WO2021185343A1 - 格列本脲脂质体组合物及其制备方法 - Google Patents

格列本脲脂质体组合物及其制备方法 Download PDF

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WO2021185343A1
WO2021185343A1 PCT/CN2021/081704 CN2021081704W WO2021185343A1 WO 2021185343 A1 WO2021185343 A1 WO 2021185343A1 CN 2021081704 W CN2021081704 W CN 2021081704W WO 2021185343 A1 WO2021185343 A1 WO 2021185343A1
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Prior art keywords
liposome composition
liposome
glibenclamide
composition according
lipid
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PCT/CN2021/081704
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English (en)
French (fr)
Inventor
刘伊娜
董平
袁开红
孙琼
刘廷
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江苏恒瑞医药股份有限公司
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Publication of WO2021185343A1 publication Critical patent/WO2021185343A1/zh

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present disclosure belongs to the field of pharmacy, and relates to a liposome composition of glibenclamide and a preparation method thereof.
  • Glyburide namely 5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide, is used for treatment Sulfonylurea drugs for diabetes preferentially bind and affect sulfonylurea receptor 1 (SUR1), but also bind and affect sulfonylurea receptor 2 (SUR2) at higher concentrations. Glibenclamide was approved by the FDA in 2017 as an orphan drug for the treatment of acute ischemic stroke.
  • CN108553428A discloses a freeze-dried powder injection of glibenclamide, which can be used for the treatment of stroke-induced cerebral edema. According to AAPS J. 2013 Oct; 15(4): 1082-1090. published animal experiment results, the brain penetration rate of glibenclamide is low.
  • Liposomes also called lipid vesicles, are completely enclosed lipid bilayer membranes that contain an internal volume containing an aqueous medium.
  • the lipid bilayer is usually composed of phospholipids such as lecithin and related materials such as glycolipids.
  • Lipid bilayer membranes generally function in a manner similar to cell membranes, and therefore exhibit some biological properties, such as the ability to be easily accepted into the living cell environment. Therefore, in recent years, there have been more and more researches using liposomes as carriers for delivering compounds with special biological or pharmacological properties to patients.
  • Liposomes can be divided into unilamellar liposomes and multilamellar liposomes according to the number of phospholipid membrane layers contained in the structure.
  • Unilamellar liposomes are divided into small unilamellar vesicular (SUV) and large unilamellar vesicular (LUV).
  • the present disclosure relates to a liposome composition for injection, which comprises a sulfonylurea compound and a lipid, and the lipid comprises at least one phospholipid.
  • the sulfonylurea compound can be selected from, but not limited to, glibenclamide, gliquidone, glimepiride, gliclazide, glipizide, glibocarbamide, gliclapide, glibenclamide Libicyclic urea, gliclazamide, glibenclamide, gliclazamide, glixin uride, chlorpropamide, tolazamide or tolbutamide, preferably glibenclamide.
  • the present disclosure relates to a liposome composition for injection, comprising glibenclamide and lipid, and the lipid comprises at least one phospholipid.
  • the liposome composition may be a colloidal solution.
  • the liposome composition may be a suspension.
  • the present disclosure provides a medicine for preventing or treating diseases and disorders affected by neuronal damage, which is a liposome composition comprising a sulfonylurea compound and a lipid, and the lipid comprises at least one phospholipid.
  • the present disclosure provides a medicine for preventing or treating diseases and disorders affected by neuronal damage, which is a liposome composition comprising glibenclamide and lipids, and the lipids comprise at least one phospholipid.
  • the present disclosure provides a method for treating patients with acute stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, ischemic injury, hypoxia/ischemia or other injury conditions and disorders
  • the drug which is a liposome composition, comprises a sulfonylurea compound and a lipid, and the lipid comprises at least one phospholipid.
  • the present disclosure provides a medicine for preventing or treating diseases and disorders affected by neuronal damage, which is a liposome composition comprising glibenclamide and lipids, and the lipids comprise at least one phospholipid.
  • the present disclosure relates to a drug for intravenous injection, which is a glibenclamide liposome composition, comprising glibenclamide and lipids, and the lipids comprise at least one phospholipid.
  • the lipids described in the present disclosure include completely neutral or negatively charged phospholipids.
  • phospholipid refers to a hydrophobic molecule containing at least one phosphorus group, which may be natural or synthetic.
  • the phospholipid may comprise a phosphorus-containing group and a saturated or unsaturated alkyl group optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups.
  • Phospholipids differ from each other in the length and degree of unsaturation of their acyclic (acylic) chains.
  • the phospholipids include one or more of phosphatidylcholine, fatty acid ethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, and phosphatidylinositol.
  • phosphatidylcholine refers to phosphatidylcholine and its derivatives.
  • phospholipids suitable for use in the present disclosure include dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), 1-palmitoyl- 2-linoleyl-sn-glycerol-3-phosphatidylcholine (PLPC), phosphorylcholine (DOPC), egg yolk phosphatidylcholine (EPC), dilauroylphosphatidylcholine (DLPC), hydrogenated soybean Phosphatidylcholine (HSPC), l-myristoyl-2-palmitoylphosphatidylcholine (MPPC), l-palmitoyl-2-myristoylphosphatidylcholine (PMPC), l-palmitoyl-2 -Stearoylphosphatidylcholine (PSPC), l-stearoyl-2-palmitoylphosphatidylcholine (SPPC),
  • the lipids of the present disclosure may also include other neutral lipids, cationic lipids and/or anionic lipids.
  • Examples of other neutral lipids that can be used in the present disclosure include: one or more of steroids such as cholesterol and its derivatives, lecithin, soybean phospholipids, cephalin, sphingomyelin, and hydrogenated soybean phospholipids.
  • steroids such as cholesterol and its derivatives, lecithin, soybean phospholipids, cephalin, sphingomyelin, and hydrogenated soybean phospholipids.
  • the lipid may comprise at least one phospholipid and cholesterol.
  • the lipid may comprise at least one phosphatidylcholine and cholesterol.
  • the liposome composition may comprise glibenclamide, cholesterol, HSPC and MPEG2000-DSPE.
  • the liposome composition may comprise glibenclamide, cholesterol, HSPC and MPEG2000-DSPE, wherein the weight ratio of cholesterol, HSPC and MPEG2000-DSPE is about 1:3:1.
  • the liposome composition may comprise glibenclamide, cholesterol, HSPC and MPEG2000-DSPE, wherein the weight ratio of drug to lipid is 1:8.
  • the liposome composition may comprise glibenclamide, HSPC, cholesterol and DSPG.
  • the liposome composition may comprise glibenclamide, HSPC, cholesterol and DSPG, wherein the weight ratio of HSPC, cholesterol and DSPG is about 4:1:1.5.
  • the liposome composition may comprise glibenclamide, HSPC, cholesterol and DSPG, wherein the weight ratio of drug to lipid is 1:8.
  • the liposome composition may comprise glibenclamide, DOTAP, cholesterol and MPEG2000-DSPE.
  • the liposome composition may comprise glibenclamide, DOTAP, cholesterol and MPEG2000-DSPE, wherein the weight ratio of DOTAP, cholesterol and MPEG2000-DSPE is about 16:9:7.
  • the liposome composition may comprise glibenclamide, DOTAP, cholesterol and MPEG2000-DSPE, wherein the weight ratio of drug to lipid is 1:8.
  • the liposome composition may comprise glibenclamide, DMPC, DOTAP and cholesterol.
  • the liposome composition may comprise glibenclamide, DMPC, DOTAP and cholesterol, wherein the weight ratio of DMPC, DOTAP and cholesterol is about 1:1:1.
  • the liposome composition may comprise glibenclamide, DMPC, DOTAP and cholesterol, wherein the weight ratio of drug to lipid is 1:8.
  • the liposome composition may include glibenclamide, EPC and cholesterol.
  • the liposome composition may comprise glibenclamide, EPC and cholesterol, wherein the weight ratio of EPC to cholesterol is about 5:4.
  • the liposome composition may comprise glibenclamide, EPC and cholesterol, wherein the weight ratio of drug to lipid is 1:8.
  • the liposome composition may include glibenclamide, cholesterol, and DSPC.
  • the liposome composition may include glibenclamide, cholesterol, DSPC and MPEG2000-DSPE.
  • the liposome composition may include glibenclamide, cholesterol, and sphingomyelin.
  • the liposome composition may include glibenclamide, DOPS, and POPC.
  • the liposome composition may include glibenclamide and DMPC.
  • the liposome composition may include glibenclamide and DMPC, wherein the weight ratio of the drug to the lipid is 1:8.
  • the liposome composition may include a sulfonylurea compound and a lipid, and the lipid includes at least one phospholipid, wherein the weight ratio of the sulfonylurea compound to the lipid is selected from 1:1-1000, preferably 1:1-100, more preferably 1:1-50, 1:1-30, 1:1-20, 1:1-10, 1:5-50, 1:5-30 , 1:5-20 or 1:5-10.
  • the liposome composition may comprise glibenclamide and lipid, and the lipid comprises at least one phospholipid, wherein the weight ratio of the glibenclamide to lipid is selected from 1: 1-1000, preferably 1:1-100, more preferably 1:1-50, 1:1-30, 1:1-20, 1:1-10, 1:5-50, 1:5-30, 1 :5-20 or 1:5-10.
  • the liposome composition may comprise sulfonylurea compounds, phospholipids and cholesterol, wherein the weight ratio of cholesterol to phospholipids is selected from 1:0.1-20, preferably 1:1-10, It is preferably 1:1-5, more preferably 1:2-4, 1:3-5 or 1:1-3.
  • the liposome composition may comprise glibenclamide, phospholipid and cholesterol, wherein the weight ratio of cholesterol to phospholipid is selected from 1:0.1-20, preferably 1:1-10, preferably 1:1-5, more preferably 1:2-4, 1:3-5 or 1:1-3.
  • the liposome composition may include sulfonylurea compounds and phospholipids, and does not include cholesterol.
  • the liposome composition may include glibenclamide and phospholipids, and does not include cholesterol.
  • the concentration of the sulfonylurea compound in the liposome composition can be selected from 0.005-10 mg/mL, 0.005-5 mg/mL, 0.005-3 mg/mL, 0.01-3 mg/mL, 0.01 -2mg/mL, 0.01-1mg/mL, 0.05-3mg/mL, 0.05-2mg/mL, 0.05-1mg/mL, 0.1-3mg/mL, 0.1-2mg/mL, 0.1-1mg/mL, 0.005-0.5 mg/mL, 0.01-0.5mg/mL or 0.1-0.5mg/mL.
  • the concentration of glibenclamide in the liposome composition can be selected from 0.005-10 mg/mL, 0.005-5 mg/mL, 0.005-3 mg/mL, 0.01-3 mg/mL, 0.01- 2mg/mL, 0.01-1mg/mL, 0.05-3mg/mL, 0.05-2mg/mL, 0.05-1mg/mL, 0.1-3mg/mL, 0.1-2mg/mL, 0.1-1mg/mL, 0.005-0.5mg /mL, 0.01-0.5mg/mL or 0.1-0.5mg/mL.
  • the liposome composition is in the form of a unit dose, and may contain 1-20 mg of a sulfonylurea compound. In some embodiments, the liposome composition is in the form of a unit dose, and may contain 1-10 mg of a sulfonylurea compound. In some embodiments, the liposome composition is in the form of a unit dose, and may contain 1-5 mg of a sulfonylurea compound.
  • the liposome composition is in the form of a unit dose, which may contain 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg of the sulfonylurea compound , 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg or 5mg.
  • the liposome composition is in the form of a unit dose and may contain 1-20 mg of glibenclamide. In some embodiments, the liposome composition is in the form of a unit dose and may contain 1-10 mg of glibenclamide. In some embodiments, the liposome composition is in the form of a unit dose and may contain 1-5 mg of glibenclamide.
  • the liposome composition is in the form of a unit dose, which may include glibenclamide 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg or 5mg.
  • glibenclamide 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg or 5mg.
  • the osmotic pressure of the liposome composition described in the present disclosure may be less than 600 mOsm. In some embodiments, the osmotic pressure of the liposome composition may be less than 500 mOsm. In some embodiments, the osmotic pressure of the liposome composition may be less than 400 mOsm. In some embodiments, the osmotic pressure of the liposome composition may be 300 ⁇ 30 mOsm.
  • the particle size of the liposome may be less than 500 nm. In some embodiments, the particle size of liposomes may be less than 400 nm. In some embodiments, the particle size of liposomes may be less than 300 nm. In some embodiments, the particle size of liposomes may be less than 250 nm. In some embodiments, the particle size of liposomes may be less than 200 nm.
  • the liposome composition may be a liposome composition comprising multilamellar liposomes (MLV).
  • MLV multilamellar liposomes
  • other liposome forms such as SUV or LUV may also be present in the liposome composition.
  • the liposome composition may mainly exist in the form of MLV.
  • the liposome composition may mainly exist in the form of SUV.
  • the present disclosure relates to the use of a glibenclamide liposome composition in the preparation of a medicine for preventing or treating diseases and disorders affected by neuronal damage.
  • the present disclosure provides a method for preventing or treating diseases and disorders affected by neuronal damage, which comprises administering to a subject a therapeutically effective amount of a glibenclamide liposome composition.
  • the glibenclamide liposome composition may be used in combination with crocetin or a pharmaceutically acceptable salt thereof, edaravone, or recombinant tissue-type plasminogen activator (r-tPA).
  • the diseases and conditions affected by neuronal damage may be selected from stroke, brain damage, neuropathic pain, migraine, inflammatory pain, chronic pain, or depression.
  • the diseases and conditions affected by neuronal damage are ischemic stroke.
  • the diseases and conditions affected by neuronal damage may be cerebral hemisphere infarction.
  • the diseases and conditions affected by neuronal damage may be acute subarachnoid hemorrhage.
  • the present disclosure provides a subject in need of treatment of acute stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, ischemic injury, hypoxia/ischemia or other
  • the method of damaging conditions and disorders includes administering to a subject a therapeutically effective amount of a glibenclamide liposome composition.
  • the glibenclamide liposome composition can be combined with crocetin or a pharmaceutically acceptable salt thereof, butylphthalide, edaravone, or recombinant tissue-type plasminogen activator (r-tPA) use.
  • the liposome composition can reach the peak concentration (Cmax) of the drug within about 4 hours or about 3 hours after administration to the individual, for example, the peak concentration (Cmax) of the drug within about 2.5 hours. , Or reach the peak concentration of the drug in about 2h, or reach the peak concentration of the drug in about 1.5h, or reach the peak concentration of the drug in about 1h, or reach the peak concentration of the drug in about 45min, or reach the peak concentration of the drug in about 0.5h Peak concentration, or reach the peak concentration of the drug in about 20 minutes, or reach the peak concentration of the drug in about 10 minutes.
  • the dosage range of the liposome composition can be selected from 1-10 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg , 70-80mg, 80-90mg or 90-100mg.
  • the dosage range of the glibenclamide liposome composition is selected from 1-2.5mg, 1.5-3.5mg, 2.5-4.5mg, 3.5-5.5mg, 5-6mg, 6- 7mg, 7-8mg, 8-9mg, 9-10mg.
  • the daily dosage range of the liposome composition may be selected from 0.1-20 mg. In some embodiments, the daily dosage range of the liposome composition is selected from 0.1-1 mg, 1-2 mg, 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg , 7-8mg, 8-9mg, 9-10mg.
  • the method of administration of the liposome composition may be one or more continuous infusions accumulated for at least 72 hours after the start of one or more continuous infusions.
  • the one or more continuous infusions can be started after the administration of the bolus dose.
  • one or more continuous infusions may include two or more continuous infusion doses, where the first continuous infusion dose is higher than the second continuous infusion dose.
  • the first bolus and the second bolus of glibenclamide may be used, followed by continuous infusion of glibenclamide.
  • the subject in need of treatment may be given a first bolus of glibenclamide, followed by the first and second consecutive infusions of glibenclamide.
  • glibenclamide can be (a) administered as a bolus for the first time, and (b) after the bolus administration of glibenclamide, first continuous infusion of about 125 ⁇ g/hr to about 150 ⁇ g/hr.
  • Glibenclamide (c) after the first continuous infusion of glibenclamide, the second continuous infusion gives about 100 ⁇ g/hr to about 125 ⁇ g/hr glibenclamide, (d) in the first continuous infusion, After the second continuous infusion of glibenclamide, the third continuous infusion of about 15 ⁇ g/hr to about 300 ⁇ g/hr of glibenclamide.
  • the liposome composition is preferably administered within 0.5 hours, within 1 hour, within 1.5 hours, within 2 hours, within 2.5 hours, or within 3 hours of the patient's onset.
  • the liposome composition of the present disclosure After being administered by injection, the liposome composition of the present disclosure has a greatly increased brain penetration rate compared with ordinary glibenclamide injections, for example, an increase of more than 1000 times, more than 500 times, more than 100 times, more than 50 times, 30 times or more, 20 times or more, 10 times or more, 5 times or more, 3 times or more, 2 times or more.
  • the liposome composition of the present disclosure has a brain penetration rate of 5%-90% for 10 minutes after administration of the liposome composition in MCAO focal transient cerebral ischemia SD rats.
  • the brain penetration rate may be 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%- 30%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 20%-80%, 20%-70% , 20%-60%, 20%-50%, 20%-40%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-80%, 40 %-70% or 40%-60%.
  • the liposome composition described in the present disclosure has a brain penetration rate of 1%-90% for 40 minutes after the administration of the liposome composition in MCAO focal transient cerebral ischemia SD rats.
  • the brain penetration rate may be 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%- 30%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 20%-80%, 20%-70% , 20%-60%, 20%-50%, 20%-40%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-80%, 40 %-70%, 40%-60%.
  • the said brain penetration rate the drug concentration in brain tissue/the drug concentration in plasma*100%.
  • the liposome composition of the present disclosure may have a concentration of glibenclamide in the brain tissue of 10 minutes after administration in SD rats with MCAO focal transient cerebral ischemia at 10-500ng/mL .
  • the concentration of glibenclamide in the brain tissue may be 10-450 ng/mL, 10-400 ng/mL, 10-350 ng/mL, 10-300 ng/mL, 10-250 ng/mL, 10 min after administration.
  • the liposome composition described in the present disclosure may have a concentration of glibenclamide in the brain tissue 40 min after administration in SD rats with MCAO focal transient cerebral ischemia in the range of 1-500 ng/mL .
  • the concentration of glibenclamide in brain tissue may be 1-450 ng/mL, 5-500 ng/mL, 5-450 ng/mL, 1-400 ng/mL, 5-400 ng/mL at 40 min after administration.
  • the liposome composition can be prepared by a thin film dispersion method, a reverse phase evaporation method, a freeze-drying method, an active drug loading method, a pH gradient method, an injection method, and/or an ultrasonic dispersion method.
  • it may further comprise a step of granulation (or homogenization, homogenization), and the granulation method may, but is not limited to, a high-pressure homogenizer, ultrasound, extrusion, or the like.
  • the liposome composition can be prepared by a thin film dispersion method, which specifically includes: sulfonylurea compounds and lipids are dissolved in an organic solvent or a mixture of organic solvent and water, and the solvent is removed to form a film, and then hydrated.
  • the preparation method may further include ultrasonic or high-pressure homogenization of the liposome composition obtained after hydration.
  • the liposome composition can be prepared by an active drug loading method.
  • the active drug loading method may include: preparing a blank liposome membrane; hydrating and homogenizing with a solution of pH ⁇ 7, so that the aqueous phase of the blank liposome encapsulates the low-pH solution; The phase is replaced with a solution with pH>7; the blank liposome is incubated with an aqueous solution containing sulfonylurea compounds with a pH>7 to carry the drug to obtain the drug-loaded liposome.
  • the active drug loading method may include: preparing a blank liposome membrane; hydrating and homogenizing with a solution of pH ⁇ 7, so that the aqueous phase of the blank liposome encapsulates the low-pH solution; The phase is replaced with a pH>7 solution; the blank liposomes are incubated with a pH>7 aqueous solution containing glibenclamide for drug loading to obtain drug-loaded liposomes.
  • it may include obtaining the above-mentioned drug-loaded liposomes, then adjusting the pH back to about 7, centrifuging to remove the free drug, and adjusting the osmotic pressure to be isotonic with plasma.
  • the active drug loading method may specifically be a pH gradient method.
  • Homogenization can be achieved by a method selected from but not limited to ultrasonic treatment and high-pressure homogenization.
  • the blank liposome membrane can be prepared by thin film evaporation. For example, an appropriate amount of lipids and organic solvents can be weighed, added to the container, and dissolved and then evaporated to remove the solvent to form a film.
  • a solution of lower pH for example, Na2HPO4-citrate buffer with pH 5.5
  • a solution of lower pH for example, Na2HPO4-citrate buffer with pH 5.5
  • the pH of the blank liposome solution prepared above can be adjusted to a higher pH level with a high pH solution (the pH of the solution rises relative to the inner aqueous phase, for example, the pH of the inner aqueous phase is 5.5, the pH of the external water phase is 7).
  • the blank liposome solution prepared above can be placed in a dialysis bag, and the dialysis bag can be placed in a solution containing glibenclamide with high pH (for example, pH 10.0), and incubated, A drug-loaded liposome solution is obtained.
  • the liposome composition prepared by the active drug loading method or the pH gradient method described in the present disclosure has a small and uniform particle size and a large drug loading amount.
  • the present disclosure also relates to a method for preparing a liposome composition of a drug or active ingredient with a high pH-dependent solubility, including the preparation by an active drug loading method or a pH gradient method.
  • the liposome composition of this type of drug can but does not have to be prepared by the following methods:
  • the internal water phase encapsulates the high pH solution, and a certain volume of the higher pH solution can be used for hydration for a period of time, and then sonicated to obtain a blank liposome;
  • the outer aqueous phase With a low-pH solution, and adjust the pH of the liposome solution to make it 0.5-3 units lower than the pH of the inner aqueous phase.
  • the pH of the inner aqueous phase is 7.5
  • the outer aqueous phase can be Adjust pH to 5.0;
  • the liposome composition of this type of drug can but does not have to be prepared by the following methods:
  • the internal water phase encapsulates the low pH solution, and a certain volume of the lower pH solution can be used for hydration for a period of time, and then sonicated to obtain a blank liposome;
  • the outer aqueous phase With a high pH solution, and adjust the pH of the liposome solution to make it 0.5-3 units higher than the pH of the inner aqueous phase. For example, if the pH of the inner aqueous phase is 5.0, the outer aqueous phase can be reduced Adjust the pH to 7.5;
  • the liposome composition of the drug obtained according to the active drug loading method described in the present disclosure has a uniform and small particle size.
  • the present disclosure also relates to a liposome composition of a drug or active ingredient with a highly pH-dependent solubility, which comprises a drug or an active ingredient with a highly pH-dependent solubility and a lipid, and the lipid includes at least one phospholipid.
  • the liposome composition is prepared by an active drug loading method.
  • the drugs or active ingredients with high pH-dependent solubility described in the present disclosure include, but are not limited to, weak acids, weakly basic drugs or active ingredients, for example, can be selected from but not limited to glibenclamide, nimesulide, clopidogrel, Mizoribin, Pravastatin, Naproxen, Acetylsalicylic Acid, Diclofenac Sodium, Zolpidem, Fenodol Maleate, Repaglinide, Lurasidone Hydrochloride, Risperidone, Vinpocetine, crizotinib, clarithromycin, dipyridamole, erlotinib hydrochloride, ibuprofen, dacotinib.
  • the liposome composition of the present disclosure can be prepared into a solid composition by evaporation, freeze drying or spray drying.
  • the solid composition can be powder, granules, or cakes or lumps aggregated together.
  • the solid composition can be reconstituted to obtain a liquid form that can be used for administration.
  • the reconstitution can usually be achieved by mixing the solid composition with water or an aqueous solution.
  • the aqueous solution may include, but is not limited to, isotonic solutions or buffers.
  • the isotonic solution may have an osmotic pressure substantially the same as that of human blood, and it may be prepared by an isotonic agent and water.
  • the isotonic agent may include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, and sorbitol.
  • the buffer may refer to a buffered solution, which prevents pH changes through the action of its acid-base conjugated components.
  • the pH of the buffer may range from about 4.5 to about 8.5, and examples of buffers that can control the pH in this range include, but are not limited to, PBS, Na2HPO4-citrate buffer, ammonia-ammonium chloride buffer Solution, acetic acid-sodium acetate buffer, phosphate buffer, potassium dihydrogen phosphate-sodium hydroxide buffer, Tris-hydrochloric acid buffer, boric acid-borax buffer, sodium barbiturate-hydrochloric acid buffer, acetate ( For example, sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate, carbonate, HEPES and other organic acid buffers.
  • PBS PBS
  • Na2HPO4-citrate buffer ammonia-ammonium chloride buffer Solution
  • acetic acid-sodium acetate buffer acetic acid-sodium acetate buffer
  • phosphate buffer potassium dihydrogen phosphate-sodium hydroxide buffer
  • the present disclosure also relates to a method for improving the brain penetration rate of sulfonylurea compounds such as glibenclamide, which includes injecting and administering it to an individual in the form of liposomes in the present disclosure.
  • the liposome composition of the present disclosure can be administered in the form of parenteral injection, selected from intravenous injection, subcutaneous injection, and tissue injection. Standard methods and devices, such as pens, syringe systems, needles and syringes, hypodermic delivery systems, catheters, etc., are used to accomplish the administration of the liposome composition of the present disclosure.
  • the term "about” means that the quantities, dimensions, formulations, parameters, and other quantities and characteristics are inaccurate and need not be precise, but may be the desired approximation and/or larger or smaller values, thereby reflecting tolerances , Conversion factor, rounding, measurement error, etc., and other factors known to those skilled in the art.
  • the meaning may include a change of ⁇ 10%, preferably a change of ⁇ 5%.
  • the particle size described in the present disclosure adopts a PSS particle size analyzer, model Nicomp Z3000, and the average particle size is Intensity Mean Diameter.
  • the inner water phase encapsulates the low pH medium: 50 mL of pH5.5 medium (Na 2 HPO 4 -citrate buffer) is used to hydrate the blank liposome membrane for about 30 minutes, stir evenly, and the probe is intermittently sonicated for 10 minutes. Obtained blank liposomes with an average particle size of about 123.66nm.
  • pH5.5 medium Na 2 HPO 4 -citrate buffer
  • step (3) Displace the high pH outer water phase to cause a pH gradient: adjust the pH of the blank liposome obtained in step (2) to 7.0 with NaOH solution.
  • the pH of the liposomes at this time was measured to be 9.74, the average particle size was 124.86nm, and the PI (also known as PDI) was 0.24.
  • the total concentration of glibenclamide was 50.67 ⁇ g/mL.
  • the liposome obtained in step (4) Take 3 mL of the liposome obtained in step (4), adjust its pH to about 5.0, and centrifuge to remove free API.
  • Example 3 Comparison of the tissue distribution of liposome preparations and common preparations in MCAO rats with focal transient cerebral ischemia
  • Liposome preparation preparation adjust the pH of the drug-loaded liposome obtained in step (4) of Example 1 to 6.8, concentrate and adjust the osmotic pressure to a concentration of about 100 ⁇ g/mL, and the osmotic pressure is between 280-320 mOsm.
  • the animals were randomly divided into two groups, 20 in each of the liposome preparation group and the ordinary preparation group.
  • the rat middle cerebral artery occlusion (MCAO) was caused by the suture method to cause focal cerebral ischemia. After 1 hour of ischemia, the suture was pulled out to achieve reperfusion.
  • the operation is as follows: the rat is maintained anesthetized with isoflurane, lying on its back, after a median incision in the neck, the muscle layer is bluntly separated, the right common carotid artery is exposed, and the external carotid artery, internal carotid artery and other related vascular branches are sequentially separated .
  • the average concentration of glibenclamide in the brain tissue of the liposome preparation group was 78.2 ng/mL and 8.1 ng/mL, respectively, and the average concentration in plasma was 1068 ng/mL and 726 ng, respectively /mL, the average brain penetration rate was 7.3% and 1.1%, respectively; Glyburide was not detected in the brain tissue of the ordinary preparation group at the same dose, suggesting that liposome preparations can significantly increase the brain penetration rate of glibenclamide.
  • pH6.8 isotonic buffer solution (the buffer solution preparation method: use 0.2M disodium hydrogen phosphate buffer and 0.1M citric acid buffer to prepare a pH 6.8 medium, and then dilute with purified water to match the plasma Isotonic, osmotic pressure is about 280-320mOsm), stir and hydrate.
  • the sample was stored at 4°C and taken out for observation after 18 days.
  • the light milky white and clear solution had light blue opalescence.
  • the re-measured particle size 112.31nm, PI 0.19.
  • Example 5 Comparison of the tissue distribution of liposome preparations and common preparations in MCAO rats with focal transient cerebral ischemia
  • the animal experiment was carried out according to the method in Example 3.
  • the rats were injected into the tail vein and the blood was collected for 10 minutes.
  • the PK test protocol and results are as follows:
  • Plasma drug concentration The average concentration of glibenclamide in the plasma of rats in the normal injection and prescription 7 groups was 222 and 38ng/mL, respectively, detected at the 10th minute after injection.
  • Drug concentration in brain tissue The average concentration of glibenclamide in the right and left brain tissues of the prescription 7 groups was 0.80 and 0.77 ng/g, respectively, and the ratio of left and right brain tissue to plasma concentration was detected at the 10th minute after injection. 2%;
  • the "brain tissue-plasma" concentration ratio of glibenclamide ordinary injection and prescription 7 are 0.036% and 2.09%, respectively, prescription 7 can significantly increase the brain penetration rate of glibenclamide (58 times that of ordinary injections).

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Abstract

一种磺酰脲类化合物的脂质体组合物及其制备方法，该组合物包含磺酰脲类化合物和脂质，磺酰脲类化合物为格列本脲，该脂质包含至少一种磷脂。

Description

格列本脲脂质体组合物及其制备方法
本申请要求申请日为2020年3月20日的中国专利申请CN202010200556.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于制药领域，涉及一种格列本脲的脂质体组合物及其制备方法。
背景技术
据2016年WHO统计显示，脑卒中目前已成为全球第二大最常见死亡原因。国内外对于治疗脑卒中药物的研发活跃，临床对脑卒中治疗药物的需求较大，早期干预对脑卒中具有重要作用。截止目前，rt-PA(重组组织型纤溶酶原激活因子)仍是FDA唯一批准的缺血性脑卒中急救药物，但其治疗时间窗很窄，只有在中风4.5小时内使用才有效：而且还存在出血及缺血再灌加重脑损伤的危险性。
近几年，诸多神经保护剂在临床前研究中被证实具有良好的脑缺血保护作用。格列本脲(Glyburide)，即5-氯-N-(4-[N-(环己基氨甲酰基)氨磺酰基]苯乙基)-2-甲氧基苯甲酰胺，是用于治疗糖尿病的磺酰脲药物，优先结合并且影响磺酰脲受体1(SURl)，但是在较高浓度下也结合并影响磺酰脲受体2(SUR2)。格列本脲已在2017年经FDA批准治疗急性缺血性脑卒中的孤儿药资格。Remedy公司的格列本脲注射液II期结果表明，首要终点及次要终点虽未达到，但死亡率、脑中线偏移及MMP-9浓度显著降低；且Biogen公司收购后，已于2018年启动全球Ⅲ期临床，拟治疗大脑半球梗塞。
CN108553428A公开了一种格列本脲的冻干粉针剂，可用于卒中性脑水肿的治疗药物。根据AAPS J.2013Oct；15(4):1082–1090.公开的动物实验结果，格列本脲的透脑率较低。
脂质体，也被称为脂囊泡，是完全封闭的脂类双分子层膜，其含有包含水介质的内部体积。脂类双分子层通常由磷脂如卵磷脂和相关材料如糖脂组成。脂类双分子层膜通常以类似于细胞膜的方式起作用，因此展现出一些生物性质，如容易被接受进入活细胞环境内的能力。因此，近年来利用脂质体作为递送对患者具有特别的生物或药学特性的化合物的载体的研究越来越多。脂质体根据结构中所包含的双层分子磷脂膜层数，可分为单室脂质体和多室脂质体。含有单层双分子层磷脂膜的囊泡称为单层脂质体，含有多层双分子层磷脂膜的囊泡称为多层脂质体(multilamellar vesicle，MLV)。单室脂质体又分 为小单层脂质体(small unilamellar vesicular，SUV)和大单层脂质体(1arge unilamellar vesicular，LUV)。
发明内容
本公开涉及一种注射用脂质体组合物，包含磺酰脲类化合物和脂质，所述脂质包含至少一种磷脂。
所述的磺酰脲类化合物可选自但不限于格列本脲、格列喹酮、格列美脲、格列齐特、格列呲嗪、格列波脲、格列派特、格列环脲、格列沙脲、格列生脲、格列索脲、格列辛脲、氯磺丙脲、妥拉磺脲或甲苯磺丁脲，优选格列本脲。
本公开涉及一种注射用脂质体组合物，包含格列本脲和脂质，所述脂质包含至少一种磷脂。
在一些实施方案中，所述的脂质体组合物可为胶体溶液。
在另一些实施方案中，所述的脂质体组合物可为混悬液。
本公开提供一种预防或治疗受神经元损伤影响的疾病和病症的药物，其为脂质体组合物，包含磺酰脲类化合物和脂质，所述脂质包含至少一种磷脂。
本公开提供一种预防或治疗受神经元损伤影响的疾病和病症的药物，其为脂质体组合物，包含格列本脲和脂质，所述脂质包含至少一种磷脂。
本公开提供一种治疗患者急性脑卒中、创伤性脑损伤、脊髓损伤、心肌梗塞、休克、器官缺血、室性心律失常、缺血性损伤、缺氧/缺血或其他损伤病症和障碍的药物，其为脂质体组合物，包含磺酰脲类化合物和脂质，所述脂质包含至少一种磷脂。
本公开提供一种预防或治疗受神经元损伤影响的疾病和病症的药物，其为脂质体组合物，包含格列本脲和脂质，所述脂质包含至少一种磷脂。
本公开涉及一种静脉注射用的药物，其为格列本脲脂质体组合物，包含格列本脲和脂质，所述脂质包含至少一种磷脂。
本公开所述的脂质包括完全中性或带负电荷的磷脂。术语“磷脂”指含有至少一个磷基的疏水分子，其可为天然或合成的。例如，磷脂可包含含磷基团及任选被OH、COOH、氧代、胺或者取代或未取代的芳基取代的饱和或不饱和的烷基。磷脂在其无环(acylic)链的长度和不饱和度方面互相不同。
在某些实施方案中，所述磷脂包括磷脂酰胆碱、脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、磷脂酰肌醇中的一种或多种。术语“磷脂酰胆碱”指磷脂酰胆碱及其衍生物。适合用于本公开的磷脂的示例包括二棕榈酰磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰胆 碱(DSPC)、二肉豆蔻酰磷脂酰胆碱(DMPC)、1-棕榈酰-2-亚油酰-sn-甘油-3-磷脂酰胆碱(PLPC)、磷酸胆碱(DOPC)、蛋黄磷脂酰胆碱(EPC)、二月桂酰磷脂酰胆碱(DLPC)、氢化的大豆磷脂酰胆碱(HSPC)、l-肉豆蔻酰-2-棕榈酰磷脂酰胆碱(MPPC)、l-棕榈酰-2-肉豆蔻酰磷脂酰胆碱(PMPC)、l-棕榈酰-2-硬脂酰磷脂酰胆碱(PSPC)、l-硬脂酰-2-棕榈酰磷脂酰胆碱(SPPC)、棕榈酰油酰磷脂酰胆碱(POPC)、溶血磷脂酰胆碱、二亚油酰磷脂酰胆碱、二硬脂酰磷脂酰乙醇胺(DSPE)、MPEG2000-DSPE、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二棕榈酰磷脂酰乙醇胺(DPPE)、二油酰基磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰甘油(DMPG)、二硬脂酰基磷脂酰甘油(DSPG)、二棕榈酰基甘油磷酸甘油(DPPG)、二棕榈酰基磷脂酰丝氨酸(DPPS)、1，2-二油酰基-sn-甘油-3-磷脂酰丝氨酸(DOPS)、二肉豆蔻酰基磷脂酰丝氨酸(DMPS)、二硬脂酰基磷脂酰丝氨酸(DSPS)、二棕榈酰基磷脂酸(DPPA)、1，2-二油酰基-sn-甘油-3-磷脂酸(DOPA)、二肉豆蔻酰基磷脂酸(DMPA)、二硬脂酰基磷脂酸(DSPA)、二棕榈酰基磷脂酰肌醇(DPPI)、1，2-二油酰基-sn-甘油-3-磷脂酰肌醇(DOPI)、二肉豆蔻酰基磷脂酰肌醇(DMPI)、二硬脂酰基磷脂酰肌醇(DSPI)、(2,3-二油酰基-丙基)-三甲胺(DOTAP)、大豆卵磷脂中的一种或多种。
本公开的脂质还可包含其他中性脂质、阳离子脂质和/或阴离子脂质。
可用于本公开的其他中性脂质的示例包括：类固醇如胆固醇及其衍生物、卵磷脂、大豆磷脂、脑磷脂、鞘磷脂、氢化大豆磷脂中的一种或多种。
在某些实施方案中，所述的脂质可包含至少一种磷脂和胆固醇。
在某些实施方案中，所述的脂质可包含至少一种磷脂酰胆碱以及胆固醇。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、胆固醇、HSPC和MPEG2000-DSPE。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、胆固醇、HSPC和MPEG2000-DSPE，其中胆固醇、HSPC和MPEG2000-DSPE的重量比约为1:3:1。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、胆固醇、HSPC和MPEG2000-DSPE，其中药物与脂质的重量比为1:8。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、HSPC、胆固醇和DSPG。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、HSPC、胆固醇和DSPG，其中HSPC、胆固醇和DSPG的重量比约为4:1:1.5。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、HSPC、胆固醇和DSPG，其中药物与脂质的重量比为1:8.
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DOTAP、胆固醇和 MPEG2000-DSPE。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DOTAP、胆固醇和MPEG2000-DSPE，其中DOTAP、胆固醇和MPEG2000-DSPE的重量比约为16:9:7。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DOTAP、胆固醇和MPEG2000-DSPE，其中药物与脂质的重量比为1:8.
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DMPC、DOTAP和胆固醇。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DMPC、DOTAP和胆固醇，其中DMPC、DOTAP和胆固醇的重量比约为1:1:1。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DMPC、DOTAP和胆固醇，其中药物与脂质的重量比为1:8。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、EPC和胆固醇。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、EPC和胆固醇，其中EPC和胆固醇的重量比约为5:4。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、EPC和胆固醇，其中药物与脂质的重量比为1:8。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、胆固醇和DSPC。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、胆固醇、DSPC和MPEG2000-DSPE。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、胆固醇、鞘磷脂。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DOPS、POPC。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DMPC。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、DMPC，其中药物与脂质的重量比为1:8。
在一些实施方案中，所述的脂质体组合物，可包含磺酰脲类化合物和脂质，脂质包含至少一种磷脂，其中所述磺酰脲类化合物与脂质的重量比选自1:1-1000，优选1:1-100，更优选1:1-50、1:1-30、1:1-20、1:1-10、1:5-50、1:5-30、1:5-20或者1:5-10。
在一些实施方案中，所述的脂质体组合物，可包含格列本脲和脂质，脂质包含至少一种磷脂，其中所述格列本脲与脂质的重量比选自1:1-1000，优选1:1-100，更优选1:1-50、1:1-30、1:1-20、1:1-10、1:5-50、1:5-30、1:5-20或者1:5-10。
在一些实施方案中，所述的脂质体组合物可包含磺酰脲类化合物、磷脂和胆固醇， 其中所述胆固醇与磷脂的重量比例选自1:0.1-20，优选1:1-10，优选1:1-5，更优选1:2-4、1:3-5或者1:1-3。
在一些实施方案中，所述的脂质体组合物可包含格列本脲、磷脂和胆固醇，其中所述胆固醇与磷脂的重量比例选自1:0.1-20，优选1:1-10，优选1:1-5，更优选1:2-4、1:3-5或者1:1-3。
在一些实施方案中，所述的脂质体组合物可包含磺酰脲类化合物和磷脂，并且不包含胆固醇。
在一些实施方案中，所述的脂质体组合物可包含格列本脲和磷脂，并且不包含胆固醇。
在一些实施方案中，所述的脂质体组合物中磺酰脲类化合物的浓度可选自0.005-10mg/mL、0.005-5mg/mL、0.005-3mg/mL、0.01-3mg/mL、0.01-2mg/mL、0.01-1mg/mL、0.05-3mg/mL、0.05-2mg/mL、0.05-1mg/mL、0.1-3mg/mL、0.1-2mg/mL、0.1-1mg/mL、0.005-0.5mg/mL、0.01-0.5mg/mL或者0.1-0.5mg/mL。
在一些实施方案中，所述的脂质体组合物中格列本脲的浓度可选自0.005-10mg/mL、0.005-5mg/mL、0.005-3mg/mL、0.01-3mg/mL、0.01-2mg/mL、0.01-1mg/mL、0.05-3mg/mL、0.05-2mg/mL、0.05-1mg/mL、0.1-3mg/mL、0.1-2mg/mL、0.1-1mg/mL、0.005-0.5mg/mL、0.01-0.5mg/mL或者0.1-0.5mg/mL。
在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含磺酰脲类化合物1-20mg。在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含磺酰脲类化合物1-10mg。在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含磺酰脲类化合物1-5mg。在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含磺酰脲类化合物1mg、1.25mg、1.5mg、1.75mg、2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4mg、4.25mg、4.5mg、4.75mg或5mg。
在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含格列本脲1-20mg。在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含格列本脲1-10mg。在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含格列本脲1-5mg。在一些实施方案中，所述的脂质体组合物是单位剂量的形式，可包含格列本脲1mg、1.25mg、1.5mg、1.75mg、2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4mg、4.25mg、4.5mg、4.75mg或5mg。
在一些实施方案中，本公开所述的脂质体组合物渗透压可小于600mOsm。在一些实施方案中，脂质体组合物的渗透压可小于500mOsm。在一些实施方案中，脂质体组合物 的渗透压可小于400mOsm。在一些实施方案中，脂质体组合物的渗透压可为300±30mOsm。
本公开所述的脂质体组合物中，脂质体的粒径可小于500nm。在一些实施方案中，脂质体的粒径可小于400nm。在一些实施方案中，脂质体的粒径可小于300nm。在一些实施方案中，脂质体的粒径可小于250nm。在一些实施方案中，脂质体的粒径可小于200nm。
在某些实施方案中，所述的脂质体组合物，可以是包含多层脂质体(MLV)的脂质体组合物。在某些实施方案中，所述的脂质体组合物中还可存在SUV或LUV等其他脂质体形式。在某些实施方案中，所述的脂质体组合物可主要以MLV的形式存在。在某些实施方案中，所述的脂质体组合物可主要以SUV的形式存在。
本公开涉及一种格列本脲脂质体组合物在制备预防或治疗受神经元损伤影响的疾病和病症的药物中的用途。
本公开提供一种预防或治疗受神经元损伤影响的疾病和病症的方法，包括向受试者施用治疗有效量的格列本脲脂质体组合物。在一些实施方案中，格列本脲脂质体组合物可以与藏花酸或其可药用盐、依达拉奉或重组组织型纤维蛋白酶原激活剂(r-tPA)联合使用。
在一些实施方案中，所述受神经元损伤影响的疾病和病症可选自脑卒中、脑损伤、神经性疼痛、偏头痛、炎症痛、慢性疼痛或抑郁症。在一些实施方案中，所述受神经元损伤影响的疾病和病症为缺血性脑卒中。在一些实施方案中，所述受神经元损伤影响的疾病和病症可为大脑半球梗塞。在一些实施方案中，所述受神经元损伤影响的疾病和病症可为急性蛛网膜下腔出血。
本公开提供一种治疗需要的受试者的急性脑卒中、创伤性脑损伤、脊髓损伤、心肌梗塞、休克、器官缺血、室性心律失常、缺血性损伤、缺氧/缺血或其他损伤病症和障碍的方法，包括向受试者施用治疗有效量的格列本脲脂质体组合物。在一些实施方案中，格列本脲脂质体组合物可以与藏花酸或其可药用盐、丁苯酞、依达拉奉或重组组织型纤维蛋白酶原激活剂(r-tPA)联合使用。
在某些实施方案中，所述的脂质体组合物可在给予个体后，约4h内或约3h内达到药物的峰浓度(Cmax)，例如约2.5h内达到药物的峰浓度(Cmax)，或者约2h内达到药物的峰浓度，或者约1.5h内达到药物的峰浓度，或者约1h内达到药物的峰浓度，或者约45min内达到药物的峰浓度，或者约0.5h内达到药物的峰浓度，或者约20min内达到药物的峰浓度，或者约10min内达到药物的峰浓度。
在某些实施方案中，所述的脂质体组合物的给药剂量范围可选自1-10mg、10-20mg、20-30mg、30-40mg、40-50mg、50-60mg、60-70mg、70-80mg、80-90mg或90-100mg。在一些实施方案中，所述格列本脲脂质体组合物的给药剂量范围选自1-2.5mg、1.5-3.5mg、2.5-4.5mg、3.5-5.5mg、5-6mg、6-7mg、7-8mg、8-9mg、9-10mg。
在一些实施方案中，所述的脂质体组合物的每日给药剂量范围可选自0.1-20mg。在一些实施方案中，所述的脂质体组合物的每日给药剂量范围选自0.1-1mg、1-2mg、2-3mg、3-4mg、4-5mg、5-6mg、6-7mg、7-8mg、8-9mg、9-10mg。
在一些实施方案中，所述的脂质体组合物的施用方法可以是在开始一次或多次连续输注后累积持续至少72小时的一次或多次连续输注。在一些实施方案中，可在推注剂量施用后开始所述一次或多次连续输注。在一些实施方案中，一次或多次连续输注可包括两次或更多次连续输注剂量，其中第一次连续输注剂量高于第二次连续输注剂量。在一些实施方案中，可第一次推注和第二次推注格列本脲，然后连续输注格列本脲。在一些实施方案中，可给予需要治疗的受试者第一次推注的格列本脲，然后第一次和第二次连续输注格列本脲。在一些实施方案中，可(a)第一次推注给予格列本脲，(b)在所述推注施用格列本脲后，首先连续输注约125μg/hr至约150μg/hr格列本脲，(c)在所述第一次连续输注格列本脲后，第二次连续输注给予约100μg/hr至约125μg/hr格列本脲，(d)在所述第二次连续输注格列本脲后第三次连续输注约15μg/hr至约300μg/hr格列本脲。
在一些实施方案中，所述的脂质体组合物最好是在患者发病0.5小时内、1小时内、1.5小时内、2小时内、2.5小时内或者3小时内给药。
经注射给药后，本公开所述的脂质体组合物相比于格列本脲普通注射剂，入脑率大大提高，例如提高1000倍以上、500倍以上、100倍以上、50倍以上、30倍以上、20倍以上、10倍以上、5倍以上、3倍以上、2倍以上。
经注射给药后，本公开所述的脂质体组合物在MCAO局灶性暂时性脑缺血SD大鼠中给药后10min的格列本脲入脑率为5％-90％。在某些实施方案中，在给药后10min入脑率可为5％-80％、5％-70％、5％-60％、5％-50％、5％-40％、5％-30％、10％-80％、10％-70％、10％-60％、10％-50％、10％-40％、10％-30％、20％-80％、20％-70％、20％-60％、20％-50％、20％-40％、30％-80％、30％-70％、30％-60％、30％-50％、40％-80％、40％-70％或40％-60％。
经注射给药后，本公开所述的脂质体组合物在MCAO局灶性暂时性脑缺血SD大鼠中给药后40min的格列本脲入脑率为1％-90％。在某些实施方案中，在给药后40min入脑率可为5％-80％、5％-70％、5％-60％、5％-50％、5％-40％、5％-30％、10％-80％、10％- 70％、10％-60％、10％-50％、10％-40％、10％-30％、20％-80％、20％-70％、20％-60％、20％-50％、20％-40％、30％-80％、30％-70％、30％-60％、30％-50％、40％-80％、40％-70％、40％-60％。
所述的入脑率＝脑组织的药物浓度/血浆中的药物浓度*100％。
经注射给药后，本公开所述的脂质体组合物在MCAO局灶性暂时性脑缺血SD大鼠中给药后10min的脑组织中格列本脲浓度可为10-500ng/mL。在某些实施方案中，在给药后10min脑组织中格列本脲浓度可为10-450ng/mL、10-400ng/mL、10-350ng/mL、10-300ng/mL、10-250ng/mL、10-200ng/mL、10-150ng/mL、10-100ng/mL、20-450ng/mL、20-400ng/mL、20-350ng/mL、20-300ng/mL、20-250ng/mL、20-200ng/mL、20-150ng/mL、20-100ng/mL、30-450ng/mL、30-400ng/mL、30-350ng/mL、30-300ng/mL、30-250ng/mL、30-200ng/mL、30-150ng/mL、30-100ng/mL、50-450ng/mL、50-400ng/mL、50-350ng/mL、50-300ng/mL、50-250ng/mL、50-200ng/mL、50-150ng/mL、50-100ng/mL。
经注射给药后，本公开所述的脂质体组合物在MCAO局灶性暂时性脑缺血SD大鼠中给药后40min的脑组织中格列本脲浓度可为1-500ng/mL。在某些实施方案中，在给药后40min脑组织中格列本脲浓度可为1-450ng/mL、5-500ng/mL、5-450ng/mL、1-400ng/mL、5-400ng/mL、1-350ng/mL、5-350ng/mL、1-300ng/mL、5-300ng/mL、1-250ng/mL、5-250ng/mL、1-200ng/mL、5-200ng/mL、1-150ng/mL、5-150ng/mL、1-100ng/mL、5-100ng/mL、10-450ng/mL、10-400ng/mL、10-350ng/mL、10-300ng/mL、10-250ng/mL、10-200ng/mL、10-150ng/mL、10-100ng/mL、20-450ng/mL、20-400ng/mL、20-350ng/mL、20-300ng/mL、20-250ng/mL、20-200ng/mL、20-150ng/mL、20-100ng/mL、30-450ng/mL、30-400ng/mL、30-350ng/mL、30-300ng/mL、30-250ng/mL、30-200ng/mL、30-150ng/mL、30-100ng/mL、50-450ng/mL、50-400ng/mL、50-350ng/mL、50-300ng/mL、50-250ng/mL、50-200ng/mL、50-150ng/mL、50-100ng/mL、1-80ng/mL、5-80ng/mL、1-70ng/mL、5-70ng/mL、1-60ng/mL、5-60ng/mL、1-50ng/mL、5-50ng/mL、1-40ng/mL、5-40ng/mL、1-30ng/mL、5-30ng/mL、1-20ng/mL、5-20ng/mL。
脂质体组合物可以通过薄膜分散法、逆相蒸发法、冷冻干燥法、主动载药法、pH梯度法、注入法和/或超声波分散法制备。在一些实施方案中，还可以进一步包含整粒(或者说是均质、匀化)的步骤，整粒方法可以但不限于用高压均质机、超声、挤出等方法。
在一些实施方案中，脂质体组合物可通过薄膜分散法制备，具体包括：磺酰脲类化合物和脂质溶于有机溶剂或者有机溶剂与水的混合物，除溶剂成膜，水合。在一些实施方案中，所述的制备方法还可进一步包含对水合后得到的脂质体组合物进行超声或者高 压均质。
在一些实施方案中，脂质体组合物可通过主动载药法制备。
在一些实施方案中，主动载药法可包括：制备空白脂质体膜；用pH<7的溶液水合，匀化，使空白脂质体内水相包封低pH溶液；将空白脂质体外水相置换成pH>7的溶液；将空白脂质体用包含磺酰脲类化合物的pH>7的水溶液孵育载药，得到载药的脂质体。
在一些实施方案中，主动载药法可包括：制备空白脂质体膜；用pH<7的溶液水合，匀化，使空白脂质体内水相包封低pH溶液；将空白脂质体外水相置换成pH>7的溶液；将空白脂质体用包含格列本脲的pH>7的水溶液孵育载药，得到载药的脂质体。
在一些实施方案中，可包括得到上述载药的脂质体后，再将pH调回7左右，离心除去游离药物，并将渗透压调至与血浆等渗。
在一些实施方案中，主动载药法具体可为pH梯度法。
匀化可以通过选自但不限于超声处理、高压乳匀的方式实现。
进一步地，空白脂质体膜可以是用薄膜蒸发法制备的。例如，可以称取适量的脂质、有机溶剂，加入容器中，溶解后旋蒸除溶剂成膜。
进一步地，内水相包封低pH溶液的过程中，可以用较低pH(例如pH为5.5的Na2HPO4-柠檬酸缓冲液)的溶液进行水合一段时间，然后间断性超声处理，得到空白脂质体。
进一步地，置换外水相的过程中，可用高pH的溶液将前述制备的空白脂质体溶液的pH调节至较高pH水平(溶液pH相对于内水相升高，例如内水相pH为5.5，外水相pH为7)。
进一步地，孵育载药过程中，可以将前述制备的空白脂质体溶液置于透析袋，并将透析袋置于高pH(例如pH为10.0)的含格列本脲的溶液中，孵育，得到载药的脂质体溶液。采用本公开所述的主动载药法或pH梯度法制备的脂质体组合物粒径小且均匀，载药量大。
本公开还涉及具有高度pH依赖性溶解度的药物或者活性成分的脂质体组合物制备方法，包括采用主动载药法或pH梯度法进行制备。
例如，有一些药物在低pH条件下溶解度较大，当pH变高时会慢慢析出，该类药物的脂质体组合物可以但不必须通过如下方法制备：
通过薄膜蒸发法或者其他的方法制备空白脂质体膜；
内水相包封高pH的溶液，可以用一定体积的较高pH的溶液进行水合一段时间，然后超声处理，得到空白脂质体；
置换外水相为低pH的溶液，调低脂质体溶液的pH，使其相对于内水相的pH低0.5-3个单位，例如内水相pH为7.5，则可以将外水相的pH调节至5.0；
孵育载药，将外水相调节过pH的脂质体溶液置于更低pH的药物溶液中，例如将外水相pH为5.0的空白脂质体溶液置于pH为4.0或者更低pH的药物溶液中，孵育一段时间，得到载药的脂质体。
例如，有一些药物在高pH条件下溶解度较大，当pH变低时会慢慢析出，该类药物的脂质体组合物可以但不必须通过如下方法制备：
通过薄膜蒸发法或者其他的方法制备空白脂质体膜；
内水相包封低pH的溶液，可以用一定体积的较低pH的溶液进行水合一段时间，然后超声处理，得到空白脂质体；
置换外水相为高pH的溶液，调高脂质体溶液的pH，使其相对于内水相的pH高0.5-3个单位，例如内水相pH为5.0，则可以将外水相的pH调节至7.5；
孵育载药，将外水相调节过pH的脂质体溶液置于更高pH的药物溶液中，例如将外水相pH为7.5的空白脂质体溶液置于pH为10.0或者更高pH的药物溶液中，孵育一段时间，得到载药的脂质体。
根据本公开所述的主动载药法得到的药物的脂质体组合物粒径均匀且较小。
本公开还涉及具有高度pH依赖性溶解度的药物或者活性成分的脂质体组合物，其包含具有高度pH依赖性溶解度的药物或者活性成分和脂质，所述脂质包含至少一种磷脂。在一些实施方案中，所述的脂质体组合物通过主动载药法制备得到。
本公开所述的高度pH依赖性溶解度的药物或者活性成分包括但不限于弱酸、弱碱性药物或者活性成分，例如可选自但不限于格列本脲、尼美舒利、氯吡格雷、咪唑立宾、普伐他汀、萘普生、乙酰水杨酸、双氯酚酸钠、唑吡坦、马来酸非诺多绊、瑞格列奈、盐酸鲁拉西酮、利培酮、长春西汀、crizotinib、克拉霉素、双嘧达莫、盐酸厄洛替尼、布洛芬、达可替尼。
本公开的脂质体组合物可以通过蒸发、冷冻干燥或喷雾干燥等方式制备成为固体组合物。所述的固体组合物可以是粉末、颗粒，或者聚集在一起的饼状或块状物。所述的固体组合物经过复溶即可得到可用于给药的液体形式。所述的复溶通常可通过将固体组合物与水或者水溶液混合来实现。在某些实施方案中，所述水溶液可包括但不限于等渗溶液或缓冲液。所述的等渗溶液可具有与人血基本相同的渗透压的溶液，其可通过等渗剂和水制备而成。所述的等渗剂可包括氯化钠、氯化钾、氯化镁、氯化钙、葡萄糖、木糖醇、山梨醇。所述的缓冲液可以是指经缓冲的溶液，其通过其酸-碱共轭成分的作用来阻止pH 的变化。在一些实施方案中，缓冲液的pH范围可为约4.5至约8.5，可将pH控制在该范围的缓冲液的实例包括但不限于PBS、Na2HPO4-柠檬酸缓冲液、氨-氯化铵缓冲液、醋酸-醋酸钠缓冲液、磷酸盐缓冲液、磷酸二氢钾-氢氧化钠缓冲液、Tris-盐酸缓冲液、硼酸-硼砂缓冲液、巴比妥钠-盐酸缓冲液、乙酸盐(例如乙酸钠)、琥珀酸盐(如琥珀酸钠)、葡糖酸盐、组氨酸、柠檬酸盐、碳酸盐、HEPES和其它有机酸缓冲液。
本公开还涉及一种提高磺酰脲类化合物如格列本脲入脑率的方法，包括将其以本公开中的脂质体形式向个体注射给药。
本公开的脂质体组合物可以以肠胃外注射形式给药，选自静脉注射、皮下注射、组织注射。使用标准方法和装置，例如，笔、注射器系统、针和注射器、皮下注射递送系统、导管等来完成本公开的脂质体组合物的施用。
术语“约”是指数量、尺寸、配方、参数、以及其他量和特性是不精确的并且不必是精确的，但可以是期望的近似值和/或较大值或较小值，由此反映公差、转换因子、四舍五入、测量误差等、以及本领域的技术人员已知的其他因子。其含义可包括±10％的变化，优选±5％的变化。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围。
本公开所述的粒径采用PSS粒度仪，型号Nicomp Z3000，所述平均粒径为Intensity Mean Diameter。
实施例1：处方1
(1)制备空白脂质体膜：称取胆固醇15.95mg、HSPC 47.9mg、MPEG2000-DSPE 15.95mg，置于500mL圆底烧瓶中，加有机溶剂2mL(氯仿：甲醇＝9:1)完全溶解，旋蒸除去溶剂并成膜，N 2吹干，使有机溶剂完全除去。
(2)内水相包封低pH值介质：用pH5.5介质(Na 2HPO 4-柠檬酸缓冲液)50mL水合空白脂质体膜约30min，搅拌均匀，探头间断性超声10min。得空白脂质体，平均粒径约123.66nm.
(3)置换高pH外水相，造成pH梯度：用NaOH溶液将步骤(2)得到的空白脂质体pH调至7.0。
(4)孵育载药：将步骤(3)得到的空白脂质体置于透析袋(M＝3500)，并将透析袋置于pH 10.19的格列本脲溶液中(母液浓度约50μg/mL),孵育过夜，得载药脂质体，测 得此时脂质体pH为9.74，平均粒径124.86nm，PI(又称PDI)为0.24。格列本脲总浓度为50.67μg/mL。
(5)pH调节：
取步骤(4)得到的脂质体3mL，调节其pH为约5.0，离心除去游离API，测得格列本脲浓度约18.96μg/mL。由于调pH过程中液体体积变为原来的2倍，原脂质体含药应为18.96*2＝37.93μg/mL。
实施例2：处方2-6
表1.处方2-6的成分
Figure PCTCN2021081704-appb-000001
制备方法：
按照上表精确称量50ml样品所需的格列本脲以及脂质成分，置于圆底烧瓶中，加有机溶剂2mL(氯仿：甲醇＝9:1)完全溶解(其中，处方2处有机溶剂外，另加0.3mL水溶解)，旋蒸除溶剂并成膜，N2吹干10min，使有机溶剂完全除去。
加入蒸馏水50mL，65℃搅拌，水合30min，测粒径。
探头间断性超声10min。测粒径。
表2.处方2-6的表征参数
Figure PCTCN2021081704-appb-000002
Figure PCTCN2021081704-appb-000003
实施例3：比较脂质体制剂与普通制剂在MCAO局灶性暂时性脑缺血大鼠中的组织分布
试验方法：
SPF级SD雄性大鼠40只，体重：250-300g，体重个体值在均数±20％范围内。来源：北京维通利华实验动物技术有限公司，生产许可证号：SCXK(京)2016-0011。
脂质体制剂制备：将实施例1步骤(4)得到的载药脂质体调节pH至6.8，浓缩、调节渗透压至浓度为约100μg/mL，渗透压在280-320mOsm之间。
普通制剂制备：用DMSO配制格列本脲母液5mg/mL，用纯化水稀释、用5M NaOH浓溶液调pH，得到浓度为100.94μg/mL、pH为8.60、渗透压为340mOsm的格列本脲溶液。
将动物随机分配成两组，脂质体制剂组和普通制剂组各20只。通过线栓法造成大鼠大脑中动脉闭塞(MCAO)局灶性脑缺血，缺血1小时后拔出线栓实现再灌注。手术操作如下：将大鼠以异氟烷维持麻醉，仰卧，从颈部正中切口后，钝性分离肌肉层，暴露右侧颈总动脉，依次分离出颈外、颈内动脉及其他相关血管分支。于颈外动脉作切口，将进行标记了的线栓(型号：2838-A4)缓慢向颈内动脉推进，直至稍感阻力(鱼线前端离颈内外交叉点距离约为18mm)。缺血60min后，通过神经功能行为学评分判断造模是否成功，确定造模成功后即刻解开缝合线，将线栓完全拔出，扎紧动脉残端，实现再灌注。再灌注120min后即刻通过静脉注射给与药物制剂。模型动物经静脉注射药物制剂后10min、40min、2h和4h检测血浆、脑组织和脑脊液中药物浓度，每个时间点4只动物(造模5只)。
试验结果：
在注射后第10min和第40min，检测到脂质体制剂组的脑组织中格列本脲的平均浓度分别为78.2ng/mL和8.1ng/mL，血浆中平均浓度分别为1068ng/mL和726ng/mL，入脑率平均分别为7.3％和1.1％；等剂量普通制剂组脑组织中未检测到格列本脲，提示脂质体制剂可以显著提高格列本脲的入脑率。
实施例4：处方7的制备
表3.处方7的成分
组分 质量浓度mg/mL
格列本脲 0.02
HSPC 0.96
MPEG2000-DSPE 0.32
胆固醇 0.32
1.按上表精密称量处方量API以及磷脂等辅料置于圆底烧瓶，加有机溶剂(氯仿：甲醇体积比＝9:1)，完全溶解，旋蒸除溶剂并成膜，氮气吹至机溶剂完全除去。
2.加入处方量pH6.8等渗缓冲溶液(缓冲溶液配制方法：用0.2M磷酸氢二钠缓冲液和0.1M柠檬酸缓冲液调制成pH6.8的介质，再用纯化水稀释至与血浆等渗，渗透压约280-320mOsm)，搅拌水合。
3.将上述溶液均质机均质压力800bar均质5次，后0.2μmPC膜挤出3次，得到格列本脲浓度为8.73ug/mL，HSPC 0.98mg/mL。
4.对步骤3所得的溶液进行浓缩，测得浓缩后API浓度为11.49ug/mL,HSPC3.31mg/mL。
表4.处方7的表征参数
Figure PCTCN2021081704-appb-000004
样品置于4℃保存，18天后取出观察，浅乳白色澄明溶液，有淡蓝色乳光，复测粒径：112.31nm，PI 0.19。
实施例5：比较脂质体制剂与普通制剂在MCAO局灶性暂时性脑缺血大鼠中的组织分布
试验方法：
参照实施例3中的方法进行动物实验，采用大鼠尾静脉注射给药，采血时间10min。PK试验方案以及结果如下：
表5.处方7给药结果数据
组别 给药剂量 脑组织ng/g 血浆(ng/mL) 脑组织-血浆浓度比率
普通注射剂 0.4mg/kg BLOQ 222 0.036％
处方7 0.1mg/kg 0.787 38 2.09％
BLOQ：低于检测下限
血浆药物浓度：注射后第10min检测到普通注射剂和处方7组大鼠血浆中格列本脲的平均浓度分别为222、38ng/mL。
脑组织中药物浓度：在注射后第10min检测到处方7组的右脑和左脑脑组织中格列本脲的平均浓度分别为0.80和0.77ng/g，左右脑组织-血浆浓度比例均为2％；
格列本脲普通注射剂剂和处方7的“脑组织-血浆”浓度比率分别为0.036％和2.09％，处方7可以显著提高格列本脲的入脑率(是普通注射剂的58倍)。

Claims (15)

  1. 一种注射用脂质体组合物，包含磺酰脲类化合物和脂质，所述脂质包含至少一种磷脂。
  2. 根据权利要求1所述的脂质体组合物，其中所述磺酰脲类化合物为格列本脲。
  3. 根据权利要求1所述的脂质体组合物，其为单位剂量形式，包含磺酰脲类化合物1-20mg。
  4. 根据权利要求1所述的脂质体组合物，所述磺酰脲类化合物的浓度选自0.005-10mg/mL。
  5. 根据权利要求1所述的脂质体组合物，其渗透压小于600mOsm。
  6. 根据权利要求1所述的脂质体组合物，所述脂质体的平均粒径小于500nm。
  7. 根据权利要求1所述的脂质体组合物，所述磷脂包括磷脂酰胆碱、脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、磷脂酰肌醇中的一种或多种，优选二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、1-棕榈酰-2-亚油酰-sn-甘油-3-磷脂酰胆碱、磷酸胆碱、蛋黄磷脂酰胆碱、二月桂酰磷脂酰胆碱、氢化的大豆磷脂酰胆碱、l-肉豆蔻酰-2-棕榈酰磷脂酰胆碱、l-棕榈酰-2-肉豆蔻酰磷脂酰胆碱、l-棕榈酰-2-硬脂酰磷脂酰胆碱、l-硬脂酰-2-棕榈酰磷脂酰胆碱、棕榈酰油酰磷脂酰胆碱、溶血磷脂酰胆碱、二亚油酰磷脂酰胆碱、二硬脂酰磷脂酰乙醇胺、MPEG2000-DSPE、二肉豆蔻酰磷脂酰乙醇胺、二棕榈酰磷脂酰乙醇胺、二油酰基磷脂酰甘油、二肉豆蔻酰磷脂酰甘油、二硬脂酰基磷脂酰甘油、二棕榈酰基甘油磷酸甘油、二棕榈酰基磷脂酰丝氨酸、1，2-二油酰基-sn-甘油-3-磷脂酰丝氨酸、二肉豆蔻酰基磷脂酰丝氨酸、二硬脂酰基磷脂酰丝氨酸、二棕榈酰基磷脂酸、1，2-二油酰基-sn-甘油-3-磷脂酸、二肉豆蔻酰基磷脂酸、二硬脂酰基磷脂酸、二棕榈酰基磷脂酰肌醇、1，2-二油酰基-sn-甘油-3-磷脂酰肌醇、二肉豆蔻酰基磷脂酰肌醇、二硬脂酰基磷脂酰肌醇、(2,3-二油酰基-丙基)-三甲胺、大豆卵磷脂中的一种或多种。
  8. 根据权利要求1所述的脂质体组合物，其中所述脂质还包含类固醇，优选胆固醇。
  9. 根据权利要求1所述的脂质体组合物，其中所述脂质包含磷脂和胆固醇，所述胆固醇与磷脂的重量比例选自1:0.1-20；优选1:1-10，优选1:1-5，更优选1:2-4、1:3-5或者1:1-3。
  10. 根据权利要求1所述的脂质体组合物，其中所述磺酰脲类化合物与所述脂质的重量比选自1:1-1000；优选1:1-100。
  11. 一种根据权利要求1-10任一项所述的脂质体组合物的制备方法，所述方法为薄 膜分散法、逆相蒸发法、冷冻干燥法、主动载药法、pH梯度法、注入法或超声波分散法。
  12. 根据权利要求11所述的制备方法，其为主动载药法，具体包括：制备空白脂质体膜；用pH<7的溶液水合，匀化，使空白脂质体内包封低pH溶液；将空白脂质体外水相置换成pH>7的溶液；用包含磺酰脲类化合物的pH>7的水溶液孵育载药，得到载药的脂质体。
  13. 根据权利要求11所述的制备方法，其为薄膜分散法，具体包括：将磺酰脲类化合物和脂质溶于有机溶剂，除溶剂成膜，水合，超声或者高压均质。
  14. 一种根据权利要求1-10任一项所述的脂质体组合物或由权利要求11-13任一项所述的方法制备的脂质体组合物在制备预防或治疗受神经元损伤影响的疾病和病症的药物中的用途。
  15. 根据权利要求14所述的用途，受神经元损伤影响的疾病和病症选自脑卒中、脑损伤、神经性疼痛、偏头痛、炎症痛、慢性疼痛或抑郁症，优选脑卒中，更优选缺血性脑卒中。
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