CA2848238C - Lipid containing formulations - Google Patents
Lipid containing formulations Download PDFInfo
- Publication number
- CA2848238C CA2848238C CA2848238A CA2848238A CA2848238C CA 2848238 C CA2848238 C CA 2848238C CA 2848238 A CA2848238 A CA 2848238A CA 2848238 A CA2848238 A CA 2848238A CA 2848238 C CA2848238 C CA 2848238C
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- lipid
- alkyl
- nucleic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 160
- 150000002632 lipids Chemical class 0.000 title claims description 151
- 238000009472 formulation Methods 0.000 title description 31
- 238000000034 method Methods 0.000 claims abstract description 130
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 116
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 112
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 112
- 150000001875 compounds Chemical class 0.000 claims description 278
- 125000000217 alkyl group Chemical group 0.000 claims description 161
- 238000002360 preparation method Methods 0.000 claims description 125
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 116
- 108020004459 Small interfering RNA Proteins 0.000 claims description 89
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 84
- 239000002679 microRNA Substances 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 45
- 235000012000 cholesterol Nutrition 0.000 claims description 42
- 230000000692 anti-sense effect Effects 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 33
- 239000002245 particle Substances 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 24
- 229940124597 therapeutic agent Drugs 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 239000000872 buffer Substances 0.000 claims description 14
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 12
- 150000003431 steroids Chemical class 0.000 claims description 9
- 108700011259 MicroRNAs Proteins 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 239000002502 liposome Substances 0.000 abstract description 46
- 238000002560 therapeutic procedure Methods 0.000 abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 274
- 239000000047 product Substances 0.000 description 118
- 238000006243 chemical reaction Methods 0.000 description 117
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- 125000003729 nucleotide group Chemical group 0.000 description 89
- 239000002773 nucleotide Substances 0.000 description 84
- 239000002904 solvent Substances 0.000 description 82
- -1 ebloro Chemical group 0.000 description 77
- 108091034117 Oligonucleotide Proteins 0.000 description 76
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 75
- 239000000243 solution Substances 0.000 description 72
- 239000003795 chemical substances by application Substances 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 150000001412 amines Chemical class 0.000 description 56
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- 239000007787 solid Substances 0.000 description 55
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 54
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
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- 125000005647 linker group Chemical group 0.000 description 34
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 31
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 23
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 23
- 239000004327 boric acid Substances 0.000 description 23
- 108020004999 messenger RNA Proteins 0.000 description 23
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
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Classifications
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- 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
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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
- A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
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