WO2023024513A1 - Nouveau composé lipidique cationique - Google Patents

Nouveau composé lipidique cationique Download PDF

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Publication number
WO2023024513A1
WO2023024513A1 PCT/CN2022/084284 CN2022084284W WO2023024513A1 WO 2023024513 A1 WO2023024513 A1 WO 2023024513A1 CN 2022084284 W CN2022084284 W CN 2022084284W WO 2023024513 A1 WO2023024513 A1 WO 2023024513A1
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composition
lipid
lipids
compound
glycero
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PCT/CN2022/084284
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English (en)
Chinese (zh)
Inventor
黄才古
黄铁强
谭俊荣
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广州谷森制药有限公司
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Publication of WO2023024513A1 publication Critical patent/WO2023024513A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity

Definitions

  • the present invention provides novel cationic lipids that can be used in combination with other lipid components (such as neutral lipids, steroids, and polymer-conjugated lipids) to form a nucleic acid mRNA lipid nanoparticle composition combining a A method of delivering one or more therapeutic and/or prophylactic agents to a mammalian cell or organ and/or producing a polypeptide in a mammalian cell or organ.
  • lipid components such as neutral lipids, steroids, and polymer-conjugated lipids
  • the lipid nanoparticle compositions of the invention may also include, in specified proportions, one or more cationic and/or ionizable amino lipids, neutral lipids including polyunsaturated lipids, Lipids, polymer-conjugated lipids, steroids, and/or therapeutic and/or prophylactic agents.
  • nucleic acids Efficient targeted delivery of bioactive substances such as small molecule drugs, proteins and nucleic acids presents a persistent medical problem. Specifically, delivery of nucleic acids to cells is made difficult by the relative instability and low cell permeability of these species. Accordingly, there is a need to develop methods and compositions that facilitate the delivery of therapeutic and/or prophylactic agents, such as nucleic acids, to cells.
  • compositions generally comprise one or more "cationic" lipids, neutral lipids including polyunsaturated lipids (such as phospholipids), structured lipids (such as steroids) and/or polyethylene glycol-containing Lipids of alcohols (polymer-conjugated lipids).
  • Cationic lipids include, for example, amine-containing lipids that can be readily protonated.
  • RNA degradation in plasma has been used to prevent RNA degradation in plasma and promote Cellular uptake of oligonucleotides.
  • lipid nanoparticles for the delivery of oligonucleotides.
  • Improved lipid nanoparticles would provide optimized drug delivery, protect nucleic acids from degradation and clearance in serum, be suitable for systemic or local delivery, and provide intracellular delivery of nucleic acids.
  • these preferred lipid-nucleic acid particles should be well tolerated and provide a sufficient therapeutic index such that treatment of the patient at effective doses of the nucleic acid does not create unacceptable toxicity and/or risk to the patient.
  • the present invention provides these and related advantages.
  • the present invention provides the following novel compounds and methods involving these compounds:
  • the present invention relates to compounds of the following structural formula (I):
  • R 1 and R 2 are independent hydrogen or hydroxyl, at least one of which is hydroxyl
  • the compound has one of the structures shown in Table 1 below
  • composition comprising any one or more of the compounds of structural formula (I) and a therapeutic and/or prophylactic agent.
  • compositions comprising any one or more of the compounds of structure (I) and a therapeutic and/or prophylactic agent.
  • the composition comprises any of the compounds of structure (I) and a therapeutic and/or prophylactic agent and one or more compounds selected from the group consisting of neutral lipids, steroids, and polymer conjugates. Lipid excipients. Other pharmaceutically acceptable excipients and/or carriers are also included in various embodiments of the compositions.
  • the neutral lipid is selected from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine Alkaline (DPPC), 1,2-Dimyristyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palm Acyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelin (SM) and mixtures thereof.
  • the preferred neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).
  • the steroid is selected from the group consisting of cholesterol, fecal sterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof .
  • the preferred steroid is cholesterol.
  • the pegylated lipid is 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG)
  • the composition ratio ranges from about 10 to 60 mol% of the compound, about 0 to 30 mol% of neutral lipids, about 10 to 55 mol% of steroids, and about 0 to 10 mol% of polymer-conjugated lipids. quality.
  • the therapeutic and/or prophylactic agent comprises a nucleic acid.
  • nucleic acid is RNA, and it is selected from following composition: siRNA, aiRNA, miRNA, dsRNA, shRNA, mRNA and its mixture.
  • the RNA is selected from mRNA.
  • the present invention relates to methods of administering therapeutic and/or prophylactic agents to a subject in need thereof, the method comprising preparing or providing any of the compositions described above and administering the composition to the subject combination.
  • the compounds of the invention can be administered as a drug substance, or can be formulated as a pharmaceutical composition.
  • the pharmaceutical composition of the present invention comprises a compound of structure (I) and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • Compounds of structure (I) are effective to form lipid nanoparticles and deliver therapeutic and/or prophylactic agents. Appropriate concentrations and dosages can be readily determined by those skilled in the art.
  • compositions of the present invention may be by any of the acceptable modes of administration for agents of similar utility.
  • the pharmaceutical composition of the present invention can be formulated into preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal routes.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrasternal injection or infusion techniques.
  • the pharmaceutical compositions of the invention are formulated so as to allow the active ingredient contained therein to be bioavailable upon administration of the composition to a subject.
  • Compositions to be administered to a subject or patient are in the form of one or more dosage units, where a tablet may be a single dosage unit and a container of the compound in aerosol form of the invention may hold multiple dosage units. Current methods for the preparation of such dosage forms are known, or will be apparent, to those skilled in the art.
  • the composition to be administered will contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treating the associated disease or condition in accordance with the teachings of the invention.
  • compositions of the present invention may be in solid or liquid form.
  • the carrier is particulate, such that the composition is in tablet or powder form.
  • the carrier can be a liquid in which case the composition is an oral syrup or an injectable liquid or an aerosol suitable for administration by inhalation.
  • the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, where forms considered solid or liquid herein include semi-solid, semi-liquid, suspension and gel forms.
  • the pharmaceutical compositions can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gums, flakes and the like.
  • Such solid compositions will generally contain one or more inert diluents or edible carriers.
  • binders such as gelatin, cellulose, etc.
  • excipients such as lactose, etc.
  • disintegrants such as alginic acid, etc.
  • lubricants such as magnesium stearate, etc.
  • Glidants such as silica gel, etc.
  • sweeteners such as sucrose or saccharin
  • flavoring agents such as mint
  • coloring agents such as sucrose or saccharin
  • liquid carriers other than materials of the above type, such as polyethylene glycol or oil.
  • compositions may be in liquid form, such as syrups, solutions, emulsions or suspensions.
  • Liquids can be used for oral administration or for injectable delivery, as two examples.
  • the compositions of Urim contain, in addition to the compounds of the present invention, one or more of sweetening agents, preservatives, dyeing/coloring agents and darkening agents.
  • one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents may be included.
  • the liquid pharmaceutical composition of the present invention may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride; fixed oils such as synthetic mono- or diglycerides, polyethylene glycol, glycerol, propylene glycol, or other solvents that may be used as a solvent or suspending medium; antibacterial agents , such as methylparaben, etc.; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenedipic acid; buffering agents, such as acetate, clematine, or phosphate; Reagents for tonicity, such as sodium chloride or glucose; reagents used as cryoprotectants, such as sucrose or trehalose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose via
  • compositions of the invention may consist of dosage units which can be administered as an aerosol.
  • aerosol is used to denote systems ranging from those of a colloidal nature to those consisting of pressurized packs. Delivery may be by liquefied or compressed gas, or by a suitable pump system which dispenses the active ingredient. Aerosols of the compounds of the invention may be delivered as single-phase, bi-phasic or triphasic systems to deliver the active ingredient. Aerosol delivery includes the necessary containers, activators, valves, sub-containers, etc., which together may form a kit. Preferred aerosols can be determined by those skilled in the art without undue experimentation.
  • compositions of the present invention can be prepared by methods well known in the field of pharmacy.
  • Pharmaceutical compositions intended to be administered by injection can be prepared by combining the lipid nanoparticles of the present invention with sterile distilled water or other carriers into a solution.
  • Surfactants can be added to promote the formation of a uniform solution or suspension.
  • Surfactants are compounds that interact non-covalently with the compounds of the invention in order to facilitate dissolution or uniform suspension of the compounds in aqueous delivery systems.
  • composition of the present invention is administered in a therapeutically effective amount, which will vary depending on a number of factors, including the activity of the particular therapeutic agent used; the metabolic stability and duration of action of the therapeutic agent; The patient's age, weight, general health, sex, and diet; mode and timing of administration; rate of excretion; drug combination; severity of the specific case, etc.
  • compositions of the invention may also be administered concurrently with, before or after administration of one or more other therapeutic agents.
  • combination therapy includes administration of a single pharmaceutical dosage formulation of a composition of the invention and one or more additional active agents, as well as administration of a composition of the invention and each active agent in its own separate pharmaceutical dosage formulation.
  • compositions of the invention and other active agents may be administered to a subject together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • the compound of the invention and the one or more additional active agents may be administered at substantially the same time, or sequentially at times staggered from each other; it is understood that combination therapy includes all such dosing regimens.
  • novel cationic lipid compounds have achieved more advantageous physical and chemical properties, including more suitable pKa and better chemical stability, and are used in mRNA nanoliposome compositions, which can realize anti-ionic nucleic acid
  • the drug is more effectively combined and delivered, and its chemical structure is more stable, which is convenient for synthesis and beneficial to be developed as a pharmaceutical excipient.
  • functional groups of intermediate compounds may need to be protected by suitable protecting groups.
  • suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl, tetrahydrofuranyl, benzyl, and the like.
  • Suitable protecting groups for amino include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for carboxylic acids include hydrocarbyl, aryl or arylhydrocarbyl esters. Protecting groups can be added or removed according to standard techniques, known to those skilled in the art and described herein.
  • all compounds of the present invention that exist in free base or free acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid according to methods known to those skilled in the art. Salts of compounds of the present invention may be converted to their free base or acid forms by standard techniques.
  • Compound B can be synthesized according to the representative route described in Example 1.
  • the particle size of the lipid nanoparticles is approximately 65-105 nm in diameter, and in some cases, approximately 75-100 nm in diameter.
  • liver tissue approximately 50 mg was cut for analysis in 2 mL FastPrep tubes (MP Biomedicals, Solon OH). 1/4" ceramic balls (MP Biomedicals) were added to each tube, and 500 ⁇ L of Glo Lysis Buffer-GLB (Promega, Madison WI) equilibrated to room temperature was added to the liver tissue.
  • the FastPrep24 instrument MP Biomedicals
  • the Liver tissue was homogenized at 2x6.0m/s for 15 s. The homogenate was incubated at room temperature for 5 min, then diluted 1:4 in GLB and evaluated using the SteadyGlo luciferase assay system (Promega).
  • FLuc mRNA (L-6107) from Trilink Biotechnologies will express the luciferase protein, which was originally isolated from the firefly (Photinus pyralis). Fluc is commonly used in mammalian cell culture to measure gene expression and cell viability. It emits bioluminescence in the presence of the substrate luciferin. This capped and polyadenylated mRNA is completely replaced by 5-methylcytidine and pseudouridine.
  • the pKa of the formulated cationic lipid correlates with the effectiveness of the LNP for delivery of nucleic acids.
  • the preferred pKa range is 5-7.
  • the pKa of each cationic lipid was determined in lipid nanoparticles using an assay based on the fluorescence of 2-(p-toluidino)-6-phthanesulfonic acid (TNS).
  • TNS 2-(p-toluidino)-6-phthanesulfonic acid
  • the vesicles were diluted to contain 24uM lipid in 2mL buffer solution containing 10mM HEPES, 10mM MES, 10mM sodium acetate, 130mM NaCl, wherein the pH value was 2.5-11. Aliquots of TNS solution were added to give a final concentration of 1 uM, and after vortex mixing, fluorescence intensity was measured in a SLM Aminco Series 2 Luminescence Spectrophotometer at room temperature using excitation and emission wavelengths of 321 nm and 445 nm. Sigmoid best-fit analysis was applied to the fluorescence data, and pKa was measured as the pH that yielded half the maximum fluorescence intensity.
  • lipid nanoparticles containing FLuc mRNA were also used to formulate lipid nanoparticles containing FLuc mRNA (L-6107) using the ordered mixing method as described in Example 3.
  • Lipid nanoparticles were formulated using the following molar ratios: 50% cationic lipid/10% distearoylphosphatidylcholine (DSPC)/38% cholesterol/2% PEG lipid ("PEG-DMG", i.e., ( 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoyl glycerol, the average PEG molecular weight is 2000).
  • PEG-DMG i.e., ( 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoyl glycerol, the average PEG molecular weight is 2000.
  • Relative activity was determined by measuring luciferase expression in the liver. The activity was compared at doses of 0.3 and 1.0 mg mRNA/kg and expressed as ng

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Abstract

La présente invention concerne un composé lipidique, qui peut être utilisé seul ou en combinaison avec d'autres composants lipidiques tels que des lipides neutres, des lipides chargés, des stéroïdes et/ou des analogues de ceux-ci, et/ou des lipides conjugués à un polymère, de manière à former des nanoparticules lipidiques destinées à administrer un agent thérapeutique et/ou un agent prophylactique. Dans certains modes de réalisation, les nanoparticules lipidiques sont utilisées pour administrer des acides nucléiques, par exemple, de l'ARN messager et/ou de l'ARN antisens. L'invention concerne également une méthode de traitement et/ou de prévention de diverses maladies à l'aide des nanoparticules lipidiques décrites. Dans un mode de réalisation, l'invention concerne un composé ayant la structure de formule (I) suivante : ou un sel ou un isomère ou un N-oxyde de celui-ci, R1 et R2 étant tels que définis dans la description. L'invention concerne également une composition pharmaceutique comprenant un ou plusieurs composés représentés par la formule développée (I) précédente et un agent thérapeutique et/ou un agent prophylactique. Dans certains modes de réalisation, la composition pharmaceutique comprend en outre un ou plusieurs composants choisis parmi des lipides neutres, des lipides chargés, des stéroïdes et des lipides conjugués à un polymère. Les compositions selon l'invention sont utiles pour former des nanoparticules lipidiques destinées à administrer un agent thérapeutique et/ou un agent prophylactique. Dans d'autres modes de réalisation, la présente invention concerne une méthode d'administration d'un agent thérapeutique et/ou d'un agent prophylactique à un sujet en ayant besoin. La méthode comprend la préparation d'une composition pharmaceutique comprenant des nanoparticules lipidiques contenant un composé représenté par la formule développée (I) et un agent thérapeutique et/ou un agent prophylactique, et l'administration de la composition à un sujet.
PCT/CN2022/084284 2021-08-23 2022-03-31 Nouveau composé lipidique cationique WO2023024513A1 (fr)

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CN202110970009.5 2021-08-23
CN202110970009.5A CN115710192A (zh) 2021-08-23 2021-08-23 新型阳离子脂质化合物

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CN114890907B (zh) * 2022-03-31 2023-10-31 荣灿生物医药技术(上海)有限公司 一种阳离子脂质化合物及其制备方法和应用
CN115925563B (zh) * 2023-02-28 2023-05-16 清华大学 一种可用于靶向肺部递送核酸的脂质分子及其制备方法与应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013086373A1 (fr) * 2011-12-07 2013-06-13 Alnylam Pharmaceuticals, Inc. Lipides pour l'administration d'agents actifs
CN107922364A (zh) * 2015-06-29 2018-04-17 爱康泰生治疗公司 用于递送核酸的脂质和脂质纳米颗粒制剂
CN108368028A (zh) * 2015-10-28 2018-08-03 爱康泰生治疗公司 用于递送核酸的新型脂质和脂质纳米颗粒制剂
CN110520409A (zh) * 2017-03-15 2019-11-29 摩登纳特斯有限公司 用于细胞内递送治疗剂的化合物和组合物
WO2020061284A1 (fr) * 2018-09-19 2020-03-26 Modernatx, Inc. Lipides peg et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013086373A1 (fr) * 2011-12-07 2013-06-13 Alnylam Pharmaceuticals, Inc. Lipides pour l'administration d'agents actifs
CN107922364A (zh) * 2015-06-29 2018-04-17 爱康泰生治疗公司 用于递送核酸的脂质和脂质纳米颗粒制剂
CN108368028A (zh) * 2015-10-28 2018-08-03 爱康泰生治疗公司 用于递送核酸的新型脂质和脂质纳米颗粒制剂
CN110520409A (zh) * 2017-03-15 2019-11-29 摩登纳特斯有限公司 用于细胞内递送治疗剂的化合物和组合物
WO2020061284A1 (fr) * 2018-09-19 2020-03-26 Modernatx, Inc. Lipides peg et leurs utilisations

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