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WO2013035579A1 - Nanoparticules aptes à s'accumuler dans le foie renfermant un médicament encapsulé - Google Patents

Nanoparticules aptes à s'accumuler dans le foie renfermant un médicament encapsulé Download PDF

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WO2013035579A1
WO2013035579A1 PCT/JP2012/071659 JP2012071659W WO2013035579A1 WO 2013035579 A1 WO2013035579 A1 WO 2013035579A1 JP 2012071659 W JP2012071659 W JP 2012071659W WO 2013035579 A1 WO2013035579 A1 WO 2013035579A1
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Prior art keywords
drug
liver
nanoparticles
ion
ribavirin
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English (en)
Japanese (ja)
Inventor
務 石原
水島　徹
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EDUCATIONAL Corp NIHON UNIVERSITY
LTT Bio Pharma Co Ltd
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EDUCATIONAL Corp NIHON UNIVERSITY
LTT Bio Pharma Co Ltd
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K9/5115—Inorganic compounds
    • 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
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to nanoparticles encapsulating a drug, and more particularly to liver-integrating nanoparticles encapsulating a drug that can further reduce the pharmacological effects and side effects of the drug by accumulating in the liver.
  • hepatitis C virus When infected with hepatitis C virus, it progresses to chronic hepatitis at a high rate, and may lead to cirrhosis and liver cancer. In Japan, it is estimated that there are about 2 million people infected with hepatitis C virus, and 20,000 people die each year due to liver cancer that progressed from hepatitis C caused by this infection.
  • interferon or a combination therapy of peginterferon obtained by chemically modifying polyethylene glycol with interferon and an anti-hepatitis virus drug such as ribavirin is mainly used.
  • the cure rate of combination therapy with peginterferon and ribavirin, an anti-hepatitis virus drug is only about 50% after 48 weeks of administration, and the treatment involves side effects.
  • the side effect of hemolytic anemia caused by ribavirin is a major barrier to complete healing.
  • DDS Drug ⁇ ⁇ Delivery
  • the present inventors have aimed at sustained-release targeting in which water-soluble non-peptide low-molecular-weight drugs are hydrophobized with metal ions and encapsulated in polylactic acid (PLA) or polylactic acid-glycol copolymer (PLGA) microparticles.
  • Proposed a nanoparticle preparation Patent Document 1.
  • the present inventors hydrophobized a water-soluble non-peptidic low molecular drug with a metal ion, added a basic low molecular compound, and added this to polylactic acid (PEG-PLA) or polylactic acid-glycol to which polyethylene glycol was bound.
  • PEG-PLGA polylactic acid-glycol
  • Non-patent Document 1 a preparation in which a synthetic polymer chain bonded with galactose is coated on the surface of polylactic acid (PLA) nanoparticles is known (Non-patent document 1, Non-patent document 2).
  • the therapeutic effect has been verified (Non-patent Document 3).
  • Non-patent Document 4 a preparation in which a conjugate obtained by binding arabinogalactan and polylysine and DNA (polylactic acid is not used) reaches the liver.
  • Non-patent Document 4 nanoparticles composed of a conjugate of dextran and polylysine and polylactic acid (PLA) are disclosed (Non-patent Document 5).
  • the drug is applied to nanoparticles composed of polylactic acid or poly (lactic acid / glycolic acid) copolymer, a conjugate of arabinogalactan and a biodegradable cationic polymer, a metal ion and a basic low molecular weight compound.
  • the encapsulated liver-accumulating nanoparticles are not known.
  • an object of the present invention is to provide liver-integrated nanoparticles encapsulating a drug that can encapsulate the drug efficiently, stably confine the drug in the particle, and easily accumulate in the liver.
  • the present inventors have conducted intensive studies, and as a result, the drug was converted to poly DL or L-lactic acid or poly (DL or L-lactic acid / glycolic acid) copolymer, arabinogalactan and biodegradable cation. Confirming that drug-encapsulated nanoparticles obtained by encapsulating in a nanoparticle composed of a conjugate with a functional polymer, a metal ion, and a basic low molecular weight compound exhibit excellent liver accumulation and persistence, The present invention has been completed.
  • the present invention is characterized in that it exhibits excellent liver accumulation and durability by incorporating a conjugate of arabinogalactan and a biodegradable cationic polymer into the particle surface.
  • the present invention provides nanoparticles that are particularly advantageous for drugs for treating liver diseases because they efficiently encapsulate drugs, stably confine the drugs in the particles, and accumulate in the liver.
  • ribavirin an anti-hepatitis virus drug
  • the present invention provides liver-integrating nanoparticles encapsulating in particular anti-hepatitis virus drugs, liver cancer therapeutic drugs or liver function improving drugs.
  • this invention provides the pharmaceutical which uses the said nanoparticle as an active ingredient.
  • the present invention has the following configuration. That is, (1) A drug comprising poly DL or L-lactic acid or poly (DL or L-lactic acid / glycolic acid) copolymer, a conjugate of arabinogalactan and a biodegradable cationic polymer, metal ion and basic low Drug-encapsulated liver-integrating nanoparticles, characterized in that they are encapsulated in nanoparticles composed of molecular compounds; (2) Liver-accumulating nanoparticles encapsulating the drug according to 1 above, wherein the particle diameter is 20 to 300 nm; (3) Liver-accumulating nanoparticles encapsulating the drug according to 1 above, wherein the metal ion is one or more of zinc ion, iron ion, copper ion, nickel ion, beryllium ion, manganese ion or cobalt ion ; (4) Basic low molecular weight compounds are (dimethylamino) pyridine, pyridine, piperidine, pyridine,
  • Liver-accumulated nanoparticles encapsulating the drug according to 1 above (6) Liver-integrated nanoparticles encapsulating the drug according to 1 or 5 above, wherein the drug is an anti-hepatitis virus drug, a liver cancer therapeutic drug or a liver function improving drug; (7) Liver-accumulating nanoparticles encapsulating the drug according to 6 above, wherein the anti-hepatitis virus drug is ribavirin or ribavirin-phosphate; (8) A pharmaceutical comprising liver-accumulating nanoparticles encapsulating the drug according to 1 to 7 as an active ingredient; It is.
  • the present invention relates to a drug comprising poly DL or L-lactic acid or poly (DL or L-lactic acid / glycolic acid) copolymer, a conjugate of arabinogalactan and a biodegradable cationic polymer, a metal ion and a base. It is characterized by producing liver-accumulating nanoparticles encapsulated in nanoparticles composed of a low molecular weight compound.
  • the liver-accumulating nanoparticles encapsulating a drug provided by the present invention are particularly advantageous for drugs for treating liver diseases because they efficiently encapsulate the drug, stably entrap the drug in the particle, and accumulate in the liver. Demonstrate sex. Further, since the constituent component of the nanoparticles is a biodegradable polymer, the encapsulated drug is released little by little by being gradually degraded in vivo, and as a result, the pharmacological effect can be sustained over a long period of time.
  • the greatest feature of the present invention is that liver targeting is possible because of its high accumulation in the liver. It is known that a molecule having galactose binds to a liver parenchymal cell receptor and is taken up into the cell via endocytosis. Therefore, the drug can be transported to the liver by arranging a sugar chain mainly composed of galactose on the surface of the nanoparticle of the present invention. As a result, the liver-accumulating nanoparticles encapsulating the drug provided by the present invention have the feature that they can be easily prepared into any dosage form of oral and parenteral dosage forms.
  • Example 1 It is the figure which showed the result of Example 1, and showed the production
  • Example 4 A microscopic image of the cells was shown. It is the figure which showed the result of Example 4, and showed the result of the intracellular uptake
  • the liver-accumulating nanoparticles encapsulating a drug which is a basic aspect of the present invention, comprises a drug, polyDL or L-lactic acid or poly (DL or L-lactic acid / glycolic acid) copolymer, arabinogalactan and in vivo degradation. It is obtained by encapsulating in a nanoparticle composed of a conjugate with a cationic cationic polymer, a metal ion, and a basic low molecular weight compound.
  • the liver-accumulating nanoparticles encapsulating a drug provided by the present invention has one feature in that a conjugate of arabinogalactan and a biodegradable cationic polymer is used as one of the components forming the nanoparticles. Have. That is, by using arabinogalactan and a biodegradable cationic polymer, nanoparticles can be easily accumulated in the liver.
  • Liver-accumulating nanoparticles encapsulating the drug of the present invention provided by the above are tablets, capsules, orally administered drugs such as powders, intravenous preparations, topical injection preparations, nasal drops, eye drops, inhalation It can be administered by preparing a preparation for parenteral administration such as an agent or a spray.
  • the liver-accumulating nanoparticles encapsulating the drug provided by the present invention can be prepared, for example, by the following means. That is, a drug, a poly-DL or L-lactic acid or poly (DL or L-lactic acid / glycolic acid) copolymer, a conjugate of arabinogalactan and a biodegradable cationic polymer, a metal ion, a base Nanoparticles can be produced by dissolving or suspending a low molecular weight compound in an organic solvent and gradually adding it to a large amount of water (Oil-in-Water type solvent diffusion method). In this case, nanoparticles having various physical properties can be produced by adjusting the amount and the addition rate of the drug.
  • a drug a poly-DL or L-lactic acid or poly (DL or L-lactic acid / glycolic acid) copolymer, a conjugate of arabinogalactan and a biodegradable cationic polymer, a metal ion, a base Nanoparticles can
  • biodegradable cationic polymers used in the conjugates of arabinogalactan and biodegradable cationic polymers include polylysine, polyarginine, polyhistidine, polypeptides rich in basic amino acids, chitin, chitosan, etc. Polylysine is preferably used.
  • Conjugates of arabinogalactan and biodegradable cationic polymer are prepared by dissolving dialyzed and purified arabinogalactan together with sodium cyanoborohydride and biodegradable cationic polymer in an aqueous solvent such as sodium hydroxide.
  • the base can be made basic with a pH of 7.5 to 9.0 and heated and stirred at 40 to 100 ° C.
  • the metal ions are any of zinc ions, iron ions, copper ions, nickel ions, beryllium ions, manganese ions, and cobalt ions, and one or more of these water-soluble metal salts are used. Of these, zinc ions and iron ions are preferable, and zinc chloride, iron chloride and the like can be preferably used.
  • Solvents used in the above reaction include organic solvents such as acetone, acetonitrile, ethanol, methanol, propanol, dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, and water-containing solvents thereof, acetone, dimethylformamide, dimethyl sulfoxide. , Dioxane and tetrahydrofuran are preferred.
  • the drug used in the present invention has a phosphate group, a sulfate group or a carboxyl group in the molecule so that it can be easily hydrophobized by binding to the above metal ions, or these groups are bonded to the drug molecule. It is preferable that the drug has been used.
  • the molecular weight of the drug is preferably 1,000 or less.
  • Examples of such drugs include various drugs, and among them, drug-encapsulated nanoparticles accumulate in the liver, which is particularly advantageous for drugs for treating liver diseases, such as anti-hepatitis virus drugs, liver cancer therapeutic drugs, A liver function improving drug or the like is preferable.
  • anti-hepatitis virus drugs such as ribavirin, lamivudine, adefovir, entecavir, vidarabine
  • drugs for treating liver cancer such as cyclophosphamide, fluorouracil, doxyfluridine, tegafur, cytarabine, doxorubicin, epirubicin, mitoxantrone, mitomycin
  • liver function improving drugs such as ursodeoxycholic acid, furopropion, glutathione, and glycyrrhizic acid.
  • ribavirin, and ribavirin-phosphoric acid in which ribavirin and phosphoric acid are combined is preferable.
  • the incorporation rate of the drug in the nanoparticles is increased by further mixing a basic low molecular weight compound.
  • basic low molecular weight compounds include (dimethylamino) pyridine, pyridine, piperidine, pyrimidine, pyrazine, pyridazine, quinoline, quinuclidine, isoquinoline, bis (dimethylamino) naphthalene, naphthylamine, morpholine, amantadine, aniline, spermine, spermidine , Hexamethylenediamine, putrescine, cadaverine, phenethylamine, histamine, diazabicyclooctane, diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine
  • the diameter of the particles is in the range of 20 to 300 nm, preferably 50 to 200 nm, depending on the therapeutic purpose of each drug. Its particle size can be determined.
  • the drug is an anti-hepatitis virus drug
  • nanoparticles having a particle size of 50 to 200 nm are preferably administered orally or intravenously.
  • the encapsulation rate varies depending on the amount of each drug, the rate of addition to water in the solvent diffusion method, and the amount of addition of metal ions and basic low molecular weight compounds.
  • the diameter also changes.
  • the liver-accumulating nanoparticles encapsulating the drug of the present invention are appropriately purified by operations such as centrifugation, ultrafiltration, gel filtration, filter filtration, and fiber dialysis of the nanoparticle solution or suspension. It is preferably obtained and stored by lyophilization.
  • a stabilizer and / or a dispersing agent in order to resuspend the lyophilized preparation so that it can be administered, and then lyophilized.
  • a stabilizer and / or a dispersing agent are preferably used.
  • the liver-accumulating nanoparticles encapsulating the drug provided by the present invention are used as pharmaceuticals for preparations for parenteral administration such as intravenous injection preparations, topical injection preparations, nasal drops, eye drops, inhalants, and sprays.
  • parenteral administration such as intravenous injection preparations, topical injection preparations, nasal drops, eye drops, inhalants, and sprays.
  • the characteristics and effects of the nanoparticles can be better exhibited by preparing a preparation for intravenous injection.
  • it is used as a pharmaceutical for oral administration such as tablets, capsules and powders using ordinary excipients and additives.
  • bases and other additive components used in the preparation of these parenteral preparations and oral administration preparations include various bases and ingredients that are pharmaceutically acceptable and used. . Specifically, saccharides such as physiological saline, monosaccharides, disaccharides, sugar alcohols, polysaccharides; polymer additives such as hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, crystalline cellulose; ionic or nonionic interfaces Activators; etc. can be appropriately selected and used depending on the dosage form.
  • Example 1 Synthesis of a conjugate of arabinogalactan (AG) and polylysine (PLL) (AG-PLL) Arabinogalactan (AG, manufactured by Tokyo Chemical Industry Co., Ltd.) was purified by dialysis and freeze-dried for 3 days, and then recovered. . 600 mg of this purified arabinogalactan, 300 mg of sodium cyanoborohydride, and 100 mg of polylysine (PLL, manufactured by Sigma) were dissolved in 8 mL of water, and 4N sodium hydroxide aqueous solution was added to adjust the pH to 8.5. The solution was stirred at 60 ° C. for 18 hours. The reprecipitation purification was repeated three times using 5 times the amount of ethanol, and then lyophilized.
  • the resulting reaction product was analyzed by size exclusion chromatography (SEC).
  • SEC size exclusion chromatography
  • the columns used were TSKgel ⁇ 3000 and TSKgel ⁇ 2500 (manufactured by Tosoh Corporation), and were detected by a differential refractometer and an ultraviolet / visible spectrophotometer. Further, trinitrobenzenesulfonic acid (TNBS), which is an amino group detection reagent, was added to the obtained reaction product, and analysis was similarly performed by size exclusion chromatography.
  • TNBS trinitrobenzenesulfonic acid
  • Ribavirin-phosphate was prepared according to the method described in J. Med. Chem., 21 (8), 742-746 (1978). Manufactured. That is, ribavirin, trimethyl phosphate, phosphoryl chloride and water were mixed and stirred for 5 hours while cooling with ice. 160 g of ice was added and dissolved, and then 4N aqueous sodium hydroxide solution was added to adjust the pH to 3. This solution was washed with chloroform, adsorbed on activated carbon, and eluted with a mixed solvent of water / ethanol / aqueous ammonia (10: 10: 1). The obtained ribavirin-phosphoric acid was confirmed by NMR and mass spectrometry.
  • RMP ribavirin-phosphate
  • FIG. 2 shows that the encapsulation rate of ribavirin-phosphate (RMP) has a great influence by changing the amounts of ferric chloride and diethanolamine (DEA). Specifically, 7.5, 11.25 and 15.0 ⁇ mol of iron were used, and at the same time, the amount of ribavirin-phosphoric acid encapsulated in nanoparticles adjusted by changing the amount of diethanolamine (DEA) was measured by high performance liquid chromatography. Was quantified. As a result, there was an optimal amount of diethanolamine to obtain the maximum encapsulation efficiency. It was also found that the amount of diethanolamine required increased as the amount of iron increased.
  • RMP ribavirin-phosphate
  • DEA diethanolamine
  • FIG. 4 shows the amount of ribavirin-phosphoric acid (RMP) encapsulated in nanoparticles prepared by changing the addition rate of dimethyl sulfoxide solution and the amount of diethanolamine (DEA). The results quantified by chromatography were shown. As a result, it was found that stirring was effective and there was an optimum amount of diethanolamine to obtain the maximum encapsulation efficiency. It was also found that the maximum encapsulation efficiency depends on the addition rate of the dimethyl sulfoxide solution.
  • RMP ribavirin-phosphoric acid
  • Nanoparticles were prepared using ribavirin without a phosphate group attached instead of ribavirin-phosphate.
  • Poly DL-lactic acid manufactured by Taki Chemical
  • a conjugate of arabinogalactan and polylysine, ribavirin, ferric chloride and diethanolamine are dissolved in dimethyl sulfoxide, and this solution is gradually stirred into a large amount of water while stirring with a stirrer.
  • nanoparticles were obtained.
  • the encapsulation efficiency of ribavirin was 0.53% by weight, which was lower than that of 1.58% by weight for ribavirin-phosphate, but it was found that nanoparticles encapsulating ribavirin could be prepared.
  • ribavirin-phosphate plays an important role in the encapsulation in the nanoparticles.
  • ribavirin was not encapsulated in the nanoparticles at all.
  • Drug-unencapsulated nanoparticles that do not contain drugs such as ribavirin-phosphate and ribavirin are dissolved in dimethyl sulfoxide using only a conjugate of polylactic acid, arabinogalactan, and polylysine. Adjustment was possible by law.
  • Example 3 Evaluation of Physical Properties of Nanoparticles
  • the particle size of the obtained nanoparticles was 105 nm
  • the ribavirin-phosphoric acid encapsulation rate was 1.7% by weight
  • the arabinogalactan content in the nanoparticles was 5.7% by weight.
  • the value of the zeta potential was ⁇ 43.4 mV for the nanoparticles prepared without adding arabinogalactan, whereas it was ⁇ 7.7 mV for the nanoparticles of the present invention.
  • Example 4 Evaluation of interaction with cells HepG cells (human hepatoma-derived cell line) were seeded on 50,000 Cells / 8 well chamber slides and incubated overnight. The medium was replaced with Opti-MEM, and nanoparticles encapsulating the labeled fluorescent substance rhodamine 123 were added and incubated for 3 hours. The cells were washed three times with physiological saline, fixed with 4% formaldehyde solution, and then observed with a fluorescence microscope.
  • FIG. 6 shows a microscopic image of the cells.
  • Nanoparticles prepared using a conjugate of arabinogalactan and polylysine (AG-PLL) are significantly incorporated into cells compared to nanoparticles prepared without using them (unmodified sugar nanoparticles). Turned out to be.
  • ribavirin incorporated into the cells was quantified. HepG cells were seeded at 2 million Cells / plate and incubated overnight. The medium was changed to Opti-MEM medium, and particles or ribavirin was added and incubated at 37 ° C. for 3 hours. The cells were trypsinized and the cell pellet collected by centrifugation was sonicated. Acetonitrile was added to dissolve particles, treated with acid phosphatase, dephosphorylated, purified with a cartridge column, and then the amount of ribavirin was quantified by high performance liquid chromatography.
  • Example 5 Liver-accumulating animal experimental mice (C57BL6 mice, female, 6 weeks old, body weight about 20 g) were injected with ribavirin aqueous solution or ribavirin-phosphate encapsulated nanoparticle suspension via tail vein, and after a predetermined time the liver Collected and homogenized. Acetonitrile was added to the homogenized solution to dissolve the particles, treated with acid phosphatase, dephosphorylated, purified with a cartridge column, and then ribavirin was quantified by high performance liquid chromatography.
  • ribavirin was significantly accumulated in the liver by administering nanoparticles encapsulating ribavirin, compared with the case of administering an aqueous solution of ribavirin.
  • ribavirin accumulated in the liver gradually decreased after administration and remained after 7 days, and it was found that ribavirin was gradually released from the nanoparticles in the liver and had sustained drug efficacy.
  • RBV means a ribavirin aqueous solution
  • NP means a babylin-phosphate encapsulated nanoparticle.
  • the liver-accumulating nanoparticles encapsulating the drug provided by the present invention improve targeting and sustainability to the liver, which has not been sufficiently achieved so far, and efficiently exert pharmacological effects in the affected area. Nanoparticles to be made. Therefore, it can be used for the treatment of liver diseases such as anti-hepatitis virus drugs, liver cancer therapeutic drugs, liver function improving drugs, etc., and it can achieve the sustainability in the liver. Is something.

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Abstract

La présente invention a pour but de procurer des nanoparticules aptes à s'accumuler dans le foie, renfermant un médicament encapsulé, dans lesquelles, le médicament peut être encapsulé avec un rendement élevé et le médicament peut être enfermé de façon stable, et qui permettent de faciliter l'accumulation du médicament dans le foie. L'invention concerne des nanoparticules à médicament encapsulé produites par encapsulation d'un médicament dans les nanoparticules qui comprennent n'importe quel composant choisi parmi le poly-DL, l'acide L-lactique et un copolymère poly(DL ou acide L-lactique/acide glycolique), un conjugué d'arabinogalactane et un polymère cationique biodégradable, un ion métallique et un composé à faible masse moléculaire basique, le médicament étant, par exemple, un agent anti-virus de l'hépatite, un agent thérapeutique pour le cancer du foie ou un agent pour améliorer la fonction du foie, et les nanoparticules à médicament encapsulé présentant une excellente accumulation dans le foie et une excellente durabilité.
PCT/JP2012/071659 2011-09-05 2012-08-28 Nanoparticules aptes à s'accumuler dans le foie renfermant un médicament encapsulé Ceased WO2013035579A1 (fr)

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JP2011192838A JP2013053103A (ja) 2011-09-05 2011-09-05 薬物を封入した肝臓集積性ナノ粒子
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