥钠(1ml/kg)腹腔内麻醉后，固定于鼠板上，股静脉注射试验药物或者空白辅料。
给药一定时间后(参考值为30min，根据预实验调整)，暴露腹部，沿中线剖开腹部，再剖开其胃，用小号活检钳同时钳取胃窦和胃体粘膜各一块，形成急性出血病灶，建成溃疡出血模型，记录每只大鼠胃粘膜出血时间(GMBT)，计算平均值、中位数、标准差并进行统计学检验。
(5)试验分组：每组试验均设空白对照、实施例10、组A、组B、组C，其中组A、组B、组C的制备方法与澄清度检测试验中相同，试验结果如表8所示：
表8
Figure PCTCN2018111611-appb-000017
Figure PCTCN2018111611-appb-000018
从上表所示，实施例10所述的组合物针对大鼠急性胃溃疡出血能够更有效地止血，效果更好。
应当理解的是，本文所述发明不限于特定的方法学、实验方案或试剂，因为这些是可以变化的。本文所提供的论述和实例仅是为了描述特定的实施方案呈现而非意在限制本发明的范围，本发明的范围仅受到权利要求的限度。

Claims (21)

  1. 一种药物组合物，所述药物组合物包含或由艾普拉唑或其盐和艾普拉唑的衍生物组成，其中，所述组合物中艾普拉唑衍生物的量不高于1.3wt％(≤1.3wt％)。
  2. 根据权利要求1所述的药物组合物，其中，所述组合物中艾普拉唑衍生物的量不高于1.2wt％，优选不高于1.1wt％，更优选不高于1.0wt％，进一步优选不高于0.9wt％，最优选不高于0.8wt％，例如不高于0.7wt％，不高于0.6wt％，不高于0.5wt％，不高于0.4wt％，不高于0.3wt％，或者不高于0.2wt％。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述艾普拉唑的盐为艾普拉唑钠；
    优选地，所述艾普拉唑或其盐的纯度不低于99.9％；
    优选地，所述艾普拉唑衍生物选自艾普拉唑砜、艾普拉唑硫醚和艾普拉唑的鎓内盐中的一种或多种；
    优选地，所述艾普拉唑的鎓内盐选自艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐中的一种或多种。
  4. 根据权利要求1至3中任一项所述的药物组合物，其特征在于，所述组合物中艾普拉唑的鎓内盐的量不高于0.9wt％，优选不高于0.8wt％，更优选不高于0.7wt％，进一步优选不高于0.6wt％，最优选不高于0.5wt％，例如不高于0.4wt％，不高于0.3wt％，或者不高于0.2wt％。
  5. 根据权利要求1至4中任一项所述的药物组合物，其特征在于，所述艾普拉唑衍生物为艾普拉唑砜、艾普拉唑硫醚、艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐和艾普拉唑巯甲基鎓内盐，优选地，所述组合物中所述艾普拉唑羧基鎓内盐的量不高于0.3wt％。
  6. 根据权利要求1至5中任一项所述的药物组合物，其特征在于，所述艾普拉唑砜与艾普拉唑硫醚的质量比为1：0.5-2，优选为1：0.5-1或1：1-2，更优选为1：1。
  7. 根据权利要求1至6中任一项所述的药物组合物，其特征在于，所述组合物包含或由以下重量份的物质组成：
    Figure PCTCN2018111611-appb-100001
    优选地，所述组合物包含或由以下重量份的物质组成：
    Figure PCTCN2018111611-appb-100002
  8. 一种粉针剂，所述粉针剂包含权利要求1至7中任一项所述的药物组合物和药学上可接受的载体；
    优选地，所述药学上可接受的载体为甘露醇和EDTA-2Na；
    优选地，所述甘露醇和EDTA-2Na的重量比为10-50：1，优选为30：1；
    优选地，所述粉针剂中艾普拉唑或其盐和艾普拉唑的衍生物的重量之和(即权利要求1至6中任一项所述的药物组合物)、甘露醇、EDTA-2Na三者的的重量比为1：3-5：0.1-0.3，优选为1：3：0.1。
  9. 根据权利要求8所述的粉针剂，其特征在于，所述粉针剂的pH值为10.5-11.5，优选为11。
  10. [根据细则26改正15.02.2019]
    一种制备权利要求8或9所述的粉针剂的方法，所述方法包括以下步骤：
    (1)按处方量称取艾普拉唑或其盐、艾普拉唑的衍生物、以及药用载体；
    (2)将药用载体用注射用水溶解，用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为10.5，加入处方量的艾普拉唑或其盐、艾普拉唑的衍生物，充分溶解后再用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为11，最后补加4℃注射用水至1500mg；
    (3)用孔径为0.2μm的滤膜过滤2次除菌、冻干，得到冻干粉针剂，真空压塞，出箱，轧铝盖。
    优选地，所述艾普拉唑衍生物的量不高于1.7wt％(≤1.7wt％)。
  11. [根据细则26改正15.02.2019]　
    一种药物组合物，所述药物组合物由艾普拉咬納和艾普拉咬的衍生物组成，其中，所述艾普拉咬衍生物为艾普拉咬多硫二聚体，和/或选自艾普拉唑砜、艾普拉唑硫醚和艾普拉唑的鎗内盐中的一种或多种；
  12. 根据权利要求11所述的药物组合物，其中，所述艾普拉唑衍生物的量不高于1.6wt％，优选不高于1.5wt％，更优选不高于1.4wt％，进一步优选不高于1.3wt％，例如不高于1.2wt％，不高于1.1wt％，不高于1.0wt％，不高于0.9wt％，不高于0.8wt％，不高于0.7wt％，不高于0.6wt％，不高于0.5wt％，不高于0.4wt％，或者不高于0.3wt％。
  13. 根据权利要求11或12所述的药物组合物，其特征在于，所述艾普拉唑钠的纯度不低于99.9％；
    优选地，所述艾普拉唑多硫二聚体为艾普拉唑二硫二聚体和/或艾普拉唑三硫二聚体。
    优选地，所述艾普拉唑的鎓内盐选自艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐中的一种或多种；
    优选地，所述艾普拉唑衍生物为艾普拉唑多硫二聚体、艾普拉唑砜、艾普拉唑硫醚、艾普拉唑羧基鎓内盐、艾普拉唑羟基鎓内盐、艾普拉唑巯甲基鎓内盐。
  14. 根据权利要求11至13中任一项所述的药物组合物，其特征在于，所述艾普拉唑的鎓内盐的量不高于0.9wt％，优选不高于0.8wt％，更优选不高于0.7wt％，优选不高于0.6wt％，优选不高于0.5wt％，优选不高于0.4wt％，优选不高于0.3wt％，优选不高于0.2wt％；
    优选地，所述组合物中所述艾普拉唑羧基鎓内盐的量不高于0.3wt％；
    优选地，所述艾普拉唑砜与艾普拉唑硫醚的质量比为1：0.5-2，优选为1：0.5-1或1：1-2，更优选为1：1；
    优选地，所述艾普拉唑多硫二聚体的量不高于0.4wt％，优选不高于0.3wt％。
  15. 根据权利要求11至14中任一项所述的药物组合物，其特征在于，所述艾普拉唑二聚体为艾普拉唑二硫二聚体和艾普拉唑三硫二聚体；
    优选地，所述艾普拉唑二硫二聚体和艾普拉唑三硫二聚体的重量比为1：0.5-2，优选为1：0.5-1或1：1-2，更优选为1：1。
  16. 根据权利要求11至15中任一项所述的药物组合物，其特征在于，所述药物组合物包含或由以下重量份的物质组成：
    Figure PCTCN2018111611-appb-100003
    优选地，所述组合物包含或由以下重量份的物质组成：
    Figure PCTCN2018111611-appb-100004
  17. 一种粉针剂，所述粉针剂包含权利要求11至16中任一项所述的药物组合物和药学上可接受的载体；
    优选地，所述药学上可接受的载体为甘露醇和EDTA-2Na；
    优选地，所述甘露醇和EDTA-2Na的重量比为10-50：1，优选为30：1；
    优选地，所述粉针剂中艾普拉唑或其盐和艾普拉唑的衍生物的重量之和(即权利要求1至6中任一项所述的药物组合物)、甘露醇、EDTA-2Na三者的的重量比为1：3-5：0.1-0.3，优选为1：3：0.1。
  18. 根据权利要求17所述的粉针剂，其特征在于，所述粉针剂的pH值为10.5-11.5，优选为11。
  19. 一种制备权利要求17中所述的粉针剂的方法，所述方法包括以下步骤：
    (1)按处方量称取艾普拉唑钠、艾普拉唑的衍生物、以及药学上可接受的载体；
    (2)将药学上可接受的载体用注射用水溶解，用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为10.5，加入处方量的艾普拉唑或其盐、艾普拉唑的衍生物，充分溶解后再用2mol/L氢氧化钠溶液调pH值至10.5-11.5，优选为11，最后补加4℃注射用水至1500mg；
    (3)用孔径为0.2μm的滤膜过滤2次除菌、冻干，得到冻干粉针剂，真空压塞，出箱，轧铝盖。
  20. 一种用于治疗消化道疾病的方法，该方法包括将治疗有效量的权利要求1至19中任一项所述的药物组合物施用于有需要的患者，其中，优选地，所述消化道疾病选自十二指肠溃疡、胃溃疡和反流性食管炎。
  21. [根据细则91更正 15.02.2019]　
    一种药物组合物，所述药物组合物由艾普拉咬納和艾普拉咬的衍生物组成，其中，所述艾普拉咬衍生物为艾普拉咬多硫二聚体，和/或选自艾普拉唑砜、艾普拉唑硫醚和艾普拉唑的鎗内盐中的一种或多种；
PCT/CN2018/111611 2018-06-22 2018-10-24 一种含艾普拉唑或其盐的药物组合物及其制备方法 WO2019242181A1 (zh)

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