WO2018108111A1 - 一种磺酰脲类药物的药物组合物及其制备方法 - Google Patents

一种磺酰脲类药物的药物组合物及其制备方法 Download PDF

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Publication number
WO2018108111A1
WO2018108111A1 PCT/CN2017/115993 CN2017115993W WO2018108111A1 WO 2018108111 A1 WO2018108111 A1 WO 2018108111A1 CN 2017115993 W CN2017115993 W CN 2017115993W WO 2018108111 A1 WO2018108111 A1 WO 2018108111A1
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Prior art keywords
cyclodextrin
concentration
pharmaceutical composition
sulfonylurea
additive
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PCT/CN2017/115993
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English (en)
French (fr)
Chinese (zh)
Inventor
钟武
高春生
龚伟
李松
陈虹宇
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Jiangsu Aosaikang Pharmaceutical Co Ltd
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Jiangsu Aosaikang Pharmaceutical Co Ltd
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Priority to CN201780075125.2A priority Critical patent/CN111093674B/zh
Priority to EP17881816.7A priority patent/EP3556371B1/en
Priority to US16/469,124 priority patent/US10966993B2/en
Priority to JP2019532920A priority patent/JP6888091B2/ja
Publication of WO2018108111A1 publication Critical patent/WO2018108111A1/zh
Anticipated expiration legal-status Critical
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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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K47/26—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • 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
    • A61K9/08—Solutions
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a pharmaceutical composition for injection of a sulfonylurea drug and a preparation method thereof.
  • Sulfonylureas are an insulin-promoting agent widely used in the clinical treatment of type 2 diabetes.
  • Sulfonylurea hypoglycemic drugs widely used clinically include Glibenclamide or Gliburide, Gliclazide, Glipizide, Gliquidone, Glebopol Glibornuride, Glimepiride, and the like.
  • Sulfonylurea hypoglycemic agents have been marketed as oral solid preparations.
  • glibenclamide (Formula 1, also known as glibenclamide, chemical name is 5-chloro-N-(4-[N-(cyclohexylcarbamoyl)-carbamoyl]phenethyl)
  • Intravenous administration of -2-methoxybenzamide can be used to prevent cerebral edema in stroke patients (Sheth et al, Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke, 2014, 45: 281-283).
  • Sulfonylureas act by acting on sulfonylurea receptors (SURs).
  • Sulfonylureas are weakly acidic and have poor water solubility, especially at neutral and acidic pH conditions.
  • the solubility of glibenclamide in water is less than 5 ⁇ g/ml.
  • Schrage et al. reported the preparation of 1 mg/ml glibenclamide injection using 0.1 M NaOH (Efffects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise. J Appl Physiol, 2006, 100:1506-1512).
  • the pH of the solution is as high as 11, exceeding the usual pH range of the injection (pH 4 to pH 9). If an acidic pH adjuster is used to lower the pH, there is a risk of drug precipitation.
  • the PVC infusion bag has obvious adsorption to the low concentration glibenclamide solution.
  • the present disclosure provides a novel sulfonylurea-containing drug containing an additive, a cyclodextrin, particularly a composition for injection of glibenclamide.
  • the inventors have surprisingly found that the combined use of cyclodextrins and auxiliaries, compared to the prior art, greatly improves the solubility and stability of poorly soluble sulfonylureas in water compared to cyclodextrin alone or in the use of additives alone. And can also significantly inhibit the adsorption of the drug glibenclamide in the PVC infusion bag.
  • One aspect of the present disclosure provides a pharmaceutical composition comprising a sulfonylurea, a cyclodextrin, and an additive.
  • the pharmaceutical composition of any of the present disclosure wherein the weight ratio of the additional agent to the cyclodextrin is from 1:0.1 to 4000, such as from 1:1 to 400, such as from 1:1 to 100, for example 1:1 to 50, for example, 1:5 to 50, for example, 1:50 to 400, for example, 1:1 to 10, for example, 1:1 to 8, for example, 1:1 to 6, for example, 1:1 to 4, for example, 1 : 6 ⁇ 8;
  • the additive is meglumine, the weight ratio of the additive to the cyclodextrin is 1:1 to 400;
  • the additive is sodium carbonate, the weight ratio of the additive to the cyclodextrin is 1:50-400;
  • the additive is sodium hydroxide, and the weight ratio of the additive to cyclodextrin is 1:50-4000;
  • the additional agent is sodium hydrogencarbonate
  • the weight ratio of the additive to the cyclodextrin is from 1:0.1 to 10.
  • the pharmaceutical composition according to any one of the present disclosure, wherein the weight ratio of the sulfonylurea drug to the additive is from 1:0.01 to 100, for example from 1:0.05 to 100, for example from 1:0.5 to 100.
  • 1:1 to 50 for example, 1:1 to 10.
  • the pharmaceutical composition of any of the present disclosure, wherein the weight ratio of the sulfonylurea drug to the cyclodextrin is from 1:0.2 to 1000, such as from 1:25 to 250, such as 1:0.5. 100, for example, 1:1 to 50, for example, 1:1 to 10.
  • the pharmaceutical composition of any one of the present disclosure has a weight ratio of the sulfonylurea drug, the additive, and the cyclodextrin of 1:0.05 to 100:0.2 to 1000, for example, 1:0.5 to 50. : 25 to 250, for example, 1:0.1 to 20:10 to 100.
  • the sulfonylurea is a compound that activates insulin secretion from pancreatic beta cells by transmitting a signal via a sulfonylurea receptor located in the cell membrane.
  • the pharmaceutical composition of any one of the present disclosure wherein the sulfonylurea is selected from the group consisting of glibenclamide, gliclazide, glipizide, gliclazone, and glyburide , glimepiride, gliclazide, hexyl urea acetate, gliclamide, glibenclamide, glibenclamide, glibenclamide, gliclamide, chlorpropamide, tolazamide, Tolbutamide, repaglinide and nateglinide;
  • the sulfonylurea drug is glibenclamide.
  • the pharmaceutical composition of any of the present disclosure wherein the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and a pharmaceutically acceptable cyclodextrin derivative;
  • the pharmaceutically acceptable cyclodextrin derivative is selected from the group consisting of dimethyl- ⁇ -cyclodextrin, 2-hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin. , 3-hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin and trimethyl- ⁇ -cyclodextrin;
  • the cyclodextrin is selected from ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, 2-hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, 3-hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin and trimethyl- ⁇ -cyclodextrin;
  • the cyclodextrin is 2-hydroxypropyl- ⁇ -cyclodextrin, 3-hydroxypropyl- ⁇ -cyclodextrin and/or sulfobutylether- ⁇ -cyclodextrin;
  • the cyclodextrin is 2-hydroxypropyl- ⁇ -cyclodextrin.
  • hydroxypropyl- ⁇ -cyclodextrin in the present disclosure means 2-hydroxypropyl- ⁇ -cyclodextrin unless otherwise specified.
  • the pharmaceutical composition of any of the present disclosure wherein the additional agent is selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, borax, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, Sodium dihydrogen citrate, sodium monohydrogen citrate, sodium citrate, meglumine, tris, monoethanolamine, diethanolamine, lysine, arginine and histidine.
  • the additional agent is selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, borax, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, Sodium dihydrogen citrate, sodium monohydrogen citrate, sodium citrate, meglumine, tris, monoethanolamine, diethanolamine, lysine, arginine and histidine.
  • the additive is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, borax and meglumine;
  • the additive is sodium carbonate, sodium hydrogencarbonate, sodium hydroxide and/or meglumine;
  • the additive is sodium carbonate
  • the additional agent is sodium hydrogencarbonate
  • the additional agent is sodium hydroxide
  • the additional agent is meglumine.
  • the pharmaceutical composition of any of the present disclosure further comprises glucose, sodium chloride, a lyophilized additive (eg, mannitol, lactose or gelatin), a pH adjusting agent (eg, hydrochloric acid), and/or water.
  • a lyophilized additive eg, mannitol, lactose or gelatin
  • a pH adjusting agent eg, hydrochloric acid
  • the lyophilized additive is a substance that prevents the active substance from being degraded or denatured during freezing or storage, for example, a substance that prevents the active substance from sublimating along with the water vapor and shaping the active ingredient of the active substance.
  • the pH adjusting agent refers to a substance that adjusts the pH of the solution to achieve a final desired pH range of the formulation, such as inorganic acids, inorganic bases, organic acids, organic bases, and buffer salts thereof, commonly used sodium hydroxide, Hydrochloric acid, glycine, hydrofluoric acid, triethylamine, acetic acid, phosphoric acid, malic acid, citric acid, acetate buffer salt, phosphate buffered salt, and the like, and aqueous solutions thereof.
  • inorganic acids inorganic bases, organic acids, organic bases, and buffer salts thereof, commonly used sodium hydroxide, Hydrochloric acid, glycine, hydrofluoric acid, triethylamine, acetic acid, phosphoric acid, malic acid, citric acid, acetate buffer salt, phosphate buffered salt, and the like, and aqueous solutions thereof.
  • the pharmaceutical composition according to any one of the present disclosure is an injection, preferably a solution injection (for example, an aqueous solution injection) or a powder injection.
  • the pharmaceutical composition of any one of the present disclosure is a solution-type injection (for example, an aqueous solution injection);
  • the cyclodextrin concentration in the pharmaceutical composition is from 0.5% to 40% (w/v), for example from 1% to 40% (w/v), for example from 2.5% to 40% (w/ v), for example, 5% to 20% (w/v), for example, 1% to 5% (w/v);
  • the concentration of the additive is from 0.01% to 20% (w/v), for example from 0.01% to 15% (w/v), for example from 0.01% to 10% (w/v), for example 0.01% ⁇ 5% (w/v), for example, 0.1% to 5% (w/v), for example, 0.03% to 5% (w/v), for example, 0.2% to 4% (w/v), for example 0.1% to 1% (w/v);
  • the cyclodextrin concentration in the pharmaceutical composition is from 0.5% to 40% (w/v), for example from 1% to 40% (w/v), for example from 2.5% to 40% (w/ v), for example, 5% to 20% (w/v), for example, 1% to 5% (w/v); wherein the concentration of the additive is 0.01% to 20% (w/v), for example, 0.01 % to 15% (w/v), for example, 0.01% to 10% (w/v), for example, 0.01% to 5% (w/v), for example, 0.1% to 5% (w/v), for example 0.2% to 4% (w/v), for example, 0.1% to 1% (w/v);
  • the concentration of the sulfonylurea drug in the pharmaceutical composition is less than or equal to a saturated concentration of the sulfonylurea drug in the solution-type injection; more preferably, wherein the sulfonylurea
  • concentration of the drug is 0.01 to 50 mg/ml, for example, 0.01 to 10 mg/ml, for example, 0.01 to 5 mg/ml, for example, 0.01 to 2.5 mg/ml, for example, 0.01 to 2 mg/ml.
  • the saturated concentration refers to the concentration (unit: mg/ml) of the sulfonylurea when it is saturated in the solution.
  • the pharmaceutical composition of any of the present disclosure has one or more of the following characteristics:
  • the concentration of the additive is 0.01 to 0.5% (w/v)
  • the concentration of the cyclodextrin is 0.5 to 10% (w/v)
  • the concentration of the sulfonylurea is less than or equal to the concentration a saturated concentration of the sulfonylurea drug in the solution-type injection (preferably, the concentration of the sulfonylurea drug is 0.01 to 3 mg/ml, for example, 0.1 to 3 mg/ml, for example, 1 to 3 mg/ml);
  • the concentration of the additive is 0.1 to 0.5% (w/v)
  • the concentration of the cyclodextrin is 0.5 to 10% (w/v)
  • the concentration of the sulfonylurea is less than or equal to the concentration a saturated concentration of the sulfonylurea drug in the solution-type injection (preferably, the concentration of the sulfonylurea drug is 0.01 to 3 mg/ml, for example, 0.1 to 3 mg/ml, for example, 1 to 3 mg/ml);
  • the concentration of the additive is 0.1 to 0.3% (w/v)
  • the concentration of the cyclodextrin is 1 to 5% (w/v)
  • the concentration of the sulfonylurea is less than or equal to the concentration a saturated concentration of the sulfonylurea drug in the solution-type injection (preferably, the concentration of the sulfonylurea drug is 0.01 to 2.5 mg/ml, for example, 0.1 to 2.5 mg/ml, for example, 1 to 2.5 mg/ml) ;
  • the concentration of the additive is 1 to 10% (w/v)
  • the concentration of the cyclodextrin is 1 to 30% (w/v)
  • the concentration of the sulfonylurea is less than or equal to the concentration a saturated concentration of the sulfonylurea drug in the solution-type injection (preferably, the concentration of the sulfonylurea drug is 0.01 to 50 mg/ml, for example, 0.1 to 50 mg/ml, for example, 10 to 50 mg/ml);
  • the concentration of the additive is 4 to 6% (w/v)
  • the concentration of the cyclodextrin is 5 to 20% (w/v)
  • the concentration of the sulfonylurea is less than or equal to the concentration
  • the saturated concentration of the sulfonylurea drug in the solution-type injection preferably, the concentration of the sulfonylurea drug is 0.01 to 50 mg/ml, for example, 0.1 to 50 mg/ml, for example, 25 to 50 mg/ml).
  • any of the compositions of the present disclosure are obtained by drying (e.g., freeze drying) any of the solution-type injections of the present disclosure.
  • the pharmaceutical composition of any of the present disclosure has a pH of from 5 to 11, preferably from 6 to 10, more preferably from 7 to 9, more preferably from 7 to 8.
  • a further aspect of the present disclosure provides a method of producing a pharmaceutical composition according to any of the present disclosure, comprising the steps of:
  • step b) adding a sulfonylurea to the product of step a), stirring and mixing;
  • step b) optionally adding a lyophilized additive to the product of step b) to adjust the pH;
  • step d) the product of step d) is dried to provide the desired composition
  • the drying is freeze drying
  • the solvent is water, physiological saline or a glucose solution.
  • a further aspect of the present disclosure provides the pharmaceutical composition according to any one of the present disclosure for use in the preparation of a prophylactic and/or therapeutic acute stroke, traumatic brain injury, cerebral edema, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular rhythm Use in drugs for disorders, type 1 diabetes, or type 2 diabetes.
  • Yet another aspect of the present disclosure provides for preventing and/or treating acute stroke, neurological deficit, traumatic brain injury, cerebral edema, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, type I diabetes or type II
  • a method of medicament for diabetes comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a pharmaceutical composition of any of the present disclosure.
  • the method of administering a pharmaceutical composition to a subject in need thereof comprises oral or injection, such as injection.
  • the term "therapeutically effective amount” refers to an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease and its complications.
  • An amount suitable for accomplishing this purpose is defined as a “therapeutically effective amount.”
  • the effective amount for each purpose depends on the severity of the disease or injury as well as the weight and general health of the subject. It will be appreciated that determining the appropriate dosage can be accomplished using routine experimentation by establishing a matrix of values and testing the different points of the matrix, all within the ordinary skill of a trained physician or veterinarian.
  • a further aspect of the present disclosure provides the pharmaceutical composition according to any one of the present disclosure for preventing and/or treating acute stroke, neurological deficit, traumatic brain injury, cerebral edema, spinal cord injury, myocardial infarction, shock, organ ischemia , ventricular arrhythmia, type 1 diabetes or type 2 diabetes.
  • the method of preparing a pharmaceutical composition of any of the present disclosure comprises the steps of:
  • step b) adding the active ingredient sulfonylurea to the product of step a) and stirring;
  • step c) performing sterile filtration or autoclaving on the solution obtained in step c);
  • step d) Dispense the product obtained in step d) into a vial or ampoule and seal/cap.
  • the method of preparing a pharmaceutical composition of any of the present disclosure comprises the steps of:
  • step b) adding the active ingredient sulfonylurea to the product of step a) and stirring;
  • step b) adding a lyophilized additive to the product obtained in step b) to adjust the pH;
  • step d) dispensing the product obtained in step c) in a vial or ampoule
  • step d) The solution obtained in step d) is removed by freeze drying to remove moisture and then sealed/capped.
  • the method of preparing a pharmaceutical composition of any of the present disclosure comprises the steps of:
  • an additional agent for example selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, borax, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen citrate, sodium monohydrogen citrate, citric acid a cyclodextrin (for example, selected from the group consisting of sodium, meglumine, tris, monoethanolamine, diethanolamine, lysine, arginine, histidine), such as a-cyclodextrin One or more of refined, ⁇ -cyclodextrin, ⁇ -cyclodextrin, and a pharmaceutically acceptable cyclodextrin derivative, stirred and dissolved in water;
  • an additional agent for example selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, borax, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen citrate, sodium monohydrogen citrate, citric acid
  • sulfonylurea for example, selected from glibenclamide, gliclazide, glipizide, gliclazone, glibenclamide, glimepiride, glibenclamide, Hexylacetate, gliclamide, glibenclamide, glibenclamide, glizaxobin, gliclamide, chlorpropamide, tolazamide, tolbutamide, repaglinide, that One or more of the glinides), dissolved and dissolved, that is.
  • active ingredient sulfonylurea for example, selected from glibenclamide, gliclazide, glipizide, gliclazone, glibenclamide, glimepiride, glibenclamide, Hexylacetate, gliclamide, glibenclamide, glibenclamide, glizaxobin, gliclamide, chlorpropamide, tolazamide, tolbutamide, repaglinide,
  • additive refers to a substance that is capable of interacting with an active ingredient to increase the cyclodextrin inclusion efficiency and further improve the solubility of the drug.
  • the additive does not include a cyclodextrin.
  • the term "pharmaceutical composition” or “composition” refers to one or more active ingredients, and one or more inert ingredients, as well as any product, which is produced directly or indirectly by: Combination, complexation or aggregation of any two or more components, or dissociation of one or more components, or other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition prepared by mixing a compound of the present disclosure with a pharmaceutically acceptable adjuvant.
  • the use of the composition in the meaning commonly used in the art refers to a mixture of two or more substances. Accordingly, in the composition, in addition to the above-mentioned active agents and additives, other excipients, buffers or pH adjusters, osmotic pressure adjusting agents commonly used in the art may be included as long as they are used according to the present invention. , preservatives, antioxidants, etc.
  • the pharmaceutical composition may be formulated into any dosage form, such as an oral or injectable agent, with a pharmaceutically acceptable excipient, such as a tablet, a capsule, a granule, an oral solution, an injection reagent.
  • a pharmaceutically acceptable excipient such as a tablet, a capsule, a granule, an oral solution, an injection reagent.
  • it may be a water injection or a lyophilized powder (needle) agent.
  • the injection reagent may be any preparation that can be injected into the body of the patient, and is not limited by the route of administration, the site of administration, the mode of administration, etc., but is particularly considered to be intravenous, intra-arterial, Formulation for intravesical administration.
  • the composition may be prepared by dissolving the composition of the present invention in physiological saline solution, but it may also be dissolved in water for injection or glucose injection to prepare an injection.
  • physiological saline, water for injection, and glucose injection are in accordance with Chinese Pharmacopoeia regulations.
  • the concentration "%” or “% (w/v)" of the additive and the cyclodextrin means a mass volume concentration, indicating the number of grams of solute contained per 100 ml of the solution, for example, 20% (w/v) 20 g of solute is contained per 100 ml of solution.
  • Figures 1 to 7 show the solubility curves of glibenclamide in different solutions at 25 ° C, where:
  • Figure 1 is a solubility curve of glibenclamide in a solution containing only meglumine
  • Figure 2 is a solubility curve of glibenclamide in a solution containing only 2-hydroxypropyl- ⁇ -cyclodextrin;
  • Figure 3 is a solubility curve of glibenclamide in a solution containing 2-hydroxypropyl- ⁇ -cyclodextrin and meglumine (methanolamine concentration: 0.1%);
  • Figure 4 is a solubility curve of glibenclamide in a solution containing 2-hydroxypropyl- ⁇ -cyclodextrin and meglumine (methanolamine concentration of 5%);
  • Figure 5 is a solubility curve of glibenclamide in a solution containing 2-hydroxypropyl- ⁇ -cyclodextrin and sodium carbonate (sodium carbonate concentration of 0.1%);
  • Figure 6 is a solubility curve of glibenclamide in a solution containing 2-hydroxypropyl- ⁇ -cyclodextrin and sodium hydrogencarbonate (sodium bicarbonate concentration: 4%);
  • Figure 7 is a solubility curve of glibenclamide in a solution containing 2-hydroxypropyl- ⁇ -cyclodextrin and sodium hydroxide (sodium hydroxide concentration: 0.01%);
  • MEG meglumine
  • the additional agent is the meglumine, sodium carbonate, sodium hydroxide or sodium hydrogencarbonate described in the formulation.
  • Example 1 Preparation of glibenclamide injection composition
  • Preparation method according to the prescription, the additive and the cyclodextrin are dissolved in 50-70 ml of water, and then the glibenclamide powder is added, stirred and dissolved to obtain a solution.
  • the pH of the above solution was adjusted to 7.0 with 0.1 M hydrochloric acid, and made up to 100 ml with water to obtain a glibenclamide composition for injection.
  • Example 2 the composition was prepared in a manner similar to that of Example 1, except that Example 2 adjusted the pH of the formulated solution to 8.0.
  • Example 3 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 3 adjusted the pH of the formulated solution to 7.5.
  • Example 4 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 4 adjusted the pH of the formulated solution to 9.0.
  • Example 5 the composition was prepared in a manner similar to that of Example 1.
  • Example 6 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 6 adjusted the pH of the formulated solution to 6.5.
  • Example 7 Preparation of glibenclamide injection composition
  • Example 7 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 7 adjusted the pH of the formulated solution to 6.0.
  • Example 8 Preparation of glibenclamide injection composition
  • Example 8 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 8 adjusted the pH of the formulated solution to 7.5.
  • Example 9 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 9 adjusted the pH of the formulated solution to 7.5.
  • the preparation method is as follows: according to the prescription, the additive and the cyclodextrin are dissolved in 50-70 ml of water, and then the glibenclamide powder is added and stirred to dissolve to obtain a first solution.
  • the lyophilized additive mannitol was added to the first solution, and dissolved by stirring to obtain a second solution.
  • the pH of the second solution was adjusted to 7.5 with 0.1 M hydrochloric acid to a volume of 100 ml to obtain a third solution.
  • the third solution was dispensed into a vial and lyophilized according to the freeze-drying procedure of Table 1, to obtain a product.
  • Example 11 Preparation of glibenclamide injection composition
  • Example 11 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 11 adjusted the pH of the formulated solution to 8.0.
  • Example 12 Preparation of glibenclamide injection composition
  • Example 12 the composition was prepared in a manner similar to that of Example 1. They differ in that Example 12 adjusted the pH of the formulated solution to 8.0.
  • Example 13 Preparation of glibenclamide injection composition (lyophilized powder injection)
  • Example 11 The solution prepared in Example 11 was dispensed into a vial, 1 ml per vial, and the solution in the vial was freeze-dried according to the freeze-drying procedure of Table 1 in Example 10 to obtain a lyophilized powder injection.
  • Example 14 Preparation of glibenclamide injection composition (lyophilized powder needle)
  • Preparation method firstly dissolving sodium hydroxide and hydroxypropyl- ⁇ -cyclodextrin in 80 ml volume of water, adding glibenclamide powder, stirring and dissolving to obtain a first solution.
  • a solution of the glycine solution was added to the first solution to adjust the pH of the solution to 8.8, and the volume was adjusted to 100 ml to obtain a second solution.
  • the second solution was dispensed into a vial, 1 ml per vial, and the second solution in the vial was freeze-dried to obtain a lyophilized powder.
  • the lyophilized powder needle is a white-like loose mass.
  • This test investigated the stability of the composition of glibenclamide injection combined with glucose injection and physiological saline.
  • Test method 1 ml of the composition prepared in Example 2 was added to 100 ml of glucose injection and physiological saline injection, respectively, and the appearance, pH value and related substances of the injection were observed at 0h, 24h, 48h, 72h, 96h. .
  • Impurity I 4-[2-(5-chloro-2-methoxybenzamide)-ethyl]-benzenesulfonamide
  • impurity II 4-[2-(5 -Chloro-2-methoxybenzamide)-ethyl]-benzenesulfonylamino-formic acid ethyl ester
  • Test method Take 10 tubes and number them from 1 to 10. 1 ml of a pH 7.4 phosphate buffer was added to each of 10 tubes. Then, 1 ml of the glibenclamide injection composition prepared in Example 2 was added to the No. 1 test tube, and the solution was mixed by shaking the test tube, and 1 ml of the solution was taken from the No. 1 test tube to the No. 2 test tube. The above operation was repeated until the No. 10 tube, and the clarity of the solution in the 10 tubes was observed by standing.
  • glibenclamide powder Adding excess glibenclamide powder to an aqueous solution containing different ratios of additives (eg meglumine, sodium carbonate, sodium bicarbonate or sodium hydroxide) and cyclodextrin (hydroxypropyl- ⁇ -cyclodextrin)
  • additives eg meglumine, sodium carbonate, sodium bicarbonate or sodium hydroxide
  • cyclodextrin hydroxypropyl- ⁇ -cyclodextrin
  • Figure 1 is a solubility curve of glibenclamide in a solution containing only meglumine
  • Table 4 is the corresponding solubility data.
  • the solubility of glibenclamide in water increases with increasing concentration of meglumine: meglumine concentration in the range of 0.1% (w/v) to 10% (w/v), glibenclamide
  • the solubility in water at 25 ° C was 0.96 mg / ml to 19.05 mg / ml, respectively.
  • Figure 2 is a solubility curve of glibenclamide in a solution containing only 2-hydroxypropyl- ⁇ -cyclodextrin
  • Table 5 is the corresponding solubility data. It can be seen from Figure 2 that the solubility of glibenclamide in water increases linearly with increasing cyclodextrin concentration: cyclodextrin concentration ranges from 0.5% (w/v) to 40% (w/v), glibenclamide
  • the solubility of urea in water at 25 ° C is from 0.0013 mg / ml to 0.12 mg / ml, respectively.
  • Figure 3 is a solubility curve of glibenclamide in a solution containing both 2-hydroxypropyl- ⁇ -cyclodextrin and meglumine (methanolamine concentration is fixed at 0.1%), and Table 6 shows the corresponding solubility data. It can be seen from Figure 3 that the combined use of cyclodextrin and meglumine can significantly increase the solubility of glibenclamide in water. Solubility of glibenclamide in water at 25 ° C when the meglumine concentration is 0.1% (w/v) and the cyclodextrin concentration is in the range of 0.5% (w/v) to 5% (w/v) It is from 1.25 mg/ml to 2.17 mg/ml. The cyclodextrin concentration continued to increase from 5% (w/v) to 40% (w/v) and the glibenclamide solubility remained at about 2.17 mg/ml.
  • Figure 4 is a solubility curve of glibenclamide in a solution containing both 2-hydroxypropyl- ⁇ -cyclodextrin and meglumine (methanolamine concentration is fixed at 5%), and Table 7 shows the corresponding solubility data. It can be seen from Figure 4 that the combined use of cyclodextrin and meglumine can significantly increase the solubility of glibenclamide in water. Solubility of glibenclamide in water at 25 ° C when the meglumine concentration is 5% (w/v) and the cyclodextrin concentration is in the range of 5% (w/v) to 30% (w/v) It is from 25.23 mg/ml to 49.37 mg/ml. The cyclodextrin concentration continued to increase from 30% (w/v) to 40% (w/v) and the glibenclamide solubility remained at about 49.37 mg/ml.
  • Figure 5 is a solubility curve of glibenclamide in a solution containing both 2-hydroxypropyl- ⁇ -cyclodextrin and sodium carbonate (sodium carbonate concentration fixed at 0.1%), and Table 8 shows the corresponding solubility data. It can be seen from Figure 5 that the combined use of cyclodextrin and sodium carbonate can significantly increase the solubility of glibenclamide in water. When the sodium carbonate concentration is 0.1% (w/v) and the cyclodextrin concentration is in the range of 5% (w/v) to 20% (w/v), the solubility of glibenclamide in water at 25 ° C is 2.35 mg/ml to 10.63 mg/ml. The cyclodextrin concentration continued to increase from 20% (w/v) to 40% (w/v) and the glibenclamide solubility remained at about 10.63 mg/ml.
  • Figure 6 is a solubility curve of glibenclamide in a solution containing both 2-hydroxypropyl- ⁇ -cyclodextrin and sodium hydrogencarbonate (sodium bicarbonate concentration fixed at 4%), and Table 9 shows the corresponding solubility data. It can be seen from Figure 6 that the combined use of cyclodextrin and sodium bicarbonate can significantly increase the solubility of glibenclamide in water. Solubility of glibenclamide in water at 25 ° C when sodium bicarbonate concentration is 4% (w/v) and cyclodextrin concentration is in the range of 0.5% (w/v) to 10% (w/v) It is from 0.32 mg/ml to 1.69 mg/ml. The cyclodextrin concentration continued to increase from 10% (w/v) to 40% (w/v) and the glibenclamide solubility remained at about 1.69 mg/ml.
  • Figure 7 is a solubility curve of glibenclamide in a solution containing both 2-hydroxypropyl- ⁇ -cyclodextrin and sodium hydroxide (sodium hydroxide concentration fixed at 0.01%), and Table 10 shows the corresponding solubility data. It can be seen from Figure 7 that the combined use of cyclodextrin and sodium hydroxide can significantly increase the solubility of glibenclamide in water. Solubility of glibenclamide in water at 25 ° C when sodium hydroxide concentration is 0.01% (w/v) and cyclodextrin concentration is in the range of 0.5% (w/v) to 10% (w/v) It is 0.14 mg/ml to 1.26 mg/ml, respectively. The cyclodextrin concentration continued to increase from 10% (w/v) to 40% (w/v) and the glibenclamide solubility remained at about 1.26 mg/ml.
  • a pharmaceutical composition was prepared according to the formulation of Table 11, wherein the concentration of glibenclamide was fixed at 1 mg/ml.
  • the solutions prepared in various places were divided into three equal portions, and the pH of the three portions of the solution was adjusted to 7.0, 7.5 and 8.0 with 0.1 M hydrochloric acid, respectively, to obtain glibenclamide pharmaceutical composition solutions of different pH values.
  • the solutions of the glibenclamide pharmaceutical composition solutions of the above different pH values were placed at 25 ° C, and the precipitation of the precipitate in the solution was observed.
  • the test results are shown in Table 11.
  • the pharmaceutical composition solution containing only 0.1% (w/v) meglumine was adjusted to pH 7.5 with 0.1 M hydrochloric acid, the drug precipitate was precipitated; the composition solution adjusted to pH 8.0 was allowed to stand for 24 hours. After the precipitation of a white precipitate.
  • a solution containing 0.1% (w/v) meglumine and different concentrations of cyclodextrin was adjusted to pH 8.0, and no precipitate was observed for 96 hours.
  • composition solution containing 0.1% (w/v) meglumine + 1.25% cyclodextrin was adjusted to pH 7.5, and after leaving for 96 hours, a small amount of drug crystals were precipitated; 0.1% (w/v) meglumine + 2.50% was contained.
  • the cyclodextrin composition solution was adjusted to pH 7.0, and a very small amount of drug crystals were precipitated after leaving for 96 hours; the composition solution containing 0.1% (w/v) meglumine + 5.0% cyclodextrin was adjusted to pH 7.0, and left for 96 hours. No crystal precipitation occurred after that.
  • the above results indicate that the cyclodextrin in the composition can function to inhibit the precipitation of glibenclamide and stabilize the solution of the pharmaceutical composition.
  • Test Example 5 Infusion bag adsorption test
  • compositions of Examples 2, 8 and 9 were each diluted with 0.9% sodium chloride solution (normal saline) to a glibenclamide concentration of 5 ⁇ g/ml, and the resulting solutions were numbered 5a, 5b, 5c.
  • the corresponding injection composition containing no hydroxypropyl- ⁇ -cyclodextrin was prepared and diluted with 0.9% sodium chloride solution to a concentration of glibenclamide of 5 ⁇ g/ml, number 5a', 5b. ', 5c'.
  • HPLC method Alent Eclipse XDB-C18 column (5 ⁇ m, 4.6 ⁇ 250 mm
  • the test results are shown in Table 12: Three kinds of low-concentration drug solutions (5a', 5b', 5c') containing no hydroxypropyl- ⁇ -cyclodextrin have obvious drug adsorption in the PVC infusion bag, adsorption The rate was above 10% and the drug concentration was significantly reduced. The corresponding low-concentration drug solutions (5a, 5b, and 5c) containing hydroxypropyl- ⁇ -cyclodextrin did not undergo significant drug adsorption in the PVC infusion bag, and the adsorption rates were all less than 0.1%. The above results indicate that the cyclodextrin in the composition can significantly inhibit the adsorption of the drug by the PVC infusion bag.
  • the additive and the cyclodextrin were dissolved in 50 to 70 ml of water, and then glibenclamide was added thereto, and the mixture was stirred and dissolved to a volume of 100 ml to obtain a pharmaceutical composition (groups 5d to 5i).
  • composition solutions of Groups 5e and 5f were adjusted to pH 8.0 to give pharmaceutical compositions (Groups 5j and 5k) as shown in Table 15.
  • the pharmaceutical compositions of the 5d to 5k groups were diluted 500 times with a 0.9% sodium chloride solution to give a glibenclamide concentration of 2 ⁇ g/ml.
  • the diluted drug solution was divided into two portions, one was poured into a PVC infusion bag, placed at 25 ° C, shaken at 100 rpm; the other was placed in a measuring flask at 25 ° C, shaken at 100 rpm (as a control).
  • the adsorption rate of the drug was determined by the method of 5.1.
  • Tables 13-15 indicate that the pharmaceutical compositions containing the additive and cyclodextrin of the present disclosure can significantly inhibit the adsorption of the drug by the PVC infusion bag as compared to the pharmaceutical composition containing no cyclodextrin. And hydroxypropyl- ⁇ -cyclodextrin inhibited the adsorption better than sulfobutylether- ⁇ -cyclodextrin.
  • Test Example 6 Comparison of buffering ability of cyclodextrin to prevent drug precipitation
  • the pharmaceutical composition (groups 5g, 5h, and 5i) was prepared according to the method of Test Example 5, and 0.1 M hydrochloric acid was added dropwise until precipitation was observed.
  • the prescription and experimental results are shown in Table 16.
  • the initial pH of the above three groups of the pharmaceutical composition solutions was about 10 to 11.
  • the pH of the solutions of the groups 5g, 5h and 5i were 8.33, 7.25 and 6.27, respectively.
  • the pharmaceutical composition of the present disclosure has a buffering ability to prevent precipitation of glibenclamide, and the buffering ability of hydroxypropyl- ⁇ -cyclodextrin to prevent precipitation of glibenclamide is slightly better than that of sulfobutylether- ⁇ -cyclodextrin.
  • Test Example 7 Efficacy study in rat brain MCAO model
  • mice Male Sprague-Dawley (SD) rats, clean grade, weighing 200-230 g. The temperature in the animal breeding room is maintained at 20 to 24 ° C, and the humidity is maintained at 30 to 70%; the lighting is turned on for 12 hours/lights for 12 hours per day (06:00 AM on, 18:00 PM off). During the experiment, the animals were kept in single cages, free to drink water, and fed ad libitum. 7.3. Test drug
  • the GB group was prepared by dissolving glibenclamide with a small amount of DMSO (dimethyl sulfoxide), diluting the solution with physiological saline to a DMSO concentration of 5 vol%, and adjusting the pH of the solution to 8 to 8.5 with NaOH.
  • DMSO dimethyl sulfoxide
  • a solution having a glibenclamide concentration of 200 ⁇ g/ml and 10 ⁇ g/ml was separately prepared by the above method.
  • the preparation method of the H-GB group was as follows: the lyophilized product of Example 13 was added, and an appropriate amount of physiological saline was added to prepare a solution having a glibenclamide concentration of 200 ⁇ g/ml and 10 ⁇ g/ml, respectively.
  • the rats began to experiment with a week or so. On the day of the experiment, the surgical instrument was autoclaved. Animals were anesthetized by intraperitoneal injection of chloral hydrate (330 mg/kg) into rats.
  • the common carotid artery and external carotid artery of the rat were isolated, inserted into the internal carotid artery through the external carotid artery opening, and inserted into the internal carotid artery through the external carotid artery opening, and inserted about 18 mm until the head of the sacral line reached the beginning of the middle cerebral artery, and ligated.
  • the wire is fixed.
  • the reperfusion step was performed, that is, the sacral line was removed, and the intersection of the external carotid artery and the common carotid artery was stopped at a certain resistance.
  • the blood flow of the brain was monitored by laser Doppler (model moorVMS-LDF2, manufacturer moor). The ratio of blood flow to blood flow before the procedure was less than 30%. Modeling.
  • Postoperative care Immediately after the operation, the rats were placed on an insulating blanket, subcutaneously injected with meloxicam (2 mg/kg) for analgesia, and intraperitoneal injection of gentamicin (6 mg/kg).
  • Control group 8 Ip+sc 4h+44h after ischemia GB 8 10 ⁇ g/ml+200ng/h Ip+sc 4h+44h after ischemia H-GB 8 10 ⁇ g/ml+200ng/h Ip+sc 4h+44h after ischemia
  • glibenclamide 10 ⁇ g/kg administered volume 1 ml/kg, drug concentration 10 ⁇ g/ml.
  • physiological saline was used instead of the test drug; a volume of 1 ml/kg was intraperitoneally administered, and a subcutaneous administration volume of 1 ⁇ l/h (100 ⁇ l/osmotic pump/mouse) was continued.
  • the rats were intraperitoneally injected at 4 h after ischemia, and the osmotic pump was implanted under the skin of the animals, and subcutaneous administration was continued for 44 hours.
  • the osmotic pump is implanted by first cutting a small opening in the skin between the shoulder blades, and then separating the skin and the subcutaneous connective tissue with a hemostatic forceps to form a small bag, inserting the osmotic pressure pump, the flow regulator facing in, and the skin opening can be Stitch or clip with a clip.
  • Neurobehavioral scores were performed at 24h and 48h ischemia. Longa scoring method, neurological examination is divided into 5 grades, 0 points: normal, no neurological deficit; 1 point: left front paw can not fully extend, mild neurological deficit; 2 points: when walking, rat to the left ( ⁇ side) circle, moderate neurological deficit; 3 points: When walking, the rat body is dumped to the left side ( ⁇ side). Severe neurological deficits; 4 points: unable to self-issue, loss of consciousness.
  • the effect of drugs on neurobehavioral scores in MCAO rats is shown in Table 18.
  • the results in Table 18 showed that compared with the control group, the neurobehavioral scores of the GB group and the H-GB group decreased at 24h and 48h, indicating that both the GB group and the H-GB group can improve the neurobehavioral damage of MCAO rats. .
  • the score of the H-GB group was significantly decreased, indicating that the pharmaceutical composition for injection of the present disclosure can significantly improve the neurological function score of rats with cerebral infarction.
  • the infarct size was analyzed after photographing.
  • the infarct area/total brain area is the ratio of infarct size, and the degree of swelling is the ratio of the infarcted half-brain area to the uninfarcted half-brain area.
  • the effects of drugs on cerebral infarct size and brain swelling in MCAO rats are shown in Table 19.
  • the results of this test example show that the pharmaceutical composition of the present disclosure does not have any negative effect on the efficacy of the sulfonylurea drug in the rat model of acute ischemia-reperfusion injury of the middle cerebral artery; the sulfonylurea drug is not passed through the blood.
  • the brain barrier has a negative impact.
  • the lyophilized product in a vial of Example 14 was dissolved in 1 ml of water for injection (corresponding to water prescribed under the Chinese Pharmacopoeia for water for injection), and the pH of the solution after reconstitution was determined to be 8.8.
  • Test Example 8 shows that the pH of the solution obtained after reconstitution of the lyophilized product is the same as the pH value of the solution before lyophilization. Glycine was used as the pH adjuster in Example 14, and the pH of the obtained drug injection was within the usual pH range (4 to 9).
  • the composition for injection of a sulfonylurea drug provided by the present disclosure, in combination with a cyclodextrin and an additive, greatly improves the sulfonylurea drug than the use of a cyclodextrin alone or an additive alone. Solubility and stability in water, and can significantly inhibit the adsorption of drugs in PVC infusion bags.
  • the pharmaceutical composition has the advantages of simple prescription, low cost, easy operation, stable and controllable quality, good reproducibility and the like.

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CN108210501A (zh) 2018-06-29
CN108210501B (zh) 2019-03-08
EP3556371A4 (en) 2020-08-12
EP3556371A1 (en) 2019-10-23
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