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WO2025113679A1 - Composition pharmaceutique, préparation et préparation de poudre lyophilisée de métolazone, leurs procédés de préparation et leurs utilisations - Google Patents

Composition pharmaceutique, préparation et préparation de poudre lyophilisée de métolazone, leurs procédés de préparation et leurs utilisations Download PDF

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WO2025113679A1
WO2025113679A1 PCT/CN2024/135814 CN2024135814W WO2025113679A1 WO 2025113679 A1 WO2025113679 A1 WO 2025113679A1 CN 2024135814 W CN2024135814 W CN 2024135814W WO 2025113679 A1 WO2025113679 A1 WO 2025113679A1
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metolazone
water
preparation
solvent
solution
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Chinese (zh)
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王树宽
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Xi 'an Taike Yikang Biotechnology Co Ltd
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Xi 'an Taike Yikang Biotechnology Co Ltd
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to a pharmaceutical composition, a preparation, a metolazone lyophilized powder preparation, and a preparation method and use thereof.
  • Metolazone (CAS: 17560-51-9) is a quinazoline diuretic used to treat edema caused by congestive heart failure and also used to treat hypertension. Metolazone has a strong diuretic effect and the effect is stable and long-lasting.
  • Metolazone mainly acts on the distal convoluted tubule to inhibit the reabsorption of sodium ions and increase urine volume, which is different from loop diuretics acting on the thick ascending limb of the loop of Henle. Therefore, the diuretic effects of the two can be complementary and superimposed; and loop diuretic treatment will lead to enhanced sodium ion reuptake in the distal convoluted tubule, increasing the drug sensitivity of metolazone. Therefore, metolazone and loop diuretics (such as furosemide) have synergistic effects in pharmacodynamic mechanisms.
  • Metolazone is an important therapeutic drug for acute decompensated heart failure (ADHF) after loop diuretic resistance. Metolazone has a strong diuretic effect, a long duration, and is complementary to the mechanism of loop diuretics. It can effectively solve the problem of diuretic resistance such as furosemide. In addition, unlike hydrochlorothiazide, a drug of the same mechanism, metolazone will not reduce renal blood flow and glomerular filtration rate, and can still be used in patients with severe renal damage. However, the existing formulation of metolazone limits its clinical application. As an oral preparation, it takes about 1 hour after administration to achieve a satisfactory diuretic effect, which is not timely enough for critical heart failure patients. For some patients with heart failure and severe edema, the absorption of oral drugs is impaired due to edema involving the intestines, which will further affect the diuretic and edema-removing effects of the drugs.
  • ADHF acute decompensated heart failure
  • Intravenous metolazone preparations can solve the above-mentioned problems in clinical applications, but the extremely low solubility of metolazone in water (0.02 mg/ml) limits the development of its intravenous preparations.
  • U.S. Patent US 5124152A adds a large amount of organic solvents such as ethanol, propylene glycol, polyethylene glycol, etc. to the formulation.
  • a large amount of organic solvents not only causes irritation at the administration site, but also brings clinical medication risks such as hemolysis and allergies;
  • U.S. Patent US 9427398 B2 discloses a solution system containing N, N-dimethylacetamide (DMAC) as a cosolvent to prepare metolazone injection.
  • DMAC N, N-dimethylacetamide
  • Patent US2020/0179386A1 uses homogenous dispersion technology to prepare metolazone with vegetable oils, phospholipid emulsifiers, Tween-80 and poloxamer and other emulsifiers into a fat emulsion preparation, which can be used for intravenous administration.
  • a higher content of Tween-80 and poloxamer are added to the patent formulation, and intravenous administration has a higher risk of hemolysis and allergies.
  • metolazone has only some comparative documents recording its compositions and methods for preparing injections, but there are still risks in drug safety, and these existing technologies do not solve the problem of poor stability of metolazone intravenous preparations. Therefore, no metolazone intravenous preparations that meet the drug quality requirements have been marketed.
  • a pharmaceutical composition, a preparation, a metolazone lyophilized powder preparation and a preparation method and use thereof are provided;
  • the metolazone inclusion compound prepared by the present invention has good water solubility and safe ingredients, and the lyophilized powder injection further prepared has good stability when used as an injection dosage form, which directly provides the possibility of preparing metolazone into dosage forms such as injections to be injected into the body, and is of great value for clinical treatment.
  • the present invention provides a pharmaceutical composition, which is a metolazone inclusion compound, comprising metolazone or a salt thereof and a ⁇ -cyclodextrin derivative, wherein the molecular molar ratio of the metolazone or a salt thereof to the ⁇ -cyclodextrin derivative is 1:2 to 1:8.
  • the metolazone or its salt in the metolazone inclusion compound is encapsulated in the cavity of the ⁇ -cyclodextrin derivative.
  • the salt of metolazone may be a pharmaceutically acceptable salt thereof.
  • the metolazone salt is generally a salt formed by metolazone and an inorganic base or an organic base.
  • the inorganic base can be selected from one or more inorganic bases containing sodium, potassium, magnesium, calcium and aluminum.
  • the organic base may be selected from one or more of methylamine, ethylamine, ethanolamine, lysine, arginine and ornithine.
  • the ⁇ -cyclodextrin derivative is conventionally selected in the art, preferably one or more of sulfobutyl ether ⁇ -cyclodextrin sodium, hydroxypropyl ⁇ -cyclodextrin and methyl ⁇ -cyclodextrin.
  • the molecular molar ratio of the metolazone or its salt to the ⁇ -cyclodextrin derivative is preferably 1:3 to 1:6, more preferably 1:4.
  • the ⁇ -dextrin derivative in the metolazone inclusion complex is a class of pharmaceutical excipients with low toxicity, which are approved for oral or injection administration both at home and abroad.
  • sulfobutyl ether ⁇ -cyclodextrin sodium is less toxic than other ⁇ -cyclodextrin derivatives and is safer for clinical use.
  • an amount of the ⁇ -cyclodextrin derivative is not conducive to the formation of inclusion complexes.
  • the amount of the ⁇ -cyclodextrin derivative is too low, the inclusion of the drug cannot be completed, and precipitation will occur during re-dissolution; and when the amount of the ⁇ -cyclodextrin derivative is too high, it exceeds the necessary amount, the manufacturing cost is greatly increased, and the effect has reached saturation at this time.
  • the metolazone inclusion compound may further comprise at least one pharmaceutically acceptable carrier, excipient or diluent, and may be combined with other active ingredients if necessary.
  • the present invention provides a method for preparing a pharmaceutical composition, wherein the pharmaceutical composition is as described above, comprising any of the following methods:
  • Method 1 dissolving the metolazone or its salt and the ⁇ -cyclodextrin derivative in a first solvent, and stirring until the solution is clear and transparent.
  • Method 2 dissolving the metolazone or its salt in a second solvent to obtain a metolazone solution, dissolving the ⁇ -cyclodextrin derivative in a third solvent to obtain a ⁇ -cyclodextrin derivative solution, and then mixing the two and stirring until the solution is clear and transparent.
  • Method 3 Mix the ⁇ -cyclodextrin derivative with water, then mix it with the metolazone or its salt, add an alkaline pH regulator at the same time, stir until clear and transparent, and then add an acidic pH regulator to neutralize it.
  • the first solvent can be selected from one or more of water, ethanol, methanol, propanol, isopropanol, acetone, ethylene glycol, propylene glycol, glycerol, ethyl acetate, dichloromethane, tetrahydrofuran and tert-butanol.
  • the first solvent When the first solvent is water, the first solvent also contains an alkaline pH regulator, and after the "stirring until clear and transparent" step, an acidic pH regulator is added for neutralization; preferably, the first solvent is selected from: ethanol, a mixed solvent of ethanol and water, tert-butanol, and a mixed solvent of tert-butanol and water; more preferably, the volume ratio of ethanol to water in the mixed solvent of ethanol and water is 1:3 to 3:1, and the volume ratio of tert-butanol to water in the mixed solvent of tert-butanol and water is 1:3 to 2:1.
  • the second solvent may be selected from one or more of water, ethanol, anhydrous ethanol, methanol, propanol, isopropanol, acetone, ethylene glycol, propylene glycol, glycerol, ethyl acetate, dichloromethane, tetrahydrofuran and tert-butanol.
  • the second solvent is selected from anhydrous ethanol and/or tert-butanol.
  • the second solvent and the third solvent are both water
  • the second solvent further contains a pH alkaline regulator, and after the step of "stirring until clear and transparent", a pH acidic regulator is added for neutralization.
  • the third solvent can be selected from one or more of water, ethanol, methanol, propanol, isopropanol, acetone, ethylene glycol, propylene glycol, glycerol, ethyl acetate, dichloromethane, tetrahydrofuran and tert-butanol; preferably, the third solvent is selected from: water, ethanol, a mixed solvent of ethanol and water, tert-butanol, and a mixed solvent of tert-butanol and water; more preferably, the volume ratio of ethanol to water in the mixed solvent of ethanol and water is 1:3 to 3:1, and the volume ratio of tert-butanol to water in the mixed solvent of tert-butanol and water is 1:3 to 2:1.
  • the stirring temperature may be 4°C to 60°C, for example 4°C, 10°C, 25°C, 40°C or 60°C.
  • the stirring time may be 30-120 min, for example 30 min, 60 min or 120 min.
  • the dosage of metolazone can be controlled so that the mass volume percentage of metolazone in the solution is 0.05-0.3%; the mass volume percentage refers to the ratio of the mass (g) of metolazone in the solution to the total volume (ml) of the solution.
  • a metolazone inclusion compound solution is obtained after the "stirring until clear and transparent".
  • a drying step may be included subsequently, and a metolazone inclusion compound powder is obtained after drying.
  • the drying method may be vacuum rotary evaporation, spray drying or freeze drying.
  • the alkaline pH regulator can be a conventional pharmaceutical alkaline pH regulator in the art, and can be selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethanolamine, ammonia water, potassium hydroxide, potassium sulfate, tromethamine, meglumine and basic amino acids, preferably sodium hydroxide.
  • the amount of the alkaline pH adjuster used can be an amount that can be stirred to a clear and transparent state, and can generally be used to adjust the solution to a pH of 11 to 12.
  • the acidic pH regulator can be a conventional pharmaceutical acidic pH regulator in the art, and can be selected from one or more of citric acid, hydrochloric acid, sulfuric acid, acetic acid, tartaric acid, lactic acid, malic acid, phosphoric acid, fumaric acid, maleic acid, succinic acid and acidic amino acids, preferably citric acid.
  • the acidic pH regulator may be used in an amount sufficient to achieve solution neutralization, and generally may be used to adjust the solution pH to 6-8.
  • the present invention provides a pharmaceutical preparation comprising the aforementioned metolazone inclusion compound or the pharmaceutical composition prepared by the aforementioned preparation method, and at least one pharmaceutically acceptable carrier, excipient or diluent, or other active ingredients.
  • the pharmaceutical composition is in the form of infusion, liquid injection, powder injection, tablet, capsule, granule, dispersible tablet, oral liquid or syrup.
  • the metolazone inclusion compound of the present invention can be administered parenterally in the form of a sterile injectable aqueous solution.
  • the parenteral administration includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, or other administration methods known in the art.
  • the metolazone inclusion compound for parenteral administration may also contain a pharmaceutically acceptable carrier and solvent, including water, Ringer's solution, isotonic sodium chloride solution or glucose solution. Preparations in the form of parenteral administration may include: infusion, water injection, powder injection, etc.
  • the metolazone inclusion compound of the present invention can be administered in the form of an oral preparation, and may contain a pharmaceutically acceptable solid carrier or liquid carrier.
  • the solid carrier generally includes a diluent, a flavoring agent, a lubricant, a binder, a disintegrant, etc. commonly used in pharmacy, the liquid carrier is water, ethanol, propylene glycol, glycerol, corn syrup, etc., and the liquid preparation may also contain a pharmaceutically acceptable sweetener, a flavoring agent, a preservative, etc.
  • the solid preparation may include: tablets, capsules, granules, dispersible tablets, etc.; the liquid preparation may include: oral liquid, syrup, etc.
  • the present invention further provides a metolazone lyophilized powder preparation, comprising the aforementioned metolazone inclusion compound or a pharmaceutical composition prepared by the aforementioned preparation method.
  • the lyophilized powder preparation may further include a lyoprotectant, such as one or more of mannitol, inositol, sorbitol, lactose, sucrose, glucose, trehalose, maltose, dextran, glycine, PVP and polyethylene glycol.
  • a lyoprotectant such as one or more of mannitol, inositol, sorbitol, lactose, sucrose, glucose, trehalose, maltose, dextran, glycine, PVP and polyethylene glycol.
  • the lyophilized powder preparation may further include a pH adjuster, such as one or more of sodium hydroxide, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, sodium bicarbonate and amino acids.
  • a pH adjuster such as one or more of sodium hydroxide, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, sodium bicarbonate and amino acids.
  • the present invention provides a method for preparing a metolazone lyophilized powder preparation, wherein the metolazone lyophilized powder preparation adopts the aforementioned metolazone lyophilized powder preparation, and comprises the following steps: when the pharmaceutical composition is in powder form, filtering after re-dissolving, or filtering the metolazone inclusion complex solution obtained by “stirring until clear and transparent”; and then drying.
  • the reconstituted solvent may be water, preferably water for injection, and the amount of water used is preferably 0.4-2 times the volume of the metolazone inclusion solution, and the volume of the metolazone inclusion solution is the volume of the aforementioned first solvent or the total volume of the second solvent and the third solvent.
  • the filtering method is conventional in the art, preferably membrane filtration.
  • the drying method may be freeze drying, spray drying or reduced pressure drying, preferably freeze drying.
  • a freeze-drying protective agent may be added for dissolution before the filtration.
  • the use of the lyophilized powder for injection prepared by comprising the metolazone inclusion compound of the present invention can significantly improve the stability of the metolazone preparation.
  • the present invention provides a use of a metolazone inclusion compound or a metolazone lyophilized powder preparation in the preparation of a diuretic drug, wherein the diuretic drug can be used to treat edema and hypertension.
  • the metolazone inclusion compound is the aforementioned metolazone inclusion compound, or the metolazone inclusion compound prepared by the aforementioned preparation method,
  • the metolazone lyophilized powder preparation is a metolazone lyophilized powder preparation obtained by using the aforementioned metolazone lyophilized powder preparation or the aforementioned preparation method.
  • the reagents and raw materials used in the present invention are commercially available.
  • metolazone or its salt can be included in a complex with a ⁇ -cyclodextrin derivative, thereby greatly improving the water solubility of metolazone, overcoming the disadvantage that metolazone is difficult to prepare into a water-soluble preparation, especially a liquid preparation for intravenous injection; the inclusion complex increases the water solubility of metolazone by more than 100 times, and the oral preparation prepared with it also has the characteristics of good dissolution and high bioavailability, which is more conducive to clinical application.
  • the metolazone lyophilized injection prepared by the metolazone inclusion compound of the present invention has a faster diuretic speed, a stronger diuretic effect, and a longer-lasting efficacy than the original tablets of the same dose. It can quickly exert a strong diuretic effect after administration, and is particularly suitable for emergency treatment of patients with acute heart failure accompanied by loop diuretic resistance, and has significant clinical application value.
  • Figure 1 is an X-ray diffraction pattern, wherein part a of Figure 1 is an X-ray diffraction pattern of the raw material metolazone powder used in Example 4; part b of Figure 1 is an X-ray diffraction pattern of the raw material sulfobutyl ether ⁇ -cyclodextrin powder used in Example 4; part c of Figure 1 is an X-ray diffraction pattern of a physical mixture of metolazone powder and sulfobutyl ether ⁇ -cyclodextrin; part d of Figure 1 is an X-ray diffraction pattern of the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex prepared in Example 4.
  • FIG. 2 shows the real-time rate of urine production in Experimental Example 3 (mean ⁇ SD, ⁇ L/min).
  • FIG. 3a shows the diuretic onset time of Experimental Example 3 (mean ⁇ SD, min).
  • FIG3b is the peak time of the diuretic effect of Experimental Example 3 (mean ⁇ SD, min).
  • FIG. 3 c shows the peak increase in urine production rate of Experimental Example 3 (mean ⁇ SD, min).
  • FIG. 4 shows the cumulative urine volume after administration in Test Example 3 (mean ⁇ SD, mL).
  • FIG. 5 shows the increase in the cumulative urine volume of Test Example 3 compared with the negative control group (mean ⁇ SD, %).
  • solution A 1.78 g of sodium sulfobutyl ether ⁇ -cyclodextrin was weighed and dissolved in 40 ml of water to obtain solution A. 100 mg of metolazone was weighed and dissolved in 60 ml of anhydrous ethanol to obtain solution B (the molecular molar ratio of metolazone to sodium sulfobutyl ether ⁇ -cyclodextrin was 1:3). Solution B was then slowly added to solution A and mixed. The mixture was stirred at 40°C for 60 minutes until the mixture became clear and transparent. The dry solid was obtained by rotary evaporation under reduced pressure to obtain the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex.
  • the metolazone hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared in Example 1 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, and packaged into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex prepared in Example 2 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, and dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared in Example 3 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, and dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex prepared in Example 4 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, and dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex solution prepared in Example 5 was filtered through a filter membrane, dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex solution prepared in Example 6 was filtered through a filter membrane, dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex prepared in Example 7 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex solution prepared in Example 8 was filtered through a filter membrane, dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex prepared in Example 9 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, and dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone sulfobutyl ether ⁇ -cyclodextrin sodium inclusion complex prepared in Example 10 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, and dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • the metolazone methyl ⁇ -cyclodextrin inclusion complex prepared in Example 11 was added into 100 ml of water for injection and re-dissolved until clear and transparent, filtered with a filter membrane, dispensed into vials, placed in a freeze dryer, freeze-dried, and capped.
  • Example 2 in U.S. Patent US 5124152A a metolazone injection was prepared, containing 1.17 mg/ml of metolazone, 10% by volume of ethanol solution (95%), and 40% by volume of propylene glycol.
  • a metolazone injection was prepared, containing 150 mg of metolazone, 0.1 mL of dimethylacetamide (DMAC), and 9.9 mL of polyethylene glycol 400.
  • DMAC dimethylacetamide
  • Example 26 in U.S. Patent US 2020/0179386 A1 document prepares a metolazone fat emulsion injection containing 1 mg/ml metolazone, 20% soybean oil, 12 mg/ml soybean lecithin, 2.25% glycerol, and 3% poloxamer.
  • the X-ray diffraction pattern of the inclusion complex prepared in Example 4 shows that the characteristic crystal peaks of metolazone in the sample disappear, indicating that it has been successfully included with the ⁇ -cyclodextrin derivative ( Figure 1).
  • part a of Figure 1 is the X-ray diffraction pattern of the raw material metolazone powder used in Example 4
  • part b of Figure 1 is the X-ray diffraction pattern of the raw material sulfobutyl ether ⁇ -cyclodextrin powder used in Example 4
  • part c of Figure 1 is the X-ray diffraction pattern of the physical mixture of metolazone powder and sulfobutyl ether ⁇ -cyclodextrin
  • part d of Figure 1 is the X-ray diffraction pattern of the inclusion complex of metolazone sulfobutyl ether ⁇ -cyclodextrin sodium prepared in Example 4.
  • the metolazone powder X-ray diffraction spectrum in part a of Figure 1 has characteristic peaks at 7.36, 19.6 and 25.89;
  • the X-ray diffraction spectrum of sulfobutyl ether ⁇ -cyclodextrin powder in part b of Figure 1 also has a peak at around 20;
  • the inclusion complex prepared in Example 4 in part d of FIG. 1 shows that the characteristic peak of the crystal of metolazone disappears, which indicates that the inclusion result shows that metolazone is encapsulated in the cavity of the ⁇ -cyclodextrin derivative.
  • the inclusion compounds prepared in Examples 1-11 were added with 100 ml of physiological saline and stirred, and all of them were quickly dissolved to become clear and transparent, and were stable without precipitation after being placed at room temperature, as shown in Table 1 below. This indicates that the inclusion compounds were successfully prepared.
  • the metolazone lyophilized powder for injection prepared in Examples 12 to 22 and the metolazone injection prepared in Comparative Examples 1, 2 and 3 were subjected to high temperature tests and strong light irradiation tests according to the guidelines for stability tests of drug preparations in the Chinese Pharmacopoeia.
  • High temperature test conditions Place the test sample at 60°C for 10 days, take samples on the 5th and 10th days, and detect changes in the preparation properties, main drug content and related substances.
  • Strong light irradiation test conditions Place the test sample in a lighting device at 4500lx ⁇ 500x for 10 days, take samples on the 5th and 10th days, and detect changes in the preparation properties, main drug content and related substances.
  • test products prepared in the examples of the stability test were respectively re-dissolved with physiological saline for injection to 1 mg/ml according to the labeled amount of the preparation, and the content of the main drug and related substances were detected by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Agilent 1260 liquid chromatograph was used, equipped with G7115A UV detector, detection wavelength 230nm; chromatographic column was Agilent ZORBAX Eclipse XDB C18 analytical column (4.6 ⁇ 150mm, 5 ⁇ m); mobile phase A: 95% aqueous solution containing 0.1% formic acid + 5% methanol, mobile phase B: 90% acetonitrile solution containing 0.05% formic acid + 10% methanol. Flow rate 1.0mL/min; column temperature 30°C; injection volume 15 ⁇ L. Gradient elution is shown in Table 2 below;
  • the result data showed that under the high temperature and light conditions of this test, the freeze-dried powder injection preparations prepared in Examples 12-22 of the present invention were stable, with no significant changes in properties, and very little changes in content and related substances; the preparations prepared in the comparative examples had slightly reduced main drug content to varying degrees in the high temperature test, and significantly increased related substances, among which the fat emulsion prepared in comparative example 3 showed oil floating and stratification phenomena; and under strong light irradiation conditions, the main drug content of the comparative examples decreased significantly, and the related substances increased significantly, and the stability of the preparations was seriously damaged.
  • the rats were fed a standard diet and had free access to water during the feeding period, and fasted overnight before the experiment.
  • the specific experimental steps are as follows:
  • Intraperitoneal injection of sodium pentobarbital 50mg/kg for anesthesia The skin of the right hind limb was incised, and a 0.9mm OD PE catheter was placed in the femoral vein at a depth of 15mm to maintain anesthesia; the abdominal wall was incised at the midline, and a 1.2mm OD silicone tube was inserted into the bladder at a depth of 5mm, fixed with biological glue for urine collection, and an 1.2mm OD silicone tube was placed in the abdominal cavity through the incision for peritoneal fluid replacement, and the incision was covered with gauze soaked in saline.
  • a microinjection pump (Baoding Langer) was used to continuously infuse 8 mg/mL sodium pentobarbital through a silicone tube connected to a PE catheter to maintain animal anesthesia at a rate of 0.5 mL/h; another silicone tube was used to continuously infuse normal saline into the peritoneal cavity for fluid replacement at a rate of 0.5 mL/h. The infusion started from the baseline period until the end of the experiment.
  • the intravenous group was injected with the sample prepared in Example 15 via the tail vein at a dose of 2 mg/kg (0.1 mL/100 g body weight); the oral group was directly injected with a metolazone tablet grinding suspension 2 mg/kg (0.1 mL/100 g body weight) via gastric wall puncture; the control group was injected with an equal volume of normal saline via the tail vein.
  • Urine collection 2 ml centrifuge tubes were used to collect urine outflowing from the bladder. The baseline period was 70 minutes, with 20 minutes for each of the first three points and 10 minutes for the last point. In the first hour after administration, urine was collected every 10 minutes, and from the second hour onwards, urine was collected every 20 minutes, for a total of 420 minutes.
  • the collected urine is weighed to calculate the urine volume, urine volume rate, cumulative urine volume and cumulative urine volume increase percentage.
  • the urine volume rate is the ratio of the urine volume collected in the interval to the duration of the interval. ( ⁇ Vm: drug administration group, cumulative urine volume after each drug administration (mL); Average value of cumulative urine volume after administration in the control group (mL).
  • Dosing groups intravenous group (lyophilized powder prepared in Example 15, recorded as iv) and oral group (tablets, ig).
  • Control group saline control group.
  • the oral group (ig) had a relatively slow onset of action, with an average onset time of 53.33 ⁇ 12.11min.
  • the intravenous group (iv) had a rapid onset of action after administration, with an onset speed of about 5.33 times that of the oral group, as shown in Figure 3a for the onset time of diuretic effect (mean ⁇ SD, min).
  • the oral group (ig) had a slow peak effect, with an average peak time of 151.67 ⁇ 67.06min, while the intravenous group (iv) had a rapid peak effect after administration, with an average peak time of 31.25 ⁇ 16.15min, which was about 4.85 times that of the oral group (ig), as shown in Figure 3b for the peak time of diuretic effect (mean ⁇ SD, min).
  • the average peak urination rate of the intravenous group (iv) increased by 19.69 ⁇ 5.51 ⁇ L/min compared with the baseline period, and the average peak urination rate of the oral group (ig) was 12.87 ⁇ 2.98 ⁇ L/min.
  • the intravenous group (iv) was approximately 1.53 times that of the oral group (ig). For details, see Figure 3c, peak increase in urine production rate (mean ⁇ SD, min).
  • the cumulative urine volume of the intravenous group increased the most compared with the control group at 30 minutes after administration, and the cumulative urine volume of the oral group increased the most compared with the control group at 140 minutes after administration; by 5 hours after administration, the increase in the cumulative urine volume of the two groups tended to be stable; after 7 hours, the cumulative urine volume of the intravenous group and the oral group increased by 129.31 ⁇ 55.35% and 74.59% ⁇ 44.82% compared with the control group, and the increase percentage of the intravenous group was 1.73 times that of the oral group, as shown in Figure 5 for the increase in the cumulative urine volume compared with the negative control group (mean ⁇ SD, %).

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Abstract

La présente invention divulgue une composition pharmaceutique, une préparation et une préparation de poudre lyophilisée de métolazone, ainsi que leurs procédés de préparation et leurs utilisations. La composition pharmaceutique est un complexe d'inclusion de métolazone et contient de la métolazone ou un sel de celle-ci et un dérivé de β-cyclodextrine, le rapport molaire moléculaire de la métolazone ou du sel de celle-ci sur le dérivé de β-cyclodextrine étant de 1:2 à 1:8. Dans la présente invention, il a été découvert de manière fortuite au moyen d'expériences que la métolazone pouvait subir une inclusion avec le dérivé de β-cyclodextrine, ce qui permet d'améliorer considérablement la solubilité dans l'eau de la métolazone, et que l'injection lyophilisée de métolazone préparée en utilisant le complexe d'inclusion de métolazone présentait une vitesse diurétique plus élevée, un effet diurétique plus fort et une efficacité durable par rapport avec des comprimés innovants de même dose, pouvait rapidement exercer un fort effet diurétique après administration, était particulièrement appropriée pour le traitement en urgence de patients atteints d'une insuffisance cardiaque aiguë accompagnée d'une résistance aux diurétiques de l'anse, et présentait une valeur significative dans l'application clinique.
PCT/CN2024/135814 2023-12-01 2024-11-29 Composition pharmaceutique, préparation et préparation de poudre lyophilisée de métolazone, leurs procédés de préparation et leurs utilisations Pending WO2025113679A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5124152A (en) * 1991-01-07 1992-06-23 Fisons Corporation Parenteral formulation of metolazone
US5633240A (en) * 1994-09-01 1997-05-27 Academic Pharmaceuticals Parenteral solutions containing metolazone
WO2016124966A1 (fr) * 2014-12-23 2016-08-11 Drug Discovery Laboratory As Complexe d'inclusion entre la cyclodextrine et des tensioactifs non ioniques
US20230285306A1 (en) * 2018-09-28 2023-09-14 Axsome Therapeutics, Inc. Dosage forms comprising active pharmaceutical ingredients
CN117899084A (zh) * 2023-12-01 2024-04-19 西安泰可益康生物科技有限公司 药物组合物、制剂、美托拉宗冻干粉制剂及其制备方法与用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5124152A (en) * 1991-01-07 1992-06-23 Fisons Corporation Parenteral formulation of metolazone
US5633240A (en) * 1994-09-01 1997-05-27 Academic Pharmaceuticals Parenteral solutions containing metolazone
WO2016124966A1 (fr) * 2014-12-23 2016-08-11 Drug Discovery Laboratory As Complexe d'inclusion entre la cyclodextrine et des tensioactifs non ioniques
US20230285306A1 (en) * 2018-09-28 2023-09-14 Axsome Therapeutics, Inc. Dosage forms comprising active pharmaceutical ingredients
CN117899084A (zh) * 2023-12-01 2024-04-19 西安泰可益康生物科技有限公司 药物组合物、制剂、美托拉宗冻干粉制剂及其制备方法与用途

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