WO2010061880A1 - Préparation vésiculaire - Google Patents

Préparation vésiculaire Download PDF

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WO2010061880A1
WO2010061880A1 PCT/JP2009/069933 JP2009069933W WO2010061880A1 WO 2010061880 A1 WO2010061880 A1 WO 2010061880A1 JP 2009069933 W JP2009069933 W JP 2009069933W WO 2010061880 A1 WO2010061880 A1 WO 2010061880A1
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Prior art keywords
phosphatidylethanolamine
phosphatidylinositol
endoplasmic reticulum
phosphatidic acid
soybean
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PCT/JP2009/069933
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English (en)
Japanese (ja)
Inventor
小原　道法
善郎 中野
麗 蜂須
幸雄 水谷
正幸 須藤
Original Assignee
中外製薬株式会社
財団法人 東京都医学研究機構
北海道システム・サイエンス株式会社
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Application filed by 中外製薬株式会社, 財団法人 東京都医学研究機構, 北海道システム・サイエンス株式会社 filed Critical 中外製薬株式会社
Priority to KR1020117014582A priority Critical patent/KR101727333B1/ko
Priority to CN200980155850.6A priority patent/CN102292069B/zh
Priority to JP2010540502A priority patent/JP5600299B2/ja
Publication of WO2010061880A1 publication Critical patent/WO2010061880A1/fr
Priority to HK12104035.5A priority patent/HK1163513A1/xx

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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
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Definitions

  • the present invention relates to an endoplasmic reticulum capable of efficiently introducing a physiologically active substance into liver parenchymal cells and allowing the physiologically active substance to act effectively in liver parenchymal cells and the use thereof.
  • the present invention relates to bioactive substances such as antiviral agents, chemotherapeutic agents, peptides, nucleotides, oligonucleotides, antisense nucleic acids, aptamers, decoys and their analogs, small nucleic acid molecules such as siRNA, miRNA, dsRNA, or shRNA.
  • bioactive substances such as antiviral agents, chemotherapeutic agents, peptides, nucleotides, oligonucleotides, antisense nucleic acids, aptamers, decoys and their analogs, small nucleic acid molecules such as siRNA, miRNA, dsRNA, or shRNA.
  • the present invention relates to an endoplasmic reticulum that can be efficiently introduced into liver parenchymal cells and that allows a physiologically active substance to act effectively in liver parenchymal cells.
  • nucleic acid such as a gene or a physiologically active substance such as an antitumor agent is introduced into liver parenchymal cells to attempt gene expression, gene regulation, or tumor reduction.
  • Non-patent Document 1 Non-patent Document 1
  • Patent Document 1 published patent
  • Patent Document 2 As an example of hydrodynamic injection introduced into cells by applying water pressure
  • Patent Document 2 introduction methods using viral vectors have problems in human safety and are not suitable for general therapeutic purposes.
  • the introduction method of applying water pressure can be introduced into cells in vitro, but is not suitable for human use for therapeutic purposes.
  • Non-patent Document 3 As a delivery method to hepatocytes, a method utilizing receptor-mediated endocytosis targeting a sugar receptor on the liver surface is known.
  • the asialoglycoprotein receptor (Non-patent Document 3) is specific to hepatocytes and binds to glycoproteins having a galactose terminus, such as asialo orthomucoid.
  • a liposome composition (Patent Document 3) containing galactose-modified cationic cholesterol utilizing this principle has been introduced.
  • Patent Document 3 containing galactose-modified cationic cholesterol utilizing this principle has been introduced.
  • siRNA in the examples where siRNA is delivered, although the effect is slightly higher than when galactose is not modified, gene expression is also observed in the lung, kidney, spleen, and heart. It turns out that siRNA has not been delivered, so it is not an effective technique.
  • Non-patent Document 4 Compositions in which lactose is bound to phospholipid phosphatidylethanolamine and incorporated into cationic liposomes (Non-patent Document 4), and delivery using sugar-modified peptides to target liver sugar receptors in the same way as liposomes (patents) Reference 4) has also been proposed.
  • the delivery of liposomes targeting the liver sugar receptor has the problem that, after being incorporated by endocytosis, the nucleic acid is degraded in the endosome and the effects of gene expression and gene regulation are hardly exhibited. It was.
  • vitamin E tocopherol
  • a fat-soluble vitamin has an antioxidant function
  • a small amount (generally about 0.2%) is added to the endoplasmic reticulum to prevent the oxidation of unsaturated fatty acids in the lipid endoplasmic reticulum.
  • dietary vitamin E is absorbed from the small intestine and transported to the liver by the serum component chylomicron in the blood, and vitamin E other than diet-derived vitamin E in the blood is HDL (high density lipoprotein) and LDL ( An example of using siRNA for liver delivery by chemically binding ⁇ -tocopherol, the main component of vitamin E, with siRNA is reported by Nishina et al. Non-patent document 5).
  • siRNA and ⁇ -tocopherol at 1: 1 on an industrial scale and high purity as a prodrug is required, it is necessary to remove unreacted raw materials and by-products. It becomes. Because of the low yield resulting from these manufacturing and purification processes and the need to release siRNA by hydrolysis after introduction into the liver, a large amount of expensive siRNA must be used to obtain a therapeutic effect. There was an economic problem of not becoming.
  • a method in which vitamin A is mixed with a commercially available cationic liposome for cell introduction and further mixed with a nucleic acid such as a plasmid or siRNA to form an emulsion and delivered to hepatic stellate cells (Patent Document 8).
  • Hepatic stellate cells like reticuloendothelial cells, are nonparenchymal cells, have lipid droplets inside the cells, and store vitamin A at a high concentration.
  • the present invention has been made in view of the above circumstances, and an object of the present invention is to deliver and introduce a physiologically active substance into hepatocytes efficiently and specifically, and to deliver the physiologically active substance into hepatocytes. It is related with the composition for making it act effectively.
  • the present inventors have adsorbed or chemically bound a sufficient amount of vitamin E to recognize serum components on the surface of the endoplasmic reticulum containing a physiologically active substance.
  • the present inventors have found that the endoplasmic reticulum whose serum component contains a physiologically active substance can be extremely efficiently delivered to hepatocytes, and that the physiologically active substance can rapidly exert its effect.
  • the present invention relates to the following [1] to [24].
  • An endoplasmic reticulum comprising the following (i) and (ii), wherein vitamin E is adsorbed on the surface of the endoplasmic reticulum or chemically bound to an amphiphile constituting the endoplasmic reticulum.
  • Endoplasmic reticulum characterized by being.
  • Amphiphile ii
  • the cationic lipid is a saturated or unsaturated aliphatic primary amine (stearylamine, oleylamine), saturated or unsaturated secondary, tertiary amine (distearoyltrimethylammoniumpropane, dioleoyltrimethylammoniumpropane), and Quaternary amine salts (DODAC (dioctadecyldimethylammonium chloride), DTDAB (ditetradecyldimethylammonium bromide), DOTMA (N- (2,3-dioleoyl) propyl-N, N, N- Trimethylammonium: N- (2,3-dioleyloxy) propyl-N, N, N-trimethylammonium), DDAB (didodecylammonium bromide), DTAB (ditetradecy
  • [5] The group in which the amphiphile is composed of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, methoxypolyethyleneglycol (mPEG) -added phosphatidylethanolamine, phosphatidic acid, sphingomyelin, cardiolipin, and plasmalogen
  • the phosphatidylcholine is egg yolk phosphatidylcholine, hydrogenated egg yolk phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoyl
  • the acidic phospholipid includes at least one selected from the group consisting of phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, methoxypolyethyleneglycol-added phosphatidylethanolamine, and phosphatidic acid, [9] ] Endoplasmic reticulum as described in].
  • the phosphatidylglycerol is egg yolk phosphatidylglycerol, hydrogenated egg yolk phosphatidylglycerol, soybean phosphatidylglycerol, hydrogenated soybean phosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleo Oil phosphatidyl glycerol, palmitoyl-oleoyl phosphatidyl glycerol, dilinoleoyl phosphatidyl glycerol, dilinolenoyl phosphatidyl glycerol, didecanoyl phosphatidyl glycerol, diercyl phosphatidyl glycerol, diaicosano
  • the endoplasmic reticulum encloses at least one physiologically active substance selected from the group consisting of plasmid DNA, siRNA, miRNA, antisense oligonucleotide, antiviral agent, and cytotoxic substance, and / or The endoplasmic reticulum according to any one of [1] to [17], wherein the physiologically active substance is hydrophobically or electrostatically bound to a component of the endoplasmic reticulum.
  • the cytotoxic substance is selected from the group consisting of antimetabolites, platinum agents, alkylating agents, plant alkaloids, molecular targeted drugs, biological response modifiers, and anticancer antibiotics.
  • the antimetabolite is enositabine, capecitabine, carmofur, cladribine, gemcitabine, cytarabine, cytarabine ocphosate, tegafur, tegafur uracil, tegafur, gimeracil, oteracil potassium, doxyfluridine, nelarabine, hydroxycarbamide, fluorouracil, fluorouracil , Selected from the group consisting of pemetrexed, pentostatin, mercaptopurine, and methotrexate;
  • the platinum preparation is selected from the group consisting of oxaliplatin, carboplatin, cisplatin, and nedaplatin;
  • the alkylating agent is selected from the group consisting of ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, melphalan, and rani
  • a kit for delivering a physiologically active substance to hepatocytes in the presence of serum comprising the endoplasmic reticulum according to any one of [18] to [22] and a pharmaceutically acceptable carrier.
  • a method for delivering a physiologically active substance to hepatocytes in a subject comprising a step of administering the endoplasmic reticulum according to any one of [18] to [22] to the subject.
  • Liposomes according to [Example 1] and [Example 2] prepared by adding liposome dispersions or tocopherols of [Comparative Example 1] and [Comparative Example 2] to HCV replicon cells R6 FLR41-14 cells containing a luciferase gene SiRNA was introduced using the dispersion, and its HCV replication inhibitory activity was examined. Results at low concentrations were shown. It is a figure which shows the gene expression principle of the transgenic (Cre / loxP / HCV-MxCre Tg) mouse which carries out switching expression of the HCV gene.
  • the present invention is an endoplasmic reticulum comprising the following (i) and (ii), wherein vitamin E is adsorbed on the surface of the endoplasmic reticulum, or vitamin E is chemically bound to an amphiphilic substance constituting the endoplasmic reticulum. It is related with the endoplasmic reticulum characterized by having. (i) Amphiphile (ii) Organic substances including substances having cationic properties and / or substances having anionic properties
  • the amphiphiles used in the present invention preferably associate with each other in water to form nano to submicron vesicles.
  • the amphipathic substance of the present invention is represented by phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, polyethyleneglycol (PEG) -added phosphatidylethanolamine, phosphatidic acid, sphingomyelin, cardiolipin, and plasmalogen.
  • polypolysaccharides pullulan, mannan etc.
  • polyamino acids polyaspartic acid etc.
  • the phospholipid and / or the polymer condensate and cholesterol may be used in combination as an amphiphilic substance.
  • phosphatidylcholine includes egg yolk phosphatidylcholine, hydrogenated egg yolk phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, , Dilinoleoyl phosphatidylcholine, dilinolenoyl phosphatidylcholine, didecanoyl phosphatidylcholine, dielcylyl phosphatidylcholine, dieicosanoyl phosphatidylcholine, dieicosatrienoylphosphatidylcholine, dieicosapentaenoyl phosphatidylcholine, didocosa Examples thereof
  • Phosphatidylethanolamine includes egg yolk phosphatidylethanolamine, soybean phosphatidylethanolamine, hydrogenated soybean phosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, dioleoyl Phosphatidylethanolamine, palmitoyl-oleoylphosphatidylethanolamine, dilinoleoylphosphatidylethanolamine, dilinolenoylphosphatidylethanolamine, didecanoylphosphatidylethanolamine, diercylylphosphatidylethanolamine, dieicosanoylphosphatidylethanolamine And dieicosatrienoylphosphatidylethanolamine, dieicosapentaenoylphosphatidylethanolamine, didocosaeno
  • phosphatidylglycerol egg yolk phosphatidylglycerol, hydrogenated egg yolk phosphatidylglycerol, soybean phosphatidylglycerol, hydrogenated soybean phosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol , Palmitoyl-oleoylphosphatidylglycerol, dilinoleoylphosphatidylglycerol, dilinolenoylphosphatidylglycerol, didecanoylphosphatidylglycerol, diercylylphosphatidylglycerol, dieicosanoylphosphatidylglycerol, die
  • phosphatidylserine egg yolk phosphatidylserine, hydrogenated egg yolk phosphatidylserine, soybean phosphatidylserine, hydrogenated soybean phosphatidylserine, dilauroylphosphatidylserine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, distearoylphosphatidylserine, dioleoylphosphatidylserine , Palmitoyl-oleoylphosphatidylserine, dilinoleoylphosphatidylserine, dilinolenoylphosphatidylserine, didecanoylphosphatidylserine, diercylylphosphatidylserine, dieicosanoylphosphatidylserine, dieicosatrienoylphosphatidylserine,
  • Phosphatidylinositol includes egg yolk phosphatidylinositol, hydrogenated egg yolk phosphatidylinositol, soybean phosphatidylinositol, hydrogenated soybean phosphatidylinositol, dilauroyl phosphatidylinositol, dimyristoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol , Palmitoyl-oleoyl phosphatidylinositol, dilinoleoyl phosphatidylinositol, dilinolenoyl phosphatidylinositol, didecanoyl phosphatidylinositol, diercyloxyphosphatidylinositol, dieicosanoyl phosphat
  • Methoxy polyethylene glycol (mPEG) -added phosphatidylethanolamine includes mPEG2000-yolk phosphatidylethanolamine, mPEG3400-yolk phosphatidylethanolamine, mPEG5000-yolk phosphatidylethanolamine, mPEG2000-hydrogenated egg yolk phosphatidylethanolamine, mPEG3400-hydrogenated egg yolk phosphatidylethanol.
  • phosphatidic acid egg yolk phosphatidic acid, hydrogenated egg yolk phosphatidic acid, soybean phosphatidic acid, hydrogenated soybean phosphatidic acid, dilauroyl phosphatidic acid, dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, distearoyl phosphatidic acid, dioleoylphosphatidic acid , Dilinoleoyl phosphatidic acid, palmitoyl-oleoyl phosphatidic acid, dilinolenoyl phosphatidic acid, didecanoyl phosphatidic acid, dielciloyl phosphatidic acid, dieicosanoyl phosphatidic acid, dieicosatrienoyl phosphatidic acid, dieicosapentaenoyl Examples include phosphatidic acid, didocosaenoyl phosphatidic acid, didocosahexaenoyl phosphatidic acid, and the like.
  • sphingomyelin can include egg yolk-derived sphingomyelin or milk-derived sphingomyelin
  • Cardiolipins include egg yolk cardiolipin, hydrogenated egg yolk cardiolipin, soybean cardiolipin, hydrogenated soybean cardiolipin, dilauroyl cardiolipin, dimyristoyl cardiolipin, dipalmitoyl cardiolipin, distearoyl cardiolipin, dioleoyl cardiolipin, palmitoyl-oleoyl cardiolipin dioliporiolipiolipiolipiolipiolipin oil , Dilinolenoyl cardiolipin, didecanoyl cardiolipin, dielciloyl cardiolipin, dieicosanoyl cardiolipin, dieicosatrienoyl cardiolipin, dieicosapentaenoyl cardiolipin, didocosaenoyl cardiolipin, zidocosa hexaenoyl cardiolipin, etc.
  • a substance having a cationic property for electrical coupling can be used as a constituent component of the endoplasmic reticulum.
  • a substance having a cationic property preferably a cationic lipid can be exemplified, and more preferably, a compound represented by the following formula (I) can be exemplified.
  • Formula (I) (Wherein R1 and R2 are the same or different and each represents a saturated or unsaturated hydrocarbon group having 12 to 22 carbon atoms, and R3 represents an alkyl group having 1 to 6 carbon atoms or a hydroxy group having 1 to 6 carbon atoms. Represents an alkyl group, m represents an integer of 1 to 10, and X represents a halogen atom.)
  • the compounds include N- ( ⁇ -trimethylammonioacetyl) -didodecyl-D-glutamate chloride, N- ( ⁇ -trimethylammonioacetyl) -didodecyl-L-glutamate chloride, N- ( ⁇ -trimethylammonioacetyl).
  • cationic substances include saturated or unsaturated aliphatic primary amines such as stearylamine and oleylamine; saturated or unsaturated secondary and tertiary amines such as distearoyltrimethylammoniumpropane and dioleoyltrimethylammoniumpropane; or DODAC (dioctadecyldimethylammonium chloride), DOTMA (N- (2,3-dioleoyl) propyl-N, N, N-trimethylammonium: N- (2,3-dioleyloxy) propyl-N, N, N -trimethylammonium), DDAB (didodecylammonium bromide), DOTAP (1,2-dioleoyloxy-3-trimethylammoninopropane: 1,2-dioleoyloxy-3-trimethylammoniopropane), DC-Chol (3 ⁇ -N- (N ′, N ′,-dimethylamino
  • polyethylenimine and polylysine which are polycations can also be used.
  • a non-polar substance such as a cytotoxic substance or a low molecular weight antiviral agent or a substance that does not have many polar groups
  • a membrane Either of the following methods can be used: hydrophobic bonding with the constituent components and placement in the membrane.
  • an anionic substance can be used for the purpose of preventing aggregation of the endoplasmic reticulum using electrostatic repulsion.
  • Preferred examples of the anionic substance include acidic phospholipids.
  • acidic phospholipid examples include phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, methoxypolyethyleneglycol-added phosphatidylethanolamine, and phosphatidic acid.
  • phosphatidylglycerol egg yolk phosphatidylglycerol, hydrogenated egg yolk phosphatidylglycerol, soybean phosphatidylglycerol, hydrogenated soybean phosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol , Palmitoyl-oleoylphosphatidylglycerol, dilinoleoylphosphatidylglycerol, dilinolenoylphosphatidylglycerol, didecanoylphosphatidylglycerol, diercylylphosphatidylglycerol, dieicosanoylphosphatidylglycerol, die
  • phosphatidylserine egg yolk phosphatidylserine, hydrogenated egg yolk phosphatidylserine, soybean phosphatidylserine, hydrogenated soybean phosphatidylserine, dilauroylphosphatidylserine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, distearoylphosphatidylserine, dioleoylphosphatidylserine , Palmitoyl-oleoylphosphatidylserine, dilinoleoylphosphatidylserine, dilinolenoylphosphatidylserine, didecanoylphosphatidylserine, diercylylphosphatidylserine, dieicosanoylphosphatidylserine, dieicosatrienoylphosphatidylserine,
  • Phosphatidylinositol includes egg yolk phosphatidylinositol, hydrogenated egg yolk phosphatidylinositol, soybean phosphatidylinositol, hydrogenated soybean phosphatidylinositol, dilauroyl phosphatidylinositol, dimyristoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol , Palmitoyl-oleoyl phosphatidylinositol, dilinoleoyl phosphatidylinositol, dilinolenoyl phosphatidylinositol, didecanoyl phosphatidylinositol, diercyloxyphosphatidylinositol, dieicosanoyl phosphat
  • Methoxy polyethylene glycol (mPEG) -added phosphatidylethanolamine includes mPEG2000-yolk phosphatidylethanolamine, mPEG3400-yolk phosphatidylethanolamine, mPEG5000-yolk phosphatidylethanolamine, mPEG2000-hydrogenated egg yolk phosphatidylethanolamine, mPEG3400-hydrogenated egg yolk phosphatidylethanol.
  • phosphatidic acid egg yolk phosphatidic acid, hydrogenated egg yolk phosphatidic acid, soybean phosphatidic acid, hydrogenated soybean phosphatidic acid, dilauroyl phosphatidic acid, dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, distearoyl phosphatidic acid, dioleoylphosphatidic acid , Dilinoleoyl phosphatidic acid, palmitoyl-oleoyl phosphatidic acid, dilinolenoyl phosphatidic acid, didecanoyl phosphatidic acid, dielciloyl phosphatidic acid, dieicosanoyl phosphatidic acid, dieicosatrienoyl phosphatidic acid, dieicosapentaenoyl
  • Illustrative examples include phosphatidic acid, didocosaenoyl phosphatidic acid, and didocosahexaenoyl phosphatidic acid
  • vitamin E adsorbed or chemically bound to the surface of the endoplasmic reticulum is not particularly limited, but is preferably selected from the group consisting of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, and ⁇ -tocopherol. At least one or more types of vitamin E can be exemplified. A more preferred example of vitamin E is dl- ⁇ -tocopherol.
  • the amount of vitamin E that is adsorbed or chemically bound to the surface of the endoplasmic reticulum is an amount sufficient for particles in the serum to recognize, but specifically, the number of moles of the whole substance constituting the endoplasmic reticulum, preferably 3 to It needs to be adsorbed or chemically bound in the range of 30%, more preferably in the range of 5 to 20%.
  • these binding ratios are small, vitamin E recognition ability of serum particles is weak and delivery efficiency to hepatocytes is poor.
  • the amount is too large, the adsorbed vitamin E tends to associate with each other by hydrophobic bonds, so that the average particle size increases. Increasing the average particle size facilitates trapping by RES in blood, resulting in a decrease in delivery efficiency to hepatocytes.
  • an ester or the like in which a dibasic acid such as glutaric acid is bonded to the tip of the amino group of phosphatidylethanolamine, which is an amphiphilic substance, and one carboxylic acid and the hydroxyl group of vitamin E are condensed is used.
  • a dibasic acid such as glutaric acid
  • polyethylene glycol having a terminal substituted with an active group may be used instead of dibasic acid.
  • the method for binding vitamin E is not limited to these, and any of the generally known methods is possible.
  • vitamin E By adding vitamin E within the above range, the recognition ability by serum particles is optimized and the association between the endoplasmic reticulum can be prevented, so that efficient delivery to hepatocytes can be realized.
  • the particle size of the endoplasmic reticulum can be 20-500 nm for delivery to parenchymal hepatocytes in vitro, but it can be trapped in the RES by controlling it to 50-150 nm for intravenous administration in vivo. Without being transported to hepatocytes by particles typified by LDL in serum.
  • the endoplasmic reticulum having a particle size of 50 to 150 nm is 60% or more of the whole in order to sufficiently exhibit the delivery effect in vivo.
  • the present invention also includes an endoplasmic reticulum population characterized in that the endoplasmic reticulum having a particle size of 50 nm to 150 nm is 60% or more of the entire endoplasmic reticulum population.
  • the endoplasmic reticulum encloses at least one physiologically active substance selected from the group consisting of plasmid DNA, siRNA, miRNA, antisense oligonucleotide, antiviral agent, and cytotoxic substance, and / or Alternatively, the present invention relates to an endoplasmic reticulum in which the physiologically active substance is hydrophobically or electrostatically bound to a component of the endoplasmic reticulum.
  • the present invention relates to an endoplasmic reticulum having an anionic zeta potential on the surface of the endoplasmic reticulum.
  • the physiologically active substance is preferably anionic by electrostatically binding to a component of the endoplasmic reticulum, but the form is not particularly limited.
  • the siRNA used as a physiologically active substance in the present invention is not particularly limited, but preferably, an siRNA containing the oligoribonucleotide represented by SEQ ID NO: 1 and the oligonucleotide represented by SEQ ID NO: 2 can be exemplified.
  • the antiviral agent used as a physiologically active substance in the present invention is not particularly limited as long as it is a drug for the treatment of viral liver disease such as an anti-HCV agent or an anti-HBV agent, but is preferably an anti-HCV agent.
  • the antiviral agent of the present invention includes not only nucleic acid drugs such as plasmid DNA, siRNA, miRNA, and antisense oligonucleotides against HCV and HBV but also low molecular weight antiviral agents.
  • the low molecular weight antiviral agent is not particularly limited, but may be an inhibitor such as a polymerase or protease encoded by a viral gene, or any other low molecular weight compound having antiviral activity. Specific compounds include ribavirin (1- ⁇ - D-ribofuranosyl-1H-1,2,4-tri-azole-3-carboxamide) and the like.
  • the cytotoxic substance is selected from the group consisting of antimetabolites, platinum-based agents, alkylating agents, plant alkaloids, molecular targeted drugs, biological response modifiers, and anticancer antibiotics. Examples thereof include cytotoxic substances containing at least one kind.
  • Antimetabolites include enocitabine, capecitabine, carmofur, cladribine, gemcitabine, cytarabine, cytarabine ocphosate, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, doxyfluridine, nelarabine, hydroxycarbamide, fluorouradofludurafludurafludurafludurafludurafludurafulful Examples include pentostatin, mercaptopurine, and methotrexate.
  • platinum preparations include oxaliplatin, carboplatin, cisplatin, and nedaplatin.
  • alkylating agents examples include ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, melphalan, and ranimustine.
  • the plant alkaloid is selected from irinotecan, etoposide, sobuzoxan, docetaxel, nogitecan, paclitaxel, vinorelbine, vincristine, vindesine, vinblastine, and the molecular target drugs are imatinib, erlotinib, sunitinib, cetuximab, soratizib Can be illustrated.
  • biological response modifiers include interferon- ⁇ , interferon- ⁇ , interferon- ⁇ , and interleukin.
  • anticancer antibiotics examples include aclarubicin, epirubicin, daunorubicin, doxorubicin, pirarubicin, bleomycin, mitomycin C, and mitoxantrone.
  • the present invention relates to a kit used for delivering a physiologically active substance to hepatocytes in the presence of serum, comprising the endoplasmic reticulum and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition and kit of the present invention may contain a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include sterilized water and physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffering agents (such as phosphoric acid, citric acid, and other organic acids). , Preservatives, surfactants (PEG, Tween, etc.), chelating agents (EDTA, etc.), binders and the like.
  • low molecular weight polypeptides serum albumin, proteins such as gelatin and immunoglobulin, amino acids such as glycine, glutamine, asparagine, arginine and lysine, sugars and carbohydrates such as polysaccharides and monosaccharides, and sugars such as mannitol and sorbitol Alcohol may be included.
  • aqueous solution for injection for example, isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, You may use together with adjuvants, such as alcohol (ethanol etc.), polyalcohol (propylene glycol, PEG, etc.), nonionic surfactant (polysorbate 80, HCO-50), etc.
  • adjuvants such as alcohol (ethanol etc.), polyalcohol (propylene glycol, PEG, etc.), nonionic surfactant (polysorbate 80, HCO-50), etc.
  • microcapsules such as hydroxymethylcellulose, gelatin, poly [methylmethacrylic acid]
  • colloid drug delivery systems liposomes, albumin microspheres, microemulsions, nanoparticles, nanocapsules, etc.
  • kit of the present invention may be accompanied by an instruction manual that describes a method for using the kit.
  • the present invention relates to a method for delivering a physiologically active substance to hepatocytes in a subject, comprising a step of administering the endoplasmic reticulum to the subject. After being administered to a subject, the endoplasmic reticulum of the present invention is selectively delivered to hepatocytes by a serum component within the subject.
  • administration to a subject can be either oral or parenteral, but is preferably parenteral.
  • the form (dosage form) of the composition comprising the endoplasmic reticulum of the present invention is not particularly limited, and is an injection form, a nasal dosage form, a pulmonary dosage form, a transdermal dosage form, a lyophilized dosage form, Examples include solution dosage forms.
  • an injection type it can be administered systemically or locally by, for example, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, or the like.
  • the administration method can be appropriately selected depending on the state of the subject (when the subject is a human patient, the age and symptoms of the patient).
  • the endoplasmic reticulum containing a physiologically active substance delivered by serum particles immediately exerts a physiologically active action in liver parenchymal cells.
  • the physiologically active substance is siRNA
  • the physiologically active substance delivered via the glycoprotein receptor on the surface of hepatocytes which is a conventional technique, is metabolized and degraded in lysosomes. According to this, a knockdown effect can be seen within 48 hours.
  • cationic liposomes are known in which siRNA is electrostatically bound to the surface of the endoplasmic reticulum, but an anion siRNA is added in a lower amount than the cationic lipid or cationic polymer for interaction with the cell surface.
  • the zeta potential on the surface of the endoplasmic reticulum is used as a plus (cationic).
  • RES cationic lipid
  • RES cationic
  • a solution (tocopherol solution) obtained by dissolving 400 ⁇ L of ethyl alcohol in 5 ⁇ mol of DL- ⁇ -tocopherol (Tokyo Kasei Co., Ltd., Japan) and filtering with a 0.2 ⁇ m filter was prepared.
  • 10 mL of the liposome dispersion was added, and 400 ⁇ L of the tocopherol solution was added (20% with respect to the total number of moles of lipids), followed by mixing and stirring for 20 seconds by vortexing.
  • the mixture was further incubated for 1 hour at room temperature to obtain a vitamin E-adsorbed liposome dispersion.
  • the average particle size was 124.2 nm.
  • Example 2 A solution (tocopherol solution) obtained by dissolving 400 ⁇ L of ethyl alcohol in 2.5 ⁇ mol of DL- ⁇ -tocopherol (Tokyo Kasei Co., Ltd., Japan) and filtering with a 0.2 ⁇ m filter was prepared. In a 50 mL vial, 10 mL of the liposome dispersion prepared in [Example 1] was added, and 400 ⁇ L of tocopherol solution was added (10.0% with respect to the total number of moles of lipids), followed by mixing and stirring by vortexing for 20 seconds. Further, the mixture was incubated at room temperature for 1 hour to obtain a vitamin E-adsorbed liposome dispersion. The average particle size was 136.7 nm.
  • Example 3 A solution (tocopherol solution) obtained by dissolving 400 ⁇ L of ethyl alcohol in 3.75 ⁇ mol of DL- ⁇ -tocopherol (Tokyo Kasei Co., Ltd., Japan) and filtering with a 0.2 ⁇ m filter was prepared. In a 50 mL vial, 10 mL of the liposome dispersion prepared in [Example 1] was added, and 400 ⁇ L of tocopherol solution was added (15.0% with respect to the total number of moles of lipids), and mixed and stirred for 20 seconds by vortexing. The mixture was further incubated for 1 hour at room temperature to obtain a vitamin E-adsorbed liposome dispersion. The average particle size was 133.5 nm.
  • Example 4 N- ( ⁇ -trimethylammonioacetyl) -dioleyl-D-glutamate chloride (Mutaku Pharmaceutical Co., Ltd., Japan; product name: DC-3-18: 1D), dioleoylphosphatidylethanolamine (Nissho Corporation, Japan) and cholesterol (Wako Pure Chemical Industries, Ltd., Japan) were dissolved in an appropriate amount of chloroform at a compounding ratio of 40:30:30 (molar ratio), and this was dried to dryness while distilling off the solvent under reduced pressure. It was a lipid mixture.
  • the average particle size was 138.7 nm.
  • Nano-Mizer mark II NM2-L200 (Yoshida Kikai Kogyo Co., Ltd., Japan)
  • it was passed three times under a pressure of 100 MPa for further micronization treatment.
  • the average particle size was 55.7 nm. there were.
  • a solution (tocopherol solution) obtained by dissolving 400 ⁇ L of ethyl alcohol in 5 ⁇ mol of DL- ⁇ -tocopherol (Tokyo Kasei Co., Ltd., Japan) and filtering with a 0.2 ⁇ m filter was prepared.
  • 10 mL of the liposome dispersion was added, and 320 ⁇ L of the tocopherol solution was added (16% with respect to the total number of moles of lipids), and mixed and stirred by vortex for 20 seconds.
  • the mixture was further incubated for 1 hour at room temperature to obtain a vitamin E-adsorbed liposome dispersion.
  • the average particle size was 58.0 nm.
  • siRNAs short double-stranded RNAs
  • IFN interferon
  • siRNA also induces an IFN response due to the Off-Target effect, and not only shortening the length of double-stranded RNA (dsRNA) but also improvements such as sequence and nucleic acid modification are being studied.
  • RNARNAi RNA interference
  • HCV targeting by siRNA for therapeutic application.
  • DDS drug delivery system
  • siRNA assay was performed using R6 FLR41-14 cells (Watanabe, T. et al., Gene Theraphy 13: 883-892 (2006)) as HCV replicon cells containing a luciferase gene. Count each cell and suspend in DMEM + GlutaMax-I containing 10% inactivated FCS. R6 FLR41-14 cells are seeded in 96 wells at 4500cells / 100 ⁇ L / well, and the next day siRNA transfection is performed. went.
  • siRNA used was si197-1 (sense strand 5′-AUCAUGAGCACAAAUCCUAAA-3 ′, SEQ ID NO: 1, antisense strand (3′-CGUAGUACUCGUGUUUAGGAU-5 ′, SEQ ID NO: 2).
  • the final concentration of siRNA was 0.01, 0.04, 0.11, 0.33, 1, 1.1, 3, 3.3, 10, 30, 90 nM.
  • Each siRNA sample was prepared in 10-step dilution series from 90 nM to 3-fold serial dilution with opti-MEM containing 0.23% NaHCO 3 .
  • Opti-MEM containing 0.23% NaHCO 3 .
  • To the 50 ⁇ L siRNA solution 0.5 ⁇ L of the liposome dispersion liquid of [Comparative Example 1] or the liposome dispersion liquid described in [Example 1] and [Example 2] prepared by adding tocopherol was added. After thorough mixing, the mixture was incubated at room temperature for 20 minutes to produce a siRNA-Liposome complex. Samples of each dilution series were added to the cell culture multiplate 96FII (white) for luciferase assay (Sumitomo Bakelite, Japan cat.
  • Table 1 shows that the zeta potential can be converted from cationic to anionic before and after conjugation of siRNA.
  • luciferase activity For measurement of luciferase activity, Bright-Glo Luciferase Assay System (Promega, cat. # E2620) was used. The method was according to the paper (Watanabe, T. et al., Gene Therapy 13: 883-892 (2006)). The medium in all wells of the 96-well plate for luciferase assay was discarded, and the medium was changed by adding DMEM + GlutaMax-I containing 5% inactivated FCS at 75 ⁇ L / well. Bright-Glo Luciferase Assay System was added at 75 ⁇ L / well, shaken with Mithras LB 940 (Berthold) for 1 minute, and then luciferase activity was measured.
  • ⁇ Cytotoxicity measurement> In the cytotoxicity measurement, Cell Counting Kit-8 (Dojindo, cat. # 343-07623) was used. Cell Counting Kit-8 solution was diluted to 7% with DMEM + GlutaMax-I containing 5% inactivated FCS to prepare an assay solution. The medium in all wells of a 96-well plate for cytotoxicity test was discarded, and the above assay solution was added at 100 ⁇ L / well and incubated at 37 ° C., 5% CO 2 for 1 hour. Using a microplate reader (Bio-Rad model 550), the wavelength 450 nm (reference wavelength 655 nm) was measured.
  • AxCANCre recombinant adenovirus
  • Cre DNA recombinase
  • the AxCANCre method also elicits an immune response against mouse adenovirus. Therefore, the present inventors crossed a transgenic mouse introduced with an HCV gene with the Cre / loxP system and a Mx-Cre transgenic mouse that induces Cre, thereby producing a transgenic (Cre / loxP / HCV-MxCre Tg) mice were produced.
  • Cre DNA recombinase is expressed by an interferon (IFN) -reactive Mx1 promoter, and thus switching occurs upon induction of IFN by administration of poly-IpC (hereinafter referred to as pIpC, double-stranded RNA).
  • IFN interferon
  • pIpC poly-IpC
  • PIpC was intraperitoneally administered to this mouse three times every other day.
  • Expression of HCV core protein was observed from day 0.5 after the first administration, and peaked at 915 pg / mg (total liver protein mass) on day 7. After that, although it is decreasing, the expression was maintained at 435 pg / mg even on the 21st day. Furthermore, this expression was maintained at the same level even after 6 months (FIGS. 3 and 4).
  • composition of the present invention a physiologically active substance can be introduced not only in vitro but also into hepatocytes in vivo in the presence of serum. Useful for.
  • the present invention allows vitamin L to be adsorbed or chemically bound to the particles so that serum LDL (low density lipoprotein) or the like recognizes the vitamin E and enters the particles into the liver parenchymal cells via the liver parenchymal cell receptor. It is characterized in that it is delivered. Since the particle size and surface charge of the particles are optimized, these particles are not taken up by non-parenchymal cells, allowing the endoplasmic reticulum particles to be specifically delivered into hepatic parenchymal cells.
  • serum LDL low density lipoprotein

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Abstract

Il est apparu qu'une substance biologiquement active contenue dans un réticulum endoplasmique peut être administrée efficacement et spécifiquement à un hépatocyte par adsorption ou liaison chimique de vitamine E à la surface du réticulum endoplasmique. Cela peut être réalisé en utilisant une propriété du composant du sérum pour administrer la vitamine E à un hépatocyte.
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