Lipid nanoparticles for drug delivery

Abstract

This disclosure provides a composition that enables the delivery of a cargo containing a therapeutic agent, such as RNA, to organs or tissues such as the liver, lungs, spleen, brain, heart, kidneys, and muscle tissue. More specifically, the composition comprises a plurality of lipid particles comprising a drug, cationic lipids, and ionized lipids.

Description

[Technical Field]

[0001] Related applications This application claims the benefits of U.S. Provisional Application No. 63 / 495,958, filed on April 13, 2023. All teachings of the said application are incorporated herein by reference. [Background technology]

[0002] Nucleic acid-based therapies represent a novel and promising class of drugs, offering the potential for a broad range of therapeutic approaches to many currently untreatable diseases. Lipid nanoparticles (LNPs) are self-assembling nanostructures that encapsulate and deliver nucleic acids. Liver-targeted LNPs encapsulating therapeutic small interfering RNA (siRNA) have been clinically approved for the treatment of patients with trans tiretin-mediated amyloidosis (ONPATTRO®). Incorporating cationic lipids into liver-targeted LNPs has been demonstrated to potentially reorient the LNPs to the lungs and spleen. However, despite significant efforts to broaden the range of intravenously administered LNPs, delivery of LNPs to organs other than the liver, lungs, and spleen remains a challenge. [Overview of the project] [Problems that the invention aims to solve]

[0003] Therefore, there remains a need for compositions that enable the delivery of drugs to organs other than the liver, lungs, and / or spleen, or to organs including the liver, lungs, and / or spleen. [Means for solving the problem]

[0004] This disclosure is at least in part based on the discovery of compositions that enable the delivery of drugs, in particular therapeutic agents, to organs or tissues, including the liver, lungs, and / or spleen.

[0005] One embodiment provides a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a fully saturated cationic lipid, and wherein the lipid nanoparticles do not contain an amphoteric ionizable phospholipid.

[0006] One embodiment provides a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and wherein the cationic lipid is a lipid according to Formula VI:

Chemical formula

[0007] One embodiment provides a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and wherein the ionizable lipid is a lipid according to Formula I or a pharmaceutically acceptable salt thereof:

Chemical formula

[0008] One embodiment provides a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and at least one of EDPPC and DPTAP, and wherein the ionizable lipid is a lipid according to Formula I or II or a pharmaceutically acceptable salt thereof:

Chemical formula

[0009] In some embodiments, the Disclosure further provides a method for delivering a drug to one or more of the brain, heart, muscles, and kidneys of a subject that requires it, comprising systemically administering a composition comprising a plurality of lipid nanoparticles to the subject, wherein the lipid nanoparticles comprise a drug, ionizable lipids, and fully saturated cationic lipids.

[0010] Some embodiments provide a method for delivering a drug to a subject in need thereof, which includes administering a composition of the Disclosure to the subject.

[0011] Some embodiments provide a method for treating a subject having a disease, disorder or condition that is advantageously treated with a drug, comprising administering to the subject a therapeutically effective amount of a composition of the present disclosure comprising the drug.

[0012] Also provided herein are, in some embodiments, the use of the compositions of the Disclosure in accordance with the methods described herein, for example, the use of the compositions of the Disclosure including a drug for delivering the drug to a subject (e.g., a subject that needs it), and the use of the compositions of the Disclosure including a drug for treating a subject having a disease, disorder or condition that is favorably treated by the drug. Also provided herein is, in some embodiments, the use of the compositions of the Disclosure in the manufacture of a pharmaceutical for use in the methods described herein, for example, for delivering the drug to a subject (e.g., a subject that needs it) and treating a subject having a disease, disorder or condition that is favorably treated by the drug. Also provided herein are, in some embodiments, compositions for use in accordance with the methods described herein, for example, for delivering the drug to a subject (e.g., a subject that needs it) and treating a disease, disorder or condition that is favorably treated by the drug.

[0013] Remarkably, by incorporating specific cationic lipids in an optimized molar percentage into hepatocyte-targeting LNPs, it was discovered that the LNPs could deliver RNA to various organs, including the liver, lungs, and spleen, as well as brain and muscle endothelial cells. Furthermore, by adjusting the cationic lipid ratio in the LNPs, RNA was successfully delivered to organs including the liver and lungs. Active formulation screening identified the cationic lipids 1,2-dipalmitoyl-sn-glycero-O-ethyl-3-phosphocholine (EDPPC), 1,2-dipalmitoyl-3-trimethylammonium-propane (DPTAP), and O,O'-ditetradecanoyl-N-(α-trimethylammonioacetyl)diethanolamine (DC-6-14), which enable far more effective RNA delivery to endothelial cells than 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dimyristoyl-sn-glycero-O-ethyl-3-phosphocholine (EDMPC). [Brief explanation of the drawing]

[0014] [Figure 1]The names and structures of several ionizable lipids that may be suitable for use in this disclosure, as well as classes of ionizable lipids, are shown.

[0015] [Figure 2] The results of replacing amphoteric phospholipids with cationic lipids are shown. In this study, LNPs encapsulating siRNA in VE cadherin (Cdh5) were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE cadherin (Cdh5) mRNA was quantified against the housekeeping gene Gusb using RT-qPCR. Figure 2A shows data from this study in the liver. Figure 2B shows data from this study in the spleen. Figure 2C shows data from this study in the kidney. Figure 2D shows data from this study in the lung. Figure 2E shows data from this study in the heart. Figure 2F shows data from this study in the brain. Figure 2G shows data from this study in the muscle.

[0016] [Figure 3] This study compares 20% EDOPC versus 50% DOTAP in LNPs for delivery to selected organs. LNPs encapsulating siRNA in VE-cadherin (Cdh5) were administered intravenously to mice at a dose of 0.3 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE-cadherin (Cdh5) mRNA was quantified against the housekeeping gene Gusb using RT-qPCR. Figure 3A shows data from this study in the liver. Figure 3B shows data from this study in the spleen. Figure 3C shows data from this study in the kidney. Figure 3D shows data from this study in the lung. Figure 3E shows data from this study in the heart.

[0017] [Figure 4]The results of screening for cationic lipids at 20 mol% LNP in selected organs are shown. The formulation containing siRNA against VE-cadherin was administered intravenously to mice at 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE-cadherin (Cdh5) mRNA was quantified against the housekeeping gene Gusb. A PBS control was also tested. Figure 4A shows data from this study in the liver. Figure 4B shows data from this study in the spleen. Figure 4C shows data from this study in the kidney. Figure 4D shows data from this study in the lung. Figure 4E shows data from this study in the heart. Figure 4F shows data from this study in the brain. Figure 4G shows data from this study in the muscle.

[0018] [Figure 5] This figure shows a comparison of EDPPC and EDMPC at 20 mol% using LNPs containing MC3 and MD1 as ionizable lipids. LNPs encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, Cdh5 mRNA was quantified against the housekeeping gene Gusb. Figure 5A shows data from this study in the liver. Figure 5B shows data from this study in the spleen. Figure 5C shows data from this study in the kidney. Figure 5D shows data from this study in the lung. Figure 5E shows data from this study in the heart. Figure 5F shows data from this study in the brain. Figure 5G shows data from this study in the muscle.

[0019] [Figure 6]This figure shows a comparison of DPTAP and DOTAP at 20 mol% using LNPs containing MC3 and MD1 as ionizable lipids. LNPs encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, Cdh5 mRNA was quantified against the housekeeping gene Gusb. Figure 6A shows data from this study in the liver. Figure 6B shows data from this study in the spleen. Figure 6C shows data from this study in the kidney. Figure 6D shows data from this study in the lung. Figure 6E shows data from this study in the heart. Figure 6F shows data from this study in the brain. Figure 6G shows data from this study in the muscle.

[0020] [Figure 7] This study compares ionizable lipids and cationic lipids separately and demonstrates the improvement in RNA delivery when used in combination. LNPs encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.3 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, Cdh5 mRNA was quantified against the housekeeping gene Gusb. Figure 7A shows data from this study in the liver. Figure 7B shows data from this study in the lungs. Figure 7C shows data from this study in the heart. Figure 7D shows data from this study in the muscles.

[0021] [Figure 8]The results of 20 mol% EDPPC in combination with various ionizable lipids are shown. Formulations encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE cadherin mRNA was quantified against the housekeeping gene GusB. PBS controls were also tested. Figure 8A shows data from this study in the liver. Figure 8B shows data from this study in the spleen. Figure 8C shows data from this study in the kidney. Figure 8D shows data from this study in the lung. Figure 8E shows data from this study in the heart. Figure 8F shows data from this study in the brain. Figure 8G shows data from this study in the muscle.

[0022] [Figure 9] The results of 20 mol% EDPPC in combination with various ionizable lipids are shown. Formulations encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE cadherin mRNA was quantified against the housekeeping gene GusB. PBS controls were also tested. Figure 9A shows data from this study in the liver. Figure 9B shows data from this study in the spleen. Figure 9C shows data from this study in the kidney. Figure 9D shows data from this study in the lung. Figure 9E shows data from this study in the heart. Figure 9F shows data from this study in the brain. Figure 9G shows data from this study in the muscle.

[0023] [Figure 10]The results of 20 mol% EDPPC in combination with various ionizable lipids are shown. Formulations encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE cadherin mRNA was quantified against the housekeeping gene GusB. PBS controls were also tested. Figure 10A shows data from this study in the liver. Figure 10B shows data from this study in the spleen. Figure 10C shows data from this study in the kidney. Figure 10D shows data from this study in the lung. Figure 10E shows data from this study in the heart. Figure 10F shows data from this study in the brain. Figure 10G shows data from this study in the muscle.

[0024] [Figure 11] The results of 20 mol% DPTAP in combination with various ionizable lipids are shown. The formulation containing siRNA against VE-cadherin was administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE-cadherin mRNA was quantified against the housekeeping gene GusB. A PBS control was also tested. Figure 11A shows data from this study in the liver. Figure 11B shows data from this study in the spleen. Figure 11C shows data from this study in the kidney. Figure 11D shows data from this study in the lung. Figure 11E shows data from this study in the heart. Figure 11F shows data from this study in the brain. Figure 11G shows data from this study in the muscle.

[0025] [Figure 12]The results of 20 mol% DPTAP in combination with various ionizable lipids are shown. The formulation containing siRNA against VE-cadherin was administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE-cadherin mRNA was quantified against the housekeeping gene GusB. A PBS control was also tested. Figure 12A shows data from this study in the liver. Figure 12B shows data from this study in the spleen. Figure 12C shows data from this study in the kidney. Figure 12D shows data from this study in the lung. Figure 12E shows data from this study in the heart. Figure 12F shows data from this study in the brain. Figure 12G shows data from this study in the muscle.

[0026] [Figure 13] The results for 20 mol% DC-6-14 combined with various ionizable lipids are shown. Formulations containing siRNA against VE cadherin were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE cadherin mRNA was quantified against the housekeeping gene GusB. PBS controls were also tested. Figure 13A shows data from this study in the liver. Figure 13B shows data from this study in the spleen. Figure 13C shows data from this study in the kidney. Figure 13D shows data from this study in the lung. Figure 13E shows data from this study in the heart. Figure 13F shows data from this study in the brain. Figure 13G shows data from this study in the muscle.

[0027] [Figure 14]The results for 20 mol% DC-6-14 combined with various ionizable lipids are shown. Formulations containing siRNA against VE cadherin were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, VE cadherin mRNA was quantified against the housekeeping gene GusB. A PBS control was also tested. Figure 14A shows data from this study in the liver. Figure 14B shows data from this study in the spleen. Figure 14C shows data from this study in the kidney. Figure 14D shows data from this study in the lung. Figure 14E shows data from this study in the heart. Figure 14F shows data from this study in the brain. Figure 14G shows data from this study in the muscle.

[0028] [Figure 15] The results of a study optimizing the EDPPC ratio in LNPs are presented. To optimize the cationic lipid ratio for extrahepatic delivery, a series of LNPs with systematically increasing EDPPC percentages were prepared and tested in vivo with a single 0.5 mg / kg siCdh5 dose. LNPs containing 10–50% EDPPC showed effective Cdh5 gene silencing in the liver, spleen, kidney, lung, and brain. LNPs containing 20–30% EDPPC showed the most potent gene silencing in the heart and skeletal muscle. PBS controls were also tested. Figure 15A shows data from this study in the liver. Figure 15B shows data from this study in the spleen. Figure 15C shows data from this study in the kidney. Figure 15D shows data from this study in the lung. Figure 15E shows data from this study in the heart. Figure 15F shows data from this study in the brain. Figure 15G shows data from this study in muscle.

[0029] [Figure 16]The results of a study optimizing the ratio of DPTAP in LNPs are shown. To optimize the cationic lipid ratio for extrahepatic delivery, a series of LNPs with systematically increasing DPTAP percentages were prepared and tested in vivo with a single 0.5 mg / kg siCdh5 dose. LNPs containing 10–50% DPTAP showed effective Cdh5 gene silencing in the liver, spleen, kidney, lung, heart, and skeletal muscle. PBS controls were also tested. Figure 16A shows data from this study in the liver. Figure 16B shows data from this study in the spleen. Figure 16C shows data from this study in the kidney. Figure 16D shows data from this study in the lung. Figure 16E shows data from this study in the heart. Figure 16F shows data from this study in the brain. Figure 16G shows data from this study in muscle.

[0030] [Figure 17] The results of a study optimizing the DC-6-14 ratio in LNPs are shown. To optimize the cationic lipid ratio for extrahepatic delivery, a series of LNPs with systematically increasing percentages of DC-6-14 were prepared and tested in vivo with a single 0.5 mg / kg dose of siCdh5. LNPs containing 10–50% DC-6-14 showed effective Cdh5 gene silencing in the liver, spleen, kidney, lung, heart, and skeletal muscle. PBS controls were also tested. Figure 17A shows data from this study in the liver. Figure 17B shows data from this study in the spleen. Figure 17C shows data from this study in the kidney. Figure 17D shows data from this study in the lung. Figure 17E shows data from this study in the heart. Figure 17F shows data from this study in the brain. Figure 17G shows data from this study in muscle.

[0031] [Figure 18]This study demonstrates the efficacy of siRNA delivery to the lungs when using liver-targeted ionizable lipids in combination with DOTAP. To examine whether 50% DOTAP integration into liver-targeted LNPs containing ionizable lipids of formula I or III reorients the lungs, five LNPs were prepared with different ionizable lipids (MC3 as a positive control), including one LNP without ionizable lipids as a negative control. The in vivo pulmonary endothelial delivery efficiency of these LNPs was tested using a single intravenous dose of 0.4 mg / kg of siCdh5. Data from this experiment are presented.

[0032] [Figure 19] This report presents the results of tissue affinity studies for altering the alkyl tail length of PEG lipids in LNPs. To investigate whether the alkyl chain length of PEG lipids affects the tissue affinity of LNPs containing 50% DOTAP, three LNPs containing different PEG lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single intravenous administration of 1.0 mg / kg of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs showed similar levels of Cdh5 gene silencing in all collected tissues. Figure 19A shows data from this study in the liver. Figure 19B shows data from this study in the spleen. Figure 19C shows data from this study in the kidney. Figure 19D shows data from this study in the lung. Figure 19E shows data from this study in the heart.

[0033] [Figure 20]The results of 20 mol% EDOPC combined with various ionizable lipids are shown. To examine the generalization of EDOPC for extrahepatic delivery, various ionizable lipids were formulated with 20% EDOPC. LNPs containing five different ionizable lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single 1.0 mg / kg intravenous administration of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs containing 20% ​​EDOPC showed significant Cdh5 gene silencing in all tissues tested, indicating that these novel formulations can be used for RNA delivery to endothelial RNA delivery in various tissues. Figure 20A shows data from this study in the liver. Figure 20B shows data from this study in the spleen. Figure 20C shows data from this study in the kidney. Figure 20D shows data from this study in the lung. Figure 20E shows data from this study in the heart. Figure 20F shows data from this study in the brain. Figure 20G shows data from this study in the muscle.

[0034] [Figure 21] This report shows the results of tissue affinity for altering the alkyl tail length of PEG lipids in LNPs containing 18.5% EDOPC. To investigate whether the alkyl chain length of PEG lipids affects the tissue affinity of LNPs containing 18.5% EDOPC, three LNPs containing different PEG lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single intravenous administration of 1.0 mg / kg of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs showed similar levels of Cdh5 gene silencing in all collected tissues. Figure 21A shows data from this study in the liver. Figure 21B shows data from this study in the spleen. Figure 21C shows data from this study in the kidney. Figure 21D shows data from this study in the lung. Figure 21E shows data from this study in the heart.

[0035] [Figure 22]The results of 10 mol% DPTAP combined with various ionizable lipids are shown. To examine the generalization of DPTAP for extrahepatic delivery, various ionizable lipids were formulated with 10% DPTAP. Six different LNPs containing ionizable lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single 0.5 mg / kg intravenous administration of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs containing 10% DPTAP showed significant Cdh5 gene silencing in all tissues tested, indicating that these novel formulations can be used for RNA delivery to endothelial RNA delivery in various tissues. Figure 22A shows data from this study in the liver. Figure 22B shows data from this study in the kidney. Figure 22C shows data from this study in the lung. Figure 22D shows data from this study in the heart. Figure 22E shows data from this study in the brain. Figure 22F shows the data from this study in muscle tissue. [Modes for carrying out the invention]

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. Methods and materials similar to or equivalent to those described herein may be used in accordance with this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents and other references described herein are incorporated by reference in their entirety. In addition, materials, methods and examples are illustrative and not intended to be limiting. Other features and advantages of this disclosure are evident from the following detailed description and claims.

[0037] A. Definition The compounds described herein include all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, salts (e.g., pharmaceutically acceptable salts), and solvates thereof. Thus, the terms “compound” and “compounds,” as used in this disclosure, refer to the compounds disclosed and any of their possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, and solvates thereof. This applies unless specifically designated by any notation indicating a particular positional isomer, stereoisomer, epimer, enantiomer, or configuration, or by the use of standard notation in the art.

[0038] The compounds described herein may have chiral centers, chiral axes, and chiral planes (e.g., E.L. Eliel and SH. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and unless otherwise indicated, they may occur as racemic mixtures, individual isomers (e.g., diastereomers, enantiomers, geometric isomers (including cis and trans double bond isomers), conformational isomers (including rotational and atropic isomers), tautomers, and intermediate mixtures, including all possible isomers and mixtures thereof.

[0039] When a compound is represented in a structure that does not exhibit stereochemistry and the compound has one or more chiral centers, the structure should be understood to include one enantiomer or diastereomer of the compound separated or substantially separated from its corresponding optical isomer(s), a racemic mixture of the compound, and a mixture rich in one enantiomer or diastereomer relating to its corresponding optical isomer(s). When a compound is represented in a structure that exhibits stereochemistry and the compound has two or more chiral centers, the stereochemistry represents the relative stereochemistry of substituents around one or more chiral carbon atoms, rather than the absolute stereochemistry. Unless otherwise indicated in this specification, when a compound is represented in a structure that exhibits stereochemistry using solid and / or dashed wedge shapes and the compound has one or more chiral centers, the stereochemistry represents the absolute stereochemistry of substituents around one or more chiral centers. Unless otherwise indicated herein, compounds are represented in structures showing stereochemistry using solid and / or dashed thick lines, and if the compound has one or more chiral centers, the stereochemistry represents the relative stereochemistry of the unspecified absolute configurations of substituents around one or more chiral centers. "R" and "S" can also be used, or alternatively, to indicate the absolute configurations of substituents around one or more chiral centers (e.g., carbon atoms).

[0040] Therefore, for example, a single stereoisomer containing the known relative and absolute configurations of two chiral centers can be specified using the conventional RS system (e.g., (1S,2S)), and diastereomers in a racemic mixture can be specified using the two-letter RS ​​system (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S), and (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)).

[0041] The articles “a, an” used in this disclosure refer to one or more (i.e., at least one) grammatical objects of the article. For example, “element” means one or more elements. Similarly, when introducing elements disclosed herein, the articles “a, an,” “the,” and “said” are intended to mean that there are one or more elements. Furthermore, the one or more elements may be the same or different.

[0042] The term "or" is used in this disclosure to mean the term "and / or" unless otherwise indicated, and is used interchangeably with "and / or".

[0043] "Approximately" means within the range of error that is permissible for a particular value as determined by those skilled in the art. Typically, the range of error that is permissible for a particular value depends at least in part on how the value is measured or determined, for example, on limitations of the measurement system. For example, "Approximately" may mean within the standard deviation that is permissible by convention in the art. Alternatively, "Approximately" may mean within ±20% of a given value, for example, ±10%, ±5%, or ±1%. It should be understood that the term "Approximately" may precede any particular value specified herein, except for the specific values ​​used in examples.

[0044] Unless otherwise specifically defined, "alkyl" refers to a linear or branched hydrocarbon group, which may be fully saturated and, when saturated, may contain a divalent group having 1 to about 30 carbon atoms, or, when unsaturated, may contain a divalent group having 2 to about 30 carbon atoms. Examples of saturated alkyls are not limited to but include groups such as methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl, 1,1-dimethylheptyl, and 1,2-dimethylheptyl. Unsaturated alkyls may contain one or more double bonds, triple bonds, or combinations thereof. Examples of unsaturated alkyls are not limited to vinyl, propenyl, isopropenyl, clotyl, 2-isopentenyl, allenyl, butenyl, butadienyl, pentenyl, pentadienyl, 3-(1,4-pentadienyl), hexenyl, hexadienyl, ethynyl, propynyl, butynyl, and other isomers. The term “divalent alkyl group” refers to the general formula: -alkyl- unless otherwise specifically defined. A divalent alkyl group is an alkyl group having two bonds to a larger structure and / or other substituents. The term “C 1~n "Alkyl" refers to an alkyl group having 1 to approximately n carbon atoms, where n is an integer greater than 1.

[0045] "Alkenyl" refers to a branched or linear aliphatic group having a predetermined number of carbon atoms and at least one (e.g., one, two, three, four, five, etc.) carbon-carbon double bonds. Therefore, "(C1~C 15 An "alkenyl" refers to a group having 1 to 15 carbon atoms and at least one carbon-carbon double bond in a branched or linear arrangement. In some embodiments, an alkenyl is (C1~C 30 ) Alkenyl, for example, (C1~C 20 ) Alkenil, (C1~C 15 ) Alkenil, (C1~C 10The alkenyl is a (C1-C5) alkenyl or a (C1-C3) alkenyl. Examples of alkyl groups include vinyl and allyl. In some embodiments, the alkenyl is optionally substituted with one or more substituents, for example, as described herein.

[0046] The term "alkynyl" refers to a branched or linear aliphatic group containing a carbon atom as a bonding site and at least one carbon-carbon triple bond. As used herein, the term alkynyl does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. Groups of -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkyne" refers to a class of compounds having formula HR where R is an alkynyl.

[0047] As used herein, the term "hydrocarbon" refers to an aliphatic moiety consisting of carbon and hydrogen. A "hydrocarbon group" is considered to be an alkyl, alkenyl, or alkynyl group, or a combination thereof.

[0048] "Alkoxy" refers to an alkyl group bonded through an oxygen-linked atom, and alkyl groups are defined herein. Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0049] "Aryl" refers to monocyclic or polycyclic (e.g., bicyclic, tricyclic), carbocyclic, or aromatic ring systems having a predetermined number of ring atoms, and includes aromatic rings (multiple) fused to a non-aromatic ring, as long as one of the fused rings is an aromatic ring consisting of hydrogen and carbon. Therefore, "(C6~C 15 "Aryl" refers to an aromatic ring system containing 6 to 15 ring atoms. In some embodiments, aryl is (C6~C 25 ) Aryl, for example, (C6~C 20 )aryl, (C6~C 15 )aryl, (C6~C 12 )aryl or (C6~C 10The aryl is an aryl. Examples of aryls include phenyl, naphthyl, and fluorenyl. In some embodiments, the aryl is phenyl or fluorenyl.

[0050] The term "heteroaryl" refers to a monovalent aromatic group containing an aromatic carbon or nitrogen atom as a bonding site, wherein the carbon or nitrogen atom forms part of one or more aromatic ring structures, and at least one of the ring atoms is nitrogen, oxygen, or sulfur, and the heteroaryl group consists of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. A heteroaryl ring may contain one, two, three, or four ring atoms selected from nitrogen, oxygen, and sulfur. If two or more rings are present, the rings may or may not be condensed. As used herein, this term does not exclude the presence of one or more alkyl, aryl, and / or aralkyl groups (with limited carbon number) bonded to an aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term “heteroaryl” also refers to a divalent aromatic group comprising two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as two bonding sites, wherein the atoms form part of one or more aromatic ring structures, at least one of the ring atoms is nitrogen, oxygen, or sulfur, and the divalent group consists of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If two or more rings are present, the rings may or may not be condensed. Non-condensed rings can be linked via one or more covalent, alkyl, or alkenyl groups (with no limitation on the number of carbon atoms). As used herein, this term does not exclude the presence of one or more alkyl, aryl, and / or aralkyl groups (with no limitation on the number of carbon atoms) bonded to an aromatic ring or aromatic ring system.

[0051] Unless otherwise specifically defined, the term “cycloalkyl” refers to a fully saturated cyclic alkyl group containing 1 to 4 rings and 3 to 8 carbon atoms per ring. Exemplary such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and bicyclo[1.1.1]pentane.

[0052] Generally, “substituted” or “optionally substituted” refers to a group (e.g., alkyl, aryl group) in which one or more bonds to a hydrogen atom contained herein can be replaced by bonds to a non-hydrogen atom or a non-carbon atom. Substituents also include groups in which one or more bonds to a carbon atom or hydrogen atom are replaced by one or more bonds to a heteroatom, including double or triple bonds. Thus, a substituent is substituted with one or more substituents, which may be the same or different unless otherwise specified. In some embodiments, a substituent is substituted with one, two, three, four, five, or six substituents. It will be understood that “substituted” or “substituted with” implies the implicit condition that such substitution is subject to the allowable valence of the substituted atom. Examples of substituent groups, but not limited to, include alkyl, alkynyl, alkenyl, aryl, heteroaryl, aralkyl, alkaryl, alcohol, halogen, and hydroxyl; This product contains alkoxy, alkeneoxy, alkyneoxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkoxy groups, carbonyl, carboxyl, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, sulfonamide, sulfonate, sulfate, amine, N-oxide, hydrazine, hydrazide, hydrazone, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro group, nitrile, =CF2, -CF3, -CF2H, =CH2, -CHO, C(halogen)3, -ONO2, -alkyl-ONO2, -C(O)OP(O)(O-alkyl)2, -OPO3H2, and polyethylene glycol.

[0053] "Hydroxy" refers to the -OH group.

[0054] Unless otherwise specifically defined, "alkylamino" refers to the general formula -(NH)-alkyl. Unless otherwise specifically defined, "dialkylamino" refers to the general formula -N-(alkyl)2. Unless otherwise specifically limited, dialkylamino includes cyclic amine compounds, such as piperidine, piperazine, azetidine, pyrrolidine, morpholine, and their derivatives.

[0055] As used in this disclosure, the terms “salt” and “salts” refer to acidic salts and / or basic salts formed by inorganic and / or organic acids and bases.

[0056] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within the bounds of appropriate medical judgment, is suitable for use in contact with mammalian tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that has a reasonable benefit-to-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19, describe pharmaceutically acceptable salts in detail, and their relevant teachings are incorporated herein by reference in their entirety. pharmaceutically acceptable salts of compounds and lipids described herein include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. In some embodiments, one or more components of a pharmaceutically acceptable salt are not acid addition salts or base addition salts. The term “pharmaceutically acceptable salt” is intended to include salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2sulfonic acid, and other acids. Forms of pharmaceutically acceptable salts may also include forms in which the ratio of salt-containing molecules is not 1:1. For example, a salt may contain two or more molecules of inorganic or organic acid per molecule of base, for example, two molecules of hydrochloric acid per molecule of the formula provided herein. Alternatively, a salt may contain two or more molecules of inorganic or organic acid per molecule of base, for example, two molecules of lipids or compounds of the formula provided herein per molecule of tartaric acid. Additional examples of pharmaceutically acceptable acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange.Other pharmaceutically acceptable acid addition salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxyethanesulfonate, and hydroxym This includes leates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 2-phenoxybenzoates, phenylacetates, 3-phenylpropionates, phosphonates, pivalates, propions, pyruvates, salicylates, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, valersates, and the like. They can form monoacids, diacids, or triacids, and such salts may exist in hydrated, solvated, or substantially anhydrous forms.

[0057] pharmaceutically acceptable base addition salts include salts formed with inorganic bases, such as alkali metals, alkaline earth metals, and ammonium bases, as well as salts formed with aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or N +This includes ((C1-C4) alkyl) tetrasalts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and barium. Further pharmaceutically acceptable base addition salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxyls, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0058] Where used herein, “treatment” is an approach to obtain a favorable or desired outcome, including clinical outcomes, as is commonly understood in the art. Favorable or desired clinical outcomes may include, but are not limited to, the alleviation or remission of one or more symptoms or conditions, whether detectable or undetectable, a reduction in the severity of the disease, a stabilized (i.e., non-exacerbating) state of the disease, prevention of disease progression, delay or slowing of disease progression, remission or temporary relief and recovery (whether partial or whole) of a disease state. “Treatment” also means extended survival compared to the survival expected without treatment.

[0059] In some embodiments, “treating” means, as used herein, the step of delivering a therapy to a subject in need, such as a mammal (for example, by administering one or more therapeutic agents to the subject). In some embodiments, “treating” also includes inhibiting a disease or condition and alleviating symptoms resulting from a disease or condition (for example, by slowing or halting its progression or causing regression of the disease or condition).

[0060] As used herein, “Subject” includes humans, livestock, such as laboratory animals (e.g., dogs, monkeys, pigs, rats, mice, etc.), domestic pets (e.g., cats, dogs, rabbits, etc.) and livestock (e.g., pigs, cattle, sheep, goats, horses, etc.), as well as non-domesticated animals. In some embodiments, the subject is humans.

[0061] As used herein, “effective dose” or “therapeutic dose” of a composition is the amount of the composition that, when administered to a subject, produces a discernible physiological effect in an individual or animal. The compositions disclosed herein may have pharmacological properties when administered in therapeutic doses to provide a useful physiological effect for treating certain physiological conditions. Actual doses, including “effective dose” or “therapeutic dose,” vary depending on several factors, including, but not limited to, the drug, the specific disorder being treated, the severity of the disorder, the patient’s physique and health, and the route of administration. A skilled healthcare professional can readily determine an appropriate dose using methods known in the medical field.

[0062] In addition, “therapeutic dose” can refer to the amount effective in achieving the desired therapeutic outcome (e.g., treatment, cure, inhibition, or remission of a physiological response or condition) in the required dosage and duration. Complete therapeutic effect does not necessarily have to occur with a single dose, but may occur only after a series of doses. Therefore, a therapeutic dose can be administered in one or more doses. The therapeutic dose may vary depending on factors such as the disease state of the mammal, age, sex, and weight, the mode of administration, and the ability of the therapeutic agent or combination of therapeutic agents to induce the desired response in the individual. A person skilled in the art can determine the therapeutic dose of the drug to be administered using the guidance provided herein and other methods known in the art.

[0063] B. Exemplary Embodiments 1. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles contain a drug, an ionizable lipid, and a fully saturated cationic lipid, and the lipid nanoparticles do not contain an amphoteric phospholipid. 2. The composition according to embodiment 1, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 4.5 to about 7. 3. The composition according to embodiment 1 or 2, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 5 to about 7. 4. The composition according to any one of embodiments 1 to 3, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 5.5 to about 7. 5. The composition according to any one of four embodiments, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 6 to about 7. 6. The composition according to any one of embodiments 1 to 5, wherein the cationic lipid is less than about 50 mole percent of the lipid nanoparticles. 7. The composition according to any one of embodiments 1 to 6, wherein the cationic lipid is less than about 30 mole percent of the lipid nanoparticles. 8. The composition according to any one of claims 7, wherein the cationic lipid is less than about 20 mole percent of the lipid nanoparticles. 9. Completely saturated cationic lipids are C 12 ~C 18 A composition according to any one of embodiments 1 to 8, wherein the composition is a fully saturated cationic lipid. 10. The composition according to any one of embodiments 1 to 9, further comprising sterols. 11. The composition according to any one of embodiments 1 to 10, further comprising PEG lipids. 12. The composition according to any one of embodiments 1 to 11, wherein the drug is a biological agent. 13. The composition according to embodiment 12, wherein the bioactive agent is a therapeutic agent. 14. The composition according to embodiment 13, wherein the therapeutic agent is a dietary therapy agent. 15. The composition according to any one of embodiments 1 to 11, wherein the drug is a contrast agent. 16. A composition according to any one of embodiments 1 to 11, wherein the drug is a diagnostic agent. 17. The composition according to any one of embodiments 1 to 11, wherein the drug is a nucleic acid. 18. The composition according to embodiment 17, wherein the nucleic acid is ribonucleic acid. 19. The composition according to embodiment 17, wherein the nucleic acid is deoxyribonucleic acid. 20. The composition according to embodiment 17, wherein the nucleic acid is a non-natural nucleic acid. 21. The composition according to any one of embodiments 1 to 20, wherein the ionizable lipid is a lipid of formula I or II or a pharmaceutically acceptable salt thereof. [ka] [In the formula, X is -NR 1 - or -O-, R 1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5, R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from can be linked to each other to form a 4- to 7-membered ring of carbon atoms and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)O-R 41 , -O(CO)-R 42 , -(CO)O-R 43 , -O-R 44 , or R 34 is an aryl or heteroaryl group optionally substituted with. R 34 is an alkyl group having 1 to 18 carbon atoms, a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)O-R 41 , -O(CO)-R 42 , -(CO)O-R 43 , or -O-R 44 and R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 are each independently a hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independently an integer from 0 to 3, a + b is 1 or more, and c + d is 1 or more. R 51 and R 52 are each independently an alkyl group having 1 to 18 carbon atoms optionally substituted with R 35 . R 35 is a hydroxyl group, -G 20 -CH(R 55 )(R 56 ), -N(R 58 )(R 59 ), or -G 20 -R 60 And, G 20 is -(CO)O- or -O(CO)-, R 55 and R 56 Each is independently a hydrogen atom or an alkyl group having 1 to 18 carbon atoms. R 58 and R 59 Each of them independently consists of hydrogen or R 36 A cycloalkyl group having 3 to 6 carbon atoms, which may be substituted in some cases. R 60 This is an alkyl group having 1 to 18 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. R 36 is -N(R 61 )(R 62 ), or -G 20 -R 65 And, R 61 and R 62 Each is independently a cycloalkyl group having hydrogen or 3 to 6 carbon atoms. R 65 -L is an alkyl group having 1 to 18 carbon atoms. 40 -CH(R 66 )(R 67 ), or -G 20 -R 66 And, L 40 It is a divalent alkyl group containing 1 to 6 carbon atoms, R 66 and R 67 Each of these is independently an alkyl group containing 1 to 10 carbon atoms or an alkoxy group containing 1 to 10 carbon atoms. L 10 It is a divalent alkyl group containing 1 to 10 carbon atoms, G30 is -S(CO)N(R 64 )- and, R 64 ha-L 30 -G 20 -CH(R 55 )(R 56 ) and a' is either 0 or 1. G 10 is G 20 -O(CO)O-, or -N(R 63 )C(O)-, R 63 It is an alkyl group containing 1 to 18 carbon atoms, L 20 It is a divalent alkyl group containing 1 to 6 carbon atoms, b' is either 0 or 1. R 53 , R 54 , and R 57 Each of them independently consists of hydrogen or R 36 It is an alkyl group containing 1 to 18 carbon atoms, which may be substituted in some cases. L 30 [It is an alkyl group containing a single bond or 1 to 18 carbon atoms.] 22. The composition according to any one of embodiments 1 to 20, wherein the ionizable lipid is a lipid of formula VII or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 1 and R 2 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, and R 3 This indicates a hydrocarbon group with 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon groups indicated are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , and -OR 56They may be substituted with one or more substituents selected from the following: R 4 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 5 and R 6 Each of these independently forms a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 This indicates, however, R 5 and R 6 Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. R 7 is, -R 10 -L 2 -R 11 -L 3 -R 12 Show, R 51 and R 52 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 53 ,R 54 ,R 55 , and R 56 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 58 It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 , or -R 59 -R 57 It may also be replaced with R 58 and R 59 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R 57 -OH, COOH, -NR 61 R 62-OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 This indicates. R 61 and R 62 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 63 ,R 64 ,R 65 , and R 66 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 63 ,R 64 ,R 65 , and R 66 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 68 It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 , or -R 69 -R 67 It may also be replaced with R 68 and R 69 This represents a hydrocarbon group having 1 to 12 carbon atoms. R 67 -OH, COOH, -NR 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 This indicates. L 1 , L 2 , and L 3 Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 8 This represents a hydrocarbon group having 1 to 12 carbon atoms. R 9This represents a hydrocarbon group with 1 to 24 carbon atoms. R 10 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 11 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 12 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 9 , and R 12 The hydrocarbon group indicated is an aryl group, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -SR 58 It may also be replaced with R 11 The hydrocarbon group indicated is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 It may be replaced with . 23. The composition according to any one of embodiments 1 to 21, wherein the ionizable lipid is a lipid according to formula III or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or R 31 -L 2 -R 32 -and, R 31 This represents a hydrocarbon group with 1 to 24 carbon atoms. L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 32 This is a divalent hydrocarbon linking group having 1 to 18 carbon atoms. R 5 is a hydrogen atom, or R 33A C1-C18 alkyl group which may be substituted by R 7 and R 8 Each of these is independently a hydrogen atom, or R 33 A C1-C18 alkyl group which may be substituted by R 33 -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. e is an integer, either 2 or 3. 24. Ionizable lipids, [ka] A composition according to any one of embodiments 1 to 23, selected from the group consisting of the following. 25. Ionizable lipids, [ka] A composition according to any one of embodiments 1 to 20 and 22, selected from the group consisting of the following. 26. The composition according to any one of embodiments 1 to 25, wherein the cationic lipid is a lipid according to formula IV. [ka] [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C8~C 24 ) alkyl or optionally substituted (C8~C 24 ) Alkenil, In each case, R 103 These are independently (C1-C6) alkyl groups that are optionally substituted. R 104 These are (C1-C6) alkyl groups that may be substituted in some cases. X - [is a monovalent anion] 27. The composition according to any one of embodiments 1 to 26, wherein the cationic lipid is 1,2-dilauroyl-sn-glycero-O-ethyl-3-phosphocholine (EDLPC), 1,2-dimyristoyl-sn-glycero-O-ethyl-3-phosphocholine (EDMPC), 1,2-dimyristreoyl-sn-glycero-O-ethyl-3-phosphocholine (14:1 EPC), 1,2-dipalmitoyl-sn-glycero-O-ethyl-3-phosphocholine (EDPPC), 1,2-distearoyl-sn-glycero-O-ethyl-3-phosphocholine (EDSPC), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EDOPC), or 1-palmitoyl-2-oleoyl-sn-glycero-O-ethyl-3-phosphocholine (16:0-18:1 EPC). 28. The composition according to any one of embodiments 1 to 27, wherein the cationic lipid is EDPPC. 29. The composition according to any one of embodiments 1 to 25, wherein the cationic lipid is a lipid according to formula V. [ka] [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C8~C 24) alkyl or optionally substituted (C8~C 24 ) Alkenil, In each case, R 103 These are independently (C1-C6) alkyl groups that are optionally substituted. X - [is a monovalent anion] 30. The composition according to any one of embodiments 1 to 25 and 29, wherein the cationic lipid is selected from the group consisting of 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP), 1,2-dipalmitoyl-3-trimethylammonium-propane (DPTAP), 1,2-distearoyl-3-trimethylammonium-propane (DSTAP), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-aminium (DORI). 31. The composition according to any one of embodiments 1 to 25, 29, and 30, wherein the cationic lipid is DPTAP. 32. The composition according to any one of embodiments 1 to 25, wherein the cationic lipid is a lipid according to formula VI. [ka] [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C8~C 24 ) alkyl or optionally substituted (C8~C 24 ) Alkenil, R 105 Each of them is independently an (C1-C6) alkyl group. X - [is a monovalent anion] 33. Cationic lipids, [ka] The composition according to any one of embodiments 1 to 25 and 32. 34. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and the cationic lipid is a lipid according to formula VI. [ka] [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C8~C 24 ) alkyl or optionally substituted (C8~C 24 ) Alkenil, R 105 Each of them is independently an (C1-C6) alkyl group. X - [is a monovalent anion] 35. Cationic lipids, [ka] The composition according to embodiment 34. 36. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and the ionizable lipid is a lipid according to formula I or a pharmaceutically acceptable salt thereof. [ka] [In the formula, X is -NR 1 - or -O-, R 1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from may be linked together to form a 4- to 7-membered ring of carbon and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independent integers between 0 and 3, a+b is greater than or equal to 1, and c+d is greater than or equal to 1. 37. The composition according to embodiment 36, wherein the ionizable lipid is a lipid according to formula III or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or R 31 -L 2 -R 32 -and, R 31 This represents a hydrocarbon group with 1 to 24 carbon atoms. L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R32 This is a divalent hydrocarbon linking group having 1 to 18 carbon atoms. R 5 is a hydrogen atom, or R 33 A C1-C18 alkyl group which may be substituted by R 7 and R 8 Each of these is independently a hydrogen atom, or R 33 A C1-C18 alkyl group which may be substituted by R 33 -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. e is an integer, either 2 or 3. 38. Ionizable lipids, [ka] A composition according to embodiment 36 or 37, selected from the group consisting of the following. 39. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and the ionizable lipid is a lipid according to formula VII or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 1 and R 2 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, and R 3 This indicates a hydrocarbon group with 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon groups indicated are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , and -OR 56 They may be substituted with one or more substituents selected from the following: R 4 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 5 and R 6 Each of these independently forms a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 This indicates, however, R 5 and R 6 Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. R 7 is, -R 10 -L 2 -R 11 -L 3 -R 12 Show, R 51 and R 52 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 53 ,R 54 ,R 55 , and R 56 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 58It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 , or -R 59 -R 57 It may also be replaced with R 58 and R 59 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R 57 -OH, COOH, -NR 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 This indicates. R 61 and R 62 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 63 ,R 64 ,R 65 , and R 66 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 63 ,R 64 ,R 65 , and R 66 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 68 It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 , or -R 69 -R 67 It may also be replaced with R 68 and R 69This represents a hydrocarbon group having 1 to 12 carbon atoms. R 67 -OH, COOH, -NR 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 This indicates. L 1 , L 2 , and L 3 Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 8 This represents a hydrocarbon group having 1 to 12 carbon atoms. R 9 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 10 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 11 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 12 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 9 , and R 12 The hydrocarbon group indicated is an aryl group, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -SR 58 It may also be replaced with R 11 The hydrocarbon group indicated is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 It may be replaced with . 40. Ionizable lipids, [ka] A composition according to embodiment 39, selected from the group consisting of the following. 41. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and at least one of EDPPC and DPTAP, and the ionizable lipid is a lipid according to formula I or II or a pharmaceutically acceptable salt thereof. [ka] [In the formula, X is -NR 1 - or -O-, R 1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7, R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from may be linked together to form a 4- to 7-membered ring of carbon and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independent integers between 0 and 3, a+b is greater than or equal to 1, and c+d is greater than or equal to 1. R 51 and R 52 Each is independent of R 35 It is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. R 35 is a hydroxyl group, -G 20 -CH(R 55 )(R 56 ), -N(R 58 )(R 59 ), or -G 20 -R 60 And, G 20 is -(CO)O- or -O(CO)-, R 55 and R 56 Each is independently a hydrogen atom or an alkyl group having 1 to 18 carbon atoms. R 58 and R 59 Each of them independently consists of hydrogen or R 36 A cycloalkyl group having 3 to 6 carbon atoms, which may be substituted in some cases. R 60 This is an alkyl group having 1 to 18 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. R 36 is -N(R 61 )(R 62 ), or -G 20 -R 65 And, R 61 and R 62 Each is independently a cycloalkyl group having hydrogen or 3 to 6 carbon atoms. R 65 -L is an alkyl group having 1 to 18 carbon atoms. 40 -CH(R 66 )(R 67 ), or -G 20 -R 66 And, L 40It is a divalent alkyl group containing 1 to 6 carbon atoms, R 66 and R 67 Each of these is independently an alkyl group containing 1 to 10 carbon atoms or an alkoxy group containing 1 to 10 carbon atoms. L 10 It is a divalent alkyl group containing 1 to 10 carbon atoms, G 30 is -S(CO)N(R 64 )- and, R 64 ha-L 30 -G 20 -CH(R 55 )(R 56 ) and a' is either 0 or 1. G 10 is G 20 -O(CO)O-, or -N(R 63 )C(O)-, R 63 It is an alkyl group containing 1 to 18 carbon atoms, L 20 It is a divalent alkyl group containing 1 to 6 carbon atoms, b' is either 0 or 1. R 53 , R 54 , and R 57 Each of them independently consists of hydrogen or R 36 It is an alkyl group containing 1 to 18 carbon atoms, which may be substituted in some cases. L 30 [It is an alkyl group containing a single bond or 1 to 18 carbon atoms.] 42. The composition according to any one of embodiments 34 to 41, wherein the drug is a biological agent. 43. The composition according to embodiment 42, wherein the bioactive agent is a therapeutic agent. 44. The composition according to embodiment 43, wherein the therapeutic agent is a dietary therapy agent. 45. The composition according to any one of embodiments 34 to 41, wherein the drug is a contrast agent. 46. ​​A composition according to any one of embodiments 34 to 41, wherein the drug is a diagnostic agent. 47. The composition according to any one of embodiments 34 to 41, wherein the drug is a nucleic acid. 48. The composition according to embodiment 47, wherein the nucleic acid is ribonucleic acid. 49. The composition according to embodiment 47, wherein the nucleic acid is deoxyribonucleic acid. 50. The composition according to embodiment 47, wherein the nucleic acid is a non-natural nucleic acid. 51. A method for delivering a drug to one or more of the brain, heart, muscles, and kidneys of a subject in need thereof, comprising systemically administering to the subject a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a fully saturated cationic lipid. 52. The method according to aspect 51, wherein the drug is administered to the brain. 53. The method according to embodiment 51, wherein the drug is administered to the heart. 54. The method according to embodiment 51, wherein the drug is administered into the muscle. 55. The method according to embodiment 51, wherein the drug is administered to the kidney. 56. The method according to any one of embodiments 51 to 55, wherein the ionizable lipid is a lipid of formula (I). 57. The method according to any one of embodiments 51 to 56, wherein the ionizable lipid is a lipid of formula (III). 58. The method according to any one of embodiments 51 to 55, wherein the ionizable lipid is a lipid of formula (II). 59. The method according to any one of embodiments 51 to 55, wherein the ionizable lipid is a lipid of formula (VII). 60. The method according to any one of embodiments 51 to 59, wherein the cationic lipid is a lipid of formula (IV). 61. The method according to any one of embodiments 51 to 59, wherein the cationic lipid is a lipid of formula (V). 62. The method according to any one of embodiments 51 to 59, wherein the cationic lipid is a lipid of formula (VI). 63. A method for delivering a drug to a subject in need thereof, comprising administering to the subject a composition described in any one of embodiments 1 to 33. 64. A method for delivering a drug to a subject in need thereof, comprising administering to the subject a composition according to any one of embodiments 34 to 35. 65. A method for delivering a drug to a subject in need thereof, comprising administering to the subject a composition described in any one of embodiments 36 to 38. 66. A method for delivering a drug to a subject in need thereof, comprising administering to the subject a composition described in any one of embodiments 39 to 50. 67. A method for treating a subject having a disease, disorder or condition that is advantageously treatable with a drug, comprising administering to the subject a therapeutically effective amount of a composition described in any one of embodiments 1 to 50.

[0064] C. Lipid particles In some embodiments, the lipid particles of this disclosure include ionizable lipids, cationic lipids, and pharmaceuticals. In some embodiments, the lipid particles further include sterols. In some embodiments, the lipid particles further include phospholipids. In some embodiments, the lipid particles further include PEG lipids. Exemplary preferred lipids of each type are provided herein. In some embodiments, the molar percentage distribution of ionizable lipids and cationic lipids is 10-90:10-90, each and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, and sterols is 10-90:10-90:10-90, each and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, and sterols is 15-75:5-75:25-80, each and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, and sterols is 20-60:15-50:20-60, respectively, and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, sterols, and phospholipids is 15-75:5-75:25-80:0.1-10, respectively, and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, sterols, and phospholipids is 20-60:15-50:20-60:2.5-7.5, respectively, and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, sterols, phospholipids, and PEG lipids is 20-60:15-50:20-60:2.5-7.5:0.5-2.5, respectively, and the sum of each molar percentage must be 100. In some embodiments, the molar percentage distribution of ionizable lipids, cationic lipids, sterols, and PEG lipids is 20-60:15-50:20-60:0.5-2.5, respectively, and the sum of each molar percentage must be 100.

[0065] As used herein, “lipid particle” refers to a particle consisting of at least one lipid. Lipid particles can have a variety of structures, and for example, they may be in the form of lipid aggregates, micelles, liposomes, lipoplexes, lipid nanoparticles, etc., according to this disclosure. For example, in some embodiments, lipid particles have a single lipid bilayer and an internal aqueous phase. In other embodiments, lipid particles are liposomes comprising multiple lipid bilayers stacked together with multiple internal aqueous phase portions. The bilayers of the lipid particles of this disclosure may be substantially gel-like, substantially fluid, or substantially solid. In some embodiments, the phase of the bilayer may change (for example, by dissolution). This phase change may result from, for example, temperature changes, pH changes, composition changes, storage, administration, solvent changes, or any other factors.

[0066] In some embodiments, the lipid particles are lipid nanoparticles. As used herein, “lipid nanoparticles” refers to nanoparticles containing multiple lipid molecules. Furthermore, “nanoparticles” refers to particles with a diameter of 1 to 1000 nm, but more specifically, particles with a diameter of 10 to 1000 nm. More specifically, the particles have a diameter of 30 to 500 nm, even more specifically, a diameter of 50 to 250 nm, particularly specifically, a diameter of 50 to 200 nm, and most specifically, a diameter of 50 to 150 nm.

[0067] In some embodiments, the drug is contained within the aqueous phase of the lipid particles. In other embodiments, the drug is bound (covalently or noncovalently) to the surface of the lipid particles. In some embodiments, all or part of the drug is contained within the lipid bilayer of the lipid particles. In some embodiments, the drug is covalently bound to the lipid particles.

[0068] In some embodiments, the drug is a bioactive agent. Examples of bioactive agents include pharmaceutical compounds (e.g., small molecules), nucleic acids, oligonucleotides, nutritional supplements, proteins, peptides, amino acids, and the like. In some embodiments, the drug is a therapeutic agent.

[0069] In some embodiments, the drug is a nucleic acid. The nucleic acid drug may be double-stranded or single-stranded. In addition, the nucleic acid drug may be a linear or cyclic nucleic acid molecule. In some embodiments, the nucleic acid is DNA, RNA, or a non-natural nucleic acid. The RNA drug may be peptide-coding RNA or non-coding RNA. The RNA drug may be mRNA, siRNA, miRNA, enhancer RNA, long non-coding RNA, etc. Among other possibilities, the nucleic acid may be able to regulate gene expression, encode peptides, or be an aptamer. In some embodiments, the nucleic acid has a length of about 15 to about 30 nucleotides, for example, about 20 to 25 nucleotides (e.g., 20, 21, 22, 23, 24, or 25 nucleotides). In some embodiments, nucleic acids have a length of approximately 30 or more nucleotides, for example, approximately 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 750, 1000 or more nucleotides.

[0070] In some embodiments, the agent is a nutraceutical agent, such as a vitamin, antioxidant, or nutritional supplement.

[0071] In some embodiments, the drug is a contrast agent. Examples of contrast agents include, but are not limited to, chemical or biological dyes, fluorescent probes, radioisotopes, and spin-labeled tracers.

[0072] The lipid particles of this disclosure may contain one or more drugs (for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 drugs).

[0073] As used herein, “zeta potential” refers to the potential at the interface between a particle in a bulk solution and a steady solvent and solute. The zeta potential reflects the degree of electrostatic repulsion between particles in a solution. As a result, the zeta potential of lipid particles can be used as a prediction of the stability of the particles in a solution (e.g., resistance to coagulation or aggregation). In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than -20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than -10 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than -5 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than 0 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than 5 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than 10 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of less than 20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than -20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than -10 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than -5 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than 0 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than 5 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than 10 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential greater than 20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential between -20 and 20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential between -10 and 20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential between 0 and 20 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential between -20 and 10 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential between -20 and 0 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of -10 to 10 millivolts. In some embodiments, the lipid particles of the Disclosure have a zeta potential of 0 to 10 millivolts.In some embodiments, the lipid particles of this disclosure have a zeta potential of 5 to 10 millivolts. In some embodiments, the zeta potential is measured by light scattering, for example, using a Zetasizer Nano ZS (Malvern Instruments) in a 0.1× PBS solution as described in the examples.

[0074] As used herein, “pKa” refers to, for example, the apparent ionization constant of lipid nanoparticles. The pKa of the lipid nanoparticles of this disclosure may be about 4 to about 9. In some embodiments, the pKa of the lipid nanoparticles of this disclosure is about 5 to about 8. In some embodiments, the pKa of the lipid nanoparticles of this disclosure is about 5.5 to about 7. Preferably, the pKa of the lipid nanoparticles of this disclosure is about 6 to about 7. In some embodiments, the pKa is measured using the 2-(p-toluidinyl)naphthalene-6-sulfonic acid (TNS) assay, as described, for example, by Heyes J. et al., Journal of Controlled Release 107 (2005), pp. 276-287 and examples.

[0075] As used herein, encapsulation efficiency refers to the amount of drug encapsulated within particles of the composition and is expressed as a percentage of the total amount of drug. In some embodiments, the encapsulation efficiency is greater than 50%. In some embodiments, the encapsulation efficiency is greater than 60%. In some embodiments, the encapsulation efficiency is greater than 70%. In some embodiments, the encapsulation efficiency is greater than 80%. In some embodiments, the encapsulation efficiency is greater than 90%. In some embodiments, the encapsulation efficiency is greater than 91%. In some embodiments, the encapsulation efficiency is greater than 93%. In some embodiments, the encapsulation efficiency is greater than 95%. In some embodiments, the encapsulation efficiency is greater than 97%. In some embodiments, the encapsulation efficiency is greater than 98%. In some embodiments, the encapsulation efficiency is greater than 99%. In some embodiments, the encapsulation efficiency is determined, for example, by a modified Quant-iT RiboGreen RNA assay (Thermo Fisher) as described in Walsh C. et al. Methods Mol Biol. 2014;1141:109-1020 and illustrated.

[0076] As used herein, “polydispersibility index,” “PDI,” and “degree of dispersion” are used interchangeably and are measures of size heterogeneity of lipid particles in a population of lipid particles. Lower values ​​indicate a more uniform size distribution. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.5. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.3. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.2. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.15. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.1. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.08. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.07. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.06. In some embodiments, the PDI of lipid particles in the compositions described herein is less than 0.05. In some embodiments, as illustrated, for example, PDI is measured by dynamic light scattering using a Zetasizer Nano ZS (Malvern Instruments).

[0077] As used herein, “Z-average” refers to the strength-weighted average diameter of lipid nanoparticles in the compositions described herein. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be 10 to 500 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be 10 to 300 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be 10 to 200 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be 10 to 150 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be 10 to 100 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be less than 300 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be less than 250 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be less than 200 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be less than 150 nm. In some embodiments, the Z-average particle size of the lipid nanoparticles of the Disclosure may be less than 100 nm. In some embodiments, the Z-mean particle size of the lipid nanoparticles of this disclosure is determined by dynamic light scattering, for example, as illustrated by the example, by measuring using a Zetasizer Nano ZS (Malvern Instruments).

[0078] D. Ionizable lipids In some embodiments of the compositions of this disclosure, the compositions include ionizable lipids. In some embodiments, the ionizable lipids contain one or more groups that are ionic at physiological pH but cannot have a charge at certain pH values ​​outside the range of physiological pH. Typically, the ionizable lipids of this disclosure are ionizable cationic lipids that have a cationic charge at physiological pH values. The ionizable cationic groups may contain one or more protonable amines that can form cationic groups at physiological pH. The ionizable lipid compounds also contain one or more lipid components, e.g., C1-C1 30The composition may further contain two or more fatty acids containing alkyl or alkenyl carbon groups. In some embodiments of the compositions of this application, ionizable cationic lipids refer to lipids and lipid-like molecules containing nitrogen atoms capable of acquiring charge (pKa). These molecules having amino groups typically have 2 to 6 hydrophobic chains, often alkyl or alkenyl, for example, C1 to C 30 It has an alkyl or alkenyl group, but may have at least one or more than six tails.

[0079] The ionizable lipid components of the lipid nanoparticles of the present invention may contain 1 to 99 mole percent of lipid molecules in the nanoparticles. In other embodiments, the ionizable lipid components may contain 5 to 90 mole percent of lipid molecules in the lipid nanoparticles. In some embodiments, the ionizable lipid components may contain 10 to 75, 20 to 75, 20 to 60, or 20 to 55 mole percent of lipid molecules in the lipid nanoparticles.

[0080] The ionizable lipids of this application may contain one or more asymmetrically substituted carbon or nitrogen atoms and can be isolated in an optically active form or a racemic form. Therefore, unless otherwise specifically indicated, all chiral forms, diastereomers, racemic forms, epimers, and all geometric isomers of the chemical formula are intended. Ionizable lipids may arise as racemates and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the cationic ionizable lipids of this application may have an S or R stereoconfiguration.

[0081] The ionizable lipids of this application may also have the advantages of being more effective, less toxic, longer-acting, more potent, producing fewer side effects, being more readily absorbed, and / or having a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than compounds known in the art, whether or not they are used for the symptoms described herein, and / or having other useful pharmacological, physical, or chemical properties that surpass those of compounds known in the art.

[0082] In some embodiments, the ionizable cationic lipid contains an ammonium group that is positively charged at physiological pH and contains at least two hydrophobic groups. In some embodiments, the ammonium group is positively charged at pH about 6 to about 8. In some embodiments, the ionizable cationic lipid contains at least two C1-C 30 Contains an alkyl or alkenyl group.

[0083] In some embodiments, ionizable lipids suitable for use in this disclosure are biodegradable. As used herein, “biodegradable” refers to the property of a lipid or other compound to be broken down into smaller groups that are subsequently metabolized, catabolized, excreted, and / or removed from the body by natural chemical and biological processes within the subject. Biodegradation can be carried out by chemical methods that do not involve enzymatic action, such as the breakdown of esters into carboxylates and alcohols in a high or low pH environment. In other embodiments, biodegradation is catalyzed by enzymes, such as esterase enzymes, breaking down esters. Certain groups are biodegradable more easily or rapidly than others, contributing to how quickly larger molecules, such as lipids or lipid particles, are biodegraded. Incorporation of biodegradable groups into ionizable lipids results in more rapid metabolism and removal from the body of the ionizable lipid following delivery of the activator to the target region. As a result, these ionizable lipids may have lower toxicity than similar ionizable lipids that do not contain biodegradable groups.

[0084] Examples of biodegradable groups suitable for use in this disclosure include, but are not limited to, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -OC(S)-, -C(S)O-, -SS-, and -C(Z 3 )=N-, -N=C(Z 3 )-,-C(Z 3 )=NO-, -ON=C(Z 3 )-,-C(O)(NZ 3 )-,-N(Z 3 )C(O)-, -C(S)(NZ 3 )-,-N(Z 3 )C(O)-, -N(Z 3 )C(O)N(Z 3 )-, -OC(O)O-, -OSi(Z 3 )2O-, -C(O)(CZ 1 Z 2 )C(O)O-, or -OC(O)(CZ 1 Z 2 )Includes C(O)-, Z 1 and Z 2 Z is independently H, OH, alkyl, alkoxy, -NH2, alkylamino, or dialkylamino, 3 The group is either H or alkyl. Typically, compounds containing a more biodegradable group are said to be more biodegradable. In some embodiments, the biodegradable lipids of this disclosure contain two or more biodegradable groups. In some embodiments, the biodegradable lipids of this disclosure contain three or more biodegradable groups. In some embodiments, the biodegradable lipids of this disclosure contain four or more biodegradable groups. In some embodiments, the lipids are considered biodegradable even if they do not contain any of the biodegradable groups listed above.

[0085] In some embodiments, the ionizable lipid for use in this disclosure is a lipid of formula (I) or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, X is -NR 1 - or -O-, R 1is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from may be linked together to form a 4- to 7-membered ring of carbon and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independent integers between 0 and 3, a+b is greater than or equal to 1, and c+d is greater than or equal to 1.

[0086] R 1 A hydrocarbon group having 6 to 24 carbon atoms, and R 2 and R 3The hydrocarbon group having 3 to 24 carbon atoms in this compound is preferably an alkyl group, an alkenyl group, or an alkynyl group, and more preferably an alkyl group or an alkenyl group. The alkyl group having 6 to 24 carbon atoms and the alkyl group having 3 to 24 carbon atoms may be linear or branched, and may be linear or cyclic. The alkyl group having 6 to 24 carbon atoms is preferably an alkyl group having 6 to 20 carbon atoms, and the alkyl group having 3 to 24 carbon atoms is more preferably an alkyl group having 6 to 20 carbon atoms. Specifically, examples include hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, trimethyldodecyl group (preferably 3,7,11-trimethyldodecyl group), tetradecyl group, pentadecyl group, hexadecyl group, tetramethylhexadecyl group (preferably 3,7,11,15-tetramethylhexadecyl group), heptadecyl group, octadecyl group, nonadecyl group, and eicosyl group. The alkenyl groups having 6 to 24 carbon atoms and the alkenyl groups having 3 to 24 carbon atoms may be linear or branched, and may be linear or cyclic. The alkenyl groups having 6 to 24 carbon atoms are preferably alkenyl groups having 6 to 20 carbon atoms, and the alkenyl groups having 3 to 24 carbon atoms are more preferably alkenyl groups having 6 to 20 carbon atoms. Specifically, hexenyl group, heptenyl group, octenyl group, nonenyl group, decenyl group, undecenyl group, dodecenyl group, dodecadienyl group, tridecenyl group, tetradecenyl group, pentadecenyl group, hexadecenyl group (preferably (Z)-hexadeca-9-enyl group), hexadecadienyl group, heptadecenyl group (preferably (Z)-heptadeca-8-enyl group), heptadecadienyl group (preferably (8Z, Examples include (11Z)-heptadeca-8,11-dienyl group), octadecenyl group (preferably (Z)-octadeca-9-enyl group), octadecadienyl group (preferably (9Z,12Z)-octadeca-9,12-dienyl group), nonadecenyl group, icosenyl group (preferably (Z)-icosa-11-enyl group), icosadienyl group (preferably (11,14)-icosa-11,14-dienyl group), and so on.Alkynyl groups having 6 to 24 carbon atoms are preferably alkynyl groups having 6 to 20 carbon atoms, and alkynyl groups having 3 to 24 carbon atoms are more preferably alkynyl groups having 6 to 20 carbon atoms. Specifically, examples include hexynyl groups, heptynyl groups, octinyl groups, noninyl groups, desinyl groups, undecynyl groups, dodecynyl groups, tetradecynyl groups, pentadecynyl groups, hexadecynyl groups, heptadecynyl groups, and octadecynyl groups. All of the above alkenyl groups preferably have one or two double bonds, and all alkynyl groups preferably have one or two triple bonds.

[0087] R 21 and R 31The hydrocarbon group having 1 to 24 carbon atoms is preferably an alkyl group having 10 to 24 carbon atoms, an alkenyl group having 10 to 24 carbon atoms, or an alkynyl group having 10 to 24 carbon atoms. The alkyl group having 10 to 24 carbon atoms may be linear or branched, and may be linear or cyclic. The alkyl group having 10 to 24 carbon atoms is preferably an alkyl group having 12 to 24 carbon atoms. Specifically, decyl group, undecyl group, dodecyl group, tridecyl group, trimethyldodecyl group (preferably 3,7,11-trimethyldodecyl group), tetradecyl group, pentadecyl group, hexadecyl group, tetramethylhexadecyl group (preferably 3,7,11,15-tetramethylhexadecyl group), heptadecyl group, octadecyl group, 2-butylhexyl group, 2-butyloctyl group, 1-pentylhexyl group, 2-pentylheptyl group, 3-pentyloctyl group, 1-hexylheptyl group, 1-hexylnonyl group, Examples include 2-hexyloctyl group, 2-hexyldecyl group, 3-hexylnonyl group, 1-heptyloctyl group, 2-heptylnonyl group, 2-heptylundecyl group, 3-heptyldecyl group, 1-octylnonyl group, 2-octyldecyl group, 2-octyldodecyl group, 3-octylundecyl group, 2-nonylundecyl group, 3-nonyldodecyl group, 2-decyldodecyl group, 2-decyltetradecyl group, 3-decyltridecyl group, and 2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl group. The alkenyl group having 10 to 24 carbon atoms may be linear or branched, and may be linear or cyclic.Specifically, decenyl group, undecenyl group, dodecenyl group, dodecadienyl group, tridecenyl group (preferably (Z)-trideca-8-enyl group), tetradecenyl group (preferably tetradeca-9-enyl group), pentadecenyl group (preferably (Z)-pentadeca-8-enyl group), hexadecenyl group (preferably (Z)-hexadeca-9-enyl group), hexadeca Examples include dienyl groups, heptadecenyl groups (preferably (Z)-heptadeca-8-enyl group), heptadecadienyl groups (preferably (8Z,11Z)-heptadeca-8,11-dienyl group), octadecenyl groups (preferably (Z)-octadeca-9-enyl group), and octadecadienyl groups (preferably (9Z,12Z)-octadeca-9,12-dienyl group). The alkynyl groups having 10 to 24 carbon atoms may be linear or branched, and may be linear or cyclic. Specifically, examples include desinyl groups, undecinyl groups, dodecinyl groups, tetradecinyl groups, pentadecinyl groups, hexadecinyl groups, heptadecinyl groups, and octadecinyl groups. The above alkenyl groups preferably have one or two double bonds, and the alkynyl groups preferably have one or two triple bonds.

[0088] R 22 and R 32 Regarding the divalent linking group, the hydrocarbon linking group having 1 to 18 carbon atoms is preferably an alkylene group having 1 to 18 carbon atoms or an alkenylene group having 2 to 18 carbon atoms. The alkylene group having 1 to 18 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 1 to 12, more preferably 1 to 10, and even more preferably 2 to 10. Specifically, examples include methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, undecamethylene group, dodecamethylene group, etc. The alkenylene group having 2 to 18 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 1 to 12, and more preferably 2 to 10.

[0089] L1 and L 2 Preferred ranges include -O(CO)O-, -O(CO)-, and -(CO)O-. 1 and L 2 More preferred ranges are -O(CO)- and -(CO)O-.

[0090] R 4 , R 6 , R 9 , R 10 , R 11 , and R 12 The C1-C18 alkyl group, which may be substituted, may be linear or branched, linear or cyclic. C1-C2 is preferred. Specifically, examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl groups. Substituents for alkyl groups include hydroxyl, carboxyl, and -O(CO)OR groups. 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 The group represented by -O(CO)-R is preferred. 42 or -(CO)OR 43 The group indicated by is more preferable.

[0091] R 5 , R 7 , and R 8The C1-C18 alkyl group, which may be substituted, may be linear or branched, linear or cyclic. The number of carbon atoms is preferably C1-C12, and more preferably C1-C8. Specifically, examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl groups. Substituents for alkyl groups include hydroxyl, carboxyl, and -O(CO)OR groups. 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 The group represented by -O(CO)-R is preferred. 42 ,-(CO)OR 43 , or -OR 44 The group indicated by is more preferable.

[0092] Examples of 4- to 7-membered rings that may contain an O atom include azetidine rings, pyrrolidine rings, piperidine rings, morpholine rings, and azepane rings, with 6-membered rings being preferred, and piperidine rings and morpholine rings being preferred.

[0093] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Regarding this, when the substituent on a C1-C18 alkyl group that may be substituted is a substituted or unsubstituted aryl group, the aryl group is preferably C6-C22, more preferably C6-C18, and even more preferably C6-C10. Specifically, examples include phenyl group, naphthyl group, anthracenyl group, phenantrenyl group, etc. Substituents on the aryl group include C1-C18 alkyl groups, hydroxyl group, carboxyl group, -NR 45 R 46The amino group shown is -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 The group represented by is preferred, and a hydroxyl group or a carboxyl group is more preferred. Specific examples of substituted aryl groups include a hydroxyphenyl group and a carboxyphenyl group.

[0094] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Regarding this, when the substituent on a C1-C18 alkyl group that may be substituted is a substituted or unsubstituted heteroaryl group, the heteroaryl group is preferably C1-C12, and more preferably C1-C6. Specifically, examples include pyridyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, thiazolyl group, oxazolyl group, etc. Substituents on the heteroaryl group include C1-C18 alkyl groups, hydroxyl group, carboxyl group, -NR 45 R 46 The amino group shown is -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 The group represented by is preferred, and a hydroxyl group or a carboxyl group is more preferred. Specific examples of substituted or unsubstituted heteroaryl groups include a hydroxypyridyl group, a carboxypyridyl group, a pyridonyl group, and the like.

[0095] R 41 , R 42 , R 43 , R 44 , R 45 and R 46The hydrocarbon group having 1 to 18 carbon atoms is preferably an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or an alkynyl group having 2 to 18 carbon atoms, and more preferably an alkyl group having 1 to 18 carbon atoms or an alkenyl group having 2 to 18 carbon atoms. The alkyl group having 1 to 18 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 18, and more preferably 5 to 18. Specifically, examples include propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, tert-butyl group, cyclobutyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, trimethyldodecyl group (preferably 3,7,11-trimethyldodecyl group), tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, and the like. The alkenyl group having 2 to 18 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 18, and more preferably 5 to 18. Specifically, allyl group, prenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group (preferably (Z)-2-nonenyl group or (E)-2-nonenyl group), decenyl group, undecenyl group, dodecenyl group, dodecadienyl group, tridecenyl group (preferably (Z)-trideca-8-enyl group), tetradecenyl group (preferably tetradeca-9-enyl group), pentadecenyl group (preferably (Z)-pentadeca-8-enyl group) Examples include hexadecenyl groups (preferably (Z)-hexadeca-9-enyl group), hexadecadienyl groups, heptadecenyl groups (preferably (Z)-heptadeca-8-enyl group), heptadecadienyl groups (preferably (8Z,11Z)-heptadeca-8,11-dienyl group), octadecenyl groups (preferably (Z)-octadeca-9-enyl group), and octadecadienyl groups (preferably (9Z,12Z)-octadeca-9,12-dienyl group). The alkynyl groups having 2 to 18 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 18, and more preferably 5 to 18.Specifically, examples include propargyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octinyl group, noninyl group, desinyl group, undecynyl group, dodecynyl group, tetradecynyl group, pentadecynyl group, hexadecinyl group, heptadecynyl group, and octadecynyl group.

[0096] X is -NR 1 When - indicates, R 1 is a hydrocarbon group having 6 to 24 carbon atoms, or R 21 -L 1 -R 22 It is preferable that the group is represented by -. In this case, R 2 and R 3 One of them is a hydrogen atom; R 2 and R 3 The other is a hydrocarbon group having 6 to 24 carbon atoms, or R 31 -L 2 -R 32 It is preferable that the group is represented by -.

[0097] When X indicates -O-, R 2 and R 3 Each of these independently consists of a hydrocarbon group with 6 to 24 carbon atoms, or R 31 -L 2 -R 32 It is preferable that the group is represented by -.

[0098] R 4 , R 6 , R 9 , R 10 , R 11 , and R 12 It is preferable that it is a hydrogen atom.

[0099] R 5 Preferably, it consists of a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, and -O(CO)-R 42 or -(CO)OR 43 These are C1-C18 alkyl groups that may be substituted with an aryl group, or C1-C18 alkyl groups that may be substituted with a hydroxyl group. In particular, R 5Preferably, the alkyl group has 1 to 18 carbon atoms, -O(CO)-R 42 or -(CO)OR 43 A C1-C18 alkyl group which may be substituted with an aryl group, a C1-C18 alkyl group which may be substituted with an aryl group, or a C1-C18 alkyl group which may be substituted with a hydroxyl group, more preferably a C1-C18 alkyl group, or -O(CO)-R 42 or -(CO)OR 43 R is an alkyl group having 1 to 18 carbon atoms that may be substituted. 5 When R is an alkyl group, 5 Haha, R 4 , R 6 , R 10 and R 12 They may be linked together to form a ring that may contain oxygen atoms.

[0100] R 7 and R 8 Each of these independently consists of a hydrogen atom, a hydrocarbon group with 1 to 18 carbon atoms, and -O(CO)-R 42 or -(CO)OR 43 A C1-C18 alkyl group which may be substituted with, a C1-C8 alkyl group which may be substituted with an aryl group, or a C1-C8 alkyl group which may be substituted with a hydroxyl group, or R 7 and R 8 It is preferable that these elements are linked to each other to form a 4- to 7-membered ring, which may contain oxygen atoms.

[0101] R 5 and R 7 or R 8 These elements are not connected to each other and do not form a ring.

[0102] a+b is preferably 1 or 2, and more preferably 1. c+d is preferably 1 or 2, and more preferably 1.

[0103] Lipids represented by formula (I) and methods for producing the same are described in US2021 / 0085604 and US2022 / 0273817, which are incorporated herein by reference.

[0104] The compound represented by formula (I) is preferably the compound represented by formula (III) or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or R 31 -L 2 -R 32 -and, R 31 This represents a hydrocarbon group with 1 to 24 carbon atoms. L 2 is -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or [ka] And, R 32 This is a divalent hydrocarbon linking group having 1 to 18 carbon atoms. R 5 is a hydrogen atom, or R 33 A C1-C18 alkyl group which may be substituted by R 7 and R 8 Each of these is independently a hydrogen atom, or R 33 A C1-C18 alkyl group which may be substituted by R 33 -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 ,-(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. e is an integer, either 2 or 3.

[0105] Examples of salts in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0106] Examples of salts in acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-efenamine, and N,N'-dibenzylethylenediamine.

[0107] Among the salts mentioned above, preferred salts include those that are pharmacologically acceptable.

[0108] Lipids represented by formula (III) and methods for producing the same are described in US2021 / 0085604 and US2022 / 0273817, which are incorporated herein by reference.

[0109] Examples of lipids represented by formula (III) are as follows: [ka]

[0110] In some embodiments, the ionizable lipids suitable for use in this disclosure are ionizable lipids of formula (II) or pharmaceutically acceptable salts thereof. [ka] [In the formula, R 51 and R 52 Each is independent of R 35 A hydrocarbon group having 1 to 21 carbon atoms, which may be substituted in some cases. R 35 is a hydroxyl group, -G 20 -CH(R 55 )(R 56 ), -N(R 58 )(R 59 ), or -G 20 -R 60 And, G 20 is -(CO)O- or -O(CO)-, R 55 and R 56 Each of these is independently a hydrocarbon group having hydrogen or 1 to 18 carbon atoms. R 58 and R 59 Each of them independently consists of hydrogen or R 36 A cyclic hydrocarbon group having 3 to 6 carbon atoms, which may be substituted in some cases. R 60 It is a hydrocarbon group having 1 to 18 carbon atoms. R 36 is -N(R 61 )(R 62 ), or -G20 -R 65 and is R 61 and R 62 are each independently hydrogen or a cyclic hydrocarbon group having 3 to 6 carbon atoms, R 65 is a hydrocarbon group having 1 to 18 carbon atoms, -L 40 -CH(R 66 )(R 67 ), or -G 20 -R 66 and is L 40 is a divalent hydrocarbon group containing 1 to 6 carbon atoms, R 66 and R 67 are each independently a hydrocarbon group containing 1 to 10 carbon atoms or an alkoxy group containing 1 to 10 carbon atoms, L 10 is a divalent hydrocarbon group containing 1 to 18 carbon atoms, G 30 is -S(CO)N(R 64 ), and is R 64 is -L 30 -G 20 -CH(R 55 )(R 56 ), and is a' is 0 or 1, G 10 is G 20 , -O(CO)O-, or -N(R 63 )(C(O)-, and is R 63 is a hydrocarbon group containing 1 to 18 carbon atoms, L 20 is a divalent hydrocarbon group containing 1 to 6 carbon atoms, b' is 0 or 1, R 53 , R 54 , and R 57 are each independently hydrogen or a hydrocarbon group containing 1 to 18 carbon atoms optionally substituted by R 36 , and is L 30[A hydrocarbon group is a single bond or a hydrocarbon group containing 1 to 18 carbon atoms.]

[0111] The compound represented by formula (II) can also be represented by formula (IIa). [ka] [In the formula, R 51 and R 52 Each is independent of R 35 A hydrocarbon group having 1 to 21 carbon atoms, which may be substituted in some cases. R 35 is a hydroxyl group or -G 20 -CH(R 55 )(R 56 ) and G 20 is -(CO)O- or -O(CO)-, R 55 and R 56 Each of these is independently a hydrocarbon group having hydrogen or 1 to 18 carbon atoms. L 10 It is a divalent hydrocarbon group containing 1 to 18 carbon atoms. G 10 is -(CO)O- or -O(CO)-, R 53 , R 54 and R 57 Each of these is independently a hydrocarbon group containing hydrogen or 1 to 18 carbon atoms.

[0112] The compound represented by formula (II) can also be represented by formula (IIb). [ka] [In the formula, R 51 and R 52 Each of these is an independent hydrocarbon group having 1 to 21 carbon atoms. L 10 It is a divalent hydrocarbon group containing 1 to 18 carbon atoms. G 10 is -O(CO)O-, L 20 It is a divalent hydrocarbon group containing 1 to 6 carbon atoms. R 53 , R 54 , and R 57 Each of them independently consists of hydrogen or R 36 A hydrocarbon group containing 1 to 18 carbon atoms, which may be substituted in some cases. R 36 is -O(CO)-R 65 And, R 65 This is a hydrocarbon group having 1 to 18 carbon atoms or -L 40 -CH(R 66 )(R 67 ) and L 40 It is a divalent hydrocarbon group containing 1 to 6 carbon atoms. R 66 and R 67 Each of these is an alkoxy group having 1 to 10 carbon atoms independently.

[0113] The compound represented by formula (II) can also be represented by formula (IIc). [ka] [In the formula, R 51 and R 52 Each of these is an independent hydrocarbon group having 1 to 21 carbon atoms. L 10 It is a divalent hydrocarbon group containing 1 to 18 carbon atoms. G 10 is -N(R 63 )C(O)-, R 63 It is a hydrocarbon group containing 1 to 18 carbon atoms. R 53 , R 54 , and R 57 Each of them independently consists of hydrogen or R 36 A hydrocarbon group containing 1 to 18 carbon atoms, which may be substituted in some cases. R 36 is -(CO)OR 65and R 65 is -L 40 -CH(R 66 )(R 67 ), and L 40 is a divalent hydrocarbon group containing 1 to 6 carbon atoms, R 66 and R 67 are each independently a hydrocarbon group containing 1 to 10 carbon atoms]

[0114] The compound represented by formula (II) can be represented by formula (IId). [Chemical formula] [In the formula, R 51 and R 52 are each independently a hydrocarbon group having 1 to 21 carbon atoms, L 10 is a divalent hydrocarbon group containing 1 to 18 carbon atoms, G 30 is -S(CO)NR 64 -, R 64 is -L 30 -G 20 -CH(R 55 )(R 56 ), L 30 is a single bond or a hydrocarbon group containing 1 to 18 carbon atoms, G 20 is -(CO)O-, R 55 and R 56 are each independently hydrogen or a hydrocarbon group having 1 to 18 carbon atoms, G 10 is -(CO)O-, R 53 , R 54 and R 57 are each independently hydrogen or a hydrocarbon group containing 1 to 18 carbon atoms]

[0115] In some embodiments, the compound of formula (II), (IIa), (IIb), (IIc), or (IId) may be in the form of a salt.

[0116] In one embodiment, an ionizable lipid suitable for use in the present disclosure is an ionizable lipid of formula (VII) or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 1 and R 2 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, and R 3 This indicates a hydrocarbon group with 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon groups indicated are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , and -OR 56 They may be substituted with one or more substituents selected from the following: R 4 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 5 and R 6 Each of these independently forms a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 This indicates, however, R 5 and R 6 Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. R 7 is, -R 10 -L 2 -R 11 -L 3 -R 12 Show, R 51 and R 52 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 53 ,R 54 ,R 55, and R 56 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 58 It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 , or -R 59 -R 57 It may also be replaced with R 58 and R 59 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R 57 -OH, COOH, -NR 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 This indicates. R 61 and R 62 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 63 ,R 64 ,R 65 , and R 66 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 63 ,R 64 ,R 65 , and R 66 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 68 It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 61 R 62 -OC(O)OR 63, -C(O)OR 64 -OC(O)-R 65 , -OR 66 , or -R 69 -R 67 It may also be replaced with R 68 and R 69 This represents a hydrocarbon group having 1 to 12 carbon atoms. R 67 -OH, COOH, -NR 61 R 62 -OC(O)OR 63 , -C(O)OR 64 -OC(O)-R 65 , -OR 66 This indicates. L 1 , L 2 , and L 3 Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 8 This represents a hydrocarbon group having 1 to 12 carbon atoms. R 9 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 10 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 11 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 12 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 9 , and R 12 The hydrocarbon group indicated is an aryl group, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -SR 58 It may also be replaced with R 11 The hydrocarbon group indicated is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 It may be replaced with .

[0117] The hydrocarbon groups having 1 to 24 carbon atoms, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 2 to 8 carbon atoms, and 1 to 8 carbon atoms are preferably alkyl groups, alkenyl groups, or alkynyl groups, respectively.

[0118] Alkyl groups may be linear or branched, and may be linear or cyclic. Specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, tetramethylhexadecyl (preferably 3,7,11,15-tetramethylhexadecyl), heptadecyl, octadecyl, 2-butylhexyl, and 2-butyloctyl groups. Examples include 1-pentylhexyl group, 2-pentylheptyl group, 3-pentyloctyl group, 1-hexylheptyl group, 1-hexylnonyl group, 2-hexyloctyl group, 2-hexyldecyl group, 3-hexylnonyl group, 1-heptyloctyl group, 2-heptylnonyl group, 2-heptylundecyl group, 3-heptyldecyl group, 1-octylnonyl group, 2-octyldecyl group, 2-octyldodecyl group, 3-octylundecyl group, 2-nonylundecyl group, 3-nonyldodecyl group, 2-decyldodecyl group, 2-decyltetradecyl group, 3-decyltridecyl group, and 2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl group.

[0119] The alkenyl group may be linear or branched, and may be linear or cyclic. Specifically, allyl group, prenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group (preferably (Z)-2-nonenyl group or (E)-2-nonenyl group), decenyl group, undecenyl group, dodecenyl group, dodecadienyl group, tridecenyl group (preferably (Z)-trideca-8-enyl group), tetradecenyl group (preferably tetradeca-9-enyl group), pentadecenyl group (preferably (Z)-pentadeca-8-enyl group) Examples include hexadecenyl groups (preferably (Z)-hexadeca-9-enyl group), hexadecadienyl groups, heptadecenyl groups (preferably (Z)-heptadeca-8-enyl group), heptadecadienyl groups (preferably (8Z,11Z)-heptadeca-8,11-dienyl group), octadecenyl groups (preferably (Z)-octadeca-9-enyl group), and octadecadienyl groups (preferably (9Z,12Z)-octadeca-9,12-dienyl group).

[0120] The alkynyl group may be linear or branched, and may be linear or cyclic. Specifically, examples include propargyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desinyl, undecynyl, dodecynyl, tetradecynyl, pentadecynyl, hexadesynyl, heptadecynyl, and octadecynyl groups. The above alkenyl groups preferably have one or two double bonds, and the alkynyl groups preferably have one or two triple bonds.

[0121] -R 69 It is preferable that the group is an alkylene group having 1 to 12 carbon atoms or an alkenylene group having 2 to 12 carbon atoms. The alkylene group having 1 to 12 carbon atoms and the alkenylene group having 2 to 12 carbon atoms may be linear or branched, and may be linear or cyclic. Specifically, examples include methylene groups, ethylene groups, trimethylene groups, tetramethylene groups, pentamethylene groups, hexamethylene groups, heptamethylene groups, octamethylene groups, nonamethylene groups, decamethylene groups, and undecamethylene groups.

[0122] The aryl group preferably has 6 to 20 carbon atoms, more preferably 6 to 18, and even more preferably 6 to 10. Specifically, examples include the phenyl group, naphthyl group, anthracenyl group, and phenantrenyl group.

[0123] R 1 and R 2 Each of these groups independently represents a hydrocarbon group preferably having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms.

[0124] R 3 Preferably, it represents a hydrocarbon group having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0125] R 1 , R 2 and R 3 The hydrocarbon group shown may preferably be substituted with -OH.

[0126] L 1 , and L 3 Each of these independently preferably represents -C(O)O- or -OC(O)-.

[0127] L 2 Preferably, this represents -OC(O)O-, -C(O)O-, or -OC(O)-.

[0128] R 8 Preferably, it represents a hydrocarbon group having 1 to 10 carbon atoms, and more preferably, a hydrocarbon group having 1 to 8 carbon atoms.

[0129] R 9 Preferably, it represents a hydrocarbon group having 1 to 20 carbon atoms, and more preferably, a hydrocarbon group having 1 to 16 carbon atoms.

[0130] R 11 Preferably, it represents a hydrocarbon group having 1 to 16 carbon atoms, and more preferably, a hydrocarbon group having 1 to 9 carbon atoms.

[0131] R 12 Preferably, it represents a hydrocarbon group having 1 to 20 carbon atoms, and more preferably, a hydrocarbon group having 1 to 16 carbon atoms.

[0132] R 9 , and R 12 The hydrocarbon group represented is preferably an aryl group or -SR. 58 It may be replaced with R. 58 Preferably, it represents a hydrocarbon group having 1 to 8 carbon atoms.

[0133] R 11 The hydrocarbon group indicated is preferably -C(O)OR 55 , or -OC(O)-R 56 It may also be replaced with, where R 55 , and R 56 Each of these independently represents a hydrocarbon group having 1 to 16 carbon atoms.

[0134] R 55 , and R 56 Each hydrocarbon group represented is independently preferably an aryl group or -SR having 6 to 20 carbon atoms. 58 It may be replaced with .

[0135] In one embodiment, an ionizable lipid suitable for use in the present disclosure is an ionizable lipid of formula (VIII) or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 1 and R 2 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, and R 3 This indicates a hydrocarbon group with 2 to 8 carbon atoms, and R 1 , R 2 and R3 The hydrocarbon groups indicated are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -OR 56 It may also be replaced with R 4 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 5 and R 6 Each of these independently forms a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 This indicates, however, R 5 and R 6 Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. L 1 and L 4 This represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 8 This represents a hydrocarbon group having 1 to 12 carbon atoms. R 9 R represents a hydrocarbon group with 1 to 24 carbon atoms. 9 The hydrocarbon group indicated is an aryl group, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -SR 58 It may also be replaced with R 51 and R 52 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 21 ,R 23 ,R 25 ,R 53 ,R 54 ,R 55 , and R 56 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R 53 ,R 54 ,R 55 , and R 56The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 58 It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 , or -R 59 -R 57 It may also be replaced with R 58 and R 59 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R 57 -OH, COOH, -NR 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 This indicates. R 13 This represents a hydrocarbon group having 1 to 8 carbon atoms. R 14 is, -R 15 -L 5 -R 16 Show, R 15 This represents a hydrocarbon group with 1 to 24 carbon atoms, L 5 represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-, and R 16 This represents a hydrocarbon group with 1 to 24 carbon atoms. R 15 The hydrocarbon group with 1 to 24 carbon atoms indicated by -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 It may also be replaced with R 16 The hydrocarbon groups with 1 to 24 carbon atoms shown are aryl groups with 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -SR 58It may be replaced with .

[0136] In equation (VIII), R 1 and R 2 Each of these groups independently represents a hydrocarbon group preferably having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms.

[0137] R 3 Preferably, it represents a hydrocarbon group having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0138] R 1 , R 2 and R 3 The hydrocarbon group shown may preferably be substituted with -OH.

[0139] L 1 Preferably, it represents -C(O)O- or -OC(O)-.

[0140] R 8 Preferably, it represents a hydrocarbon group having 1 to 10 carbon atoms, and more preferably, a hydrocarbon group having 1 to 8 carbon atoms.

[0141] R 9 Preferably, R represents a hydrocarbon group having 1 to 18 carbon atoms. 9 The hydrocarbon group indicated is an aryl group having 6 to 20 carbon atoms, or -SR. 58 It may be replaced with.

[0142] R 14 Preferably, -R 15 -L 5 -R 16 Show, R 15 This indicates a hydrocarbon group with 1 to 18 carbon atoms, L 5 represents -OC(O)O-, and R 16 This indicates a hydrocarbon group having 1 to 18 carbon atoms.

[0143] R 15The hydrocarbon group having 1 to 18 carbon atoms indicated is preferably -C(O)OR 55 , or -OC(O)-R 56 It may be replaced with R. 55 , and R 56 Each of these independently represents a hydrocarbon group having 1 to 16 carbon atoms, and R 55 , and R 56 The hydrocarbon group indicated is an aryl group or -SR with 6 to 20 carbon atoms. 58 It may be replaced with .

[0144] R 16 The hydrocarbon group having 1 to 18 carbon atoms indicated by is preferably an aryl group or -SR. 58 It may be replaced with .

[0145] In one embodiment, an ionizable lipid suitable for use in the present disclosure is an ionizable lipid of formula (IX) or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 1 and R 2 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, and R 3 This indicates a hydrocarbon group with 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon groups indicated are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -OR 56 It may also be replaced with R 4 and R 8 Each of these independently represents a hydrocarbon with 1 to 8 carbon atoms. R 21 and R 22 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms. R 23 and R 24Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R 25 and R 26 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. L 21 and L 22 Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 25 and R 26 The hydrocarbon group indicated is an aryl group with 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -SR 58 They may be substituted with, and the above aryl groups with 6 to 20 carbon atoms are OH, COOH, -NR 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 , or -R 59 -R 57 It may be replaced by, R 51 and R 52 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 53 , R 54 , R 55 and R 56 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms. R 57 -OH, COOH, -NR 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 This indicates.

[0146] R 58 and R 59 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. In equation (IX), R 1and R 2 Each of these independently represents a hydrocarbon group preferably having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms. 1 and R 2 The hydrocarbon group represented by may preferably be substituted with -OH, but more preferably it is an unsubstituted hydrocarbon.

[0147] R 3 Preferably, it represents a hydrocarbon group having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0148] R 21 and R 22 Each of these groups independently preferably represents a hydrocarbon group having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 8 carbon atoms, and even more preferably a hydrocarbon group having 1 to 6 carbon atoms.

[0149] R 23 and R 24 Each of these groups independently represents a hydrocarbon group preferably having 1 to 10 carbon atoms, and more preferably a hydrocarbon group having 1 to 8 carbon atoms.

[0150] R 25 and R 26 Each of these groups independently represents a hydrocarbon group preferably having 1 to 20 carbon atoms, more preferably a hydrocarbon group having 1 to 16 carbon atoms, and even more preferably a hydrocarbon group having 1 to 12 carbon atoms.

[0151] L 21 and L 22 Each of these independently represents, preferably, -C(O)O- or -OC(O)-.

[0152] In one embodiment, an ionizable lipid suitable for use in the present disclosure is an ionizable lipid of formula (X) or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R1 and R 2 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, and R 3 This indicates a hydrocarbon group with 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon groups indicated are -OH, COOH, and -NR. 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or -OR 56 It may also be replaced with R 4 and R 8 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 31 , R 32 , R 33 , and R 34 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R 35 , R 36 , R 37 , and R 38 Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. L 31 , L 32 , L 33 , and L 34 Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 35 , R 36 , R 37 , and R 38 The hydrocarbon group indicated is an aryl group with 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , or SR 58 They may be substituted with, and the above aryl groups with 6 to 20 carbon atoms are OH, COOH, -NR 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR56 , or -R 59 -R 57 It may be replaced by, R 51 and R 52 Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R 53 , R 54 , R 55 , and R 56 Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms. R 57 -OH, COOH, -NR 51 R 52 -OC(O)OR 53 , -C(O)OR 54 -OC(O)-R 55 , -OR 56 This indicates. R 58 and R 59 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms.

[0153] In equation (X), R 1 and R 2 Each of these independently represents a hydrocarbon group preferably having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms. 1 and R 2 The hydrocarbon group represented by may preferably be substituted with -OH, but more preferably it is an unsubstituted hydrocarbon.

[0154] R 3 Preferably, it represents a hydrocarbon group having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0155] R 31 , R 32 , R 33 , and R 34 Each of these groups independently preferably represents a hydrocarbon group having 1 to 10 carbon atoms, more preferably a hydrocarbon group having 1 to 8 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms.

[0156] R 35 , R 36 , R 37 , and R 38 Each of these is independently carbonized, preferably with 1 to 20 carbon atoms. It represents a hydrogen group, more preferably a hydrocarbon group having 1 to 16 carbon atoms, and even more preferably a hydrocarbon group having 1 to 12 carbon atoms. 35 , R 36 , R 37 , and R 38 The hydrocarbon group indicated is preferably an aryl group having 6 to 20 carbon atoms, or SR 58 It may be replaced with -SR. 58 It may be replaced with .

[0157] R 35 , R 36 , R 37 , and R 38 Each is independently, and particularly preferably, -SR 58 This indicates a hydrocarbon group having 1 to 12 carbon atoms substituted with , or a hydrocarbon group having 1 to 12 carbon atoms.

[0158] L 31 , L 32 , L 33 , and L 34 Each of these independently represents, preferably, -C(O)O- or -OC(O)-.

[0159] R 58 Preferably, it represents a hydrocarbon group having 1 to 10 carbon atoms, and more preferably, a hydrocarbon group having 1 to 8 carbon atoms.

[0160] Compounds of one embodiment of the present invention may form salts (e.g., pharmaceutically acceptable salts).

[0161] Examples of salts in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0162] Examples of salts in acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-efenamine, and N,N'-dibenzylethylenediamine.

[0163] Among the salts mentioned above, preferred salts include those that are pharmacologically acceptable.

[0164] The lipid represented by formula (VII) and the method for producing the same are described in publication WO2022 / 230964, and its contents are incorporated herein by reference in their entirety.

[0165] Examples of lipids represented by formula (VII) are shown below. [ka]

[0166] R 51 or R 52The hydrocarbon group having 1 to 21 carbon atoms is preferably an alkyl group having 1 to 21 carbon atoms, an alkenyl group having 2 to 21 carbon atoms, or an alkynyl group having 2 to 21 carbon atoms, and more preferably an alkyl group having 1 to 21 carbon atoms or an alkenyl group having 2 to 21 carbon atoms. The alkyl group having 1 to 21 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 21, and more preferably 5 to 21. Specifically, examples include propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, tert-butyl group, cyclobutyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, trimethyldodecyl group (preferably 3,7,11-trimethyldodecyl group), tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, and the like. The alkenyl group having 2 to 18 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 18, and more preferably 5 to 18. Specifically, allyl group, prenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group (preferably (Z)-2-nonenyl group or (E)-2-nonenyl group), decenyl group, undecenyl group, dodecenyl group, dodecadienyl group, tridecenyl group (preferably (Z)-trideca-8-enyl group), tetradecenyl group (preferably tetradeca-9-enyl group), pentadecenyl group (preferably (Z)-pentadeca-8-enyl group) Examples include hexadecenyl groups (preferably (Z)-hexadeca-9-enyl group), hexadecadienyl groups, heptadecenyl groups (preferably (Z)-heptadeca-8-enyl group), heptadecadienyl groups (preferably (8Z,11Z)-heptadeca-8,11-dienyl group), octadecenyl groups (preferably (Z)-octadeca-9-enyl group), and octadecadienyl groups (preferably (9Z,12Z)-octadeca-9,12-dienyl group). The alkynyl groups having 2 to 21 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 21, and more preferably 5 to 21.Specifically, examples include propargyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl, undecynyl, dodecynyl, tetradecynyl, pentadecynyl, hexadecinyl, heptadecynyl, and octadecynyl groups. As for hydrocarbon groups with 1 to 18 carbon atoms, those with 1 to 18 carbon atoms among hydrocarbon groups with 1 to 21 carbon atoms can be cited.

[0167] Preferred cyclic hydrocarbon groups include cycloalkyl groups having 3 to 10 carbon atoms, cycloalkenyl groups having 3 to 10 carbon atoms, cycloalkynyl groups having 3 to 10 carbon atoms, and aryl groups having 6 to 10 carbon atoms.

[0168] The hydrocarbon group having 1 to 6 carbon atoms is preferably an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or an alkynyl group having 2 to 6 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms. The alkyl group having 1 to 6 carbon atoms may be linear or branched, and may be linear or cyclic. Specifically, examples include propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, tert-butyl group, cyclobutyl group, pentyl group, cyclopentyl group, and hexyl group. The alkenyl group having 2 to 6 carbon atoms may be linear or branched, and may be linear or cyclic. Specifically, examples include allyl group, prenyl group, pentenyl group, and hexenyl group. The alkynyl group having 2 to 6 carbon atoms may be linear or branched, and may be linear or cyclic. Specifically, examples include propargyl group, butynyl group, pentynyl group, and hexynyl group.

[0169] The hydrocarbon group having 1 to 10 carbon atoms is preferably an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and more preferably an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms. The alkyl group having 1 to 10 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 10, and more preferably 5 to 10. Specifically, examples include propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, tert-butyl group, cyclobutyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, octyl group, nonyl group, and decyl group. The alkenyl group having 2 to 10 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 10, and more preferably 5 to 10. Specifically, examples include allyl groups, prenyl groups, pentenyl groups, hexenyl groups, heptenyl groups, octenyl groups, nonenyl groups (preferably (Z)-2-nonenyl or (E)-2-nonenyl), and decenyl groups. Alkynyl groups having 2 to 10 carbon atoms may be linear or branched, and may be linear or cyclic. The number of carbon atoms is preferably 3 to 10, and more preferably 5 to 10. Specifically, examples include propargyl groups, butynyl groups, pentynyl groups, hexynyl groups, heptynyl groups, octinyl groups, noninyl groups, and decinyl groups.

[0170] Examples of ionizable lipids of formula (II) are shown below. MC3; ([(6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl]4-(dimethylamino)butanoic acid) WO2010 / 054405 [ka] L-319; (Bis[(Z)-non-2-enyl]9-[4-(dimethylamino)butanoyloxy]heptadecanedioate) WO2011 / 153493, WO2013 / 086354, WO2013 / 086322 [ka] ALC-0315; (6-[6-(2-hexyldecanoyloxy)hexyl-(4-hydroxybutyl)amino]hexyl 2-hexyldecanoate) WO2017 / 075331 [ka] SM-102; (Heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecoxyhexyl)amino]octanoic acid) WO2017 / 099823 [ka] Lipid5; (Nonyl 8-[(8-heptadecane-9-yloxy-8-oxooctyl)-(2-hydroxyethyl)amino]octanoic acid) WO2017 / 099823 [ka] Lipid29; (Undecane-3-yl 8-[(8-heptadecane-9-yloxy-8-oxooctyl)-[3-[[2-(methylamino)-3,4-dioxocyclobuten-1-yl]aminopropyl]amino]octanoic acid) Adv. Funct. Mater. 2021, 2106727, DOI: 10.1002 / adfm.202106727 [ka] ATX-100; (Pentadecane-8-yl 4-[3-(dimethylamino)propylsulfanylcarbonyl-(4-oxo-4-pentadecane-8-yloxybutyl)amino]butanoic acid) WO2019 / 191780 [ka] LipidA9; (Bis(2-butyloctyl)10-[3-(dimethylamino)propylnonanoylamino]nonadecanedioic acid) WO2017 / 004143 [ka] Lp01; ([2-[3-(diethylamino)propoxycarbonyloxymethyl]-3-(4,4-dioctoxybutanoyloxy)propyl](9Z,12Z)-octadeca-9,12-dienoate) WO2015 / 09534, WO2020 / 219876 [ka] TCL053; ([2-[4-(dimethylamino)butanoyloxymethyl]-3-[(Z)-tetradeca-9-enoyl]oxy-2-[[(Z)-tetradeca-9-enoyl]oxymethyl]propyl](Z)-tetradeca-9-enoate) WO 2020 / 032184 [ka] TCL065; ([2-[5-(dimethylamino)pentanoyloxymethyl]-3-(3-pentyloctanoyloxy)-2-(3-pentyloctanoyloxymethyl)propyl]-3-pentyloctanoate) WO 2020 / 032184 [ka] Lipid9; ([(6Z,16Z)-12-[6-(dimethylamino)hexanoyloxy]docosa-6,16-dien-11-yl](Z)-undec-5-enoate) WO2021 / 188389 [ka] Lipid19; ([(6Z,16Z)-12-[6-(dimethylamino)hexanoyloxy]docosa-6,16-dien-11-yl](9Z,12Z)-octadeca-9,12-dienoate) WO2021 / 188389 [ka] 13-B43; ([(6Z,16Z)-12-[(Z)-deca-4-enyl]docosa-6,16-dien-11-yl]5-(dimethylamino)pentanoate) WO2020 / 219941 [ka]

[0171] Examples of other ionizable lipids suitable for use in this disclosure are listed below. 306Oi10; (8-methylnonyl 3-[3-[3-[bis[3-(8-methylnonoxy)-3-oxopropyl]amino]propylmethylamino]propyl-[3-(8-methylnonoxy)-3-oxopropyl]amino]propanoate) [ka] 93-O17S; (2-tetradecylsulfanylethyl 3-[3-imidazole-1-ylpropyl-[3-oxo-3-(2-tetradecylsulfanylethoxy)propyl]amino]propanoate) [ka] 93-O17O; (2-Tetradecoxyethyl 3-[3-Imidazole-1-ylpropyl-[3-oxo-3-(2-tetradecoxyethoxy)propyl]amino]propanoate) [ka] 80-O16B; (2-(dodecyldisulfanyl)ethyl 3-[3-(dimethylamino)propyl-[3-[2-(dodecyldisulfanyl)ethoxy]-3-oxopropyl]amino]propanoate) [ka] CL4H6; ([7-[4-(dipropylamino)butyl]-7-hydroxy-13-[(Z)-octadeca-9-enoyl]oxytridecyl](Z)-octadeca-9-enoate) [ka] YSK05; (1-methyl-4,4-bis[(9Z,12Z)-octadeca-9,12-dienoxy]piperidine) [ka] LipidC24; (2-Octyldodecyl 3-[4-(4-Methylpiperazin-1-yl)butyl-[3-(2-Octyldodecoxy)-3-Oxopropyl]amino]propanoate) [ka] 5A2-SC8; Bis(2-((2-methyl-3-(octylthio)propanoyl)oxy)ethyl)4,10,16-Tris(3-(2-((2-methyl-3-(octylthio)propanoyl)oxy)ethoxy)-3-oxopropyl)-4,7,10,13,16-pentaazanonadecanediato(5 ionic amine groups + 10 ester groups) [ka]

[0172] Examples of other ionizable lipids suitable for this disclosure are listed below. cKK-E12, MD1; (3,6-bis[4-[bis(2-hydroxydodecyl)amino]butyl]piperazine-2,5-dione) [ka] C12-200; (1-[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2-hydroxydodecyl)amino]ethyl]piperazine-1-yl]ethyl]amino]dodecane-2-ol) [ka]

[0173] E. Cationic lipids Cationic lipids suitable for use in the compositions of this disclosure include, for example, a variety of cationic lipids. As used herein, “cationic lipid” includes at least one permanently positively charged moiety. The permanently positively charged moiety can be positively charged at physiological pH so that the cationic lipid contains a positive charge upon delivery of a drug or therapeutic agent to cells. In some embodiments, the positively charged moiety is a quaternary amine or a quaternary ammonium ion. In some embodiments, the cationic lipid contains a counterion, or complexes with or interacts with a counterion. Cationic lipids useful in this disclosure include one or more hydrophobic components and a permanent cationic group. The permanent cationic lipid may contain a group that is positively charged regardless of pH. One permanent cationic group that can be used in a permanent cationic lipid is a quaternary ammonium group.

[0174] The cationic lipid component of the lipid nanoparticles of the present invention may contain 1 to 99 mole percent of lipid molecules in the nanoparticles. In other embodiments, the cationic lipid component may contain 5 to 90 mole percent of lipid molecules in the lipid nanoparticles. In some embodiments, the cationic lipid component may contain 10 to 75, 10 to 60, 10 to 50, or 15 to 40 mole percent of lipid molecules in the lipid nanoparticles.

[0175] In some embodiments, cationic lipids suitable for use in this disclosure are biodegradable. Cationic lipids suitable for use in this disclosure may have one or more biodegradable groups located in the hydrophobic portion (e.g., within the hydrocarbon chain) of the cationic lipid. Incorporation of biodegradable groups into cationic lipids can result in more rapid metabolism and removal from the body of the cationic lipid following delivery of the activator to the target region. As a result, these cationic lipids may have lower toxicity than similar cationic lipids that do not contain biodegradable groups. These cationic lipids can be incorporated into lipid particles to deliver activators, such as nucleic acids.

[0176] The cationic lipids used in this disclosure may be lipids of formula (IV). [ka] [In the formula, R 101 and R 102 Each of them independently comprises alkyl (C8~C 24 ), Alkenil (C8~C 24 ), or any of the substituted derivatives, In each case, R 103 These are independently alkyl (C1-C6) or substituted alkyl (C1-C6), R 104 is an alkyl (C1-C6) or substituted alkyl (C1-C6), X - [is a monovalent anion]

[0177] Examples of cationic lipids suitable for use in this disclosure are not limited to, but include, in particular, 14:1 EPC (1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine) as an OTf salt, in particular EDLPC (1,2-dilauroyl-sn-glycero-3-ethylphosphocholine) as a chloride salt, in particular EDMPC (1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine) as a chloride salt, in particular EDPPC (1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine) as a chloride salt, in particular EDSPC (1,2-distearioyl-sn-glycero-3-ethylphosphocholine) as a chloride salt, in particular EDOPC (1,2-dioleoyl-sn-glycero-3-ethylphosphocholine) as a chloride salt, and in particular 16:0-18:1 as a chloride salt. Contains EPC (1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine). 14:1 EPC [ka] EDLPC [ka] EDMPC [ka] EDPPC [ka] EDSPC [ka] EDOPC [ka] 16:0-18:1 EPC: [ka]

[0178] In some embodiments, the cationic lipid preferred for use in this disclosure is the cationic lipid of formula (V). [ka] [In the formula, R 101 and R 102 Each of them independently comprises alkyl (C8~C 24 ), Alkenil (C8~C 24 ), or any of the substituted derivatives, In each case, R 103 These are independently alkyl (C1-C6) or substituted alkyl (C1-C6), X - [is a monovalent anion]

[0179] Additional examples of cationic lipids suitable for use in this disclosure include, but are not limited to, DMTAP (1,2-dimyristoyl-3-trimethylammonium-propane) as a chloride salt, DPTAP (1,2-dipalmitoyl-3-trimethylammonium-propane) as a chloride salt, DSTAP (1,2-distearioyl-3-trimethylammonium-propane) as a chloride salt, DOTAP (1,2-dioleoyl-3-trimethylammonium-propane) as a chloride salt, and DORI (N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-aminium) as a bromide salt. DMTAP: [ka] DPTAP: [ka] DSTAP: [ka] DOTAP: [ka] DORI: [ka]

[0180] In some embodiments, the cationic lipids suitable for use in this disclosure are lipids of formula (VI). [ka] [In the formula, R 101 and R 102 Each of them independently comprises alkyl (C8~C 24 ), Alkenil (C8~C 24 ), or any of the substituted derivatives, R 105 Each of these is independently an alkyl group (C1-C6), X - [is a monovalent anion]

[0181] An additional example of a cationic lipid suitable for use in this disclosure is DC-6-14(O,O'-ditetradecanoyl-N-(α-trimethylammonioacetyl)diethanolamine) as a chloride salt. DC-6-14 [ka]

[0182] F. Phospholipids In some embodiments, the compositions of this disclosure include phospholipids. As used herein, “phospholipid” means a lipid molecule comprising at least one hydrocarbon tail group, a glycerol or sphingosine moiety, and optionally a smaller organic moiety preferentially selected from amino acids, sugars, choline, or ethanolamine. The phospholipids of this disclosure, for example those containing choline, ethanolamine, or amino acid moieties, may have positively charged groups. However, the phospholipids as defined herein differ from ionizable lipids or cationic lipids as defined herein due to the presence of negative charges on the lipid molecule. Thus, the phospholipids of this disclosure are amphoteric, and the term “phospholipid” can be understood to be synonymous with “amphoteric phospholipid” as used herein.

[0183] The phospholipid components of the lipid nanoparticles of the present invention may contain 0.1 to 99 mole percent of lipid molecules in the nanoparticles. In other embodiments, the phospholipid components may contain 0.1 to 75 mole percent of lipid molecules in the lipid nanoparticles. In some embodiments, the phospholipid components may contain 1 to 50, 1 to 30, 1 to 15, or 5 to 10 mole percent of lipid molecules in the lipid nanoparticles.

[0184] Phospholipids that may be suitable for this disclosure are not limited to, but include DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DMPC (1,2-dimyristyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), DMPE (1,2-dimyristyl-sn-glycero-3-phosphoethanolamine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), and DSPE (1,2-distearoyl This includes loyl-sn-glycero-3-phosphoethanolamine, DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DLoPE (1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine), D(Phy)PE (1,2-difitanoyl-sn-glycero-3-phosphoethanolamine), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), 1,2-ditetradecyl-sn-glycero-3-phosphoethanolamine, 1,2-dihexadecyl-sn-glycero-3-phosphoethanolamine, 1,2-dioctadecyl-sn-glycero-3-phosphoethanolamine, 1,2-diphytanyl-sn-glycero-3-phosphoethanolamine, etc. In some embodiments, the phospholipid is phosphatidylcholine. In some embodiments, the phospholipid is phosphatidylethanolamine. In some embodiments, the phospholipid is DSPC.

[0185] G. sterol In some embodiments, the compositions of the present disclosure include sterols. As used herein, “sterol” means steroids and steroid derivatives, and the term “steroid” is a class of compounds comprising a tetracyclic 17-carbon ring structure, which may further include one or more substitutions comprising alkyl groups, alkoxy groups, hydroxyl groups, oxo groups, acyl groups, or double bonds between two or more carbon atoms. In one embodiment, the ring structure of the steroid comprises three condensed cyclohexyl rings and a condensed cyclopentyl ring in the structure of cholesterol.

[0186] In some embodiments preferred to the present disclosure, the sterol is a derivative of cholestane. As described above, the cholestane derivatives include one or more non-alkyl substitutions in the condensed ring system. In some embodiments, the cholestane or cholestane derivative is cholestene or cholestene derivative.

[0187] The sterols that may be suitable in this disclosure include, but are not limited to, cholesterol, sitosterol, stigmasterol, fucosterol, spinasterol, brassicasterol, ergosterol, cholestanone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, and the like. In some embodiments, the sterols of this disclosure are phytosterols. In some embodiments, the sterols of this disclosure are cholesterol.

[0188] The sterol components of the lipid nanoparticles of the present invention may contain 1 to 99 mole percent of lipid molecules in the nanoparticles. In other embodiments, the sterol components may contain 1 to 75 mole percent of lipid molecules in the lipid nanoparticles. In some embodiments, the sterol components may contain 5 to 75, 5 to 60, 10 to 50, or 15 to 45 mole percent of lipid molecules in the lipid nanoparticles.

[0189] H. PEG lipid In some embodiments, the compositions of this disclosure include PEG lipids. As used herein, “PEG lipid” refers to a polyethylene glycol (PEG) polymer bonded to one or more hydrocarbon chains having a carbon-to-carbon length of 1 to 30. In some embodiments, the PEG lipid is one or more hydrocarbon chains of compounds having a carbon-to-carbon length of 1 to 30 bonded to a linker group that is also bonded to a PEG chain. In some embodiments, the PEG lipid is a diglyceride that also includes a PEG chain bonded to a glycerol group.

[0190] The PEG lipid component of the lipid nanoparticles of the present invention may contain 0.1 to 99 mole percent of lipid molecules in the nanoparticles. In other embodiments, the PEG lipid component may contain 0.1 to 75 mole percent of lipid molecules in the lipid nanoparticles. In some embodiments, the PEG lipid component may contain 0.1 to 25, 0.1 to 10, 0.1 to 5, or 0.1 to 3 mole percent of lipid molecules in the lipid nanoparticles.

[0191] Some non-limiting examples of PEG lipids include PEG-modified phosphatidylethanolamine or phosphatidic acid, PEG-ceramide conjugates, PEG-modified dialkylamines, PEG-modified 1,2-diacyloxypropane-3-amines, PEG-modified diacylglycerols, and dialkylglycerols. In some embodiments, suitable PEG lipids for use in this disclosure are PEG-modified distearoylphosphatidylethanolamine or PEG-modified dimyristoyl-sn-glycerol. In some embodiments, the PEG modification is measured by the molecular weight of the PEG component of the lipid. In some embodiments, the PEG modification has a molecular weight of about 100 to about 15,000. In some embodiments, the molecular weight is about 200 to about 500, about 400 to about 5,000, about 500 to about 3,000, or about 1,200 to about 3,000. The molecular weights of PEG-modified lipids are approximately 100, 200, 400, 500, 600, 800, 1,000, 1,250, 1,500, 1,750, 2,000, 2,250, 2,500, 2,750, 3,000, 3,500, 4,000, 4,500, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 12,500 to approximately 15,000. In some embodiments, PEG modification is measured by the number of PEG molecules in the polymer chain or by the number of repeating subunits. Some non-limiting examples of lipids that can be used in this application are taught in U.S. Patent No. 5,820,873, WO 2010 / 141069, or U.S. Patent No. 8,450,298, which are incorporated herein by reference. PEG lipids that may be suitable for this disclosure include, but are not limited to, DMG-mPEG2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000), DPG-mPEG2000 (1,2-dipalmitoyl-rac-glycero-3-methoxypolyethylene glycol-2000), and DSG-mPEG2000 (1,2-distearoyl-rac-glycero-3-methoxypolyethylene glycol-2000). PEG modifications can be incorporated into the PEG group in a positional manner, and the number of repeating monomers changes, so the listed molecular weights represent average values. Typical structures representing DMG-mPEG2000 include, for example, the following. [ka]

[0192] I. Administration The compositions of this disclosure comprise a plurality of lipid particles (e.g., lipid nanoparticles, e.g., any of the lipid nanoparticles described herein). In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0193] "Pharmacologically acceptable carrier" means a non-toxic carrier or excipient that does not impair the pharmacological activity of a drug that is non-toxic when formulated and administered in a dose sufficient to deliver a therapeutic amount of the drug. Pharmaceutically acceptable carriers that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partially glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-blocks, polymers, polyethylene glycol, and lanolinic tallow.

[0194] The compositions described herein are parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) and can be administered orally, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. The terms “parenteral” and “in a parenteral manner,” as used herein, include techniques of injection or infusion, including subcutaneous, intradermal, intravenous, intramuscular, intraocular, intravitreous, intra-articular, intra-arterial, intra-synovial, intrasternal, intra-sternal, intra-shear, intra-lesional, intrahepatic, intraperitoneal, intra-lesional, and intracranial. In some embodiments, the compositions described herein are administered intravenously and / or intraperitoneally. In some embodiments, the compositions described herein are administered orally. In some embodiments, the compositions described herein are administered subcutaneously. Preferably, the compositions described herein are administered orally, subcutaneously, intraperitoneally, or intravenously. More preferably, the compositions described herein are administered intravenously.

[0195] The compositions described herein may also be administered subcutaneously, intraperitoneally, or intravenously, for example, in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oily suspensions. These suspensions may be formulated by techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions, for example, in a solution in 1,3-butanediol, in a non-toxic, parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be used include mannitol, dextrose, water, phosphate-buffered saline, Ringer's solution, lactated Ringer's solution, and isotonic sodium chloride solution. Commonly used surfactants, such as Tweens or Spans, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms may also be used for formulation purposes.

[0196] Administration may be topical or systemic, as indicated. In some embodiments, administration (e.g., of the compositions of this disclosure) is oral. In some embodiments, administration (e.g., of the compositions of this disclosure) is intravenous. The preferred mode of administration may vary depending on the specific composition or agent being delivered.

[0197] J. How to use The lipid compositions of this disclosure can be used to deliver a drug to various tissues and organs within a subject. In some embodiments, this disclosure describes a method for delivering a drug to one or more of the brain, heart, muscles, and kidneys of a subject that requires it, comprising systemically administering a composition comprising a plurality of lipid nanoparticles to the subject, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a fully saturated cationic lipid. In some embodiments, the drug is delivered to the brain. In some embodiments, the drug is delivered to the muscles. In some embodiments, the drug is delivered to the heart. In some embodiments, the drug is delivered to the kidneys. In some embodiments, the drug is delivered to the heart and muscles. In some embodiments, the drug is delivered to the heart and brain. In some embodiments, the drug is delivered to the heart and kidneys. In some embodiments, the drug is delivered to the brain and muscles. In some embodiments, the drug is delivered to the brain and kidneys. In some embodiments, the drug is delivered to the muscles and kidneys. In some embodiments, the drug is delivered to the muscles, kidneys, and heart. In some embodiments, the drug is delivered to the muscles, kidneys, and brain. In some embodiments, the drug is delivered to the brain, kidneys, and heart. In some embodiments, the drug is delivered to the muscles, brain, and heart.

[0198] In some embodiments, the Disclosure describes a method for delivering a drug to a subject in need thereof, comprising administering a composition of the Disclosure to the subject. In some embodiments, the Disclosure describes a method for treating a subject having a disease, disorder or condition that is advantageously treated by the drug, comprising administering a therapeutically effective amount of a composition of the Disclosure to the subject. In some embodiments, the ionizable lipid in the administered composition is an ionizable lipid of formula (I). In some embodiments, the ionizable lipid in the administered composition is an ionizable lipid of formula (II). In some embodiments, the ionizable lipid in the administered composition is an ionizable lipid of formula (III). In some embodiments, the ionizable lipid in the administered composition is an ionizable lipid of formula (VII). In some embodiments, the cationic lipid in the administered composition is a cationic lipid of formula (IV). In some embodiments, the cationic lipid in the administered composition is a cationic lipid of formula (V). In some embodiments, the cationic lipid in the administered composition is a cationic lipid of formula (VI).

[0199] Typically, the compositions of the Disclosure are administered every 1 to about 30 days. In some embodiments, administration is every 30 days. In some embodiments, administration is every 25 days. In some embodiments, administration is every 20 days. In some embodiments, administration is every 10 days. In some embodiments, administration is every 9 days. In some embodiments, administration is every 8 days. In some embodiments, administration is every 7 days. In some embodiments, administration is every 6 days. In some embodiments, administration is every 5 days. In some embodiments, administration is every 4 days. In some embodiments, administration is every 3 days. In some embodiments, administration is every 2 days. In some embodiments, administration (e.g., of the compositions of the Disclosure) is QD or BID (e.g., QD). In some embodiments, administration (e.g., of the compositions of the Disclosure) is daily.

[0200] In some embodiments, the compositions described herein further include one or more additional agents for use in combination with, for example, a first agent. Some embodiments provide combinations (e.g., combinations of agents) that include one or more therapeutic agents. Such combinations are particularly useful when, for example, the first agent and one or more additional therapeutic agents should be administered separately. In the combinations provided herein, the two or more agents can be administered via the same route of administration or via different routes of administration. In some embodiments, the additional agents are therapeutic agents. In some embodiments, the additional agents are diagnostic agents. In some embodiments, the agents are contrast agents. In some embodiments, the additional agents are small molecules. In some embodiments, the additional agents are peptides. In some embodiments, the additional agents are proteins. In some embodiments, the additional agents are antibodies or antibody fragments.

[0201] In some embodiments of the present disclosure, the agents in the compositions are therapeutic agents for the treatment of a disease, disorder, or condition. The compositions of the present disclosure may also be administered in combination with one or more additional therapies for the treatment of a disease, disorder, or condition. When administered “in combination” with such additional therapies, the compounds of the present disclosure may be administered before, after, or concurrently with the other therapy(s) (e.g., additional therapeutic agent(s)). When administered simultaneously (e.g., concurrently), the compositions of the present disclosure and the other therapy(s) may be separate formulations or the same formulation. Furthermore, the additional therapy may be a solvent for the formulation or may be related to lipid nanoparticles, including being covalently or noncovalently bonded to a surface, embedded in a membrane, or encapsulated in nanoparticles. Alternatively, the compositions of the present disclosure and the other therapy(s) may be administered sequentially as separate formulations at approximately the same time or at different times. When the compositions of the present disclosure and the other therapy(s) (e.g., therapeutic agent(s)) are administered as separate formulations or compositions, the compositions of the present disclosure and the other therapy(s) may be administered via the same or different routes of administration. A skilled clinician can determine the appropriate timing for the application of each therapy used in combination (e.g., sufficient timing to allow for the overlap of multiple medical effects). Typically, combination therapy provides the advantageous effects of a combination of therapeutic agents in treating the diseases, conditions, or disorders described herein.

[0202] The compositions or other therapeutic agents of this disclosure may be administered in doses ranging from about 0.001 mg / kg of body weight to about 100 mg / kg of body weight, or in doses ranging from about 1 mg / dose to about 5,000 mg / dose, or according to the requirements of the particular agent. For example, preferred doses per treatment may be about 0.001 mg / kg of body weight to about 100 mg / kg of body weight, about 0.01 mg / kg of body weight to about 100 mg / kg of body weight, about 0.01 mg / kg of body weight to about 10 mg / kg of body weight, or about 0.01 mg / kg of body weight to about 1 mg / kg of body weight. In some embodiments, preferred doses per treatment may be about 0.1 mg / kg of body weight to about 10 mg / kg of body weight, for example, about 0.1 mg / kg of body weight to about 5 mg / kg of body weight, about 0.1 mg / kg of body weight to about 2.5 mg / kg of body weight, or about 0.1 mg / kg of body weight to about 1.0 mg / kg of body weight. Suitable doses may range from approximately 0.001 mg / dose to approximately 100 mg / dose, approximately 0.01 mg / dose to approximately 100 mg / dose, approximately 0.01 mg / dose to approximately 50 mg / dose, approximately 0.1 mg / dose to approximately 10 mg / dose, approximately 0.05 mg / dose to approximately 50 mg / dose, approximately 0.1 mg / dose to approximately 100 mg / dose, approximately 1 mg / dose to approximately 7,500 mg / dose, approximately 1 mg / dose to approximately 5,000 mg / dose, approximately 10 mg / dose to approximately 2,500 mg / dose, or approximately 100 mg / dose to approximately 1,000 mg / dose.

[0203] Lower or higher doses than those described above may be required. Specific dosages and treatment regimens for any particular patient depend on various factors, such as the specific medication used, age, weight, overall health, sex, diet, timing of administration, frequency of administration, elimination rate, drug combinations, severity and course of the disease, condition, or symptom, the patient's tendency towards the disease, condition, or symptom, and the judgment of the treating physician. Determining the dosage for a specific medication, patient, and disease, disorder, or condition is within the scope of the skills of those skilled in the art.

[0204] K. Examples Materials and methods: All chemicals obtained from commercially available suppliers were stored according to the manufacturer's instructions and used without further purification. Lipids represented by formula (I), (III), or (VII) and methods for producing them are described in US2021 / 0085604 and US2022 / 0273817. Each publication in its entirety is incorporated herein by reference.

[0205] siRNA: One of the most common evaluation systems for extrahepatic delivery is bioluminescence imaging (BLI) using firefly luciferase (FLuc) mRNA. When administered on a non-toxic, stable substrate, FLuc emits luminescence at wavelengths that penetrate tissue, which can be imaged in vivo and ex vivo, making it useful for identifying tissues that successfully deliver and translate mRNA. While these BLI techniques are simple and convenient, quantifying bioluminescence from most tissues may miss RNA delivery to cell types that are underrepresented in the tissue. This is particularly true for endothelial cells. For example, the lungs and liver consist of 15–30% endothelial cells, while the kidneys and brain consist of less than 5%, and even effective FLuc mRNA delivery to endothelial cells results in low bioluminescence. Essentially, mRNA encoding fluorescent proteins can facilitate cell type-level analysis by microscopy and flow cytometry. However, it has been reported that currently available GFP and tdTomato mRNAs do not induce sufficient protein expression to be visualized in vivo beyond background fluorescence. To address this sensitivity issue, we developed an evaluation system in which Cre recombinant enzyme mRNA is administered to genetically modified mice (Ai14) in which the transcription of the CAG promoter-driven tdTomato protein is inhibited by a STOP cassette adjacent to loxP, enabling highly sensitive evaluation. However, the Ai14 / Cre mRNA model is an "on / off" binary system in which the successful transfection of one Cre mRNA results in the same tdTomato expression as many Cre mRNAs, and the efficiency of RNA delivery (input) and fluorescence intensity and protein expression (output) are not proportional.

[0206] Instead, siRNA is a useful therapeutic and powerful tool for in vivo screening of LNPs. For example, early efforts to improve the efficacy of ionizable lipids were supported by screening systems using siRNA against factor VII (FVII), a blood coagulation factor secreted by hepatocytes. Since FVII expression is strictly limited to hepatocytes, the efficiency of RNA delivery to hepatocytes can be easily assessed by quantifying serum FVII protein levels. For endothelial cells, the use of siRNA against genes specifically expressed in the endothelium, such as Icam2, Tie2, and Cdh5, may be effective.

[0207] Cadherin (Cdh5), also known as vascular endothelial cadherin (VE cadherin), is a useful target gene for evaluating siRNA delivery to endothelial cells, where Cdh5 expression is severely restricted. By quantifying the Cdh5 mRNA remaining in tissue after siCdh5 administration, the efficiency of RNA delivery to endothelial cells can be evaluated.

[0208] The following custom siRNAs were manufactured by Horizon: siRNA against mouse VE-cadherin (siVEcad, siCdh5): Sense: 5'-mCmCAAAAGAGAGAmCmUGGAmUmUdTsdT-3'(Sequence ID 1) Antisense: 5'-AAUCmCAGUCUCUCUUUUGGdTsdT-3'(Sequence ID 2) Abbreviation A. Adenosine-3'-phosphate C cytidine-3'-phosphate G guanosine-3'-phosphate U Uridine-3'-phosphate mA 2'-O-methyladenosine-3'-phosphate mC 2'-O-methylcytidine-3'-phosphate mG 2'-O-methylguanosine-3'-phosphate mU 2'-O-methyluridine-3'-phosphate dT 2'-deoxythymidine-3'-phosphate sdT 2'-deoxythymidine-5'-phosphate-phosphorothioate

[0209] Formulation of lipid nanoparticles: Lipid nanoparticles were synthesized using a microfluidic chip device as previously described (Chen, D., J. Am. Chem. Soc. (2012). Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation.). Briefly, the lipid-containing ethanol phase was mixed with the siRNA-containing aqueous phase through a microfluidic channel in a PDMS (polydimethylsiloxane) chip. The siRNA was diluted in 10 mM citrate buffer, pH 3.0 (aqueous phase), and an appropriate amount of lipid was co-dissolved in 200 proof ethanol (ethanol phase). The ethanol and aqueous phases were mixed together using a syringe pump at a volume ratio of 1:3 (total flow rate 1.2 mL / min).

[0210] The resulting LNPs were dialyzed overnight at 4°C or room temperature in phosphate-buffered saline (PBS) in a 20 kDa molecular weight cutoff (MWCO) cassette and stored at 4°C until use. In some studies, the LNP solution was further concentrated using a 100 kDa MWCO Amicon centrifugal ultrafilter (Millipore Sigma). For animal studies, the LNP solution was sterilized by passing it through a 0.22 μm filter (Millipore Sigma).

[0211] Particle size and zeta potential measurements: The diameter (Z-mean) and polydispersity index (PDI) of LNPs were measured using dynamic light scattering (Zetasizer Nano ZS (Malvern Instruments)). Zeta potential was measured in 0.1×PBS solution using the same instrument.

[0212] Quantification of siRNA concentration and encapsulation: To quantify siRNA concentration and determine RNA encapsulation efficiency, the modified Quant-iT RiboGreen RNA assay (Thermo Fisher) was used as previously described (Walsh C. et al. Methods Mol Biol. 2014;1141:pp. 109-1020). This assay measured RNA levels in samples containing untreated LNPs to determine the amount of unencapsulated RNA, and in LNP samples disrupted by Triton X-100 to quantify total RNA. Briefly, 0.5 μL of LNP or serial dilutions of siRNA at known concentrations were diluted in 100 μL of final volume TE buffer (10 mM Tris-HCl and 20 mM EDTA) in or without 2% Triton X-100 (Sigma-Aldrich) in a black 96-well plate. The plates were incubated at 37°C for 15 minutes with shaking at 350 rpm. After incubation, 99.5 μl of TE buffer and 0.5 μl of RiboGreen reagent were added to each well. The plate was incubated at 37°C for 2 minutes while shaking at 350 rpm. RiboGreen fluorescence was measured using a plate reader (Tecan) (excitation wavelength 485 nm and emission wavelength 528 nm). RNA encapsulation efficiency (EE%) was determined by the following formula.

number

[0213] pKa value measurement by TNS assay: The apparent pKa values ​​of lipid nanoparticles were determined using the 2-(p-toluidinyl)naphthalene-6-sulfonic acid (TNS) assay as previously described (Heyes J. et al., Journal of Controlled Release 107 (2005), pp. 276-287). Briefly, pH buffers ranging from 3.0 to 9.0, increasing by 0.5 increments, were prepared by mixing solutions of 20 mM sodium phosphate buffer, 20 mM sodium citrate buffer, 20 mM sodium borate buffer, and 150 mM NaCl. 300 μM TNS solution was added to the above pH buffers to a final concentration of 6 μM. 46 μL of each pH buffer containing 6 μM TNS was added to a black 384-well plate. Finally, 4 μL of LNP solution containing 500 ng / μL of ionizable lipid was added to each well (quadruple). Fluorescence intensity was measured using a plate reader (Tecan) with excitation at 320 nm and emission at 465 nm. The resulting pH-fluorescence S-curve was evaluated using curve fitting analysis with Prism (Graphpad), and the apparent pKa value was obtained as the inflection point of the S-curve.

[0214] Animal Testing: All animal testing was approved by the MIT Institutional Animal Care and Use Committee (CAC) and complied with local, state, and federal regulations as necessary. All experimental procedures were carried out using ethical compliance and approval under the guidelines of the Massachusetts Institute of Technology's Department of Comparative Medicine. Female C57BL / 6 mice (6 weeks old) were obtained from Jackson Laboratory, housed at the MIT Animal Facility, and acclimatized at least 3 days prior to the start of the study.

[0215] For intravenous administration, the animals were gently warmed using a heating lamp, and then siRNA-lipid nanoparticles diluted in PBS were injected via the tail vein using a 29g, 3 / 10cc insulin syringe (BD Biosciences). For intramuscular administration, siRNA-lipid nanoparticles diluted in PBS were injected via the tail vein using a 29g, 3 / 10cc insulin syringe (BD Biosciences).

[0216] 48–72 hours after injection, organs or tissues including the heart, liver, spleen, lungs, kidneys, muscles (quadriceps femoris), and brain were collected, immersed in RNAlater solution (Thermo Fisher) at 4°C for 12–48 hours to remove RNAlater, and then stored at -20°C.

[0217] Tissue mRNA quantification by RT-qPCR: Total RNA was isolated from tissue using TRIzol (Thermo Fisher) and Direct-zol-96 MagBead (Zymo Research), or Quick-RNA MagBead (Zymo Research). Briefly, tissue punches were placed in a 96-well plate containing 4 mm stainless steel beads and lysed with 350 μL of TRIzol or 250 μL of DNA / RNA Shield (Zymo Research) using GenoGrinder2010. Total RNA was further purified using Direct-zol-96 MagBead (Zymo Research) or Quick-RNA MagBead (Zymo Research) according to the manufacturer's protocol.

[0218] cDNA was synthesized using the ABI High Capacity cDNA Reverse Transcription Kit (Applied Biosystems #4368814) according to the manufacturer's instructions. Briefly, for each reaction, a 5 μl master mix containing 1 μl 10× buffer, 0.4 μl 25× dNTPs, 1 μl 10× random primers, 0.5 μl reverse transcriptase, and 2.1 μl water was added to a 5 μl total RNA solution isolated using the protocol described above. The plate was sealed, mixed, and incubated in a thermal cycler at 25°C for 10 minutes, followed by 37°C for 2 hours and 85°C for 5 minutes.

[0219] Gene expression was analyzed by qPCR using the Luna® Universal Probe RT-qPCR Kit (NEB) and the Taqman probe-Cdh5 (Mm00486938_m1), along with either Gusb (Mm01197698_m1) or B2m (Mm00437762_m1). Samples were amplified using a LightCycler 480 qPCR machine (Roche). Cdh5 expression was normalized to either B2m or Gusb.

[0220] [Example 1] 20% EDPOC LNP vs. conventional liver-targeted LNP To investigate the potential of cationic lipids for extrahepatic RNA delivery, DSPC was initially used to replace EDOPC in a standard hepatocyte-targeted LNP formulation. The resulting LNPs were formulated with siRNA against Cdh5, and gene silencing was evaluated in vivo in endothelial cells. Details of the formulations are shown in Table 1. The physicochemical properties of the LNPs are shown in Table 2. The results are shown in Figures 2A-2G. These results indicate that substitution of amphoteric phospholipids with cationic lipids in hepatocyte-targeted LNPs can alter the tissue and cell type affinity of the LNPs.

[0221] Table 1: Prescription [Table 1]

[0222] Table 2: Physicochemical properties [Table 2]

[0223] [Example 2] 20% EDOPC LNP vs. 50% DOTAP LNP While it has been reported that incorporating 33-50% DOTAP into liver-targeted LNPs enables pulmonary RNA delivery (Q. Cheng, Nat. Nanotechnol., 2020; KJ Kauffman, Mol. Ther. - Nucleic Acids, 2018; RJ Dorkin, MIT Thesis, 2016), RNA delivery using LNPs to endothelial cells in organs including the liver, spleen, and lungs has not been reported. To explore this possibility, we formulated LNPs using 20% ​​EDOPC and compared them to previously reported LNPs containing 50% DOTAP. Details of the formulations are shown in Table 3. The physicochemical properties of the LNPs are shown in Table 4. The results are shown in Figures 3A-3E.

[0224] Table 3: Prescription [Table 3]

[0225] Table 4: Physicochemical properties [Table 4]

[0226] [Example 3] Screening of cationic lipids at 20 mol% To elucidate the relationship between the chemical structure of cationic lipids and the efficiency of RNA delivery outside the liver, spleen, and lungs, numerous biodegradable cationic lipids were evaluated. Three different classes of cationic lipids were prepared: Class 1 consisted of cationic phospholipids; Class 2 consisted of trimethylammonium-propane (TAP) lipids and DORI, an analog of DOTAP containing an ethanolamine head group; and Class 3 consisted of DC-6-14. All of these lipids contain a hydrophilic quaternary amine head group and a biodegradable ester bond in their hydrophobic tails, but differ in tail length, saturation, and linker structure between their heads and tails. LNPs containing 20% ​​of each cationic lipid were formulated and characterized. All cationic lipids yielded pKa values ​​of 6-7 and zeta potentials ranging from nearly zero to slightly positive. Details of the formulations are shown in Table 5. The physicochemical properties of the LNPs are shown in Table 6. The results are shown in Figures 4A-4G. LNPs containing EDSPC and DMTAP were excluded from in vivo evaluation due to their large particle size (>150 nm) and the impossibility of sterilization by filtration.

[0227] Next, RNA delivery to endothelial cells was 0.5 mg kg. -1The efficacy of siCdh5 was evaluated in various organs by intravenous administration at the specified dose. While all cationic lipids showed similar levels of endothelial gene silencing in the liver and spleen, differences in tail structure resulted in dramatic effects on delivery efficiency in other organs. For example, in terms of unsaturation, C14:0 EPC LNP delivered siRNA more effectively to endothelial cells in organs such as the lungs, heart, brain, and skeletal muscle compared to C14:0 EPC and C14:1 EPC. On the other hand, compared to DSTAP(18:0 TAP)LNP and DOTAP(18:1 TAP)LNP, DOTAP LNP showed more effective endothelial cell delivery in organs such as the kidneys, heart, brain, and skeletal muscle. Tail chain length also significantly affected endothelial delivery efficiency. For example, although DSTAP(18:0 TAP) and DPTAP(16:0 TAP) differ by only two carbon atoms in their tails, DPTAP showed significantly more effective endothelial delivery. Similarly, although EDLPC (12:0 EPC) and EDMPC (14:0 EPC) differ by only two carbon atoms, EDMPC exhibited more effective endothelial delivery. Furthermore, when comparing EDPPC (16:0 EPC) and EDOPC (18:1 EPC) with 16:0-18:1 EPC, which has an asymmetric tail structure and can be considered an intermediate structure between EDPPC and EDOPC, 16:0-18:1 EPC did not exhibit intermediate properties between EDPPC and EDOPC, but rather showed delivery efficiencies similar to or slightly lower than EDOPC.

[0228] These results indicate that, in addition to the positive charge of the head, the tail structure of cationic lipids significantly contributes to their endothelial delivery efficiency. In particular, cationic lipids with symmetrical tails of saturated C14 and saturated C16, such as EDPPC, DPTAP, and DC-6-14, showed the most effective delivery to endothelial cells.

[0229] Table 5: Prescription [Table 5]

[0230] Table 6: Physicochemical properties [Table 6]

[0231] [Example 4] Advantages of EDPPC and DPTAP over EDMPC and DOTAP To further confirm the superiority of EDPPC over EDMPC and DPTAP over DOTAP, these cationic lipids were formulated using MC3 and MD-1 and evaluated for their in vivo endothelial RNA delivery efficiency. LNPs encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.5 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, Cdh5 mRNA was quantified against the housekeeping gene Gusb. Details of the formulations are shown in Table 7. The physicochemical properties of the LNPs are shown in Table 8. The results are shown in Figures 5A-5G and 6A-6G.

[0232] Table 7: Prescription [Table 7]

[0233] Table 8: Physicochemical properties [Table 8]

[0234] [Example 5] Combination of ionizable lipids and cationic lipids To further confirm the necessity of a combination of ionizable and cationic lipids for endothelial RNA delivery, LNPs without ionizable lipids were prepared and compared with LNPs containing both ionizable and cationic lipids. LNPs encapsulating siRNA against Cdh5 were administered intravenously to mice at a dose of 0.3 mg / kg, and organs were collected 72 hours after injection. After isolating and purifying total RNA from the organs, Cdh5 mRNA was quantified against the housekeeping gene Gusb. Details of the formulations are shown in Table 9. The physicochemical properties of the LNPs are shown in Table 10. The results are shown in Figures 7A-7D.

[0235] Table 9: Prescription [Table 9]

[0236] Table 10: Physicochemical properties [Table 10]

[0237] [Example 6] Generalization of ionizable lipids (20% EDPPC) To examine the generalization of these cationic lipids for extrahepatic delivery, various ionizable lipids were formulated into LNPs containing 20% ​​EDPPC, 20% DPTAP, and 20% DC-6-14. Initially, LNPs containing 20% ​​EDPPC with 15 different ionizable lipids were prepared. Surprisingly, all LNPs showed effective Cdh5 gene silencing in endothelial cells in all organs tested with a single 0.5 mg / kg siCdh5 dose. Details of the formulations are shown in Table 11. The physicochemical properties of the LNPs are shown in Table 12. The results are shown in Figures 8A-8G, 9A-9G, and 10A-10G.

[0238] Table 11: Prescription [Table 11]

[0239] Table 12: Physicochemical properties [Table 12]

[0240] [Example 7] Generalization of ionizable lipids (20% DPTAP) To continue exploring the generalization of these cationic lipids for extrahepatic delivery, various ionizable lipids were formulated into LNPs containing 20% ​​EDPPC, 20% DPTAP, and 20% DC-6-14. LNPs containing 20% ​​DPTAP and 11 different ionizable lipids were prepared. Surprisingly, all LNPs showed effective Cdh5 gene silencing in endothelial cells in all organs tested with a single 0.5 mg / kg siCdh5 dose. Details of the formulations are shown in Table 13. The physicochemical properties of the LNPs are shown in Table 14. The results are shown in Figures 11A-11G and 12A-12G.

[0241] Table 13: Prescription [Table 13]

[0242] Table 14: Physicochemical properties [Table 14]

[0243] [Example 8] Generalization of ionizable lipids (20% DC-6-14) To continue examining the generalization of these cationic lipids for extrahepatic delivery, various ionizable lipids were formulated into LNPs containing 20% ​​EDPPC, 20% DPTAP, and 20% DC-6-14. Finally, the generalization of DC-6-14 was further examined. LNPs containing 20% ​​DC-6-14 and 13 different ionizable lipids were further examined. Surprisingly, all LNPs showed effective Cdh5 gene silencing in endothelial cells in all organs tested with a single 0.5 mg / kg siCdh5 dose. Details of the formulations are shown in Table 15. The physicochemical properties of the LNPs are shown in Table 16. The results are shown in Figures 13A-13G and 14A-14G.

[0244] Table 15: Prescription [Table 15]

[0245] Table 16: Physicochemical properties [Table 16]

[0246] [Example 9] Optimization of EDPPC ratio (0-50 mol%) To optimize the cationic lipid ratio for extrahepatic delivery, a series of LNPs were prepared by systematically increasing the percentage of cationic lipids identified through screening. The resulting LNPs were tested in vivo using a single 0.5 mg / kg dose of siCdh5. LNPs containing 10–50% EDDPC showed effective Cdh5 gene silencing in the liver, spleen, kidney, lung, and brain, while LNPs containing 20–30% EDPPC showed the most potent gene silencing in the heart and skeletal muscle. Details of the formulations are shown in Table 17. The physicochemical properties of the LNPs are shown in Table 18. The results are shown in Figures 15A–15G.

[0247] Table 17: Prescription [Table 17]

[0248] Table 18: Physicochemical properties [Table 18]

[0249] [Example 10] Optimization of DPTAP ratio (0-50 mol%) Next, a series of LNPs containing 5-50% DPTAP were prepared and tested in vivo with a single dose of 0.5 mg / kg of siCdh5. LNPs containing 10-50% DPTAP showed effective Cdh5 gene silencing in the liver, spleen, kidney, lung, heart, and skeletal muscle. Details of the formulations are shown in Table 19. The physicochemical properties of the LNPs are shown in Table 20. The results are shown in Figures 16A-16G.

[0250] Table 19: Prescription [Table 19]

[0251] Table 20: Physicochemical properties [Table 20]

[0252] [Example 11] Optimization of DC-6-14 ratio (0-50 mol%) Next, a series of LNPs containing 5-50% DC-6-14 were prepared and tested in vivo with a single dose of 0.5 mg / kg of siCdh5. LNPs containing 10-50% DPTAP showed effective Cdh5 gene silencing in the liver, spleen, kidney, lung, heart, and skeletal muscle. Details of the formulations are shown in Table 21. The physicochemical properties of the LNPs are shown in Table 22. The results are shown in Figures 17A-17G.

[0253] Table 21: Prescription [Table 21]

[0254] Table 22: Physicochemical properties [Table 22]

[0255] [Example 12] 50% DOTAP containing lipids of formula I or III To examine whether 50% DOTAP incorporation into liver-targeted LNPs containing lipids of formula I or III reorients them to the lungs, five LNPs containing different ionizable lipids (MC3 as a positive control) were prepared along with one LNP without ionizable lipids as a negative control. The in vivo pulmonary endothelial delivery efficiency of these LNPs was tested using a single intravenous administration of 0.4 mg / kg of siCdh5. Three days after administration, lung samples were collected and Cdh5 mRNA was quantified by RT-qPCR. All LNPs containing 50% DOTAP in addition to ionizable lipids selected from FL-A, FL-B, FL-C, and FL-D showed 80–90% Cdh5 gene silencing, indicating that these novel formulations can be used for RNA delivery to the lungs. Details of the formulations are shown in Table 23. The physicochemical properties of the LNPs are shown in Table 24. The results are shown in Figure 18.

[0256] Table 23: Prescription [Table 23]

[0257] Table 24: Physicochemical properties [Table 24]

[0258] [Example 13] 50% DOTAP containing different PEG lipids To investigate whether the alkyl chain length of PEG lipids affects the tissue affinity of LNPs containing 50% DOTAP, three LNPs containing different PEG lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single intravenous administration of 1.0 mg / kg of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs showed similar levels of Cdh5 gene silencing in all collected tissues. Details of the formulations are shown in Table 25. The physicochemical properties of the LNPs are shown in Table 26. The results are shown in Figures 19A-19E.

[0259] Table 25: Prescription [Table 25]

[0260] Table 26: Physicochemical properties [Table 26]

[0261] [Example 14] 20% EDOPC containing different ionizable lipids To examine the generalizability of EDOPC for extrahepatic delivery, various ionizable lipids were formulated with 20% EDOPC. LNPs containing five different ionizable lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single 0.5 mg / kg intravenous administration of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs containing 20% ​​EDOPC showed significant Cdh5 gene silencing in all tested tissues, indicating that these novel formulations can be used for RNA delivery to endothelial RNA in various tissues. Details of the formulations are shown in Table 27. The physicochemical properties of the LNPs are shown in Table 28. The results are shown in Figures 20A-20G.

[0262] Table 27: Prescription [Table 27]

[0263] Table 28: Physicochemical properties [Table 28]

[0264] [Example 15] 18.5% EDOPC containing different PEG lipids To investigate whether the alkyl chain length of PEG lipids affects the tissue affinity of LNPs containing 18.5% EDOPC, three LNPs containing different PEG lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single intravenous administration of 1.0 mg / kg of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs showed similar levels of Cdh5 gene silencing in all collected tissues. Details of the formulations are shown in Table 29. The physicochemical properties of the LNPs are shown in Table 30. The results are shown in Figures 21A-21E.

[0265] Table 29: Prescription [Table 29]

[0266] Table 30: Physicochemical properties [Table 30]

[0267] [Example 16] 10% DPTAP containing different ionizable lipids To examine the generalizability of DPTAP for extrahepatic delivery, various ionizable lipids were formulated with 10% DPTAP. Six different LNPs containing ionizable lipids were prepared, and their endothelial delivery efficiency was tested in vivo using a single 0.5 mg / kg intravenous administration of siCdh5. Three days after administration, tissue was collected, and Cdh5 mRNA was quantified by RT-qPCR. All LNPs containing 10% DPTAP showed significant Cdh5 gene silencing in all tested tissues, indicating that these novel formulations can be used for RNA delivery to endothelial RNA in various tissues. Details of the formulations are shown in Table 31. The physicochemical properties of the LNPs are shown in Table 32. The results are shown in Figures 22A-22F.

[0268] Table 31: Prescription [Table 31]

[0269] Table 32: Physicochemical properties [Table 32]

Claims

1. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles contain a drug, an ionizable lipid, and a fully saturated cationic lipid, and the lipid nanoparticles do not contain an amphoteric phospholipid.

2. The composition according to claim 1, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 4.5 to about 7.

3. The composition according to claim 1 or 2, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 5 to about 7.

4. The composition according to any one of claims 1 to 3, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 5.5 to about 7.

5. The composition according to any one of claims 1 to 4, wherein the lipid nanoparticles have an apparent ionization constant (pKa) of about 6 to about 7.

6. The composition according to any one of claims 1 to 5, wherein the cationic lipid is less than about 50 mole percent of the lipid nanoparticles.

7. The composition according to any one of claims 1 to 6, wherein the cationic lipid is less than about 30 mole percent of the lipid nanoparticles.

8. The composition according to any one of claims 1 to 7, wherein the cationic lipid is less than about 20 mole percent of the lipid nanoparticles.

9. Completely saturated cationic lipids are C 12 ~C 18 The composition according to any one of claims 1 to 8, wherein the composition is a fully saturated cationic lipid.

10. The composition according to any one of claims 1 to 9, further comprising sterols.

11. The composition according to any one of claims 1 to 10, further comprising PEG lipids.

12. The composition according to any one of claims 1 to 11, wherein the drug is a bioactive agent.

13. The composition according to claim 12, wherein the bioactive agent is a therapeutic agent.

14. The composition according to claim 13, wherein the therapeutic agent is a dietary therapy agent.

15. The composition according to any one of claims 1 to 11, wherein the drug is a contrast agent.

16. The composition according to any one of claims 1 to 11, wherein the drug is a diagnostic agent.

17. The composition according to any one of claims 1 to 11, wherein the drug is a nucleic acid.

18. The composition according to claim 17, wherein the nucleic acid is ribonucleic acid.

19. The composition according to claim 17, wherein the nucleic acid is deoxyribonucleic acid.

20. The composition according to claim 17, wherein the nucleic acid is a non-natural nucleic acid.

21. The composition according to any one of claims 1 to 20, wherein the ionizable lipid is a lipid of formula I or II or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, X is -NR 1 - or -O-, R 1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or 【Chemistry 2】 And, R 22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or 【Transformation 3】 And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from can be linked together to form a 4- to 7-membered ring of carbon and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 , -(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 , -(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independent integers between 0 and 3, a+b is greater than or equal to 1, and c+d is greater than or equal to 1. R 51 and R 52 Each is independent of R 35 It is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. R 35 is a hydroxyl group, -G 20 -CH(R 55 )(R 56 ), -N(R 58 )(R 59 ), or -G 20 -R 60 And, G 20 is -(CO)O- or -O(CO)-, R 55 and R 56 Each is independently a hydrogen atom or an alkyl group having 1 to 18 carbon atoms. R 58 and R 59 Each of them independently consists of hydrogen or R 36 A cycloalkyl group having 3 to 6 carbon atoms, which may be substituted in some cases. R 60 This is an alkyl group having 1 to 18 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. R 36 is -N(R 61 )(R 62 ), or -G 20 -R 65 and is R 61 and R 62 Each is independently a cycloalkyl group having hydrogen or 3 to 6 carbon atoms. R 65 is an alkyl group having 1 to 18 carbon atoms, -L 40 -CH(R 66 )(R 67 ), or -G 20 -R 66 and is L 40 It is a divalent alkyl group containing 1 to 6 carbon atoms, R 66 and R 67 Each of these is independently an alkyl group containing 1 to 10 carbon atoms or an alkoxy group containing 1 to 10 carbon atoms. L 10 It is a divalent alkyl group containing 1 to 10 carbon atoms, G 30 is -S(CO)N(R 64 )- and, R 64 ha-L 30 -G 20 -CH(R 55 )(R 56 ) and a' is either 0 or 1. G 10 is G 20 -O(CO)O-, or -N(R 63 )C(O)-, R 63 It is an alkyl group containing 1 to 18 carbon atoms, L 20 It is a divalent alkyl group containing 1 to 6 carbon atoms, b' is either 0 or 1. R 53 , R 54 , and R 57 Each of them independently consists of hydrogen or R 36 It is an alkyl group containing 1 to 18 carbon atoms, which may be substituted in some cases. L 30 [It is an alkyl group containing a single bond or 1 to 18 carbon atoms.]

22. The composition according to any one of claims 1 to 20, wherein the ionizable lipid is a lipid of formula VII or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 During the ceremony, R １ and R ２ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ３ R represents a hydrocarbon group having 2 to 8 carbon atoms. １ , R ２ and R ３ The hydrocarbon groups indicated are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , and -O-R ５６ They may be substituted with one or more substituents selected from the following: R ４ This represents a hydrocarbon group having 1 to 8 carbon atoms. R ５ and R ６ Each of these independently comprises a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ This indicates, however, R ５ and R ６ Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. R ７ is, -R １０ -L ２ -R １１ -L ３ -R １２ Show, R ５１ and R ５２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ５３ , R ５４ , R ５５ , and R ５６ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R ５３ , R ５４ , R ５５ , and R ５６ The hydrocarbon group indicated is an aryl group or -S-R with 6 to 20 carbon atoms. ５８ It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ , or -R ５9 -R ５７ It may also be replaced with R ５８ and R ５9 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R ５７ -OH, COOH, -NR ６１ R ６２ , -OC(O)OR ６３ , -C(O)O-R ６４ , -OC(O)-R ６５ , -O-R ６６ This indicates. R ６１ and R ６２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ６３ , R ６４ , R ６５ , and R ６６ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R ６３ , R ６４ , R ６５ , and R ６６ The hydrocarbon group indicated is an aryl group or -S-R with 6 to 20 carbon atoms. ６８ It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR ６１ R ６２ , -OC(O)OR ６３ , -C(O)O-R ６４ , -OC(O)-R ６５ , -O-R ６６ , or -R ６９ -R ６７ It may also be replaced with R ６８ and R ６９ This represents a hydrocarbon group having 1 to 12 carbon atoms. R ６７ -OH, COOH, -NR ６１ R ６２ , -OC(O)OR ６３ , -C(O)O-R ６４ , -OC(O)-R ６５ , -O-R ６６ This indicates. L １ , L ２ , and L ３ Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R ８ This represents a hydrocarbon group having 1 to 12 carbon atoms. R ９ This represents a hydrocarbon group having 1 to 24 carbon atoms. R １０ This represents a hydrocarbon group having 1 to 8 carbon atoms. R １１ This represents a hydrocarbon group having 1 to 24 carbon atoms. R １２ This represents a hydrocarbon group having 1 to 24 carbon atoms. R ９ , and R １２ The hydrocarbon group indicated is an aryl group, -OC(O)O-R ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -S-R ５８ It may also be replaced with R １１ The hydrocarbon group indicated is -OC(O)O-R ５３ , -C(O)O-R ５４ , or -OC(O)-R ５５ It may be replaced with .

23. The composition according to any one of claims 1 to 20, wherein the ionizable lipid is a lipid of formula VIII or a pharmaceutically acceptable salt thereof. 【Transformation 5】 During the ceremony, R １ and R ２ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ３ R represents a hydrocarbon group having 2 to 8 carbon atoms. １ , R ２ and R ３ The hydrocarbon groups indicated are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -OR ５６ It may also be replaced with R ４ This represents a hydrocarbon group having 1 to 8 carbon atoms. R ５ and R ６ Each of these independently comprises a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ This indicates, however, R ５ and R ６ Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. L １ and L ４ This represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R ８ This represents a hydrocarbon group having 1 to 12 carbon atoms. R ９ R represents a hydrocarbon group having 1 to 24 carbon atoms. ９ The hydrocarbon group indicated is an aryl group, -OC(O)O-R ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -S-R ５８ It may also be replaced with R ５１ and R ５２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ２１ , R ２３ , R ２５ , R ５３ , R ５４ , R ５５ , and R ５６ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R ５３ , R ５４ , R ５５ , and R ５６ The hydrocarbon group indicated is an aryl group or -S-R with 6 to 20 carbon atoms. ５８ It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ , or -R ５９ -R ５７ It may also be replaced with R ５８ and R ５９ Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R ５７ -OH, COOH, -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ This indicates. R １３ This represents a hydrocarbon group having 1 to 8 carbon atoms. R １４ is, -R １５ -L ５ -R １６ R １５ This represents a hydrocarbon group having 1 to 24 carbon atoms, L ５ represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-, R １６ This represents a hydrocarbon group having 1 to 24 carbon atoms. R １５ The hydrocarbon group with 1 to 24 carbon atoms shown is -OC(O)O-R ５３ , -C(O)O-R ５４ , or -OC(O)-R ５５ It may also be replaced with R １６ The hydrocarbon groups with 1 to 24 carbon atoms shown are aryl groups with 6 to 20 carbon atoms, -OC(O)O-R ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -S-R ５８ It may be replaced with .

24. The composition according to any one of claims 1 to 20, wherein the ionizable lipid is a lipid according to formula IX or a pharmaceutically acceptable salt thereof. 【Transformation 6】 During the ceremony, R １ and R ２ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ３ R represents a hydrocarbon group having 2 to 8 carbon atoms. １ , R ２ and R ３ The hydrocarbon groups indicated are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -OR ５６ It may also be replaced with R ４ and R ８ Each of these independently represents a hydrocarbon having 1 to 8 carbon atoms. R ２１ and R ２２ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms. R ２３ and R ２４ Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R ２５ and R ２６ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. L ２１ and L ２２ Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R ２５ and R ２６ The hydrocarbon group indicated is an aryl group having 6 to 20 carbon atoms, -OC(O)O-R ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -S-R ５８ They may be substituted with, and the above aryl groups having 6 to 20 carbon atoms are OH, COOH, -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ , or -R ５９ -R ５７ It may be replaced by, R ５１ and R ５２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ５３ , R ５４ , R ５５ and R ５６ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms. R ５７ -OH, COOH, -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ Show, R ５８ and R ５９ Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms.

25. The composition according to any one of claims 1 to 20, wherein the ionizable lipid is a lipid according to formula X or a pharmaceutically acceptable salt thereof. 【Transformation 7】 During the ceremony, R １ and R ２ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ３ R represents a hydrocarbon group having 2 to 8 carbon atoms. １ , R ２ and R ３ The hydrocarbon groups indicated are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -OR ５６ It may also be replaced with R ４ and R ８ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ３１ , R ３２ , R ３３ , and R ３４ Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R ３５ , R ３６ , R ３７ , and R ３８ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. L ３１ , L ３２ , L ３３ , and L ３４ Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R ３５ , R ３６ , R ３７ , and R ３８ The hydrocarbon group indicated is an aryl group having 6 to 20 carbon atoms, -OC(O)O-R ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or S-R ５８ They may be substituted with, and the above aryl groups having 6 to 20 carbon atoms are OH, COOH, -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ , or -R ５９ -R ５７ It may be replaced by, R ５１ and R ５２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ５３ , R ５４ , R ５５ , and R ５６ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms. R ５７ -OH, COOH, -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ This indicates. R ５８ and R ５９ Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms.

26. The composition according to any one of claims 1 to 21, wherein the ionizable lipid is a lipid according to formula III or a pharmaceutically acceptable salt thereof. 【Transformation 8】 During the ceremony, R ２ and R ３ Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R ３１ -L ２ -R ３２ - and R ３１ This represents a hydrocarbon group having 1 to 24 carbon atoms. L ２ は、-O(CO)O-、-O(CO)-、-(CO)O-、-O-、or 【Chemistry 9】 And, R ３２ This is a divalent hydrocarbon linking group having 1 to 18 carbon atoms. R ５ is a hydrogen atom, or R ３３ A C1-C18 alkyl group which may be substituted with R ７ and R ８ Each of these is independently a hydrogen atom, or R ３３ A C1-C18 alkyl group which may be substituted with R ３３ -NR ４５ R ４６ , -O(CO)OR ４１ , -O(CO)-R ４２ ,-(CO)O-R ４３ , -O-R ４４ , or R ３４ These are aryl or heteroaryl groups that may be substituted in some cases. R ３４ is an alkyl group having 1 to 18 carbon atoms, a hydroxyl group, a carboxyl group, -NR ４５ R ４６ , -O(CO)OR ４１ , -O(CO)-R ４２ ,-(CO)O-R ４３ , or -OR ４４ And, R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , and R ４６ Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. e is an integer of 2 or 3.

27. Ionizable lipids, 【Chemistry 10】 A composition according to any one of claims 1 to 21 and 26, selected from the group consisting of the following.

28. Ionizable lipids, 【Chemistry 11】 A composition according to any one of claims 1 to 20 and 22, selected from the group consisting of the following.

29. The composition according to any one of claims 1 to 28, wherein the cationic lipid is a lipid of formula IV. 【Chemistry 12】 [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C 8 ~C 24 ) alkyl or optionally substituted (C 8 ~C 24 ) Alkenil, In each case, R 103 These are independently and are sometimes substituted (C 1 ~C 6 ) is alkyl, R 104 (C 1 ~C 6 ) is alkyl, X - [is a monovalent anion]

30. The composition according to any one of claims 1 to 29, wherein the cationic lipid is 1,2-dilauroyl-sn-glycero-O-ethyl-3-phosphocholine (EDLPC), 1,2-dimyristoyl-sn-glycero-O-ethyl-3-phosphocholine (EDMPC), 1,2-dimyristreoyl-sn-glycero-O-ethyl-3-phosphocholine (14:1 EPC), 1,2-dipalmitoyl-sn-glycero-O-ethyl-3-phosphocholine (EDPPC), 1,2-distearoyl-sn-glycero-O-ethyl-3-phosphocholine (EDSPC), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EDOPC), or 1-palmitoyl-2-oleoyl-sn-glycero-O-ethyl-3-phosphocholine (16:0-18:1 EPC).

31. The composition according to any one of claims 1 to 30, wherein the cationic lipid is EDPPC.

32. The composition according to any one of claims 1 to 28, wherein the cationic lipid is a lipid of formula V. 【Chemistry 13】 [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C 8 ~C 24 ) alkyl or optionally substituted (C 8 ~C 24 ) Alkenil, In each case, R 103 These are independently and are sometimes substituted (C 1 ~C 6 ) is alkyl, X - [is a monovalent anion]

33. The composition according to any one of claims 1 to 28 and 32, wherein the cationic lipid is selected from the group consisting of 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP), 1,2-dipalmitoyl-3-trimethylammonium-propane (DPTAP), 1,2-distearoyl-3-trimethylammonium-propane (DSTAP), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-aminium (DORI).

34. The composition according to any one of claims 1 to 28, 32, and 33, wherein the cationic lipid is DPTAP.

35. The composition according to any one of claims 1 to 28, wherein the cationic lipid is a lipid of formula VI. 【Chemistry 14】 [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C 8 ~C 24 ) alkyl or optionally substituted (C 8 ~C 24 ) Alkenil, R 105 Each is independent of (C 1 ~C 6 ) is alkyl, X - [is a monovalent anion]

36. Cationic lipids 【Chemistry 15】 The composition according to any one of claims 1 to 28 and 35.

37. A composition comprising multiple lipid nanoparticles, wherein the lipid nanoparticles include a drug, an ionizable lipid, and a cationic lipid, and the cationic lipid is a lipid according to formula VI. 【Chemistry 16】 [In the formula, R 101 and R 102 Each is independently substituted depending on the case (C 8 ~C 24 ) alkyl or optionally substituted (C 8 ~C 24 ) Alkenil, R 105 Each is independent of (C 1 ~C 6 ) is alkyl, X - [is a monovalent anion]

38. Cationic lipids 【Chemistry 17】 The composition according to claim 37.

39. A composition comprising multiple lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and the ionizable lipid is a lipid according to formula I or a pharmaceutically acceptable salt thereof. [Chemistry 18] [In the formula, X is -NR 1 - or -O-, R 1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or 【Chemistry 19】 And, R 22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or 【Chemistry 20】 And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from can be linked together to form a 4- to 7-membered ring of carbon and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 , -(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 , -(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independent integers between 0 and 3, a+b is greater than or equal to 1, and c+d is greater than or equal to 1.

40. The composition according to claim 39, wherein the ionizable lipid is a lipid according to formula III or a pharmaceutically acceptable salt thereof. 【Chemistry 21】 During the ceremony, R ２ and R ３ Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R ３１ -L ２ -R ３２ - and R ３１ This represents a hydrocarbon group having 1 to 24 carbon atoms. L ２ は、-O(CO)O-、-O(CO)-、-(CO)O-、-O-、or 【Chemistry 22】 And, R ３２ This is a divalent hydrocarbon linking group having 1 to 18 carbon atoms. R ５ is a hydrogen atom, or R ３３ A C1-C18 alkyl group which may be substituted with R ３３ -NR ４５ R ４６ , -O(CO)OR ４１ , -O(CO)-R ４２ ,-(CO)O-R ４３ , -O-R ４４ , or R ３４ These are aryl or heteroaryl groups that may be substituted in some cases. R ７ and R ８ Each of these is independently a hydrogen atom, or R ３３ A C1-C18 alkyl group which may be substituted with R ３４ is an alkyl group having 1 to 18 carbon atoms, a hydroxyl group, a carboxyl group, -NR ４５ R ４６ , -O(CO)OR ４１ , -O(CO)-R ４２ ,-(CO)O-R ４３ , or -OR ４４ And, R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , and R ４６ Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. e is an integer of 2 or 3.

41. Ionizable lipids, 【Chemistry 23】 A composition according to claim 39 or 40, selected from the group consisting of the following.

42. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a cationic lipid, and the ionizable lipid is a lipid according to formula VII or a pharmaceutically acceptable salt thereof. 【Chemistry 24】 During the ceremony, R １ and R ２ Each of these independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ３ R represents a hydrocarbon group having 2 to 8 carbon atoms. １ , R ２ and R ３ The hydrocarbon groups indicated are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , and -O-R ５６ They may be substituted with one or more substituents selected from the following: R ４ This represents a hydrocarbon group having 1 to 8 carbon atoms. R ５ and R ６ Each of these independently comprises a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ This indicates, however, R ５ and R ６ Cases where both are hydrocarbon groups having 1 to 8 carbon atoms are excluded. R ７ is, -R １０ -L ２ -R １１ -L ３ -R １２ Show, R ５１ and R ５２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ５３ , R ５４ , R ５５ , and R ５６ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R ５３ , R ５４ , R ５５ , and R ５６ The hydrocarbon group indicated is an aryl group or -S-R with 6 to 20 carbon atoms. ５８ It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , -O-R ５６ , or -R ５9 -R ５７ It may also be replaced with R ５８ and R ５9 Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. R ５７ -OH, COOH, -NR ６１ R ６２ , -OC(O)OR ６３ , -C(O)O-R ６４ , -OC(O)-R ６５ , -O-R ６６ This indicates. R ６１ and R ６２ Each of these independently represents a hydrocarbon group having 1 to 8 carbon atoms. R ６３ , R ６４ , R ６５ , and R ６６ Each of these independently represents a hydrocarbon group having 1 to 24 carbon atoms. R ６３ , R ６４ , R ６５ , and R ６６ The hydrocarbon group indicated is an aryl group or -S-R with 6 to 20 carbon atoms. ６８ It may also be replaced with The above aryl groups with 6 to 20 carbon atoms are -OH, COOH, and -NR ６１ R ６２ , -OC(O)OR ６３ , -C(O)O-R ６４ , -OC(O)-R ６５ , -O-R ６６ , or -R ６９ -R ６７ It may also be replaced with R ６８ and R ６９ This represents a hydrocarbon group having 1 to 12 carbon atoms. R ６７ -OH, COOH, -NR ６１ R ６２ , -OC(O)OR ６３ , -C(O)O-R ６４ , -OC(O)-R ６５ , -O-R ６６ This indicates. L １ , L ２ , and L ３ Each of these independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R ８ This represents a hydrocarbon group having 1 to 12 carbon atoms. R ９ This represents a hydrocarbon group having 1 to 24 carbon atoms. R １０ This represents a hydrocarbon group having 1 to 8 carbon atoms. R １１ This represents a hydrocarbon group having 1 to 24 carbon atoms. R １２ This represents a hydrocarbon group having 1 to 24 carbon atoms. R ９ , and R １２ The hydrocarbon group indicated is an aryl group, -OC(O)O-R ５３ , -C(O)O-R ５４ , -OC(O)-R ５５ , or -S-R ５８ It may also be replaced with R １１ The hydrocarbon group indicated is -OC(O)O-R ５３ , -C(O)O-R ５４ , or -OC(O)-R ５５ It may be replaced with .

43. Ionizable lipids, 【Chemistry 25】 A composition according to claim 42, selected from the group consisting of the following.

44. A composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and at least one of EDPPC and DPTAP, and the ionizable lipid is a lipid according to formula I or II or a pharmaceutically acceptable salt thereof. 【Chemistry 26】 [In the formula, X is -NR 1 - or -O-, R 1 is a hydrogen atom, a hydrocarbon group having 6 to 24 atoms, or R 21 -L 1 -R 22 -and, R 21 It is a hydrocarbon group having 1 to 24 carbon atoms, L 1 -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or 【Chemistry 27】 And, R 22 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 2 and R 3 Each of these independently consists of a hydrogen atom, a hydrocarbon group having 3 to 24 carbon atoms, or R 31 -L 1 -R 32 -and, R 31 It is a hydrocarbon group having 1 to 24 carbon atoms, L 2 -O(CO)O-, -O(CO)-, -(CO)O-, -O-, or 【Chemistry 28】 And, R 32 It is a divalent hydrocarbon linking group having 1 to 18 carbon atoms, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of them independently represents a hydrogen atom or R 33 R is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 One or more pairs of groups selected from can be linked together to form a 4- to 7-membered ring of carbon and nitrogen atoms that may contain an oxygen atom. R 33 is a hydroxyl group, a carboxyl group, -NR 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 , -(CO)OR 43 , -OR 44 , or R 34 These are aryl or heteroaryl groups that may be substituted in some cases. R 34 These are alkyl groups, hydroxyl groups, carboxyl groups, and -NR groups having 1 to 18 carbon atoms. 45 R 46 , -O(CO)OR 41 ,-O(CO)-R 42 , -(CO)OR 43 , or -OR 44 And, R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 Each of these is an independent hydrocarbon group having 1 to 18 carbon atoms. a, b, c, and d are each independent integers between 0 and 3, a+b is greater than or equal to 1, and c+d is greater than or equal to 1. R 51 and R 52 Each is independent of R 35 It is an alkyl group having 1 to 18 carbon atoms, which may be substituted in some cases. R 35 is a hydroxyl group, -G 20 -CH(R 55 )(R 56 ), -N(R 58 )(R 59 ), or -G 20 -R 60 And, G 20 is -(CO)O- or -O(CO)-, R 55 and R 56 Each is independently a hydrogen atom or an alkyl group having 1 to 18 carbon atoms. R 58 and R 59 Each of them independently consists of hydrogen or R 36 A cycloalkyl group having 3 to 6 carbon atoms, which may be substituted in some cases. R 60 This is an alkyl group having 1 to 18 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. R 36 is -N(R 61 )(R 62 ), or -G 20 -R 65 And, R 61 and R 62 Each is independently a cycloalkyl group having hydrogen or 3 to 6 carbon atoms. R 65 -L is an alkyl group having 1 to 18 carbon atoms. 40 -CH(R 66 )(R 67 ), or -G 20 -R 66 And, L 40 It is a divalent alkyl group containing 1 to 6 carbon atoms, R 66 and R 67 Each of these is independently an alkyl group containing 1 to 10 carbon atoms or an alkoxy group containing 1 to 10 carbon atoms. L 10 It is a divalent alkyl group containing 1 to 10 carbon atoms, G 30 is -S(CO)N(R 64 )- and, R 64 ha-L 30 -G 20 -CH(R 55 )(R 56 ) and a' is either 0 or 1. G 10 is G 20 -O(CO)O-, or -N(R 63 )C(O)-, R 63 It is an alkyl group containing 1 to 18 carbon atoms, L 20 It is a divalent alkyl group containing 1 to 6 carbon atoms, b' is either 0 or 1. R 53 , R 54 , and R 57 Each of them independently consists of hydrogen or R 36 It is an alkyl group containing 1 to 18 carbon atoms, which may be substituted in some cases. L 30 [It is an alkyl group containing a single bond or 1 to 18 carbon atoms.]

45. The composition according to any one of claims 1 to 44, wherein the drug is a biologically active agent.

46. The composition according to claim 45, wherein the bioactive agent is a therapeutic agent.

47. The composition according to claim 46, wherein the therapeutic agent is a dietary therapy agent.

48. The composition according to any one of claims 1 to 44, wherein the drug is a contrast agent.

49. The composition according to any one of claims 1 to 44, wherein the drug is a diagnostic agent.

50. The composition according to any one of claims 1 to 44, wherein the drug is a nucleic acid.

51. The composition according to claim 50, wherein the nucleic acid is ribonucleic acid.

52. The composition according to claim 50, wherein the nucleic acid is deoxyribonucleic acid.

53. The composition according to claim 50, wherein the nucleic acid is a non-natural nucleic acid.

54. A method for delivering a drug to one or more of the brain, heart, muscles, and kidneys of a subject in need thereof, comprising systemically administering to the subject a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles comprise a drug, an ionizable lipid, and a fully saturated cationic lipid.

55. The method according to claim 54, wherein the drug is administered to the brain.

56. The method according to claim 54, wherein the drug is administered to the heart.

57. The method according to claim 54, wherein the drug is administered to the muscle.

58. The method according to claim 54, wherein the drug is administered to the kidney.

59. The method according to any one of claims 54 to 58, wherein the ionizable lipid is a lipid of formula (I).

60. The method according to any one of claims 54 to 59, wherein the ionizable lipid is a lipid of formula (III).

61. The method according to any one of claims 54 to 60, wherein the ionizable lipid is a lipid of formula (II).

62. The method according to any one of claims 454 to 558, wherein the ionizable lipid is a lipid of formula (VII).

63. The method according to any one of claims 54 to 58 and 62, wherein the ionizable lipid is a lipid of formula (VII-1).

64. The method according to any one of claims 54 to 58 and 62, wherein the ionizable lipid is a lipid of formula (VII-2).

65. The method according to any one of claims 54 to 58 and 62, wherein the ionizable lipid is a lipid of formula (VII-3).

66. The method according to any one of claims 54 to 65, wherein the cationic lipid is a lipid of formula (IV).

67. The method according to any one of claims 54 to 65, wherein the cationic lipid is a lipid of formula (V).

68. The method according to any one of claims 54 to 65, wherein the cationic lipid is a lipid of formula (VI).

69. A method for delivering a drug to a subject in need thereof, comprising administering to the subject a composition according to any one of claims 1 to 53.

70. A method for treating a subject having a disease, disorder or condition that is advantageously treatable with a drug, comprising administering to the subject a therapeutically effective amount of the composition described in any one of claims 1 to 53.

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