WO2023216423A1 - Composé lipidique, composition, préparation et utilisation associées - Google Patents

Composé lipidique, composition, préparation et utilisation associées Download PDF

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WO2023216423A1
WO2023216423A1 PCT/CN2022/107846 CN2022107846W WO2023216423A1 WO 2023216423 A1 WO2023216423 A1 WO 2023216423A1 CN 2022107846 W CN2022107846 W CN 2022107846W WO 2023216423 A1 WO2023216423 A1 WO 2023216423A1
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acid
lipid
compound
sodium
composition
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PCT/CN2022/107846
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English (en)
Chinese (zh)
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赵凤翔
路青青
胡洪鹏
耿亦程
蒋剑豪
钟天翼
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苏州慧疗生物医药科技有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—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 non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • 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
    • A61K47/50—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
    • A61K47/69—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention specifically relates to a type of lipid compound and its composition, preparation and use, especially its application in the preparation of nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs.
  • Nucleic acid drugs refer to artificially designed DNA or RNA with disease prevention or treatment functions. They act on disease-causing target genes or target mRNA to fundamentally regulate the expression of disease-causing genes to achieve the purpose of disease prevention or treatment. Nucleic acid drugs mainly include antisense oligonucleotide (ASO), small interference RNA (siRNA), microRNA (miRNA), messenger RNA (message, mRNA), etc. As of the end of 2021, the FDA has approved more than 10 nucleic acid drugs, and multiple drug candidates are in clinical trials or preclinical trials.
  • ASO antisense oligonucleotide
  • siRNA small interference RNA
  • miRNA microRNA
  • messenger RNA messenger RNA
  • RNA vaccines BNT162b2 Pfizer/BioNTech
  • mRNA-1273 Moderna
  • my country also has multiple new coronavirus vaccines based on mRNA technology in clinical trials or preclinical trials.
  • mRNA technology has proven its unique advantages over traditional biopharmaceutical and vaccine technologies.
  • Therapeutic nucleic acids have the potential to revolutionize vaccinations, gene therapies, protein replacement therapies and the treatment of other genetic diseases.
  • RNA degradation determines the need for a high-quality delivery system to deliver it into the body.
  • the present invention focuses on providing a new delivery carrier for RNA drugs.
  • the present invention provides a new class of lipid compounds for delivering therapeutic or preventive drugs, namely lipids based on cholic acid or its derivatives, which enriches the types of lipid compounds and can be used for nucleic acid drugs, gene vaccines, polypeptides, and proteins.
  • lipids based on cholic acid or its derivatives which enriches the types of lipid compounds and can be used for nucleic acid drugs, gene vaccines, polypeptides, and proteins.
  • the delivery of antibodies, small molecule drugs, etc. provides more options.
  • the present invention provides a lipid compound represented by the following general formula 1, general formula 2, or a pharmaceutically acceptable salt thereof, including stereoisomers, tautomers, solvates, chelates, and non-covalent compounds.
  • a pharmaceutically acceptable salt thereof refers to an acid addition salt or a base addition salt.
  • the core of the lipid compound is cholic acid or a derivative thereof; wherein the linker includes one or more of an ester group, an amide group, a carbamate group, a carbonate group or a urea group. kind.
  • the lipid compound, wherein cholic acid or its derivatives is optionally selected from cholic acid, obeticholic acid, ursodeoxycholic acid, ursolic acid, 3 ⁇ -hydroxy-D5-cholenoic acid, Chenodeoxycholic acid, lithocholic acid, deoxycholic acid, taurocholic acid, 5 ⁇ -cholic acid, dehydrocholic acid, hyocholic acid, cholic acid, glycinechenodeoxycholic acid, tauroursodeoxycholic acid Acid, taurochenodeoxycholic acid, glycocholic acid, hyodeoxycholic acid, hyodeoxycholic acid methyl ester, taurohodeoxycholic acid sodium, sodium dehydrocholate, sodium cholate, sodium deoxyglycholate , sodium taurodeoxycholate, sodium taurocholate, sodium taurochenodeoxycholate, glycocholic acid sodium salt, taurocholic acid-3-sulfate diso
  • the lipid compound is one or more lipid compounds selected from ursodeoxycholic acid derivatives, or one or more obeticholic acid derivative lipid compounds. kind.
  • a composition of lipid compounds includes a therapeutic or preventive agent and a carrier for delivering the therapeutic or preventive agent, and the carrier includes one or more of the aforementioned lipid compounds.
  • the composition, therapeutic or preventive agent includes one or more of nucleic acid molecules, polypeptides, proteins, antibodies and small molecule drugs.
  • the mass ratio of the carrier to the therapeutic or preventive agent is 1:1 to 100:1.
  • the composition is a nanoparticle preparation
  • the average size of the nanoparticle preparation is 20 nm to 1000 nm
  • the polydispersity coefficient of the nanoparticle preparation is ⁇ 0.5.
  • the carrier contains three different lipid components, one of which is a lipid based on cholic acid or its derivatives.
  • the composition is characterized in that the carrier further includes a charge-assisted lipid with neutral charge, negative charge or bipolar charge.
  • the composition is characterized in that the charge-auxiliary lipid is one or more of the following: distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC) , dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE- mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearoylphosphati
  • the carrier further includes a structurally modified lipid.
  • the structurally modified lipid includes polyethylene glycol, dextran, polylactic acid or amino acid modified phosphatidylethanolamine, phosphatidic acid, ceramide, dialkylamine, diacylglycerol, One or more dialkylglycerols.
  • the composition and the carrier also include but are not limited to lipids of cholic acid or its derivatives, charge-assisted lipids, and structurally modified lipids.
  • the cholic acid lipids, the charge-assisted lipids And the molar ratio of the structurally modified lipid is (30-80): (5-50): (0.5-10).
  • the composition further includes one or more pharmaceutically acceptable excipients or diluents.
  • the lipid compound or composition of the present invention can be used in the preparation of nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs.
  • the lipid compound or composition of the present invention is used in the preparation of nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs, wherein the lipid nanoparticles have a particle size of 20 to 1000 nm.
  • compositions for preparing nucleic acid drugs, gene vaccines, polypeptides, proteins, antibodies and small molecule drugs which include nucleic acids and lipid nanoparticles encapsulating the nucleic acids, wherein each individual lipid nanoparticle contains a variety of lipids A lipid component, wherein one of the lipid components is a cholic acid-based lipid compound, including compounds thereof or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non- A covalent compound or prodrug, and wherein the lipid nanoparticle has a nucleic acid encapsulation ratio of at least 70%.
  • the lipid nanoparticles are formed by mixing an mRNA solution and a lipid solution of any lipid compound described in this patent, wherein the medium of the mRNA solution is HEPES, sodium phosphate , sodium acetate, ammonium sulfate, sodium bicarbonate or sodium citrate; the medium of the lipid solution is ethanol, isopropyl alcohol or dimethyl sulfoxide; wherein the lipid nanoparticles are further purified by dialysis or ultrafiltration.
  • HEPES sodium phosphate
  • sodium acetate sodium acetate
  • ammonium sulfate sodium bicarbonate or sodium citrate
  • the medium of the lipid solution is ethanol, isopropyl alcohol or dimethyl sulfoxide
  • composition described in this patent also contains one or more of buffers, carbohydrates, mannitol, proteins, polypeptides or amino acids, antioxidants, bacteriostatic agents, chelating agents, and adjuvants.
  • the acid described in the present invention includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzene
  • Base addition salts refer to salts prepared by adding an inorganic base or an organic base to a free base compound.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, etc.;
  • the organic bases include, but are not limited to, ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dealcoholization, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, Procaine, hydrazine, choline, betaine, benethamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resin.
  • the organic bases include
  • the present invention provides a composition comprising a therapeutic or preventive agent and a carrier for delivering the therapeutic or preventive agent, the carrier comprising a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable agent thereof.
  • a composition comprising a therapeutic or preventive agent and a carrier for delivering the therapeutic or preventive agent, the carrier comprising a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable agent thereof.
  • the carrier comprising a lipid based on cholic acid or a derivative thereof, or a pharmaceutically acceptable agent thereof.
  • the therapeutic or preventive agent is encapsulated in or associated with a carrier.
  • the therapeutic or preventive agent includes one or more of nucleic acid molecules, genetic vaccines, polypeptides, proteins, antibodies and small molecule drugs.
  • the nucleic acid includes any form of nucleic acid molecule, including but not limited to single-stranded DNA, double-stranded DNA, short isomers, agomir, antagomir, antisense molecules, small interfering RNA (siRNA), asymmetric interfering RNA ( aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA) and other forms of RNA molecules known in the art, or locked nucleic acids Nucleic acid mimics such as (LNA), peptide nucleic acid (PNA) and morpholino cyclic oligonucleotides.
  • LNA small interfering RNA
  • aiRNA asymmetric interfering RNA
  • miRNA microRNA
  • dsRNA Dicer-substrate RNA
  • shRNA small hairpin RNA
  • tRNA transfer RNA
  • mRNA messenger RNA
  • the therapeutic or preventive agent comprises at least one mRNA encoding an antigen or a protein or a peptide or a fragment or epitope thereof.
  • the mRNA is monocistronic or polycistronic.
  • the antigen is a pathogenic antigen.
  • the mRNA contains one or more functional nucleotide analogs, including but not limited to pseudouridine, 1-methyl-pseudouridine and one or more of 5-methylcytosine.
  • the small molecule compounds include, but are not limited to, the active ingredients of therapeutic and/or preventive agents.
  • the therapeutic and/or preventive agents are currently known drugs, such as anti-tumor drugs, anti-infective drugs, and local anesthetics. , antidepressants, anticonvulsants, antibiotics/antimicrobials, antifungals, antiparasitics, hormones, hormone antagonists, immunomodulators, neurotransmitter antagonists, antiglaucoma agents, anesthetics, or contrast media.
  • the lipids comprise three different lipid components, one of which is a cholic acid or derivative thereof based lipid.
  • the lipid further includes an auxiliary lipid with a neutral charge, a negative charge, or a bipolar charge.
  • the lipid includes one or more of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, sterols and derivatives thereof.
  • the lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine base (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 11,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 2-(((2,3- Bis(oleoyloxy)propyl)dimethylammonium phosphate)ethylhydrogen (DOCP), sphingomyelin (SM), ceramide and its derivatives.
  • the lipids may be synthetic or derived from (isolated or modified) natural sources or compounds.
  • the carrier further includes a structurally modified lipid.
  • the structurally modified lipids mainly include disclosed or undisclosed lipid compounds, which can improve the stability of liposomes and reduce protein absorption of liposomes, such as polyethylene glycol, dextran, polyethylene glycol, and polyethylene glycol.
  • lipid compounds which can improve the stability of liposomes and reduce protein absorption of liposomes, such as polyethylene glycol, dextran, polyethylene glycol, and polyethylene glycol.
  • lactic acid or amino acid modified phosphatidylethanolamine, phosphatidic acid, ceramide, dialkylamine, diacylglycerol, and dialkylglycerol are examples of lactic acid or amino acid modified phosphatidylethanolamine, phosphatidic acid, ceramide, dialkylamine, diacylglycerol, and dialkylglycerol.
  • the structurally modified lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEGDMPE, PEG-DPPC, PEG-DSPE, ceramide-PEG2000, Chol-PEG2000, 1-(monomethyl Oxy-polyethylene glycol)-2,3-dimyristylglycerol (PEG-DMG), PEGylated phosphatidylethanolamine (PEG-PE), 4-O-(2',3'-bis( Tetradecanoyloxy)propyl-1-O-( ⁇ -methoxy(polyethoxy)ethyl)succinate (PEG-S-DMG), polyglycolated ceramide (PEG- cer), ⁇ -methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecyloxy)propyl)carbamate, or 2,3-di(tetradecyloxy) methyl)propyl-
  • the mass ratio of the carrier to the therapeutic or preventive agent is 5:1 to 50:1, more preferably 5:1 to 35:1, and more preferably 10:1 to 30:1.
  • the carrier further includes, but is not limited to, lipids of cholic acid or its derivatives, charge-assisted lipids, and structurally modified lipids.
  • the molar ratio of the cholic acid lipid, the charge-assisted lipid, and the structurally modified lipid is (30-80): (5-50): (0.5-10).
  • lipid nanoparticles are formed by mixing an mRNA solution and a lipid solution. In some embodiments, lipid nanoparticles are further purified by tangential flow filtration.
  • the lipid nanoparticles are formed by mixing an mRNA solution and a lipid solution.
  • the medium of the mRNA solution is HEPES, phosphate, acetate, ammonium sulfate, sodium bicarbonate or citrate.
  • the medium of lipid solution is ethanol, isopropyl alcohol or dimethyl sulfoxide. 29.
  • the pharmaceutical composition is a nanoparticle preparation, and the average size of the nanoparticle preparation is 20 nm to 1000 nm, preferably 40 nm to 150 nm, further preferably 50 nm to 100 nm, and more preferably 70 nm to 100 nm.
  • the polydispersity index of the nanoparticle preparation is ⁇ 0.5, further preferably ⁇ 0.3, and more preferably ⁇ 0.25.
  • compositions of the present invention also typically include one or more buffers (eg neutral buffered saline or phosphate buffered water), carbohydrates (eg glucose, mannitol, sucrose, trehalose, dextrose or dextran). sugar), mannitol, proteins, peptides or amino acids (such as glycine and lysine), antioxidants (vitamin E and butylated hydroxytoluene), bacteriostatic agents, chelating agents (such as EDTA and glutathione), adjuvants (e.g. aluminum hydroxide), suspending agents/thickening agents/preservatives, etc. that make the formulation isotonic with the recipient's blood, or the composition of the invention can be formulated as a lyophilisate.
  • buffers eg neutral buffered saline or phosphate buffered water
  • carbohydrates eg glucose, mannitol, sucrose, trehalose, dextrose or dextran. sugar
  • the technical solution of the present invention provides a new class of lipid compounds for delivering therapeutic or preventive drugs, namely lipids based on cholic acid or its derivatives.
  • the technical solution of the present invention is different from the existing patented technical solutions of foreign pharmaceutical companies. , enriches the types of lipid compounds, provides more options for the delivery of nucleic acid drugs, gene vaccines, peptides, proteins, antibodies and small molecule drugs, and can be significantly different from the technical routes of foreign companies such as Pfizer and Moderna. .
  • Figure 1 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 1 (compound 1);
  • Figure 2 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 2 (compound 2);
  • Figure 3 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 7 (compound 7);
  • Figure 4 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 9 (compound 9);
  • Figure 5 is a proton nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 10 (compound 10);
  • Figure 6 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 13 (compound 13);
  • Figure 7 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 16 (compound 16);
  • Figure 8 is a hydrogen nuclear magnetic resonance spectrum of ursodeoxycholic acid derivative 17 (compound 17);
  • Figure 9 is a proton nuclear magnetic resonance spectrum of obeticholic acid derivative 18 (compound 18).
  • Figure 10 shows the experimental results of cells transfected with LNP-encapsulated cy3-siRNA, including a) bright field of fluorescence microscope, b) dark field of fluorescence microscope, c) cell flow cytometry;
  • Figure 11 shows the experimental results of cells transfected with LNP-encapsulated EGFP mRNA, including a) bright field of fluorescence microscope, b) dark field of fluorescence microscope, c) cell flow cytometry;
  • Figure 12 shows the fluorescence imaging results of LNP containing Luciferase mRNA 12h after intravenous injection in mice;
  • Figure 13 shows the fluorescence imaging results of LNP encapsulating Luciferase mRNA 12 hours after intramuscular injection in mice.
  • Cholic acid is a naturally ubiquitous steroid molecule in humans and mammals, synthesized in the liver from cholesterol. After eating, bile acid is actively secreted by liver cells, enters the gallbladder with bile, and then enters the intestine from the gallbladder to perform its digestive function. Cholic acid enters the small intestine in the form of sodium salt to help digest and absorb lipids, and then passes through the terminal ileum. It is returned to the liver through the portal vein through active absorption or passive transport, processed and transformed in liver cells, and then secreted into the small intestine together with newly synthesized bile acids.
  • This EHC (enterohepatic circulation) process of bile acids circulates 4 to 12 times a day, and about 95% of the bile acids are reabsorbed and utilized. If the EHC of bile acids is destroyed, it will not only affect the digestion and absorption of lipids in the body, but also cause the body to form cholesterol stones. Therefore, the biggest advantage of compound delivery carriers designed based on bile acid is that it has high enterohepatic circulation efficiency and participates in the enterohepatic circulation of bile acid, thereby improving drug absorption in the liver and gallbladder.
  • the structural formula of cholic acid is as follows.
  • the three six-membered rings and one five-membered ring on the steroid skeleton of the cholic acid molecule are on the same plane, and ring A and ring B are connected in reverse, making the molecule form a cave-like structure.
  • three methyl groups are distributed on one side of the plane where the steroid ring is located, forming the hydrophobic part of the molecule.
  • Three hydroxyl groups are distributed on the other side of the plane where the steroid ring is located, and together with the C24 carboxyl group, form the hydrophilic part of the molecule.
  • cholic acid The special structure of the cholic acid molecule determines that it is amphiphilic, acid-base, and easy to undergo chemical modification. Therefore, this patent uses cholic acid as a building block to prepare polymers or oligomers. These cholic acid-based products Functional molecules have good technical effects in drug delivery.
  • Cholic acid drugs have been on the market in China or the United States for many years, including ursodeoxycholic acid, obeticholic acid, chenodeoxycholic acid, and tauroursodeoxycholic acid.
  • ursodeoxycholic acid is used to treat cholesterol gallstones and bile reflux gastritis
  • obeticholic acid is used to treat primary biliary cirrhosis (PBC), and there is no adequate response to ursodeoxycholic acid or Patients who cannot tolerate it.
  • PBC primary biliary cirrhosis
  • Years of clinical application have shown that cholic acid compounds have good safety.
  • cholic acid compounds have hydrophilic and lipophilic amphiphilic properties, and can improve the bioavailability of small molecule chemical drugs through encapsulation or coupling.
  • Cholic acid compounds and cholesterol are both steroidal compounds with similar structures and more sites that can be chemically modified. Structural modification of cholic acid compounds to prepare new lipid components may potentially replace the ionizable lipids and cholesterol in the original four-component LNP to achieve similar or better mRNA delivery effects.
  • This patented study constructs lipid nanoparticle carriers based on bile acid analogs and explores their application in mRNA drug delivery.
  • the LNP of the present invention can simplify the production process and reduce costs; at the same time, it can avoid the patent blockade of four-component LNP, which is beneficial to promoting the localization of nucleic acid drugs.
  • cholic acid or its derivatives are composed of a rigid steroid ring and an aliphatic side chain
  • the steroid ring includes three six-membered rings and one five-membered ring.
  • the side chain structure of cholic acid, the conformation of the steroid ring, the number of hydroxyl groups and the orientation of the steroid ring will be different.
  • the common hydroxyl group of cholic acid or its derivatives and the carboxyl group of the fatty side chain are good chemical modification sites. Therefore, we believe that cholic acid or its derivatives can achieve the desired purpose through some common modifications.
  • Cholic acid or its derivatives in this patent is optionally selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, ursolic acid, 3 ⁇ -hydroxy-D5-cholic acid, chenodeoxycholic acid, and lithocholic acid.
  • the lipid compound described in this patent is one or more compounds selected from the following structures;
  • Ursodeoxycholic acid derivative lipid 1 Ursodeoxycholic acid derivative lipid:
  • ursodeoxycholic acid (393mg, 1mmol) in DMF (8mL), add HBTU (569mg, 1.5mmol), DIEA (194mg, 1.5mmol), N,N-dimethylethylenediamine (132mg, 1.5 mmol), under nitrogen protection, stirred at room temperature overnight.
  • TLC detection after the reaction is completed, add an appropriate amount of water, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain a crude product.
  • Silica gel column chromatography eluting with DCM/CH3OH (10:1), gave a white solid (333 mg, 72%).
  • Ursodeoxycholic acid (393 mg, 1 mmol) was dissolved in DMF (8 mL), and HBTU (569 mg, 1.5 mmol), DIEA (194 mg, 1.5 mmol), and 4-pyrrole-1-butylamine (213 mg, 1.5 mmol) were added in sequence. ), under nitrogen protection, the reaction was stirred at room temperature overnight. TLC detection, after the reaction is completed, add an appropriate amount of water, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain a crude product. Silica gel column chromatography, eluting with DCM/CH 3 OH (10:1), gave white solid product X-4 (403 mg, 78%).
  • Ursodeoxycholic acid (393 mg, 1 mmol) was dissolved in acetonitrile (10 mL), K 2 CO 3 (415 mg, 3 mmol), BnBr (850 mg, 5 mmol) were added in sequence, protected by nitrogen, and the reaction was stirred at 80°C for 5 hours. TLC detection, after the reaction is completed, filter and concentrate the solvent to obtain crude product. Silica gel column chromatography, eluting with PE/EA (1:1), gave compound 6 (390 mg, 81%) as a white solid product.
  • 4-Dimethylaminobutyric hydrochloride (336 mg, 2 mmol) was dissolved in anhydrous DCM (8 mL), oxalyl chloride (1 mL) was added, and stirred at room temperature for 4 h. Concentrate under vacuum to no solvent, dissolve with anhydrous DCM (3mL), and set aside. Dissolve compound 6 (241 mg, 0.5 mmol) and TEA (202 mg, 2 mmol) in anhydrous DCM (3 mL). Add the above standby product dropwise into the reaction solution and react at room temperature overnight. Add an appropriate amount of water, extract with DCM three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain crude product.
  • Ursodeoxycholic acid (785 mg, 1 mmol) was dissolved in DMF (20 mL), K 2 CO 3 (829 mg, 6 mmol), CH 3 I (852 mg, 6 mmol) were added in sequence, protected by nitrogen, and the reaction was stirred at room temperature overnight.
  • TLC detection after the reaction is completed, add an appropriate amount of water, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain a crude product.
  • Linoleic acid (476 mg, 1.7 mmol) was dissolved in anhydrous DCM (5 mL), oxalyl chloride (0.30 mL) was added, and the mixture was stirred at room temperature for 5 h. Concentrate under vacuum to no solvent, dissolve with anhydrous DCM (2mL), and set aside. Compound 2 (240 mg, 0.34 mmol) and TEA (69 mg, 0.68 mmol) were dissolved in anhydrous DCM (5 mL). The above standby product was dropped into the reaction solution and allowed to react at room temperature overnight. Add an appropriate amount of water, extract with DCM three times, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the solvent to obtain crude product.
  • nanoparticle compositions for delivering therapeutic and/or prophylactic agents to cells
  • a series of formulations were prepared and tested. Specifically, specific ingredients and their ratios in the lipid component of the nanoparticle composition are optimized.
  • Nanoparticles can be produced by mixing two fluid streams, one of which contains therapeutic and/or prophylactic agents and the other of which has a lipid component, by mixing methods such as microfluidization and T-junctions.
  • phospholipids such as DOPE or DSPC, available from Avanti Polar Lipids (Alabaster, AL)
  • PEG lipids such as 1,2-dimyristoyl -sn-Glycerylmethoxypolyethylene glycol, also known as PEG-DMG, available from Avanti Polar Lipids (Alabaster, AL)
  • structural lipids such as cholesterol, available from Sigma-Aldrich (Tauf Wegn, Germany)
  • lipid composition such as a concentration of about 50 mM.
  • a formulation containing a therapeutic agent is prepared by combining a lipid solution with a therapeutic agent and/or prophylactic agent in a lipid component to therapeutic agent and/or prophylactic agent wt:wt ratio of between about 5:1 and about 50:1.
  • Nanoparticle compositions of agents and/or prophylactic agents and lipid components are rapidly injected into the therapeutic agent and/or preventive agent solution at a flow rate between about 10 mL/min and about 18 mL/min to create a dispersion. , wherein the water to ethanol ratio is between about 2:1 and about 5:1.
  • Zetasizer NanoZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) can be used to determine the particle size, polydispersity index (PDI) and ⁇ potential of the nanoparticle composition.
  • the particle size is measured in 1 ⁇ PBS and ⁇ Potentials were measured in 15mM PBS.
  • RNA For nanoparticle compositions containing RNA, the QUANT-ITTM RNA (Invitrogen Corporation Carlsbad, CA) assay can be used to evaluate the encapsulation of RNA by the nanoparticle composition. Samples were diluted in TE buffer solution (10mM Tris-HCl, 1mM EDTA, pH 7.5) to a concentration of approximately 5 ⁇ g/mL. Transfer 50 ⁇ L of the diluted sample to a polystyrene 96-well plate and add 50 ⁇ L of TE buffer or 50 ⁇ L of 2% Triton X-100 solution to each well. Incubate the plate at 37°C for 15 minutes.
  • TE buffer solution 10mM Tris-HCl, 1mM EDTA, pH 7.5
  • a fluorescent plate reader can be used ( Nivo TM Multimode Plate Readers, PerkinElmer, GER) measure fluorescence intensity at an excitation wavelength of, for example, about 480 nm and an emission wavelength of, for example, about 520 nm.
  • the fluorescence value of the reagent blank was subtracted from the fluorescence value of each sample and determined by dividing the fluorescence intensity of the intact sample (without the addition of Triton X-100) by the fluorescence of the disrupted sample (caused by the addition of Triton X-100). value to determine the percentage of free RNA. See Table 1 for specific data.
  • ONE-GlO+TOX Luciferase Reporter and Cell Viability Assay can be used to evaluate its transfection effect and cytotoxicity. Calculate the volume of the required nanoparticle assembly based on the RNA concentration measured in the encapsulation efficiency determination, dilute the nanoparticle assembly to 20ng/ ⁇ L, and add it according to the cell density of 2 ⁇ 10 5 cells/well in a polystyrene 96-well plate. Add 5 ⁇ L of diluent to each well for transfection. A fluorescent plate reader can be used ( Nivo TM Multimode Plate Readers, PerkinElmer, GER) were used to measure chemiluminescence intensity. See Table 2 for specific data.
  • Example 11 Preparation and detection of lipid nanoparticles (to verify the ability to deliver siRNA in vitro)
  • Lipid nanoparticle size was determined by dynamic light scattering using a nanoparticle size and potential analyzer (NS-90Z). Determine the encapsulation efficiency of lipid nanoparticles using the Quant-it Ribogreen RNA Quantitative Assay Kit. The particle size of the lipid nanoparticles was measured to be 82 nm, the PDI (polydispersity index) was 0.13, and the encapsulation efficiency was 96.5%.
  • Example 12 Preparation and detection of lipid nanoparticles (to verify the ability to deliver mRNA in vitro)
  • the lipid nanoparticles are then filtered with a 0.22 ⁇ m sterile filter to obtain a preparation encapsulating EGFP mRNA.
  • Lipid nanoparticle size was determined by dynamic light scattering using a nanoparticle size and potential analyzer (NS-90Z). Determine the encapsulation efficiency of lipid nanoparticles using the Quant-it Ribogreen RNA Quantitative Assay Kit.
  • the particle size of the LNP preparation was measured to be 95nm, PDI 0.19, and the encapsulation rate was 93.1%.
  • Example 13 Preparation and detection of lipid nanoparticles (to verify the in vivo delivery effect of mRNA)
  • the weight ratio of total lipid to mRNA is Prepare liposomes at 20:1, remove ethanol using dialysis or tangential flow filtration, and replace with PBS solution.
  • the lipid nanoparticles are then filtered with a 0.22 ⁇ m sterile filter to obtain a preparation that encapsulates mRNA.
  • Lipid nanoparticle size was determined by dynamic light scattering using a Nanoparticle Size and Potentiometric Analyzer (NS-90Z). Determine the encapsulation efficiency of lipid nanoparticles using the Quant-it Ribogreen RNA Quantitative Assay Kit. The particle size of the lipid nanoparticles was measured to be 98 nm, the PDI was 0.22, and the encapsulation rate was 88.9%.
  • Prepare liposomes use dialysis or tangential flow filtration to remove ethanol, and replace it with PBS solution.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 1249nm, the PDI was 0.67, and the encapsulation rate was 31%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 467 nm, the PDI was 0.40, and the encapsulation rate was 78%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 347nm, the PDI was 0.41, and the encapsulation rate was 81%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 94nm, the PDI was 0.50, and the encapsulation rate was 85%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 82nm, the PDI was 0.11, and the encapsulation rate was 96%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 145nm, the PDI was 0.23, and the encapsulation rate was 76%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 302nm, the PDI was 0.38, and the encapsulation rate was 73%.
  • the lipid nanoparticles were then filtered with a 0.22 ⁇ m sterile filter to obtain an mRNA-encapsulated preparation.
  • the detected particle size was 302nm, the PDI was 0.38, and the encapsulation rate was 73%.

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Abstract

La présente invention concerne un composé lipidique tel que représenté par la formule générale, une composition une préparation et une utilisation associées. Le composé lipidique selon la présente invention est un composé à base d'acide cholique ou un dérivé de celui-ci, ou un sel pharmaceutiquement acceptable du composé. Le composé lipidique et la composition de celui-ci selon la présente invention peuvent fournir un plus grand choix de vecteurs pour l'administration de médicaments à base d'acides nucléiques, de vaccins géniques, de polypeptides, de protéines, d'anticorps, de médicaments à petites molécules, etc.
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