WO2023029593A1 - Nouveau composé lipidique cationique - Google Patents
Nouveau composé lipidique cationique Download PDFInfo
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- WO2023029593A1 WO2023029593A1 PCT/CN2022/093432 CN2022093432W WO2023029593A1 WO 2023029593 A1 WO2023029593 A1 WO 2023029593A1 CN 2022093432 W CN2022093432 W CN 2022093432W WO 2023029593 A1 WO2023029593 A1 WO 2023029593A1
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- Prior art keywords
- composition
- lipid
- compound
- therapeutic
- glycero
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- -1 cationic lipid compound Chemical class 0.000 title claims abstract description 13
- 150000002632 lipids Chemical class 0.000 claims abstract description 70
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- 238000000034 method Methods 0.000 claims abstract description 20
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- 239000003883 ointment base Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- PWRIIDWSQYQFQD-UHFFFAOYSA-N sisunine Natural products CC1CCC2(NC1)OC3CC4C5CCC6CC(CCC6(C)C5CCC4(C)C3C2C)OC7OC(CO)C(OC8OC(CO)C(O)C(OC9OC(CO)C(O)C(O)C9OC%10OC(CO)C(O)C(O)C%10O)C8O)C(O)C7O PWRIIDWSQYQFQD-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- XYNPYHXGMWJBLV-OFMODGJOSA-N tomatidine Natural products O[C@@H]1C[C@H]2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]5[C@@H](C)[C@]6(O[C@H]5C4)NC[C@@H](C)CC6)CC3)CC2)CC1 XYNPYHXGMWJBLV-OFMODGJOSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000006163 transport media Substances 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 239000008243 triphasic system Substances 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
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Classifications
-
- 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
- A61K9/48—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
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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 can be alkyl, alkenyl or hydroxyalkyl
- the compound has one of the structures shown in Table 1 below
- composition comprising any one or more of the compounds of the above formulas 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-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelin (SM) or Various.
- the preferred neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).
- the steroid is selected from one of cholesterol, fecal sterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, ⁇ -tocopherol one or more species.
- 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.
- the nucleic acid is RNA, which is selected from the following composition: siRNA, aiRNA, miRNA, dsRNA, shRNA, mRNA and mixtures thereof.
- 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 to the subject combination.
- the compounds of the present invention may be used as drug substances, or may be formulated as pharmaceutical compositions (usually in the form of lipid nanoparticles in combination with therapeutic and/or prophylactic agents).
- 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 use for agents of similar utility.
- the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microgels, etc. Balls and Aerosols.
- Typical routes of use 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 present invention are formulated so that the active ingredients therein are bioavailable in the subject.
- the composition to be administered to a subject or patient may be in one or more dosage forms where a tablet may be a single dosage unit and a container of the compound of the invention in aerosol form 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 used 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 can be particulate, such that the composition is in tablet or powder form.
- the carrier can also be a liquid in which case the composition is an oral syrup or an injectable liquid or an aerosol suitable for inhalation.
- the pharmaceutical composition is preferably in solid or liquid form, where solid or liquid forms are considered herein to include semi-solids, semi-liquids, suspensions and gels.
- the pharmaceutical composition can be formulated in the form of powder, granule, tablet, pill, capsule, chewing gum, flake 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 may be for oral use or for injectable delivery, as two examples.
- preferred compositions contain, in addition to the compounds of the present invention, one or more of sweetening agents, preservatives, dyeing/coloring agents and flavor enhancers.
- 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 auxiliary materials: 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 can be used as a solvent or suspending medium; antibacterial antioxidants, such as methylparaben, etc.; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, 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
- the pharmaceutical composition of the present invention may be intended for topical use, in which case the carrier may suitably comprise a solution base, emulsion base, ointment base or gel base.
- the base may contain one or more of petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
- Thickening agents may be present in pharmaceutical compositions for topical use.
- the composition may include a transdermal patch or iontophoretic device.
- compositions of the invention can include various materials which modify the physical form of solid or liquid dosage forms.
- the composition may include materials which form a coating shell around the active ingredient.
- the materials forming the coating shell are generally inert and can be sugar, shellac and other enteric coating agents.
- the active ingredient may be enclosed in a gelatin capsule.
- compositions of the invention in solid or liquid form may include vehicles which facilitate delivery of the compound in combination with the compound of the invention.
- Such vectors include monoclonal or polyclonal antibodies or proteins.
- compositions of the invention may consist of formulations available as aerosols.
- aerosol denotes systems comprising colloidal properties and systems 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 drug delivery device. Preferred aerosols can be determined by those skilled in the art without undue experimentation.
- the pharmaceutical compositions of the present invention can be prepared by methods well known in the field of pharmacy.
- the pharmaceutical composition for 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 interact non-covalently with the compounds of the invention thereby facilitating dissolution or homogeneous suspension of said compounds in aqueous media.
- compositions of the present invention are used in therapeutically effective amounts, 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 duration of use; rate of excretion; drug combination; severity of the specific case, etc.
- compositions of the invention may also be administered concurrently with, prior to, or subsequent to administration of one or more other therapeutic agents.
- Such therapeutic combinations include formulations using the compositions of the invention alone as well as combinations using the compositions of the invention and one or more other active ingredients.
- the compositions of the present invention and other active ingredients may be administered to a subject together in a single oral dosage formulation such as a tablet or capsule, or each active ingredient may be administered in separate oral dosage formulations.
- the compound of the invention and one or more additional active ingredients may be administered at the same time, or sequentially at times staggered from each other; it is understood that combination therapy includes all such dosing regimens.
- novel deuterated 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-ion Nucleic acid-like drugs are more effectively combined and delivered, and at the same time, their chemical structure is more stable, which is convenient for synthesis and beneficial for development as pharmaceutical excipients.
- 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 hydroxy, aryl or aryl 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 1 can be synthesized according to the representative route described in Example 1.
- Compound 2 can be synthesized according to the representative route described in Example 1.
- Compound 3 can be synthesized according to the representative route described in Example 1.
- Compound 4 can be synthesized according to the representative route described in Example 1.
- Embodiment 6 is a diagrammatic representation of Embodiment 6
- Compound 6 can be synthesized according to the representative route described in Example 1.
- Embodiment 7 is a diagrammatic representation of Embodiment 7:
- Compound 7 can be synthesized according to the representative route described in Example 1.
- Ethanol was then removed and the external buffer was replaced by PBS by dialysis. Finally, filter the lipid nanoparticles through a sterile filter with a pore size of 0.2 ⁇ M.
- the particle size of the lipid nanoparticles as determined by quasi-elastic light scattering using a Malvern Zetasizer Nano ZS, 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 24 ⁇ M lipid in 2 mL of a buffer solution containing 10 mM HEPES, 10 mM MES, 10 mM sodium acetate, 130 mM NaCl, wherein the pH value was 2.5-11. Aliquots of TNS solution were added to give a final concentration of 1 ⁇ M, 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 8.
- 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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- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
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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 qu'un lipide neutre, un lipide chargé, un stéroïde et/ou un analogue de celui-ci, et/ou un lipide conjugué à un polymère pour former une nanoparticule lipidique pour l'administration d'un agent thérapeutique et/ou prophylactique. Dans certains exemples, la nanoparticule lipidique est utilisée pour administrer un acide nucléique, tel qu'un ARN messager et/ou un ARN antisens. L'invention concerne en outre une méthode de traitement et/ou de prévention de diverses maladies au moyen d'une telle nanoparticule lipidique. Dans un mode de réalisation, l'invention concerne un composé ayant une structure telle que représentée par la formule suivante (I), ou un sel, isomère ou N-oxyde de celui-ci, R étant tel que défini dans la description, et l'invention concerne en outre une composition pharmaceutique comprenant un ou plusieurs des composés mentionnés ci-dessus tels que représentés par la formule développée (I) et l'agent thérapeutique et/ou prophylactique. Dans certains modes de réalisation, la composition pharmaceutique comprend en outre un ou plusieurs composants choisis parmi un lipide neutre, un lipide chargé, un stéroïde et un lipide conjugué à un polymère. Une telle composition est utile pour former une nanoparticule lipidique pour administrer l'agent thérapeutique et/ou prophylactique. Dans d'autres modes de réalisation, la présente invention concerne une méthode d'administration de l'agent thérapeutique et/ou prophylactique à un sujet en ayant besoin, et la méthode comprend la préparation de la composition pharmaceutique de nanoparticules lipidiques contenant le composé tel que représenté dans la formule développée (I) et l'agent thérapeutique et/ou prophylactique, et l'administration de la composition au sujet.
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WO2017201346A1 (fr) * | 2016-05-18 | 2017-11-23 | Modernatx, Inc. | Polynucléotides codant pour la porphobilinogène désaminase destinés au traitement de la porphyrie intermittente aiguë |
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 |
US20190275170A1 (en) * | 2016-05-18 | 2019-09-12 | Modernatx, Inc. | Polynucleotides encoding jagged1 for the treatment of alagille syndrome |
US20190300906A1 (en) * | 2016-05-18 | 2019-10-03 | Modernatx, Inc. | Polynucleotides encoding galactose-1-phosphate uridylyltransferase for the treatment of galactosemia type 1 |
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 |
US20200268666A1 (en) * | 2017-06-14 | 2020-08-27 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
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2021
- 2021-09-03 CN CN202111031064.4A patent/CN115745819A/zh active Pending
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2022
- 2022-05-18 WO PCT/CN2022/093432 patent/WO2023029593A1/fr unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
WO2017201346A1 (fr) * | 2016-05-18 | 2017-11-23 | Modernatx, Inc. | Polynucléotides codant pour la porphobilinogène désaminase destinés au traitement de la porphyrie intermittente aiguë |
US20190275170A1 (en) * | 2016-05-18 | 2019-09-12 | Modernatx, Inc. | Polynucleotides encoding jagged1 for the treatment of alagille syndrome |
US20190300906A1 (en) * | 2016-05-18 | 2019-10-03 | Modernatx, Inc. | Polynucleotides encoding galactose-1-phosphate uridylyltransferase for the treatment of galactosemia type 1 |
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 |
US20200268666A1 (en) * | 2017-06-14 | 2020-08-27 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
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