WO2020143662A1 - Système d'administration ciblant le cerveau, modifié par un oligosaccharide de chitosane, pour nano-préparation nasale sans support et son procédé de préparation - Google Patents

Système d'administration ciblant le cerveau, modifié par un oligosaccharide de chitosane, pour nano-préparation nasale sans support et son procédé de préparation Download PDF

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WO2020143662A1
WO2020143662A1 PCT/CN2020/070897 CN2020070897W WO2020143662A1 WO 2020143662 A1 WO2020143662 A1 WO 2020143662A1 CN 2020070897 W CN2020070897 W CN 2020070897W WO 2020143662 A1 WO2020143662 A1 WO 2020143662A1
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nasal
drug
free
delivery system
preparation
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PCT/CN2020/070897
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Chinese (zh)
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刘刚
刘静怡
文磊
张金凤
张阳
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纳菲(深圳)制药科技有限公司
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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
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention belongs to the field of biomedicine, and relates to a nasal nano preparation brain targeted delivery system and a preparation method thereof. Specifically, it is a chitosan oligosaccharide modified, self-carrying carrier-free nasal nano preparation brain targeting delivery system and preparation method thereof.
  • curcumin has been reported to have significant neuroprotective pharmacological activity in vitro, but its poor water solubility limits its in vivo application.
  • curcumin under conventional oral administration, after the drug undergoes inactivated metabolism through the intestinal mucosa and liver, the amount of drug entering the systemic circulation is reduced, and the efficacy is reduced. And because of the presence of the blood-brain barrier, the amount of drugs that can enter the brain is extremely low, limiting its application in neurological diseases.
  • nano preparations have been widely used in the field of medicine and biology because of their advantages of protecting drugs from being destroyed, prolonging the effective drug maintenance time, controlling the release of drugs, and reducing the toxic and side effects of drugs.
  • the most reported nano preparations are liposomes, polyester copolymers and other carriers containing drug nanoparticles (patents CN107029247A, CN101897669B, CN102283812B, etc.).
  • nanoparticles have three major disadvantages: First, with long-term use, the concentration of the polymer and other carriers in the brain may bring potential toxic and side effects; Second, the drug is wrapped in the carrier and may lose its original Self-targeting recognition function; Third, the current polymer-based nano drug loading system, usually the drug loading is less than 10%, which becomes a thorny problem that hinders the further application of nanoparticles in the clinic. Therefore, there is an urgent need to develop a nano-delivery system with high drug loading, safe and non-toxic, simple and easy to use, and universally suitable for a large number of existing hydrophobic drugs, which is applied to the treatment of neurological diseases.
  • Nasal drug delivery is a safe and non-invasive novel drug delivery method.
  • Drugs can reach the cerebrospinal fluid or brain through the olfactory mucosa along the axons surrounding the olfactory nerve bundle or the olfactory neurons, including Macromolecule proteins and nanoparticles can bypass the blood-brain barrier and enter the central nervous system to play a role through this way, and achieve the delivery of therapeutic drugs in the brain.
  • a small amount of drugs can reach a higher brain drug concentration, so the dosage, frequency and dose-dependent side effects can be reduced.
  • nasal administration only requires nasal drip and spray, and the operation is simpler and safer, especially for patients with neurodegenerative diseases who take medicine for a long time, it can reduce the patient's pain, be easily accepted by the patient, and facilitate their own medication. And reduce the risk of long-term medication.
  • the nasal cavity has many detailed requirements for the preparation.
  • the transmembrane absorption properties of drugs are required. Serum and mucus secreted by the glands in the nasal cavity are rich in proteolytic enzymes, which is one of the factors that affect the absorption of drugs in the nasal cavity.
  • the pH value of nasal mucus is 5.5 ⁇ 6.5, which is the most suitable pH value for proteolytic enzymes, in addition to the removal of cilia of the nasal mucosa. All the above mentioned challenges to the development of nasal preparations.
  • the use of absorption enhancers can enhance the absorption of the nasal mucosa to a certain extent.
  • the commonly used absorption accelerators are anionic surfactants such as stearic acid, lauric acid, sodium lauryl sulfate, sulfonates, etc., and nonionic surfactants such as polysorbate, benzyl, etc.
  • anionic surfactants such as stearic acid, lauric acid, sodium lauryl sulfate, sulfonates, etc.
  • nonionic surfactants such as polysorbate, benzyl, etc.
  • bile salts have certain adverse reactions to the nasal mucosa, such as burning sensation, pain, etc., at low concentrations (2%) will produce strong nasal mucosa irritation, high concentrations (5%) can destroy the nose Mucosal epithelial structure, higher concentration can make nasal cilia or epithelial cells completely shed. Therefore, effective and non-toxic absorption enhancers are the key to nasal preparations.
  • the patents CN105617395A, CN105582545A and CN105617396A relate to a method for preparing a brain-targeted nano drug delivery system for nasal administration, a nasal nano-brain-targeted drug for pharmacokinetics and its preparation method, and galantamine for nasal administration Medicine nano-brain targeting medicine and preparation method thereof.
  • Three patents are directed to hydrophilic small molecule drugs, using their hydrophilic groups to esterify with carboxylated chitosan to obtain targeted drugs; and the present invention is to specifically target hydrophobic small molecule drugs Preparation and application of brain-targeted delivery system for nasal cavity nano preparations.
  • biodegradable polymers in the preparation are four times that of the drug, which may cause potential toxic and side effects due to accumulation of long-term administration.
  • a polymer carrier (patent CN107029247A)
  • the polymer carrier still has the three inherent defects as described above, which limits its clinical translation application. If such a hydrophobic small molecule, through a more optimized nano preparation brain targeted delivery system, to overcome the above defects, it is expected to further improve the therapeutic effect of drugs, which is very important to promote its therapeutic application in neurological diseases .
  • the main object of the present invention is to provide a nasal cavity nano-preparation for the problem of the low organic availability of hydrophobic organic molecules with poor neuroprotection, which leads to the disadvantage of low bioavailability, and the difficulty of crossing the blood-brain barrier by conventional drug administration Brain targeted delivery system.
  • it is a chito-oligosaccharide modified, self-carrying carrier-free nasal nano preparation brain targeting delivery system.
  • Chito-oligosaccharide modified, self-carrying carrier-free nasal cavity nano-targeted brain delivery system including chito-oligosaccharides, neuroprotective hydrophobic small molecule drugs, and polyethylene glycol derivatives; first, polyethylene glycol Alcohol derivatives 1-10mg/mL and 0.5-5mg/mL good solvent solutions of hydrophobic small molecule drugs, and then the good solvent solution is added dropwise to deionized water, the volume ratio of the good solvent solution to deionized water It is (0.5-5): 50, which is supplemented with nitrogen blowing while being added dropwise to assist the volatilization of the good solvent; a self-carrying carrier-free nanoparticle suspension emulsion with a particle size of 50-200 nm is prepared by the reprecipitation method and prepared by freeze drying Lyophilized powder; before use, the lyophilized powder is reacted with chitosan oligosaccharide in isotonic saline solution by physical adsorption
  • the concentration of chitosan oligosaccharide in isotonic saline solution is 0.01-0.2% ( w/v), remove the reactants, and purify the product to obtain the chitosan oligosaccharide-modified self-carrying carrier-free nano-drug nasal preparation.
  • chitooligosaccharides are used for the synergistic effect of nasal cavity mucosa penetration promoting performance and nerve protection.
  • the surface potential of the self-supporting carrier-free nanoparticles is -10 to -60 mV.
  • the neuroprotective hydrophobic small molecule drug is one or more of curcumin or curcumin analogues.
  • the small hydrophobic molecule is a mixture of curcumin analogs of the following structural formula and their cis isomers:
  • the weight ratio of cis isomers in the mixture accounts for 25-35% of the total mixture.
  • the mixture of the cis-isomer in a weight ratio of 25-35% of the total mixture is prepared by the following method, and the curcumin analogue methanol solution is subjected to ultraviolet irradiation for 1.5-2.5 hours.
  • the concentration of the curcumin analogue in the methanol solution is 0.5-5 mg/ml, further preferably 0.5-1.5 mg/ml. If the time of ultraviolet irradiation is shorter than 1.5h, a sufficient amount of cis isomer cannot be generated, and if more than 2.5h, by-products will start to be produced, particularly preferably 2h of ultraviolet irradiation.
  • the molecular weight range of the polyethylene glycol derivative is less than 5000, and more preferably less than 2000.
  • it is carboxypolyethylene glycol or polymaleic anhydride 18 carbonene-polyethylene glycol.
  • the gas is nitrogen or inert gas, preferably nitrogen. Assist the good solvent to dry, to ensure the formation of nanoparticles, and to prevent hidden safety hazards caused by residual solvent.
  • the reprecipitation method is that the good solvent solution is added dropwise to deionized water, stirred at a temperature of 20-30°C for 2-10 minutes, and left for 3-30 minutes to obtain a nanoparticle suspension emulsion.
  • the brain-targeted delivery system of the nasal nano preparation of the present invention has no carrier, no biodegradation problems and accumulated toxicity, and the drug loading amount is up to 25% or more. It can slowly release small-molecule drugs in a pH-responsive manner, highly retaining small molecules and targeted receptors.
  • the binding capacity of the body; polyethylene glycol derivatives can enhance the water dispersibility and stability of the particles; chitooligosaccharides are absorption promoters, which modify the negatively charged nano drug particles through the adsorption of positive and negative charges. It also has the synergy of nerve protection.
  • Chitosan is a large molecule obtained by deacetylation of chitin, with a molecular weight of hundreds of thousands to several million Da, and is insoluble in water. Chitosan is degraded by special biological enzyme technology to obtain an oligosaccharide product with a polymerization degree between 2 and 20, which is chitosan oligosaccharide, also called chitosan oligosaccharide, oligomeric chitosan, molecular weight ⁇ 3200Da has many unique functions such as higher solubility that chitosan does not, full solubility in water, and easy absorption and utilization by organisms.
  • Chitosan oligosaccharide is a non-toxic functional low molecular weight amino sugar, which is a polycation structure.
  • the present invention modifies it outside the nanoparticles to prevent the stimulation of the nasal environment by the drug; it is easy to be negatively charged with the mucosal cell surface
  • the chitosan oligosaccharide used in the present invention has a degree of polymerization of 2-20, or a molecular weight ⁇ 3200Da.
  • the chitosan oligosaccharide of the present invention has an isotonic physiological saline solution concentration of 0.01-0.2% (w/v), if less than 0.01%, it is difficult to play a role in increasing absorption, preventing irritation, etc. If it is greater than 0.2%, It is easy to cause negatively charged nanoparticles to aggregate.
  • the average particle diameter of the hydrophobic drug nanoparticles is 50-150 nm, more preferably 50-120 nm.
  • the surface potential of the hydrophobic drug nanoparticles is -30 ⁇ -60mV.
  • the drug loading rate of the hydrophobic drug nanoparticles is more than 25%.
  • the formation of self-assembled nanoparticles is influenced by the molecular structure of small hydrophobic molecules, and the non-covalent binding force between the molecules, due to different molecular configurations, can lead to differences in nanostructures.
  • a polyethylene glycol derivative is added, mixed with a hydrophobic small molecule in an organic solvent at a certain ratio, then the solvent exchange is performed, and no Nanoparticles wrapped in a carrier.
  • the hydrophobic drug nanoparticles of the present invention have no other carrier components, so their drug loading is high, low toxicity, good safety, their particle size is small and uniform, and they have high stability and long circulation time in the body.
  • the hydrophobic drug molecule is a natural product with neuroprotective effect and a modified product thereof.
  • the neuroprotective natural product and its modified product are one or more of curcumin or its analogues.
  • inventive brain-targeted delivery system for nasal nano preparations can also be added with other pharmacologically effective auxiliary materials, such as bacteriostatic agents, isotonicity adjusting agents, etc., and the dosage is the conventional dosage prescribed in pharmacy.
  • auxiliary materials such as bacteriostatic agents, isotonicity adjusting agents, etc.
  • Antioxidants can also be added in the present invention, and the antioxidants can be sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, vitamin C, vitamin E, sulfur
  • the amount of one or more of urea is the conventional amount prescribed in pharmacy.
  • the invention can also be added with a preservative.
  • the preservative can be methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzalkonium bromide, benzalkonium
  • ammonium chloride chlorobutanol, phenethyl alcohol, thimerosal, phenylmercuric nitrate, sorbic acid, chlorhexidine, the amount of which is the conventional amount prescribed in pharmacy.
  • the osmotic pressure adjusting agent can also be added in the present invention.
  • the osmotic pressure adjusting agent may be one or more of sodium chloride, glucose, lactose, and mannitol, and the dosage is the conventional dosage prescribed in pharmacy.
  • the present invention provides a method for preparing a chito-oligosaccharide-modified self-supporting carrier-free nasal nano-formulation as described in the first aspect, the method comprising the following steps:
  • the lyophilized powder and chito-oligosaccharide are reacted in isotonic saline by physical adsorption for 0.5-2 hours to remove the reactants, and the product is purified to obtain the chito-oligosaccharide modified self-supporting carrier-free nanoparticles Drug nasal preparations.
  • the method for preparing nanoparticles of the present invention is carried out by the reprecipitation method.
  • the good solvent is converted into water (poor solvent)
  • the hydrophobic drug molecules are precipitated to form nanoparticles, and the addition of polyethylene glycol derivatives can be further enhanced Its stability and water dispersibility.
  • This method is simple and easy to perform, does not require complicated operations and conditions, and can be carried out at room temperature.
  • the addition time of the polyethylene glycol derivative should be dissolved in a good solvent together with small molecules before the formation of nanoparticles, after mixing uniformly, the aqueous phase is added dropwise to prepare Nanoparticles.
  • gas preferably nitrogen blowing is used to remove the organic solvent.
  • the present invention mixes the lyophilized powder with chitosan oligosaccharide in isotonic physiological saline just before use, to avoid the aggregation and sedimentation after long standing, and to ensure the absorption of the nasal cavity during use.
  • the good solvent is miscible with water.
  • a good solvent refers to a solvent with a solute interaction parameter less than 0.5.
  • the good solvent is a mixture of one or more of acetone, methanol, ethanol and tetrahydrofuran, more preferably tetrahydrofuran.
  • the water may be deionized water, distilled water or double-distilled water, etc., preferably deionized water.
  • the concentration of the hydrophobic drug molecule dissolved in the good solvent in the step (1) is 0.5-5 mg/mL, preferably 1 mg/mL.
  • the volume ratio of the good solvent to water in the step (1) is preferably (1-3): 50, preferably 2:50.
  • the reaction temperature in the step (1) is 20-30°C, more preferably 25°C.
  • the concentration of the polyethylene glycol derivative added in the step (2) in a good solvent may be 1-10 mg/mL, such as 1 mg/mL, 2 mg/mL, 3 mg /mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL or 10 mg/mL, preferably 2 mg/mL.
  • the time of ultrasonic dispersion in the step (2) is 3-30 min, more preferably 5 min.
  • the concentration of isotonic chitosan isotonic physiological saline solution in the step (3) is 0.05-0.2 w/v, for example, 0.05% w/v, 0.1% w/v or 0.2% w/v, preferably 0.1% w/v.
  • the stirring time in the step (3) is 0.5-2h, for example 0.5h, 1h, 1.5h or 2h, preferably 1h.
  • the centrifugation condition in the step (3) is a rotation speed of 10,000-150,000*g, preferably 150,000*g, and centrifugation for 30 min.
  • Freeze-drying can significantly improve its stability.
  • the freezing temperature is lower than the low eutectic point of nanoparticles and water coexisting at 10-20°C and 10Pa pressure. 90h, preferably 48h.
  • cryoprotectants such as glucose, mannitol, lactose, NaCl, etc.
  • first add cryoprotectants such as glucose, mannitol, lactose, NaCl, etc.
  • cryoprotectants such as glucose, mannitol, lactose, NaCl, etc.
  • the present invention provides the use of a chito-oligosaccharide modified self-carrying carrier-free nasal nano preparation brain-targeted delivery system as described in the first aspect. It is used for brain-targeted delivery. Can be made into nasal spray or nasal drops.
  • chitosan oligosaccharide curcumin analog M1 self-carrying carrier-free nasal nano-preparation system was administered nasally, MPTP-induced Parkinson's model mice were explored for motor activity, anxiety, gait and other behaviors Has an improving effect.
  • the brain-targeted delivery system of the present invention is administered by nasal route in the form of spray or nasal drops.
  • the invention relates to a nano preparation brain targeted delivery drug system, which is prepared as a self-carrying carrier-free nasal cavity nano preparation brain targeted delivery system modified with chitooligosaccharides for a neuroprotective hydrophobic small molecule. Used in the treatment of a series of neurological diseases. After being made into a nasal preparation, it can avoid gastrointestinal tract degradation and liver first-pass effect, and has the characteristics of high bioavailability, fast onset, and good patient compliance. Compared with conventional dosage forms, nasal preparations deliver drugs directly into the brain through the nasal-brain pathway, bypassing the blood-brain barrier along olfactory nerves, etc., which can significantly enhance brain targeting, reduce the concentration of organs in the peripheral circulatory system, and reduce long-term consumption Potential side effects.
  • nasal preparations can reduce the accumulation of drugs in peripheral circulation organs such as the liver; compared with oral drugs, nasal preparations have no first-pass effect and reduce drug loss.
  • nasal administration only requires nasal drip, spray, etc., the operation is simpler and safer, especially for patients with neurodegenerative diseases who take medication for a long time, it can reduce the patient's pain, the patient's compliance is good, and it is convenient for him to use the medicine. And reduce the risks caused by long-term medication, has a good application prospect.
  • nasal drip, spray and other methods are simple and safe to operate, especially for patients with neurodegenerative diseases who take medicine for a long time, it is convenient to use their own medicine, and they have good application prospects in the treatment of neurological diseases.
  • the self-carrying carrier-free nasal nano preparation modified by chitosan oligosaccharide in the invention has simple operation, wide application range and strong universality. Compared with hydrophobic organic small molecule drug precursors, it has the advantages of significantly improving water dispersibility and drug formation, enhancing bioavailability, reducing the frequency of administration, and reducing toxic and side effects. It is safer to take for a long time.
  • the nano-system of the invention has no carrier, no biodegradation problems and accumulation toxicity.
  • the drug-loading rate is as high as 25% or more, and the chitosan oligosaccharide is modified to absorb through the membrane well. It can be used as a nasal preparation Very highly targeted through the olfactory nerve into the brain.
  • polyethylene glycol derivatives also reduce mucosal irritation and extend circulation time in the body.
  • the nano-preparation highly retains the target receptor binding ability of the original molecule, and has pH-responsive drug release characteristics. After being taken up by the cell, it is degraded at a specific pH (5.5) of the lysosome, releasing small molecules into the cytoplasm to exert the drug effect . At the same time, the drug of the present invention is stable during delivery.
  • Fig. 7 shows that the present invention enables long-acting circulation and slow release of small drug molecules in cerebral spinal fluid and blood (over 64 hours), thereby reducing the frequency of administration and the dose of administration.
  • the present invention has high safety, high drug loading rate, high brain targeting; low dosage, low frequency of administration (slow-release long-acting), few systemic side effects (low liver and kidney content); non-invasive administration Etc.
  • the delivery system of the present invention Compared with the original hydrophobic small molecule drugs, the delivery system of the present invention has good water dispersibility, greatly enhances the small molecule drug formation, and reduces the toxicity of small molecule drugs and enhances the neuroprotective effect; compared with other nano preparations, the present invention
  • the delivery system has no carrier, no biodegradation problems and accumulated toxicity.
  • the drug loading rate is as high as 25% or more. It highly retains the binding ability of the target receptor of the original molecule, and the chitosan oligosaccharide is modified to absorb well through the membrane.
  • As a nasal preparation it can be extremely high Targeting enters the brain through the olfactory nerve. It has pH-responsive performance and can be released slowly in cells and maintain effective concentration for a long time.
  • FIG. 1 Scanning electron microscopy (SEM) image of self-carrying carrier-free nanoparticles of hydrophobic small molecule drugs: a is curcumin nanoparticles; b is M1 nanoparticles; c is M1 nanoparticles loaded with TPAAQ probes.
  • SEM scanning electron microscopy
  • Figure 2 Particle size distribution of self-supporting carrier-free nanoparticles for hydrophobic small molecule drugs: a is curcumin nanoparticles; b is M1 nanoparticles; c is M1 nanoparticles loaded with TPAAQ probes.
  • Figure 3 Potential distribution of self-carrying carrier-free nanoparticles of hydrophobic small molecule drugs: a is curcumin nanoparticles; b is M1 nanoparticles.
  • Figure 4 Optical characterization of Tyndall effect of hydrophobic small molecule self-carrying carrier-free nanoparticles: a is curcumin nanoparticles; b is M1 nanoparticles.
  • Test chart for loading rate of self-carrying carrier-free nanoparticles for hydrophobic small molecule drugs a is curcumin nanoparticles; b is M1 nanoparticles, and c is M1 nanoparticles loaded with TPAAQ probes.
  • Figure 6 Cell uptake effect of curcumin nanoparticles modified with chitosan oligosaccharides; where a is the cell uptake graph of M1NPs without chitosan oligosaccharide modification; b is the cell uptake graph of M1NPs after chitosan oligosaccharide modification.
  • Figure 12 Transmission electron micrograph of brain slices of mice after nasal administration of curcumin nanoparticles.
  • FIG. 13 M1 drug content in the brain and plasma of mice after administration of M1 nanoparticles via nasal brain.
  • FIG. 14 Fluorescence biographs of the brain and organs of mice after nasal administration of M1 nanoparticles carrying TPAAQ fluorescent probes.
  • Fig. 15 Open field behavior diagram of Parkinson's model mice after nasal administration of the M1 nasal nanoformulation of Example 2.
  • Figure 19 is the nuclear magnetic spectrum of (e,e) compound with double trans configuration
  • Figure 20 is the nuclear magnetic spectrum of (e, z) cis-trans configuration compounds
  • Figure 21 is the HPLC-MS spectrum of the mixture.
  • curcumin used in this implementation is as follows:
  • the lyophilized powder was re-dispersed in isotonic saline, added dropwise to chitosan oligosaccharide (0.1w/v) saline solution, stirred for 0.5h, and reacted for 1 hour using physical adsorption to 10,000 * Centrifuge for 10 min at a rotating speed of g, discard the supernatant, remove the reactants, and purify the product to obtain a self-carrying carrier-free curcumin nasal nano preparation modified with chitooligosaccharides.
  • the curcumin nanoparticles prepared in Example 1 were observed, and the scanning electron microscope diagram is shown in FIG. 1a.
  • a laser particle size analyzer (Malvern, UK)
  • the curcumin nanoparticles prepared in Example 1 were subjected to dynamic light scattering measurement, and the average particle size of the curcumin nanoparticles prepared in Example 1 was measured. It is 64.57nm, and the particle size distribution is shown in Figure 2a.
  • the curcumin molecules and the curcumin nanoparticles prepared in Example 1 were dissolved in water and organic solvents, as shown in FIG. 4a, it can be seen that the small curcumin molecules are difficult to dissolve in water and soluble in tetrahydrofuran, while the curcumin nanoparticles
  • the particles can be dispersed in water and have the Tyndall effect under the laser.
  • UPLC ultra high performance liquid chromatography
  • the drug loading rate of curcumin nanoparticles is (25.12 ⁇ 2.50)%
  • Fluorescent FITC probe was modified with curcumin nanoparticles without chitosan oligosaccharide modification and curcumin nanoparticles with chitosan oligosaccharide modification respectively, and incubated with N2a cells for 6 hours. The cells were washed three times with PBS and laser Under a focused microscope, it is excited with a wavelength of 488nm and an emission wavelength of 190-540nm. The fluorescence intensity is measured and compared for analysis. As shown in Figure 5, after chitosan oligosaccharide modification, the cellular uptake of curcumin nanoparticles was significantly enhanced.
  • curcumin analog M1 used in this example is a mixture of isomers of the curcumin analog of the following structural formula:
  • curcumin analogues According to the hydrophobic properties of curcumin analogues, it is dissolved in a good solvent and given different radiation conditions, different degrees of isomer transformation can occur, and different ratios of cis-trans isomer mixtures can be obtained. Among them, the conversion rate of sunlight irradiation is the highest, but there are by-products generated; the conversion rate is followed by ultraviolet irradiation and radioactive iodine radiation, and the temperature has no effect on the structure of curcumin analogs under the condition of avoiding light.
  • the good solvent is preferably acetonitrile, methanol, ethanol, acetone, tetrahydrofuran.
  • the isomer product with a conversion rate of 30% can be obtained by UV irradiation for 2h, the preparation method is simple, and no by-product is generated.
  • a methanol solution containing 1 mg/mL of curcumin analogues seal with aluminum foil, and place them at 4°C, 25°C, and 50°C for 8 hours to obtain the reaction product 1-3; also configure the same concentration of turmeric
  • the methanol solution of the analogues was irradiated with sunlight for 2 hours, sunlight for 24 hours, ultraviolet radiation for 2 hours, and radioactive iodine 131 for 2 hours at room temperature to obtain the reaction products 4-7, to obtain various ratios of curcumin analogues. Constructor mixture.
  • the molecular weight of the product was determined by high performance liquid phase time-of-flight mass spectrometry. From Figure 17, the molecular weight of the curcumin analog and its conversion product are both 294.34. It is confirmed that the two are isomers, and the structure is further known as Cis-trans isomer.
  • the M1 nanoparticles prepared in Example 2 were observed.
  • the scanning electron microscope is shown in FIG. 1b.
  • the M1 nanoparticles prepared in Example 2 were subjected to dynamic light scattering measurement, and the average particle size of the M1 nanoparticles prepared in Example 2 was measured to be 62.73 nm, particle size distribution diagram shown in Figure 2b.
  • the M1 nanoparticles prepared in Example 2 were subjected to Zeta-potential analysis, and the average charge of the M1 nanoparticles prepared in Example 2 was measured to be -56.5mV, indicating that it was weak The negative charge is distributed as shown in Figure 3b.
  • M1 molecule Dissolve M1 molecule in acetonitrile, gradient configuration of M1 acetonitrile solution (6.25, 12.5, 25, 50 and 100ug/mL), use ultra high performance liquid chromatography (UPLC) to measure absorbance at 428nm, and make a standard curve. .
  • UPLC ultra high performance liquid chromatography
  • Three batches of 100ug/mL M1 nanoparticles were taken, dissolved in acetonitrile, and ultrasonically measured for 5min. The same method was used to determine the M1 content in the nanoparticles using a standard curve. As shown in Figure 5b, the drug loading rate of M1 nanoparticles is (31.49 ⁇ 2.03)%
  • the M1 nanoparticles prepared in Example 2 were divided into six equal parts, three parts were added to artificial nasal fluid, and three parts were added to 5% plasma. United States), then soaked in 200 ml of the same pH buffer, stirring continuously at 37 °C, at a certain time point to collect 2ml of solution from the solution. During the dialysis, 2ml of PBS was added after each sampling to keep the solution volume constant. The UV-VIS method was used to measure absorbance and calculate the amount of drug released. Each sample was tested three times, averaged, and statistically analyzed. The results are shown in Figure 7.
  • the M1 nanoparticles prepared in Example 2 have the property of slow release, and do not show the initial explosive drug release, but are released slowly and steadily, which is crucial for the application of M1 nanoparticles in vivo and can reduce the drug Toxicity, reduce drug leakage, etc.
  • M1 small molecule drugs As the concentration increases, free M1 can exhibit dose-dependent cytotoxicity, while the M1 nanoparticles in Example 2 at the same concentration have no toxic effect on N2a cells, probably due to M1 The sustained release of nanoparticles inhibits the accumulation toxicity of M1 small molecule drugs at higher concentrations.
  • the neuronal cell line PC12 cells were treated with MPP + neurotoxin, resulting in a neurotoxic cell model.
  • the M1 nanoparticles prepared in Example 2 were added to pre-treat the M1 nanoparticles group; the model control group without drug treatment and the normal control group without MPP + neurotoxin. After incubation for 48 hours, the absorbance was measured according to literature methods. The results are shown in Figure 9.
  • the cell survival rate of the M1 nanoparticle group was significantly higher than that of the MPP+ model group.
  • the M1 nanoparticles prepared in Example 2 can be dose-dependently protected.
  • PC12 nerve cells reduce the cell damage induced by MPP+neurotoxin.
  • the target protein for the neuroprotective effect of free M1 molecule is the TFEB protein in the cytoplasm.
  • M1 promotes the dephosphorylation of the TFEB protein into the nucleus and up-regulates the expression of autophagy-related genes, thereby playing a neuroprotective role.
  • the M1 nanoparticles prepared in Example 2 were added to MF7 cells overexpressing the fluorescently labeled TFEB protein, and the nucleus of TFEB was observed after 24 hours of treatment. The results are shown in FIG. 9 and the M1 nanoparticles prepared in Example 2 The particles can promote TFEB into the nucleus in a dose-dependent manner, confirming that the M1 nanoparticles retain the targeting properties of the original molecules.
  • Example 3 M1 nasal cavity nano-targeted delivery system with fluorescent probe TPAAQ
  • TPAAQ is a hydrophobic small molecule fluorescent probe excited at 473nm wavelength and emitted at 650nm wavelength, which can be used for in vivo fluorescence distribution monitoring of nanomaterials. Because it is also a hydrophobic small molecule, it is similar to the preparation process of the M1 nanoparticles of Example 2, and the M1 nasal nanoparticle preparation loaded with TPAAQ can be obtained in the same way.
  • the lyophilized powder is redispersed in isotonic saline, added dropwise to chitosan oligosaccharide (0.1w/v) saline solution, stirred for 0.5-2h, and reacted by physical adsorption for 1 hour, Centrifuge at a speed of 10000-150000*g for 5-30 min, discard the supernatant, remove the reactants, and purify the product to obtain a self-carrying carrier-free M1 nasal nano preparation modified with TPAAQ probes.
  • Nerve cells were cultured normally, the M1 nasal nano preparation containing the fluorescent probe TPAAQ prepared in Example 3 was added, and after 3 hours of culture, the cell uptake was observed at a specific wavelength with a laser confocal scanning microscope.
  • the signal shows that the fluorescent probe TPAAQ-loaded M1 nasal nano preparation prepared in Example 3 can be taken up by cells in large amounts.
  • the curcumin nasal nano preparation prepared in Example 1 was dispersed in isotonic saline at a concentration of 5 mg/ml, and given to the nasal cavity of mice for 15 ul. After 24 hours, the brain tissue was dissected out, the slice was fixed, and the nanoparticle brain was observed under transmission electron microscope. distributed. As shown in Figure 12, the distribution of curcumin nanoparticles in the olfactory bulb and cortex of the brain can be clearly seen.
  • Example 5 Application of M1 nanoparticles transnasal brain targeted delivery system
  • M1 nasal nano preparation prepared in Example 2 was dispersed in isotonic saline at a concentration of 5 mg/ml, and given to mice nasal cavity for 15 ul. After 24 hours, brain tissue, cerebrospinal fluid and plasma were dissected out, and the brain tissue was divided into olfactory bulb and For the rest of the brain, after adding methanol to all samples to remove protein, triple quadrupole LC/MS was used to analyze the M1 drug content in the samples. The results are shown in Figure 13.
  • the M1 nasal cavity nano-targeted brain delivery system delivers M1 drugs into the olfactory bulb with extremely high targeting, and has a distribution in the cerebrospinal fluid that is three times higher than that in the plasma, and in other parts of the brain. Double the amount of drug distribution in plasma. It is confirmed that its absorption route is to reach the brain through the olfactory bulb and can be transmitted to other parts of the brain. Its transmission may be time-dependent, and it will continue to be transmitted backward through cerebrospinal fluid after 24h.
  • Example 6 Application of nasal brain targeted delivery system of M1 nanoparticles carrying TPAAQ fluorescent probe
  • the fluorescent probe TPAAQ-loaded M1 nasal nano preparation prepared in Example 3 was dispersed in physiological saline at a concentration of 5 mg/ml, and given to the nasal cavity of 15 ul of mice.
  • the small animal fluorescence imaging system was used to detect mice after 24 h and 48 h, respectively.
  • Brain in vivo fluorescence, and fluorescence signals in isolated organs such as brain, heart, liver, spleen, lung, kidney and blood, as shown in Figure 14, the brain signal is significantly stronger than other parts of the body and tissues.
  • the brain-targeted delivery system can successfully deliver the M1 nasal nanoformulation into the brain with high targeting, reducing the distribution of drugs in peripheral tissues.
  • Example 7 Therapeutic application of self-carrying carrier-free M1 nasal nano preparation in Parkinson's model mice
  • mice with a body weight of 25g were divided into three groups, the first group of wild-type group (WT group), the second group of model group (MPTP group), and the third group of model administration group (M1NPs) , 10 mice per group.
  • WT group wild-type group
  • MPTP group second group of model group
  • M1NPs model administration group
  • mice of the second and third groups were injected intraperitoneally with a 20 mg/kg dose of MPTP neurotoxin for five days to cause Parkinson's disease model.
  • the WT group and the MPTP group were given saline in the nasal cavity, and the M1NPs group was given the self-carrying carrier-free M1 nasal nano preparation, that is, the M1 nasal nano preparation prepared in Example 2 was dispersed in Infiltrated with normal saline, a fresh preparation was used, with a concentration of 1 mg/ml, and 15 ul was given to the mice nasally.
  • the drug was administered four times a day at intervals, and the effect was observed two weeks after the end of modeling.
  • the MPTP Parkinson mouse model explores symptoms such as dyskinesia and significant anxiety, which can be detected by the open field test. According to literature methods, the behavioral behavior of Parkinson's model mice in Example 7 was tested. The results are shown in Figure 15a. Compared with the wild-type mice in the control group, the trajectories of the model mice changed significantly, but the trajectories tended to be normal after being treated with the M1 nasal nano preparation.
  • the clinical manifestations of Parkinson's disease mainly include resting tremor, bradykinesia, muscle stiffness, and posture and gait disorders.
  • the DigiGait imaging system is used on animals. By imaging animals under a transparent running belt, the software quantifies the characteristics of gait mechanics and posture index to detect the behavioral characteristics of Parkinson's model mice. The results are shown in Figure 16. Compared with wild-type mice, Parkinson's model mice have disordered gait signals, reduced coordination, and a marked reduction in the footprint of the foot. After treatment with the self-carrying carrier-free M1 nasal nano preparation, the above The pathological conditions were significantly improved, confirming that M1 nasal nano preparations can effectively improve the behavioral symptoms of Parkinson's disease.
  • the present invention illustrates the detailed features and detailed methods of the present invention through the above-mentioned embodiments, but the present invention is not limited to the detailed features and detailed methods, that is, it does not mean that the present invention must rely on the detailed features and detailed methods Implementation.
  • Those skilled in the art should understand that any improvement to the present invention, equivalent replacement of optional components of the present invention, addition of auxiliary components, choice of specific modes, etc., fall within the scope of protection and disclosure of the present invention.
  • the invention discloses a chitosan oligosaccharide modified self-supporting carrier-free nasal cavity nano preparation brain targeting delivery system and a preparation method thereof. Including neuroprotective hydrophobic small molecule drugs, polyethylene glycol derivatives, and chitooligosaccharides.
  • the invention also provides a preparation method of the brain targeted delivery system of the nasal cavity nano preparation.
  • the nanoparticle lyophilized powder is prepared.
  • the lyophilized powder and chitosan oligosaccharide are stirred in isotonic saline to become a nasal preparation with good membrane permeability.
  • the preparation method of the system of the invention is simple, can improve the hydrophobicity of small molecule drugs, reduce toxicity, and enhance nerve protection; no carrier, no biodegradation problems and accumulated toxicity, the drug loading rate is as high as 25% or more, and the membrane is modified after being modified by chitosan oligosaccharides Good absorption and highly targeted delivery of drugs into the brain.
  • the administration method of the dosage form is nasal drip, spray, etc., the operation is simple, and it is convenient for the patient to take the medicine for a long time. It has a good application prospect in the treatment of nervous system diseases and has good industrial practicality.

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Abstract

L'invention concerne un système d'administration ciblant le cerveau, modifié par un oligosaccharide de chitosane, pour nano-préparation nasale sans support et son procédé de préparation. Le système comprend un médicament neuroprotecteur micro-moléculaire hydrophobe, un dérivé de polyéthylène glycol et un oligosaccharide de chitosane. L'invention concerne en outre un procédé de préparation du système d'administration ciblant le cerveau pour nano-préparation nasale. Le procédé de préparation comprend les étapes suivantes : étape 1, préparation d'une poudre lyophilisée de nanoparticules ; et étape 2, agitation de la poudre lyophilisée et de l'oligosaccharide de chitosane dans du sérum physiologique isotonique avant utilisation pour former une préparation nasale présentant une bonne perméabilité membranaire. Le procédé de préparation du système est simple et peut améliorer l'hydrophobicité du médicament micro-moléculaire, réduire la toxicité et améliorer l'effet neuroprotecteur. Le système est exempt de supports et permet d'éviter les problèmes de biodégradation et de toxines qui s'accumulent. Le taux de transport de médicament atteint 25 pour cent ou plus, la perméabilité membranaire et les performances d'absorption sont bonnes après modification par l'oligosaccharide de chitosane, et le médicament est administré dans le cerveau avec une bonne précision de ciblage. Cette forme posologique est administrée par pulvérisations, gouttes nasales et analogues, et l'opération d'administration est simple, facilitant ainsi la tâche aux patients qui utilisent le médicament de façon prolongée, et offre de bonnes perspectives d'utilisation dans le traitement des maladies du système nerveux.
PCT/CN2020/070897 2019-01-09 2020-01-08 Système d'administration ciblant le cerveau, modifié par un oligosaccharide de chitosane, pour nano-préparation nasale sans support et son procédé de préparation WO2020143662A1 (fr)

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