[go: up one dir, main page]

WO2018137483A1 - Nanomédicament à libération prolongée pour le ciblage d'une maladie neurodégénérative - Google Patents

Nanomédicament à libération prolongée pour le ciblage d'une maladie neurodégénérative Download PDF

Info

Publication number
WO2018137483A1
WO2018137483A1 PCT/CN2018/071352 CN2018071352W WO2018137483A1 WO 2018137483 A1 WO2018137483 A1 WO 2018137483A1 CN 2018071352 W CN2018071352 W CN 2018071352W WO 2018137483 A1 WO2018137483 A1 WO 2018137483A1
Authority
WO
WIPO (PCT)
Prior art keywords
nanoparticles
serum albumin
human serum
nanoparticle
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/071352
Other languages
English (en)
Chinese (zh)
Inventor
王永安
杨军
范丽雪
骆媛
李万华
隋昕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Pharmacology and Toxicology of AMMS
Original Assignee
Institute of Pharmacology and Toxicology of AMMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Pharmacology and Toxicology of AMMS filed Critical Institute of Pharmacology and Toxicology of AMMS
Priority to DE212018000131.6U priority Critical patent/DE212018000131U1/de
Publication of WO2018137483A1 publication Critical patent/WO2018137483A1/fr
Anticipated expiration legal-status Critical
Priority to AU2019100932A priority patent/AU2019100932A4/en
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the field of medical technology, and in particular to a nanoparticle comprising a carrier material, an active ingredient and a targeting molecule, the carrier material being human serum albumin, the active ingredient being capable of preventing and/or treating a neurodegenerative disease. Active ingredient.
  • the present invention also relates to a method of preparing the nanoparticles, a pharmaceutical composition comprising the nanoparticles, and a medicament for preparing a neurodegenerative disease for preventing and/or treating a subject in the nanoparticle or pharmaceutical composition. Use in.
  • AD Alzheimer's disease
  • a ⁇ ⁇ - Amyloid
  • the central cholinergic system is closely related to learning and memory.
  • Acetylcholine is one of the important neurotransmitters in the central cholinergic system. Its main function is to maintain consciousness and play an important role in learning and memory.
  • the exact cause of AD is still unknown, the massive loss of neurons in specific brain regions is a direct cause of progressive decline in cognitive and memory capabilities, especially the loss of cholinergic neurons in the hippocampus.
  • there are five drugs approved by the US FDA for the treatment of AD namely tacrine, neostigmine, galantamine, donepezil and memantine. The first four are reversible acetylcholinesterase inhibitors.
  • the acetylcholinesterase inhibitor can firmly interact with the acetylcholinesterase in the body, occupying the enzyme site, and the enzyme loses the function of decomposing acetylcholine, thereby indirectly increasing the concentration of acetylcholine in the synaptic cleft, and achieving the effect of relieving AD.
  • the drugs used to treat AD are still limited, not only because the mechanism of origin is unclear, but also because the brain's complex defense system prevents the drug from penetrating the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • an extracellular transporter eg, p-glycoprotein
  • a neurodegenerative disease represented by AD is a type of chronic disease. After the diagnosis, the patient needs to take the drug for a long time without interruption or even take it for life.
  • the existing AD treatment drugs have short plasma half-life, poor blood-brain barrier penetration, and rapid metabolism, so that patients need to take the medicine on time and in time, which is very difficult for patients whose memory is diminishing. Therefore, it is urgent to prepare a drug for the treatment of AD with high efficiency, sustained release and high targeting.
  • nanomedicines targeting the central nervous system use synthetic polymer materials as carriers, that is, the carrier material is coated on the outer layer of the target drug, and the core drug is degraded when the carrier material is degraded at the target site. It is released.
  • Such nanomedicines are simple to prepare, have high stability, are non-toxic to some extent, and are easily degraded.
  • AD neurodegenerative disease represented by AD belongs to chronic diseases of the elderly, and the brain metabolic capacity of patients is reduced.
  • exogenous synthetic polymer materials and their degradation products will undoubtedly increase the burden on the brain, so when preparing AD nanomedicines More attention should be paid to the biocompatibility of materials and the toxicity of material metabolites.
  • HSA human serum albumin
  • nanoparticle refers to particles having a particle size on the order of nanometers, such as particles having a particle size of not more than 1000 nm, for example, having a particle diameter of 10 nm to 100 nm, 100 nm to 200 nm, and 200 nm to 300 nm. Particles between 300 nm and 400 nm, 400 nm to 500 nm, 500 nm to 600 nm, 600 nm to 700 nm, 700 nm to 800 nm, 800 nm to 900 nm, or 900 nm to 1000 nm.
  • particle size or “equivalent particle size” means that when a physical property or physical behavior of a particle to be measured is closest to a homogenous sphere (or combination) of a certain diameter, The diameter (or combination) of the sphere is taken as the equivalent particle diameter (or particle size distribution) of the measured particle.
  • the term "average particle size" refers to an actual population of particles consisting of particles of different sizes and shapes, compared to a group of hypothetical particles consisting of uniform spherical particles. When the total length of the diameter is the same, the diameter of the spherical particles is referred to as the average particle diameter of the actual particle group. Methods of measuring the average particle size are known to those skilled in the art, such as light scattering; and measuring instruments of average particle size include, but are not limited to, light scattering particle size analyzers.
  • choline energy transmitter supplement refers to an active ingredient (eg, a drug) that exogenously supplements a cholinergic neurotransmitter (a cholinergic transmitter).
  • prodrug refers to a compound obtained by modifying a compound which is inactive or less active in vitro and which exerts an efficacious effect by enzymatic or non-enzymatic conversion in vivo to release the active drug.
  • the design principles and preparation methods of prodrugs are known to those skilled in the art.
  • the term "pharmaceutically acceptable salts” refers to an acidic functional group (e.g. -COOH, -OH, -SO 3 H and the like) compound (1) in the presence of a suitable inorganic or organic cation (base) a salt formed, for example, a salt of a compound with an alkali metal or an alkaline earth metal, an ammonium salt of a compound, and a salt of a compound with a nitrogen-containing organic base; and (2) a basic functional group (for example, -NH 2 , etc.) present in the compound Salts formed with suitable inorganic or organic anions (acids), for example salts of the compounds with inorganic or organic carboxylic acids.
  • bases e.g. -COOH, -OH, -SO 3 H and the like
  • salts include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, lithium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; other metal salts, Such as aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic alkali salt, such as ammonium salt; organic alkali salt, such as t-octylamine salt, dibenzylamine salt, morpholine salt, Portuguese Glycosylamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'- Dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethoxysulfonium salt, diethylamine
  • neurodegenerative disease refers to a disease caused by progressive disease of the nervous system, including but not limited to Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, muscular atrophy. Lateral sclerosis and multiple sclerosis of the brain.
  • good solvent refers to a solvent capable of solubilizing human serum albumin, including but not limited to water and sodium chloride solutions.
  • the term “poor solvent” refers to a solvent that does not dissolve human serum albumin, including but not limited to ethanol.
  • room temperature means 25 ⁇ 5 °C.
  • the inventors In order to meet the therapeutic needs of neurodegenerative diseases such as Alzheimer's disease, the inventors have obtained the nanoparticles of the present application through intensive research and creative labor, which can be used to deliver poor blood-brain barrier permeability and/or plasma.
  • a drug with a short half-life effectively achieves the central targeting and sustained release targets of the drug, thereby providing the following inventions:
  • the present invention provides a nanoparticle comprising a carrier material, an active ingredient, and a targeting molecule, the carrier material being human serum albumin, the active ingredient being capable of preventing and/or treating a neurodegenerative disease ingredient.
  • human serum albumin has a high affinity with A ⁇ monomer, and has a targeting property against A ⁇ . While ensuring a large amount of drug molecules, it can rapidly target the lesion site and achieve excellent targeting performance of the material itself. .
  • natural protein materials have high biosafety, meet the requirements of use in the pharmaceutical field, are non-immunogenic, and the decomposition products are amino acids, which can be reused or converted into other nitrogen-containing substances as the body's own nutrients, minimizing The damage and burden of the central nervous system by exogenous organic or inorganic polymer materials.
  • the active ingredient is loaded into a carrier material to form human serum albumin-loaded nanoparticles.
  • the human serum albumin drug-loaded nanoparticles are formed by a method comprising the steps of:
  • Step (1-1) dissolving or dispersing human serum albumin and active ingredient in a good solvent to form a solution (1);
  • the nanoparticle has a drug loading rate of 15% to 25%, such as 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.
  • the active ingredient is selected from the group consisting of a cholinergic neurotransmitter supplement and a cholinesterase inhibitor.
  • the cholinergic transmitter supplement is selected from the group consisting of acetylcholine, a prodrug of acetylcholine, or a pharmaceutically acceptable salt of acetylcholine (eg, a hydrochloride salt).
  • the cholinergic transmitter supplement is acetylcholine or acetylcholine chloride.
  • the cholinesterase inhibitor is selected from the group consisting of lismin, galantamine or donepezil, or a pharmaceutically acceptable salt of such compounds (eg, tartrate).
  • the cholinesterase inhibitor is Lismin heavy tartrate.
  • the surface modification of nanoparticles has targeting molecules to increase the permeability of nanoparticles to the blood-brain barrier and achieve efficient central targeted transport.
  • the targeting molecule is selected from the group consisting of a surfactant, a polyethylene glycol-based polymer, and a blood brain barrier-specific antibody.
  • the targeting molecule is a surfactant.
  • the targeting molecule is Tween-80.
  • the targeting molecule is modified on the surface of the nanoparticle.
  • the targeting molecule is modified on the surface of a human serum albumin-loaded nanoparticle.
  • the targeting molecule is modified on the surface of the nanoparticle by adsorption.
  • the nanoparticles have a diameter of from 150 nm to 250 nm; for example, 150 nm to 180 nm, 180 nm to 200 nm, 200 nm to 220 nm, or 220 nm to 250 nm; for example, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm 220 nm, 230 nm, 240 nm or 250 nm.
  • the nanoparticles have a zeta potential of -30 mV to +20 mV, such as -30 mV to -20 mV, -20 mV to -10 mV, -10 mV to 0, 0 to +10 mV, or +10 mV to +20 mV; For example, -30 mV, -25 mV, -20 mV, -15 mV, -10 mV, -5 mV, 0, +5 mV, +10 mV, +15 mV or +20 mV.
  • the encapsulation efficiency of the nanoparticles is from 40% to 50%, such as 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%.
  • Fig. 1 exemplarily shows a structure of the nanoparticles of the present application.
  • HSA with A ⁇ targeting property is used as a nanocarrier, and a drug capable of treating AD is coated, and a surface molecule is modified on the surface of the HSA nanoparticle to enhance the HSA nanoparticle.
  • the blood-brain barrier (BBB) is transmissive and prolongs circulation time in the body.
  • the present application provides a method of preparing the above nanoparticles, the method comprising the steps of:
  • Step (1) preparing human serum albumin-loaded nanoparticles
  • Step (2) modifying the targeting molecule on the surface of the human serum albumin-loaded nanoparticles.
  • the method of preparing human serum albumin-loaded nanoparticles is an anti-solvent method.
  • the step (1) comprises the steps of:
  • Step (1-1) dissolving or dispersing human serum albumin and active ingredient in a good solvent to form a solution (1);
  • the mass ratio of human serum albumin to active ingredient is from 1:1 to 10:1, such as 1:1, 2:1, 3:1, 4 1: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, or 10: 1.
  • the good solvent is a sodium chloride solution.
  • the concentration of the sodium chloride solution is from 1 mmol/L to 20 mmol/L, for example, from 1 mmol/L to 5 mmol/L, from 5 mmol/L to 10 mmol/L, and 10 mmol. /L to 15 mmol / L or 15 mmol / L to 20 mmol / L.
  • the step (1-1) further comprises: adjusting the pH of the solution (1).
  • the poor solvent is ethanol.
  • the step (1-2) is carried out under agitation.
  • the crosslinking agent in step (1-2) is glutaraldehyde.
  • the addition of the crosslinking agent can cross-link and solidify the human serum albumin particles so that they do not immediately swell and disperse in the aqueous solution, thereby avoiding the release of the drug encapsulated in the particles too quickly.
  • the step (1) further comprises the step (1-3) of isolating the human serum albumin-loaded nanoparticles.
  • the human serum albumin-loaded nanoparticles are separated by centrifugation.
  • the step (2) comprises the steps of:
  • the solution of the targeting molecule is a physiological saline solution of the targeting molecule.
  • the concentration of the targeting molecule in the solution of the targeting molecule is from 0.1% to 10%, such as from 0.1% to 0.5%, from 0.5% to 1%, from 1% to 5%, or 5% to 10%.
  • step (2-2) mixing is performed by agitation and/or ultrasound.
  • the drug loading rate and encapsulation efficiency of the drug loaded human serum albumin nanoparticles are tested after step (1).
  • Figure 2 exemplarily shows a method of preparing the nanoparticles of the present application.
  • the method described in the figure comprises: mixing an active ingredient (such as acetylcholine or lissamine) with HSA, under the action of glutaraldehyde, HSA is cross-linked to form HSA-loaded nanoparticles;
  • the surface-modifying target molecule for example, Tween-80 is surface-modified to obtain a modified drug-loaded nanoparticle.
  • the application provides a pharmaceutical composition comprising the above nanoparticles.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant (e.g., a carrier and/or an excipient).
  • a pharmaceutically acceptable adjuvant e.g., a carrier and/or an excipient.
  • the carrier and/or excipient is selected from the group consisting of: an ion exchanger, alumina, aluminum stearate, lecithin, serum protein (eg, human serum albumin), glycerin, sorbic acid, sorbic acid Potassium, a partial glyceride mixture of saturated plant fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose Substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, polyethylene-polyoxypropylene block polymer and lanolin.
  • the pharmaceutical composition can be formulated into any of pharmaceutically acceptable dosage forms.
  • the pharmaceutical composition of the present invention may be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including liquid injections, powders for injection or tablets for injection), suppositories, Inhalant or spray.
  • the pharmaceutical composition of the present invention can also be administered to a subject by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical compositions are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, translingual or respiratory administration.
  • the pharmaceutical composition When used for oral administration, the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical composition may further comprise a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical composition can be formulated into an injection, including a liquid injection, an injectable powder or an injectable tablet.
  • the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • the pharmaceutical composition When the injection is formulated, no additional agent may be added to the pharmaceutical composition, and a suitable additional agent may be added depending on the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, can be formulated into a suppository or the like.
  • the pharmaceutical composition For pulmonary administration, can be formulated as an inhalant or a spray.
  • the nanoparticles of the invention are present in a pharmaceutical composition in unit dosage form.
  • the subject is administered an effective amount of the pharmaceutical composition.
  • the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect.
  • a prophylactically effective amount refers to an amount sufficient to prevent, arrest, or delay the onset of the disease; treating an effective amount of the disease means an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art.
  • the amount effective for therapeutic use will depend on the severity of the condition to be treated, the overall condition of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments for simultaneous administration. and many more.
  • the application provides the use of a nanoparticle or pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a neurodegenerative disease in a subject.
  • the application provides a method of preventing and/or treating a neurodegenerative disease in a subject, comprising administering to the subject a nanoparticle as described above.
  • the application provides a nanoparticle as described above for use in preventing and/or treating a neurodegenerative disease in a subject.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis of the brain.
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate;
  • the subject is a human.
  • the nanoparticles of the present application are particularly suitable for the delivery of drugs that are difficult to penetrate the blood-brain barrier due to their high water solubility, or drugs that have a short plasma half-life and are unable to meet long-term sustained release requirements.
  • the application provides the use of a nanoparticle as described above for enhancing the ability of an active ingredient to pass through a blood-brain barrier of a subject, and/or prolonging the release of the active ingredient in a subject
  • the active ingredient is an active ingredient capable of preventing and/or treating a neurodegenerative disease in a subject.
  • the active ingredient is selected from the group consisting of a cholinergic neurotransmitter supplement and a cholinesterase inhibitor.
  • the cholinergic transmitter supplement is selected from the group consisting of acetylcholine, a prodrug of acetylcholine, or a pharmaceutically acceptable salt of acetylcholine (e.g., hydrochloride).
  • the cholinergic transmitter supplement is acetylcholine or acetylcholine chloride.
  • the cholinesterase inhibitor is selected from the group consisting of lismin, galantamine or donepezil, or a pharmaceutically acceptable salt of such compounds (eg, tartrate).
  • the cholinesterase inhibitor is Lismin heavy tartrate.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis of the brain.
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate;
  • the subject is a human.
  • nanoparticles of the present application have one or more of the following benefits:
  • the nanoparticle of the present application solves the problem that a drug having high water solubility is difficult to pass the blood-brain barrier, and/or a drug having a short plasma half-life cannot achieve a long-term slow drug release problem.
  • the nanoparticles of the present application are highly safe.
  • the nanocarrier used in the nanoparticle of the present application is a natural protein material, has no immunogenicity, high biocompatibility, and the degradation product is a plurality of essential amino acids, and has no toxic and side effects.
  • the drug-loading methods reported in the literature mostly focus on the adsorption of drug molecules on the outer layer of nanoparticles, and the drug-loading rate is low and easy to desorb.
  • the present invention uses nano-particles to encapsulate drug molecules, and the drug molecules are wrapped and wrapped in the nano-carriers, along with the nanoparticles. Gradually disintegrating, the drug molecules are slowly released.
  • the nanoparticles of the present application can effectively improve the spatial learning and memory ability of mice, maintain the activity of the enzymes related to the cholinergic system and the dynamic balance of acetylcholine content, and reduce the level of oxidative stress, especially for the frontotemporal cortex. effect.
  • Fig. 1 exemplarily shows a structure of the nanoparticles of the present application.
  • HSA with A ⁇ targeting property is used as a carrier material, and a drug capable of treating AD is coated, and a surface molecule is modified on the surface of the HSA nanoparticle to enhance the HSA nanoparticle.
  • the BBB is transmissive and extends the circulation time in the body.
  • Figure 2 exemplarily shows a method of preparing the nanoparticles of the present application.
  • the method described in the figure comprises: mixing an active ingredient (such as acetylcholine or lissamine) with HSA, under the action of glutaraldehyde, HSA is cross-linked to form HSA-loaded nanoparticles;
  • the surface-modifying target molecule for example, Tween-80 is surface-modified to obtain a modified drug-loaded nanoparticle.
  • Figure 3 is a scanning electron micrograph of HSA nanoparticles loaded with acetylcholine unmodified Tween-80 in Example 1. As shown, the unmodified HSA drug-loaded nanoparticles are spherical and have a diameter of about 200 nm.
  • Example 4 is a scanning electron micrograph of HSA nanoparticles loaded with acetylcholine modified with Tween-80 in Example 1. As shown in the figure, the HSA drug-loaded nanoparticles modified with Tween-80 are regular cubes with a side length of about 200 nm.
  • FIG. 5 is a scanning electron micrograph of HSA nanoparticles loaded with acetylcholine modified with Tween-80 in Example 1. As shown in the figure, the HSA drug-loaded nanoparticles modified with Tween-80 are regular cubes with a side length of about 200 nm.
  • the HSA solution has a distinct characteristic absorption peak around 280 nm (curve 1), while the Ach solution has no absorption near 280 nm (curve 2).
  • the absorption peak near 280 nm was still clearly visible (curve 3); while the HSA nanoparticles loaded with Ach showed a significant decrease in the absorption peak near 280 nm (curve 4).
  • the results show that the drug molecules are successfully doped in the nanocarriers.
  • FIG. 7 shows the blank HSA nanoparticles of unloaded drug and unmodified Tween-80 in Example 3, HSA-Ach nanoparticles without Tween-80 modified, Tween-80 modified unloaded drug HSA nanoparticles XRD patterns of granules and Tween-80 modified HSA-Ach nanoparticles.
  • the results demonstrate that the targeting molecule Tween-80 has been successfully modified on the surface of nanoparticles.
  • Figure 8 is a standard curve of doxorubicin as determined by ultraviolet spectrophotometry in Example 4.
  • Figure 9 is a graph showing the in vitro cumulative release rate of the doxorubicin sample in Example 4.
  • the doxorubicin solution group reached the maximum cumulative release rate at around 10 h, and the recovery rate was over 90%, which proved that doxorubicin was completely released; while the doxorubicin-loaded drug nanoparticle group was within 80 h.
  • the cumulative release rate is steadily increasing, and the cumulative release rate in neutral saline solution is only 30% of the drug loading rate. It is concluded that the drug-loaded nanoparticles can maintain structural stability during body fluid transportation, ensuring that the nanoparticles entering the central center can still maintain a high drug loading rate.
  • Fig. 10 is a trend diagram showing the time of finding the platform time of each group of mice within 4 days of the training period of the water maze behavior evaluation in the fifth embodiment.
  • the mice in each group found no significant difference in platform time on the first day; on the third and fourth days, the blank control group found the platform time was 20s, and the model group, ACh solution group and RT solution group were found.
  • the platform time was significantly longer than that of the blank control group, and the platform time of the HSA-ACh nanoparticle group and the HSA-RT nanoparticle group was not significantly different from that of the blank control group, and was significantly lower than that of the model group.
  • Experiments have shown that the short-term spatial learning ability of mice is improved after HSA-ACh nanoparticles and HSA-RT nanoparticles are separately administered.
  • Figure 11 is a graph showing the latency of the first time a mouse was found in each group of mice during the water maze behavioral evaluation test in Example 5. As shown in the figure, the latency of the blank control group was the shortest. The analysis of variance showed that the latency of the model group, ACh solution group and RT solution group was significantly longer than that of the blank control group (P ⁇ 0.05), while the HSA-ACh nanoparticle group and HSA. There was no statistically significant difference between the -RT nanoparticle group and the blank control group.
  • Figure 12 shows the number of times each group of mice crossed the platform within 60 s during the test period of the water maze behavioral evaluation in Example 5. As shown in the figure, the number of penetrating mice in the blank control group was significantly higher than that in the model group, ACh solution group and RT solution group (P ⁇ 0.01), but no significant statistics were found with HSA-ACh nanoparticle group and HSA-RT nanoparticle group. Learn the difference.
  • Figure 13 is a graph showing the time in which the mice of each group swim in the target quadrant during the test period of the water maze behavior evaluation in Example 5. As shown in the figure, there was a statistically significant difference between the model group and the ACh solution group compared with the blank control group (P ⁇ 0.05), while there was no statistically significant difference between the other groups and the blank control group.
  • Fig. 14 is a photograph showing the HE staining pathology of the left hemisphere of each group of mice in Example 6, and Fig. AL corresponds to the blank control group hippocampus (A), cortex (B), model group hippocampus (C), cortex (D), ACh. Solution group hippocampus (E), cortex (F), HSA-ACh nanoparticle group hippocampus (G), cortex (H), RT solution group hippocampus (I), cortex (J), HSA-RT nanoparticle group hippocampus (K ), cortex (L).
  • Figure 15 is a photograph of a laser confocal microscope in Example 7.
  • Panels A-C correspond to the heart-injected saline group (control group), the acetylcholine nanoparticle group, and the Lissian nanoparticle group, respectively. It can be clearly observed from the figure that there is no fluorescence distribution in normal zebrafish; for the acetylcholine nanoparticle group and the Lissian nanoparticle group, although the heart is injected, there is obvious green fluorescence in the brain of the zebrafish. Prove that the drug can smoothly enter the center through the blood-brain barrier.
  • human serum albumin (HSA) is used as a nanocarrier material, and acetylcholine is encapsulated.
  • the active ingredient used is acetylcholine chloride
  • the preferred solvent is 10mmol/L sodium chloride solution
  • the poor solvent selected is ethanol
  • the selected cross-linking agent is 10% glutaraldehyde
  • the selected targeting molecule is spit.
  • HSA human serum albumin
  • Step (1) Preparation of HSA drug-loaded nanoparticles by an anti-solvent method: 20 mg of HSA and 10 mg of ACh are dissolved in 1 mL of sodium chloride solution (10 mmol/L), filtered through a 0.22 ⁇ m water-based filter, and then rotated at 600 rpm. This solution was added dropwise to 10 mL of ethanol at a dropping rate of 50 ⁇ L/min; after the completion of the dropwise addition, the stirring speed was increased to 800 rpm, 20 ⁇ L of 10% glutaraldehyde was added, and the reaction was protected from light for 24 hours.
  • the reaction sample was centrifuged at 13600 rpm for 10 min, the supernatant was removed, the precipitate was collected, and the sample was centrifuged three times with an equal amount of physiological saline, and the precipitate was collected to obtain acetylcholine (Ach)-loaded HSA nanoparticles, which were stored at 4 °C.
  • the mass method was used to determine the product quality, and the nano drug encapsulation rate and drug loading rate were calculated as follows:
  • the solvent in the sample prepared in the step (1) was spin-dried, the solid powder was redispersed in 8 mL of physiological saline, centrifuged at 13600 rpm for 10 min, 1 mL of the supernatant was aspirated in 8 mL of physiological saline, shaken, and the basic hydroxylamine colorimetric method was used. Or ultraviolet spectrophotometry) to determine the amount of unencapsulated drug in the supernatant, calculate the nano drug encapsulation rate and drug loading rate by the difference between the total drug amount and the unencapsulated drug amount in the supernatant, and the formula is as follows:
  • Encapsulation efficiency (m -m total dose supernatant dose) / m total dose ⁇ 100%;
  • Drug loading rate (m total dose - m supernatant amount ) / m product ⁇ 100%.
  • the amount of unencapsulated drug in the supernatant was measured for a certain period of time. After 24 hours, the amount of unencapsulated drug in the supernatant reached a stable level.
  • the encapsulation efficiency of the HSA nanoparticles loaded with Ach was calculated to be 46.14 ⁇ 1.13%, and the drug loading rate was 21.95 ⁇ 1.26%.
  • the HSA drug-loaded nanoparticles were observed using a scanning electron microscope, and the results are shown in Fig. 3.
  • the unmodified nanoparticles are spherical and have a diameter of about 200 nm.
  • Step (2) surface modification of the HSA-loaded nanoparticles: the nanoparticles prepared in the step (1) are dispersed in 1 mL of physiological saline, and 0.1 mL of a Tween-80 physiological saline solution is added, and the mixture is stirred at 800 rpm for 30 minutes. After 15 min of sonication, HSA nanoparticles (HSA-ACh NPs) modified with Tween-80 and loaded with Ach were finally obtained.
  • the modified HSA drug-loaded nanoparticles were observed using a scanning electron microscope, and the results are shown in Figs. 4 and 5.
  • the modified drug-loaded nanoparticles are regular cubes with a side length of about 200 nm.
  • the HSA drug-loaded nanoparticles modified with Tween-80 were measured using a dynamic light scattering particle size analyzer (with zeta potential test function), the average particle size was about 198.5 nm, the particle size was uniform, and the zeta potential was about -28.4. mV.
  • the test results are shown in Table 1.
  • HSA human serum albumin
  • RT Lissamine
  • the active ingredient used is Lismin heavy tartaric acid
  • the preferred solvent is 10mmol/L sodium chloride solution
  • the poor solvent selected is anhydrous ethanol (purity greater than 99.7%)
  • the selected cross-linking agent is 10°. % glutaraldehyde
  • the selected targeting molecule is Tween-80.
  • HSA drug-loaded nanoparticles by anti-solvent method: 20 mg of HSA and 10 mg of RT were dissolved in 1 ml of sodium chloride solution (10 mmol/L), and the pH of the solution was adjusted to 8.3 with 0.1 mol/L sodium hydroxide solution. After filtering through a 0.22 ⁇ m water-based filter, the solution was dropwise added to 10 mL of absolute ethanol at a flow rate of 50 ⁇ L/min at a rotation speed of 600 rpm. After the completion of the dropwise addition, the stirring speed was increased to 800 rpm, and 10% by weight of glutaraldehyde was added. 20 ⁇ L, protected from light for 24 h.
  • reaction sample was centrifuged at 13600 rpm for 10 min, the supernatant was removed, the precipitate was collected, and the sample was centrifuged three times with an equal amount of physiological saline, and the precipitate was collected to obtain spherical HSA-loaded nanoparticles, which were stored at 4 °C.
  • HSA-loaded nanoparticles Disperse the nanoparticles prepared in step (1) in 1 mL of physiological saline, add 1 mL of 0.1% Tween-80 physiological saline solution, stir at 800 rpm for 30 min, and sonicate. At 15 min, finally, RT-loaded HSA nanoparticles (HSA-RT NPs) modified with Tween-80 were obtained, which were tetragonal.
  • the HSA nanoparticles modified with Tween-80 were measured using a dynamic light scattering particle size analyzer (with zeta potential test function), the average particle size was about 198.6 nm, the particle size was uniform, and the zeta potential was about +17.4. mV.
  • the test results are shown in Table 1.
  • Example 3 Structural characterization of nanoparticles
  • the AHS aqueous solution, the HSA aqueous solution, the blank HSA nanoparticles not loaded with the active ingredient and not modified Tween-80 (preparation process refers to step (1) of Example 1), and the preparation of step (1) of Example 1
  • the HSA-ACh nanoparticles modified with Tween-80 were analyzed by UV absorption spectroscopy.
  • the UV absorption curve of the sample is shown in Fig. 6.
  • the HSA solution has a distinct characteristic absorption peak around 280 nm (curve 1), while the Ach solution has no absorption near 280 nm (curve 2).
  • the results demonstrate that the targeting molecule Tween-80 has been successfully modified on the surface of nanoparticles.
  • Example 4 Preparation of human serum albumin nanoparticles loaded with doxorubicin and evaluation of in vitro release
  • ultraviolet spectroscopy is used to quantitatively determine the release amount of nanoparticles. Since acetylcholine has no ultraviolet absorption peak, and Lismin has a distinct ultraviolet absorption peak at 263 nm (the characteristic absorption peak of HSA itself is around 280 nm, which coincides with each other), accurate quantitative analysis cannot be performed by ultraviolet spectroscopy. Therefore, a simulated alternative drug is needed to characterize the release effect of the nanoparticles.
  • the analog replacement drug selected in this embodiment is doxorubicin.
  • doxorubicin has similar solubility to acetylcholine and lysine, and is a small molecule drug with good water solubility.
  • it is due to the fact that doxorubicin has a suitable UV absorption peak.
  • doxorubicin has large absorption peaks at wavelengths of 233 nm, 252 nm, 288 nm, 480 nm, 495 nm and 530 nm, with the absorption peak intensity at 480 nm being the largest and the impurity interference being small.
  • the human serum albumin nanoparticles loaded with doxorubicin were used as an in vitro release model, and the in vitro release effect of the nanoparticles of the present application was evaluated by ultraviolet spectrophotometry with the absorption value at 480 nm as a quantitative index. .
  • the preparation of the nanoparticles was carried out by replacing the target drug with doxorubicin hydrochloride (Dox), and the synthesis procedure was the same as in Example 1.
  • Dox doxorubicin hydrochloride
  • a doxorubicin solution group and a drug-loaded nanoparticle group loaded with doxorubicin were set. According to the nanoparticle loading rate of 10%, the concentration of doxorubicin solution group was 0.5mg/mL (4mL total, equivalent to 2mg of doxorubicin), and the concentration of drug-loaded nanoparticles was 5mg/mL (4mL total, Equivalent to doxorubicin 2mg).
  • the two groups were fixed in a semi-permeable membrane with a molecular weight of 3000, and placed in a 900 mL physiological saline release system, respectively, and continuously released at 200 rpm. Take 2 mL of the release solution at regular intervals, measure the UV absorption at 480 nm, and replenish the same amount of normal saline.
  • Figure 9 shows the release results.
  • the doxorubicin solution group reached the maximum cumulative release rate in about 10h, and the recovery rate was over 90%, which proved that doxorubicin was completely released.
  • the cumulative release rate of doxorubicin-loaded nanoparticles was stable within 80h. It continues to rise, and the cumulative release rate in neutral saline solution is only 30% of the drug loading rate. It is concluded that the drug-loaded nanoparticles can maintain structural stability during body fluid transportation, ensuring that the nanoparticles entering the central center can still maintain a high drug loading rate.
  • Kunming mice They were randomly divided into 6 groups according to their body weight, including 10 animals in each group, including blank control group (not modeled and not administered), model group (modeled only), ACh aqueous solution control group (administered acetylcholine aqueous solution after modeling) ), HSA-ACh nanoparticle group (Tween-80 modified human serum albumin nanoparticles loaded with acetylcholine after modeling), RT solution group control group (applied to Lisz's aqueous solution after modeling), HSA-RT Nanoparticle group (modeled after Tween-80 modified Lismine's human serum albumin nanoparticles).
  • the feeding environment was: temperature (24 ⁇ 2) ° C; humidity (60 ⁇ 10)%; daily light / dark for 12 h; free feeding and drinking.
  • the 1Morris water maze (MWM) test period is 5 days, the first 4 days are the training period, and the 5th day is the test period;
  • the diameter of the swimming pool is 1m, divided into 4 quadrants, and 4 water inlet points are fixed in 4 quadrants respectively;
  • the swimming pool water depth is about 0.6m, and the water temperature is 22 ⁇ 2°C;
  • the black platform with a diameter of 0.1 m was placed in the third quadrant and was about 2 cm below the water surface; each mouse received four trainings per day, as follows: First, the mice were facing the pool wall. Put it into the first quadrant and fix it into the water point and swim for 1 minute. If within 1 min, the mouse finds the platform position and stays for at least 3 s, the time stops immediately, and the data such as latency and swimming speed are recorded; if within 1 min, the mouse fails to find the platform or finds the platform and fails to stay for 3 s, the artificial assisted mouse finds The platform stayed for 15 s. At this time, the recorded latency was 60 s. The mice were dried immediately after a swim, and after all the mice were swimming, the training was performed in the 2, 3, and 4 quadrants.
  • mice were free to swim for 1 min, and the data of the incubation period, the number of passages and the swimming time in the target quadrant were recorded for the first time.
  • the platform time for each group of mice was as shown in FIG. During the training period, the mice in each group found no significant difference in platform time on the first day; on the third and fourth days, the blank control group found the platform time was 20s, and the model group, ACh solution group and RT solution group were found. The platform time was significantly longer than that of the blank control group, and the platform time of the HSA-ACh nanoparticle group and the HSA-RT nanoparticle group was not significantly different from that of the blank control group, and was significantly lower than that of the model group. Experiments have shown that the short-term spatial learning ability of mice is improved after HSA-ACh nanoparticles and HSA-RT nanoparticles are separately administered.
  • the number of times of wearing and the target quadrant swimming time are two other indicators for judging the long-term spatial memory ability of mice.
  • the number of times of wearing is the number of times the experimental animal crosses the original platform within 60s. The more times the animal wears, the better the spatial learning and memory ability.
  • the number of mice in the blank control group was significantly higher than that in the model group, ACh solution group and RT solution group (P ⁇ 0.01), but not in the HSA-ACh nanoparticle group and HSA-RT nanoparticle group. Statistical differences.
  • the target quadrant swimming time is the sum of the time of the experimental animals in the original platform and the surrounding area. The longer the time, the better the spatial learning and memory ability, as shown in Figure 13, the model group and the ACh solution group have compared with the blank control group. There was significant statistical difference (P ⁇ 0.05), while there was no statistically significant difference between the other groups and the blank control group.
  • Example 6 Effect of nanoparticles on brain biochemical parameters in mice with cognitive impairment induced by D-galactose
  • DTNB 5,5'-dithiobis(2-nitrobenzoic acid)
  • 1ChAT was measured using a kit (Nanjing built, article number: A079-1), adding reagent 1 to reagent 6 in sequence, mixing, pre-warming for 5 min at 37 ° C water bath;
  • 1ACh content was determined by alkaline hydroxylamine colorimetric method.
  • the sample was first added with a cholinesterase inhibitor to prevent the cholinesterase from decomposing acetylcholine, and then added to the trichloroacetic acid to precipitate the protein;
  • 1MDA The determination of 1MDA was carried out by kit (Nanjing completed, item No. A003-1), 0.1 mL homogenate supernatant was added to the measuring tube, the same amount of absolute ethanol was added to the blank tube, and the standard tube was added with the equivalent amount of 10 nmol/mL standard, and then added. 0.1mL reagent 1, 3mL reagent 2 application solution, 1mL reagent 3 application solution, vortex and mix;
  • T-SOD total superoxide dismutase
  • 1T-SOD was measured by kit (Nanjing built, item number A001-1), reagent 1 to reagent 4 and sample were added in sequence, vortexed and mixed, placed in a constant temperature water bath at 37 ° C for 40 min;
  • the cholinergic system-related enzyme activity and brain oxidative stress level are important brain biochemical indicators for evaluating cognitive ability.
  • the measurement results of each index are shown in Table 2.
  • Figure 14 shows the results of brain histopathological examination.
  • the normal hippocampal CA2 area and the frontotemporal cortex neurons are round or elliptical, with a large nucleoplasmic ratio, a clear nuclear or nuclear membrane, and a uniform color of light blue-violet (Fig. 14A, Fig. 14B).
  • the hippocampal neurons in the model group and the ACh solution group were loosely arranged.
  • the hippocampus and cortex showed more neuronal cell shrinkage, cytoplasm condensation, nuclear condensation, and the whole cell was deeply stained purple (Fig. 14C, Fig. 14D, Fig. 14E, Fig.
  • Example 7 Central targeting of nanoparticles and penetration of blood-brain barrier
  • the fluorescein isothiocyanate (FITC) was modified onto human serum albumin, and the Tween-80 modified acetylcholine-loaded nanoparticles were prepared according to the methods of Examples 1 and 2, and the Tween-80 modified Liss was loaded. The nanoparticles of the bright, thereby obtaining nanoparticles with FITC. After diluting each group of FITC-containing nanoparticles to 0.1 mg/mL, 10 nL of the heart was injected into the zebrafish, and the successfully injected zebrafish was selected and fixed in the gel, and the zebrafish was observed by laser confocal microscopy. The distribution of fluorescence.
  • FITC fluorescein isothiocyanate
  • 15A-15C are laser confocal micrographs of a heart-injected saline group (control group), an acetylcholine nanoparticle group, and a lismin nanoparticle group, respectively.
  • FITC is a water-soluble fluorescent dye that is firmly bonded to the nanoparticles by chemical bonds. Because of chemical bonding, the fluorescein cannot be freely detached from the nanoparticles into free small molecules into the system, so under the microscope The observed fluorescence was derived from nanoparticles, and there were no free FITC small molecules in the system. It can be clearly observed from the figure that there is no fluorescence distribution in normal zebrafish (Fig.
  • the above examples comprehensively evaluated the effect of the nanoparticles of the present application on the cognitive ability of mice, and observed the changes of behavior of the mice at the overall level, and the determination of brain biochemical indicators and pathological examination. Based on the above experimental results, it can be concluded that the nanoparticles of the present application can slowly release the acetylcholine which could not enter the central nervous system and then release it to achieve the purpose of long-term low-dose supplementation of exogenous neurotransmitters; Lissamine is slowly released after being transported to the center, achieving the purpose of long-acting administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une nanoparticule à libération prolongée pour le ciblage d'une maladie neurodégénérative, un procédé pour sa préparation, une composition pharmaceutique la comprenant et une utilisation correspondante dans la préparation d'un médicament pour la prévention et/ou le traitement d'une maladie neurodégénérative chez un sujet. La nanoparticule comprend un matériau de support, un principe actif et une molécule de ciblage. Le matériau de support est l'albumine sérique humaine et le principe actif peut prévenir et/ou traiter la maladie neurodégénérative.
PCT/CN2018/071352 2017-01-26 2018-01-04 Nanomédicament à libération prolongée pour le ciblage d'une maladie neurodégénérative Ceased WO2018137483A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE212018000131.6U DE212018000131U1 (de) 2017-01-26 2018-01-04 Nano-Arzneimittel mit verzögerter Freisetzung gegen eine neurodegenerative Erkrankung
AU2019100932A AU2019100932A4 (en) 2017-01-26 2019-08-19 Sustained-release nano-drug for targeting neurodegenerative disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710056857.9A CN106806352B (zh) 2017-01-26 2017-01-26 一种可缓释、靶向应用于神经退行性疾病的纳米药物
CN201710056857.9 2017-01-26

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2019100932A Division AU2019100932A4 (en) 2017-01-26 2019-08-19 Sustained-release nano-drug for targeting neurodegenerative disease

Publications (1)

Publication Number Publication Date
WO2018137483A1 true WO2018137483A1 (fr) 2018-08-02

Family

ID=59112443

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/071352 Ceased WO2018137483A1 (fr) 2017-01-26 2018-01-04 Nanomédicament à libération prolongée pour le ciblage d'une maladie neurodégénérative

Country Status (3)

Country Link
CN (1) CN106806352B (fr)
DE (1) DE212018000131U1 (fr)
WO (1) WO2018137483A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114470508A (zh) * 2022-01-26 2022-05-13 中原工学院 一种具有药物缓释作用的理疗盐枕材料、制备方法和应用

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106806352B (zh) * 2017-01-26 2019-01-15 中国人民解放军军事医学科学院毒物药物研究所 一种可缓释、靶向应用于神经退行性疾病的纳米药物
CN108379241B (zh) * 2018-03-21 2019-09-27 湖南师范大学 胆甾醇疏水改性普鲁兰-多奈哌齐-聚山梨酯80纳米粒子及制备和应用
CN109701036A (zh) * 2019-01-03 2019-05-03 天津大学 多种阿兹海默治疗药物共载的白蛋白纳米探针及制备方法
CN115227668B (zh) * 2022-06-20 2024-04-30 广州医科大学 一种靶向多巴胺神经元的人参皂苷Rb1递药系统及其制备方法与应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102151336A (zh) * 2010-02-12 2011-08-17 复旦大学 一种乙酰胆碱受体介导跨越血脑屏障的主动靶向递药系统
CN106806352A (zh) * 2017-01-26 2017-06-09 中国人民解放军军事医学科学院毒物药物研究所 一种可缓释、靶向应用于神经退行性疾病的纳米药物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006013531A1 (de) * 2006-03-24 2007-09-27 Lts Lohmann Therapie-Systeme Ag Polylactid-Nanopartikel
CN104840448B (zh) * 2014-02-17 2017-11-17 中国人民解放军军事医学科学院毒物药物研究所 一种可高效快速穿透血脑屏障的纳米药物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102151336A (zh) * 2010-02-12 2011-08-17 复旦大学 一种乙酰胆碱受体介导跨越血脑屏障的主动靶向递药系统
CN106806352A (zh) * 2017-01-26 2017-06-09 中国人民解放军军事医学科学院毒物药物研究所 一种可缓释、靶向应用于神经退行性疾病的纳米药物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AM AVACHAT ET AL.: "Preparation and Characterization of Rivastigmine Loaded Human Serum Albumin (HSA) Nanoparticles", CURRENT DRUG DELIVERY, vol. 3, no. 11, 30 June 2014 (2014-06-30), pages 359 - 370, XP055524834, ISSN: 1567-2018 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114470508A (zh) * 2022-01-26 2022-05-13 中原工学院 一种具有药物缓释作用的理疗盐枕材料、制备方法和应用
CN114470508B (zh) * 2022-01-26 2023-07-21 中原工学院 一种具有药物缓释作用的理疗盐枕材料、制备方法和应用

Also Published As

Publication number Publication date
DE212018000131U1 (de) 2019-10-10
CN106806352A (zh) 2017-06-09
CN106806352B (zh) 2019-01-15

Similar Documents

Publication Publication Date Title
Zhou et al. Intelligently thermoresponsive flower-like hollow nano-ruthenium system for sustained release of nerve growth factor to inhibit hyperphosphorylation of tau and neuronal damage for the treatment of Alzheimer's disease
Cheng et al. Anti-Parkinsonian therapy: strategies for crossing the blood–brain barrier and nano-biological effects of nanomaterials
Liu et al. Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer's disease
WO2018137483A1 (fr) Nanomédicament à libération prolongée pour le ciblage d'une maladie neurodégénérative
Wilson et al. Chitosan nanoparticles as a new delivery system for the anti-Alzheimer drug tacrine
US20210046107A1 (en) Use of fullerene structure in preparation of medicaments for treating parkinson's disease
Xu et al. Engineered selenium/human serum albumin nanoparticles for efficient targeted treatment of Parkinson’s disease via oral gavage
US20240408063A1 (en) Encapsulated microparticles and nanoparticles of dimethyltriptamines
CN112370436B (zh) 一种预防或治疗脑缺血再灌注损伤纳米药物及其制备方法与应用
JP2017505325A (ja) 亜鉛プロトポルフィリンの微粒子送達のための製剤
JP2021507941A (ja) スフィンゴミエリンを含むリポソーム
Liu et al. Research on the loading and release kinetics of the vincristine sulfate liposomes and its anti-breast cancer activity
Wang et al. Poly (butyl cyanoacrylate) nanoparticles-delivered β-nerve growth factor promotes the neurite outgrowth and reduces the mortality in the rat after traumatic brain injury
Abbas et al. P.; Mousa, MR; Fayez, AM; Elsheikh, MA Novel luteolin-loaded chitosan decorated nanoparticles for brain-targeting delivery in a sporadic alzheimer’s disease mouse model: Focus on antioxidant, anti-inflammatory, and amyloidogenic pathways. Pharmaceutics, 2022, 14 (5), 1003
Singh et al. A review on tau targeting biomimetics nano formulations: novel approach for targeting Alzheimer's diseases
US20220000804A1 (en) Intranasal nano inducer for preventing and treating neurodegenerative diseases and method thereof
Wang et al. Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer's disease by modulating oxidative stress
Kushawaha et al. Aurothioglucose encapsulated nanoparticles fostered neuroprotection in streptozotocin-induced Alzheimer’s disease
ES2900426T3 (es) Preparaciones orales y uso de nanopartículas de rapamicina
AU2019100932A4 (en) Sustained-release nano-drug for targeting neurodegenerative disease
Varshosaz et al. Encapsulation of imatinib in targeted KIT-5 nanoparticles for reducing its cardiotoxicity and hepatotoxicity
US20160022649A1 (en) Use of inhibitors of mtor to improve vascular functions in apoe4 carriers
CN113398135B (zh) 一种用于hili原位检测与释药的纳米系统
Jain et al. Fabrication and Evaluation of Amitriptyline HC1 Loaded Nanostructured Lipid Carriers and In-Vitro Characterization
Prabhu et al. Preparation and evaluation of niosomes of brimonidine tartrate as ocular drug delivery system

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18745110

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 18745110

Country of ref document: EP

Kind code of ref document: A1