Lipid, preparation method therefor, and composition of nanoparticles for drug delivery comprising same

Abstract

The present invention relates to a lipid, a preparation method therefor, and a composition of nanoparticles for drug delivery comprising same and, more specifically, to: a lipid and a preparation method therefor, wherein the lipid is ionizable and capable of forming a complex with anionic drugs and allows various molecular designs depending on a target tissue or organ, thereby being useful for tissue- or organ-specific drug delivery; and a drug delivery composition in which a drug is encapsulated within a nanoparticle structure formed by the lipid and a polymer and a preparation method therefor.

Description

Lipids and methods for preparing the same, and compositions of nanoparticles for drug delivery containing the same

[0001] The present invention relates to lipids, a method for manufacturing the same, and a composition of nanoparticles for drug delivery containing the same. More specifically, the invention relates to a lipid that is ionizable and can form a complex with anionic drugs, and allows for various molecular designs depending on the target tissue or organ, which is useful for tissue or organ-specific drug delivery, a method for manufacturing the same, and a composition for drug delivery in which a drug is encapsulated inside a nanoparticle structure formed by the lipid and a polymer, and a method for manufacturing the same.

[0002] In the treatment of anionic drugs, including nucleic acids, safe and efficient drug delivery technologies have long been studied, and various carriers and delivery technologies have been developed. Carriers are broadly classified into viral carriers utilizing adenoviruses or retroviruses, and non-viral carriers utilizing cationic lipids and cationic polymers. Viral carriers are known to pose risks such as non-specific immune responses and face significant challenges in commercialization due to their complex production processes. Therefore, recent research trends are moving toward improving these shortcomings by utilizing non-viral carriers. Although non-viral carriers lag behind viral carriers in terms of efficiency, they offer advantages such as fewer side effects in terms of in vivo safety and lower production costs in terms of economic feasibility.

[0003] Representative non-viral delivery vehicles used for the delivery of nucleic acid materials are lipoplexes and polyplexes. These cationic lipids or polycationic polymers have been the subject of extensive research because they stabilize anionic drugs and enhance intracellular delivery by forming complexes through electrostatic interactions (De Paula D, Bentley MV, Mahato RI, Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting, RNA 13 (2007) 431-56; Gary DJ, Puri N, Won YY, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery, J Control release 121 (2007) 64-73).

[0004] However, when administering the necessary amount intravenously to achieve a sufficient effect, polycation polymers present problems for actual use as pharmaceuticals due to cytotoxicity caused by their polyvalent cation charges, although to a lesser extent than viral carriers; furthermore, nucleic acid-cationic lipid complexes are difficult to use in vivo due to their low stability in the blood. Additionally, ionic liposomes containing cationic lipids, neutral lipids, and fusogenic lipids have disadvantages, such as the complex synthesis methods of the cationic lipids used, cytotoxicity, and low efficiency of intracellular nucleic acid delivery. Therefore, there is a need to develop anionic drug delivery technologies that reduce toxicity by minimizing the use of potentially toxic cationic polymers or cationic lipids, while remaining stable in vivo and capable of intracellular delivery to achieve a sufficient effect.

[0005] Accordingly, anionic drug delivery compositions and various manufacturing methods have been disclosed, wherein a complex is formed through electrostatic interaction between a nucleic acid and a cationic lipid, and said complex is encapsulated within the nanoparticle structure of an amphiphilic block copolymer. For example, Korean Published Patent No. 2017-0032858 discloses an anionic drug delivery composition and a method thereof, comprising an anionic drug; a cationic compound; an amphiphilic block copolymer; and a polylactic acid as active ingredients, wherein the anionic drug forms a complex through electrostatic interaction with the cationic compound, and the complex thus formed is encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer and the polylactic acid. However, existing nanoparticle drug delivery systems, including those disclosed in the aforementioned published patent, still lack sufficient in vivo delivery efficiency for drugs (particularly mRNA), such as nucleic acids, polypeptides, or viruses.

[0006] The objective of the present invention is to provide a lipid that is ionizable to form a complex with anionic drugs and allows for various molecular designs depending on the target tissue or organ, which is useful for tissue or organ-specific drug delivery, and a method for manufacturing the same.

[0007] Another objective of the present invention is to provide a drug delivery composition and a method for preparing the same that can significantly improve the in vivo delivery efficiency of drugs (especially mRNA), such as nucleic acids, polypeptides, or viruses, compared to previously known nanoparticle drug delivery systems, and furthermore, is useful for target tissue or organ-specific drug delivery.

[0008] Another objective of the present invention is to provide a drug delivery composition and a method for preparing the same, which can form nanoparticles that are useful for specifically delivering drugs to target tissues, organs (e.g., liver, lung, spleen, brain, heart, etc.) or immune cells (e.g., cells, macrophages, dendritic cells, killer dendritic cells, mast cells, B cells, etc.) by effectively encapsulating and delivering drugs such as nucleic acids, thereby being suitable for protein expression in vivo and capable of inducing immunogenicity (immune response).

[0009] A first aspect of the present invention provides a lipid having a structure represented by the following chemical formula 1:

[0010] [Chemical Formula 1]

[0011]

[0012] In the above chemical formula 1,

[0013] Each R is independently a substituted or unsubstituted alkylene group, and

[0014] Each A independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one A is any one of (ii) to (iv), and

[0015] R 11 , R 13 , R 14 and R 16 Each is independently a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0016] R 12 , R 15 and R 17 Each is independently a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0017] L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0018] X is -OH or -SH, and

[0019] n is an integer greater than or equal to 1.

[0020] In one embodiment, A may be further substituted with one or more moieties specifically suitable for a target tissue or organ (e.g., liver, lung, spleen, brain, heart, etc.), preferably selected from amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof.

[0021] More specifically, the lipid of the present invention has a structure represented by any one of the following chemical formulas:

[0022]

[0023] In the above,

[0024] R1 to R5 are each independently substituted or unsubstituted alkylene groups, and

[0025] R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one of R6 to R8 is any one of (ii) to (iv), and

[0026] R 11 , R 13 , R 14 and R 16 Each is independently a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0027] R 12 , R 15 and R 17 Each is independently a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0028] L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0029] X is -OH or -SH.

[0030] In one embodiment, the above R 11 ~R 17 One or more of the may be further substituted with one or more moieties selected from one or more amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof, which are specifically suitable for a target tissue or organ (e.g., liver, lung, spleen, brain, heart, etc.).

[0031] More specifically, as mentioned above,

[0032] R1 to R5 are each independently substituted or unsubstituted C 1-4 It is an alkylene group, and

[0033] R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one of R6 to R8 is any one of (ii) to (iv), and

[0034] R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-20 It is a hydrocarbon group, and

[0035] R 12 , R 15 and R 17 Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 2-20 It is a hydrocarbon group, and

[0036] L1 and L2 are each independently -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, C 6-20 C having an arylene group and one or more heteroatoms selected from N, O, and S 3-20 Selected from the group consisting of heteroarylene groups, where L' is directly bonded, substituted, or unsubstituted C 1-13 alkylene group or substituted or unsubstituted C 1-13 It is an alkenylene group, and R' are each independently hydrogen atoms, substituted or unsubstituted C. 1-18 Alkyl groups and substituted or unsubstituted C 2-18 Selected from a group composed of alkenyl groups, and

[0037] X is -OH or -SH.

[0038] More specifically, as mentioned above,

[0039] R1 to R5 are each independently substituted or unsubstituted C 2-4 It is an alkylene group, and

[0040] R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least two of R6 to R8 are any one of (ii) to (iv), and

[0041] R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-10 It is a hydrocarbon group, and

[0042] R 12 , R 15 and R 17Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 10-20 It is a hydrocarbon group, and

[0043] L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, where R' is each independently a hydrogen atom, and a substituted or unsubstituted C 1-4 Selected from the group consisting of alkyl groups, and

[0044] X is -OH.

[0045] More specifically, the lipid of the present invention may have a structure selected from any one of the following compounds A to O:

[0046]

[0047]

[0048] A second aspect of the present invention provides a method for producing a lipid having a structure represented by Formula 1, comprising the step of reacting a compound of Formula a with a compound of Formula b:

[0049] [Chemical formula a]

[0050]

[0051] [Chemical formula b]

[0052] Hal-R 11 -L1-R 12

[0053] [Chemical Formula 1]

[0054]

[0055] In the above,

[0056] Each R is independently a substituted or unsubstituted alkylene group, and

[0057] Each A is independently a hydrogen atom (H) or However, at least one A is And,

[0058] R 11 is a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0059] R 12 is a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0060] L1 is selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0061] Hal is a halogen atom, and

[0062] n is an integer greater than or equal to 1.

[0063] A third aspect of the present invention provides a method for producing a lipid having a structure represented by Formula 1, comprising the step of reacting a compound of Formula a with a compound of Formula c:

[0064] [Chemical formula a]

[0065]

[0066] [Chemical formula c]

[0067] H2C=CH-R 18 -L1-R 14 -L2-R 15

[0068] [Chemical Formula 1]

[0069]

[0070] In the above,

[0071] Each R is independently a substituted or unsubstituted alkylene group, and

[0072] Each A is independently a hydrogen atom (H) or However, at least one A is And,

[0073] R 13 , R 14 and R 18 은 각각 독립적으로 치환되거나 비치환된 2가의 포화 혹은 불포화 탄화수소기이되, 단, -R 13 - is -CH2-CH2-R 18 - and,

[0074] R 15 is a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0075] L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0076] n is an integer greater than or equal to 1.

[0077] A fourth aspect of the present invention provides a method for producing a lipid having a structure represented by Formula 1, comprising the step of reacting a compound of Formula a with a compound of Formula d:

[0078] [Chemical formula a]

[0079]

[0080] [Chemical formula d]

[0081] YR16 -L1-R 17

[0082] [Chemical Formula 1]

[0083]

[0084] In the above,

[0085] Each R is independently a substituted or unsubstituted alkylene group, and

[0086] Each A is independently a hydrogen atom (H) or However, at least one A is And,

[0087] R 16 is a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0088] R 17 is a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0089] L1 is selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0090] Y- is or And,

[0091] X is -OH or -SH, and

[0092] n is an integer greater than or equal to 1.

[0093] A fifth aspect of the present invention provides a drug delivery composition comprising lipids of the present invention.

[0094] A sixth aspect of the present invention provides a drug delivery composition comprising: an active ingredient selected from nucleic acids, polypeptides, viruses, or combinations thereof; a lipid of the present invention; and a lipid-polymer, an amphiphilic block copolymer, or a combination thereof.

[0095] A seventh aspect of the present invention provides a method for preparing a drug delivery composition, comprising: (a) preparing a solution in which the lipid of the present invention and a lipid-polymer polymer, an amphiphilic block copolymer, or a mixture thereof are dissolved in a water-miscible organic solvent; and (b) adding and mixing an active ingredient selected from nucleic acids, polypeptides, viruses, or combinations thereof to the solution prepared in step (a).

[0096] The lipid according to the present invention is capable of ionization and can form complexes with anionic drugs. Since it has a structure in which various substituents can be introduced, it allows for diverse molecular designs depending on the target tissue or organ, making it useful for specifically delivering drugs to the target tissue or organ. Furthermore, because the lipid of the present invention has a large number of nitrogen atoms per molecule, the number of molecules (moles) required is reduced when a formulation is made with the same N / P ratio, which is advantageous in terms of toxicity and cost competitiveness. Additionally, since it is less affected by steric hinderance during synthesis, it can be manufactured with a high yield.

[0097] The drug delivery composition according to the present invention can significantly improve the in vivo delivery efficiency of drugs (especially mRNA), such as nucleic acids, polypeptides, or viruses, compared to previously known nanoparticle drug delivery systems. In particular, since the lipid of Formula 1 included in the drug delivery composition of the present invention has a structure in which various substituents can be introduced, various molecular designs are possible depending on the target tissue or organ; therefore, the drug delivery composition of the present invention is useful for specifically delivering drugs to target tissues or organs.

[0098] In addition, the nanoparticles formed by the present invention are suitable for protein expression in vivo and can induce an immune response by effectively encapsulating and delivering drugs such as nucleic acids, making them useful for specifically delivering drugs to target tissues, organs (e.g., liver, lung, spleen, brain, heart, etc.) or immune cells (e.g., cells, macrophages, dendritic cells, killer dendritic cells, mast cells, B cells, etc.).

[0099] Figure 1 is a schematic diagram of the reaction for the synthesis process of compounds A and B of formulas performed in Example A1.

[0100] Figure 2 is a schematic diagram of the reaction for the synthesis process of the compound of formula C performed in Example A2.

[0101] Figure 3 is a schematic diagram of the reaction for the synthesis process of compound D of formula performed in Example A3.

[0102] Figure 4 is a schematic diagram of the reaction for the synthesis process of compounds of formulas E and F performed in Example A4.

[0103] Figure 5 is a schematic diagram of the reaction for the synthesis process of the compound of formula G performed in Example A5.

[0104] Figure 6 is a schematic diagram of the reaction for the synthesis process of the compound of formula H performed in Example A6.

[0105] Figure 7 is a schematic diagram of the reaction for the synthesis process of the compound of formula I performed in Example A7.

[0106] Figure 8 is a schematic diagram of the reaction for the synthesis process of the compound of formula J performed in Example A8.

[0107] Figure 9 is a schematic diagram of the reaction for the synthesis process of the compound of formula K performed in Example A9.

[0108] Figure 10 is a schematic diagram of the reaction for the synthesis process of the compound of formula L performed in Example A10.

[0109] Figure 11 is a schematic diagram of the reaction for the synthesis process of the compound of formula M performed in Example A11.

[0110] Figure 12 is a schematic diagram of the reaction for the synthesis process of the compound of formula N performed in Example A12.

[0111] Figure 13 is a schematic diagram of the reaction for the synthesis process of the compound of formula O performed in Example A13.

[0112] The present invention will be described in more detail below.

[0113] [Glycerides and their manufacturing methods]

[0114] The lipid provided according to the first aspect of the present invention has a structure represented by the following chemical formula 1:

[0115] [Chemical Formula 1]

[0116]

[0117] In the above chemical formula 1,

[0118] Each R is independently a substituted or unsubstituted alkylene group, and

[0119] Each A independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one A is any one of (ii) to (iv), and

[0120] R 11 , R 13 , R 14 and R 16 Each is independently a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0121] R 12 , R 15 and R 17 Each is independently a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0122] L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0123] X is -OH or -SH, and

[0124] n is an integer greater than or equal to 1.

[0125] In one embodiment, A may be further substituted with one or more moieties specifically suitable for a target tissue or organ (e.g., liver, lung, spleen, brain, heart, etc.), preferably selected from amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof.

[0126] The range of lipids of the present invention includes not only those having the structure of Chemical Formula 1, but also their cationized forms.

[0127] In this specification, the expression “substituted or unsubstituted” means that, unless otherwise specified, the group is not substituted, or -OH, a halogen atom, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 alkyl halide group, C 1-6 Halogenated alkoxy group, C 3-20 Cycloalkyl group, C 3-20 heterocycloalkyl group, C 6-20 aryl group or C 3-20 This means that it is substituted with one or more substituents selected from heteroaryl groups. In addition, in one embodiment, the substituent may include amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof.

[0128] In this specification, the expression that any group (e.g., heteroaryl, heterocycloalkyl, etc.) is a “hetero” group means that, unless otherwise specified, the group has one or more (e.g., 1 to 3) hetero atoms selected from N, O and S.

[0129] In this specification, the “hydrocarbon group” may be branched or unbranched, annular or non-annular, or aromatic.

[0130] According to one embodiment of the present invention, in the above formula 1,

[0131] Each R is independently substituted or unsubstituted C 1-4 alkylene group (more specifically, C 2-4 An alkylene group, more specifically, C 2-3 It can be an alkylene group,

[0132] Each A independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least two A's may be any one of (ii) to (iv), and

[0133] R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-20 Hydrocarbon group (more specifically, C 2-10 Hydrocarbon group, more specifically C 2-7 It can be a hydrocarbon group,

[0134] R 12 , R 15 and R 17 Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 2-20 Hydrocarbon group (more specifically, C 10-20 Hydrocarbon group, more specifically C 12-17 It can be a hydrocarbon group,

[0135] L1 and L2 are each independently -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, C 6-20 C having an arylene group and one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S 3-20 It can be selected from the group consisting of heteroarylene groups, where L' is directly bonded, substituted, or unsubstituted C 1-13 alkylene group or substituted or unsubstituted C 2-13 It can be an alkenylene group, and R' are each independently hydrogen atoms, substituted or unsubstituted C 1-18 Alkyl groups and substituted or unsubstituted C 2-18 It can be selected from a group composed of alkenyl groups, and

[0136] n can be an integer from 1 to 5, more specifically from 1 to 4, and even more specifically from 1 to 3.

[0137] In one embodiment, the lipid of the present invention may have a structure represented by any one of the following chemical formulas:

[0138]

[0139] In the above,

[0140] R1 to R5 are each independently substituted or unsubstituted alkylene groups, and

[0141] R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one of R6 to R8 is any one of (ii) to (iv), and

[0142] R 11 , R 13 , R 14 and R 16 Each is independently a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0143] R 12 , R 15 and R 17 Each is independently a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and

[0144] L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and

[0145] X is -OH or -SH.

[0146] In one embodiment, the above R 11 ~R 17 One or more of the may be further substituted with one or more moieties selected from one or more amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof, which are specifically suitable for a target tissue or organ (e.g., liver, lung, spleen, brain, heart, etc.).

[0147] More specifically, as mentioned above,

[0148] R1 to R5 are each independently substituted or unsubstituted C 1-4 It can be an alkylene group, and

[0149] R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-20 It can be a hydrocarbon group,

[0150] R 12 , R 15 and R 17Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 2-20 It can be a hydrocarbon group,

[0151] L1 and L2 are each independently -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, C 6-20 C having an arylene group and one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S 3-20 It can be selected from the group consisting of heteroarylene groups, where L' is directly bonded, substituted, or unsubstituted C 1-13 alkylene group or substituted or unsubstituted C 2-13 It can be an alkenylene group, and R' are each independently hydrogen atoms, substituted or unsubstituted C 1-18 Alkyl groups and substituted or unsubstituted C 2-18 It can be selected from the group composed of alkenyl groups.

[0152] More specifically, as mentioned above,

[0153] R1 to R5 are each independently substituted or unsubstituted C 2-4 alkylene group (more specifically, C 2-3 It can be an alkylene group,

[0154] R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least two of R6 to R8 may be any one of (ii) to (iv), and

[0155] R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-10Hydrocarbon group (more specifically, C 2-7 It can be a hydrocarbon group,

[0156] R 12 , R 15 and R 17 Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 10-20 Hydrocarbon group (more specifically, C 12-17 It can be a hydrocarbon group,

[0157] L1 and L2 can each independently be selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, where R' is each independently a hydrogen atom, and a substituted or unsubstituted C 1-4 It can be selected from the group consisting of alkyl groups, and

[0158] X can be -OH.

[0159] More specifically, the lipid of the present invention may have a structure selected from any one of the following compounds A to O:

[0160]

[0161]

[0162] The lipid according to the present invention is capable of ionization and can form complexes with anionic drugs. Since it has a structure in which various substituents can be introduced, various molecular designs are possible depending on the target tissue or organ, making it useful for specifically delivering drugs to the target tissue or organ. To this end, if necessary, the lipid according to the present invention may include, in part of its structure, a moiety specifically suitable for the target tissue or organ, such as amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, small molecules having pharmaceutical activity, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof, or may bind to such a moiety.

[0163] In one embodiment, the “moiety specifically suited to a target tissue or organ” includes all molecules such as amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof that can interact directly or indirectly with other compounds such as receptors. The sugar may include, but is not limited to, galactose, galactosamine, N-acetylgalactosamine, or combinations thereof. The hormone may include, but is not limited to, estrogen, testosterone, progesterone, glucocortisone, adrenaline, insulin, glucagon, cortisol, vitamin D, thyroid hormone, retinoic acid, growth hormone, or combinations thereof. The neurotransmitter may include growth factors such as VEGF, EGF, NGF, and PDGF; cholesterol; bile acids; It may include, but is not limited to, GABA, glutamate, acetylcholine, or combinations thereof.

[0164] In one embodiment, a “moiety specifically suitable for a target tissue or organ” may be attached to the lipid of the present invention using a linker molecule. The linker molecule may include, but is not limited to, amides, carbonyls, esters, peptides, disulfides, silanes, nucleosides, abasic nucleosides, polyethers, polyamines, polyamides, carbohydrates, lipids, polyhydrocarbons, phosphate esters, phosphoramidates, thiophosphates, alkyl phosphates, biodegradable linkers, photolabile linkers, etc.

[0165] The lipid having the structure represented by Chemical Formula 1 of the present invention can perform both the roles of an ionizable lipid and a helper lipid in a drug delivery composition. The ionizable lipid is a lipid capable of controlling its charge according to pH and is one of the key components of a lipid nanoparticle composition useful for delivering nucleic acids such as RNA and DNA. The helper lipid is a lipid that increases the particle stability and fluidity of lipid nanoparticles and may refer to various types of lipids, such as phospholipids included in lipid nanoparticles, in addition to the ionizable lipid.

[0166] However, even if the lipid having the structure represented by Chemical Formula 1 above can perform both the role of an ionizable lipid and a helper lipid, the use of such additional lipid components in the drug delivery composition according to one embodiment of the present invention is not excluded. Accordingly, the drug delivery composition according to one embodiment of the present invention may further include one or more ionizable lipids of other types other than the lipid having the structure represented by Chemical Formula 1, or one or more helper lipids of other types, as needed.

[0167] A second aspect of the present invention provides a method for producing a lipid having a structure represented by Formula 1, comprising the step of reacting a compound of Formula a with a compound of Formula b:

[0168] [Chemical formula a]

[0169]

[0170] [Chemical formula b]

[0171] Hal-R 11 -L1-R 12

[0172] [Chemical Formula 1]

[0173]

[0174] In the above,

[0175] Each A is independently a hydrogen atom (H) or However, at least one A is And,

[0176] Hal is a halogen atom (i.e., F, Cl, Br, or I), and

[0177] R, R 11 , R 12 , L1 and n are as previously defined.

[0178] In one embodiment of the lipid preparation method according to the second aspect of the present invention, the reaction between the compound of formula a and the compound of formula b may be carried out in a solvent (e.g., acetonitrile (ACN), tetrahydrofuran (THF), etc.) in the presence of a catalyst (e.g., K2CO3, Cs2CO3, KI, etc.) under reflux conditions or at a raised temperature (e.g., 80°C to 100°C), but is not limited thereto.

[0179] A third aspect of the present invention provides a method for producing a lipid having a structure represented by Formula 1, comprising the step of reacting a compound of Formula a with a compound of Formula c:

[0180] [Chemical formula a]

[0181]

[0182] [Chemical formula c]

[0183] H2C=CH-R 18 -L1-R 14 -L2-R 15

[0184] [Chemical Formula 1]

[0185]

[0186] In the above,

[0187] Each A is independently a hydrogen atom (H) or However, at least one A is And,

[0188] R 18 is a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and

[0189] R, R 13 , R 14 , R 15 , L1, L2, and n are as previously defined, provided that -R 13 - is -CH2-CH2-R 18 - am.

[0190] In one embodiment of the lipid preparation method according to the third aspect of the present invention, the reaction between the compound of formula a and the compound of formula c may be carried out in a solvent (e.g., water, methanol (MeOH), n-butanol (n-BuOH), etc.) under reflux conditions or at a raised temperature (e.g., 100°C to 120°C), but is not limited thereto.

[0191] A fourth aspect of the present invention provides a method for producing a lipid having a structure represented by Formula 1, comprising the step of reacting a compound of Formula a with a compound of Formula d:

[0192] [Chemical formula a]

[0193]

[0194] [Chemical formula d]

[0195] YR16 -L1-R 17

[0196] [Chemical Formula 1]

[0197]

[0198] In the above,

[0199] Each A is independently a hydrogen atom (H) or However, at least one A is And,

[0200] Y- is or And,

[0201] R, R 16 , R 17 , L1, X and n are as previously defined.

[0202] In one embodiment of the lipid preparation method according to the fourth aspect of the present invention, the reaction between the compound of formula a and the compound of formula b may be carried out in a solvent (e.g., isopropanol (i-PrOH), acetonitrile (ACN), etc.) in the presence of optionally a catalyst (e.g., NaOH, etc.) under reflux conditions or at a raised temperature (e.g., 80°C to 120°C), but is not limited thereto.

[0203] [Drug delivery composition and method of manufacturing the same]

[0204] The lipid according to the present invention can easily form a complex with anionic drugs, making it useful for drug delivery, and in particular, it is useful for specifically delivering drugs to target tissues or organs (e.g., liver, lungs, spleen, brain, heart, etc.).

[0205] Accordingly, according to the fifth aspect of the present invention, a drug delivery composition comprising lipids of the present invention is provided.

[0206] In one embodiment, the drug may be selected from nucleic acids, polypeptides, viruses, or a combination thereof.

[0207] The “nucleic acid” mentioned above may be, for example, DNA, RNA, siRNA, shRNA, miRNA, mRNA, aptamers, antisense oligonucleotides, or combinations thereof, but is not limited thereto.

[0208] The above “polypeptide” may refer to a protein having activity in the body, such as an antibody or a fragment thereof, a cytokine, a hormone or an analog thereof, or a protein that can be recognized as an antigen through a series of processes in the body, including a polypeptide sequence of an antigen, an analog thereof, or a precursor thereof.

[0209] The “virus” mentioned above may be an oncolytic virus and may be one or more selected from the group consisting of, for example, adenovirus, AAV, vaccinia virus, herpes simplex virus (HSV), and vesicular stomatitis virus (VSV). In one embodiment, the oncolytic virus is an adenovirus. The adenovirus used in an embodiment of the present invention contains a luciferase gene, which can be confirmed through imaging.

[0210] The above-mentioned virus can express various types of therapeutic genes within the body of an individual and is not limited to specific molecular weight, protein, viability, or therapeutic field. The prophylactic virus can induce immunity within the body of an individual against a target disease. A composition containing a disease-preventive virus has the advantage of reducing immunity induction by the virus itself, being able to designate or expand target cells, and reducing the hyperimmune response to the virus upon re-administration, thereby enabling effective effects to be obtained through multiple inoculations.

[0211] In one embodiment, the lipid of the present invention forms a complex with a drug, and this complex can be encapsulated inside a nanoparticle structure formed by an amphiphilic block copolymer.

[0212] In one embodiment, the amphiphilic block copolymer may be an AB-type block copolymer comprising a hydrophilic A block and a hydrophobic B block. The AB-type block copolymer forms core-shell type polymer nanoparticles in an aqueous solution, wherein the hydrophobic B block forms the core (inner wall) and the hydrophilic A block forms the shell (outer wall).

[0213] In one embodiment, the hydrophilic A block may be one or more selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, and derivatives thereof.

[0214] More specifically, the hydrophilic A block may be one or more selected from the group consisting of monomethoxypolyethylene glycol (mPEG), monoacetoxypolyethylene glycol, polyethylene glycol, copolymers of polyethylene and propylene glycol, and polyvinylpyrrolidone.

[0215] Additionally, if necessary, a functional group, a ligand capable of reaching specific tissues or cells, or a functional group capable of promoting intracellular delivery can be chemically bonded to the terminal end of the hydrophilic A block to control the distribution of the nanoparticle delivery vehicle in the body or to increase the efficiency of the nanoparticle delivery vehicle being delivered into cells. In one embodiment, the functional group or ligand may be one or more selected from the group consisting of monosaccharides, polysaccharides, vitamins, peptides, proteins, and antibodies against cell surface receptors. More specifically, the functional group or ligand may be one or more selected from the group consisting of anisamide, vitamin B9 (folic acid), vitamin B12, vitamin A, galactose, lactose, mannose, hyaluronic acid, RGD peptide, NGR peptide, transferrin, and antibodies against transferrin receptors.

[0216] The above hydrophobic B block is a biocompatible biodegradable polymer, and in one embodiment, it may be one or more selected from the group consisting of polyester, polyanhydride, polyamino acid, polyorthoester, and polyphosphazine.

[0217] More specifically, the hydrophobic B block may be one or more selected from the group consisting of polylactide (PLA), polyglycolide, polycaprolactone, polydioxane-2-one, copolymers of polylactide and glycolide, copolymers of polylactide and polydioxane-2-one, copolymers of polylactide and polycaprolactone, and copolymers of polyglycolide and polycaprolactone.

[0218] In addition, in one embodiment, the hydrophobic B block may be modified by chemically bonding tocopherol, cholesterol, or a fatty acid having 10 to 24 carbon atoms to the hydroxyl group at the end of the hydrophobic B block in order to increase the hydrophobicity of the hydrophobic B block and improve the stability of the nanoparticle.

[0219] In another embodiment, the hydrophobic B block is a biocompatible biodegradable polymer having repeating units of a structure represented by the following chemical formula e.

[0220] [Chemical formula e]

[0221]

[0222] In the above chemical formula e, R represents a branched alkylene group having 3 or more carbon atoms.

[0223] In one embodiment, the number of repeating units (degree of polymerization) of the hydrophobic block having a repeating unit of the structure represented by the formula e above may be, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more, and may also be 25 or less, 24 or less, 23 or less, 22 or less, 21 or less, or 20 or less, but is not limited thereto.

[0224] In one embodiment, the number of carbon atoms of R in the above formula e may be, for example, 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more, and may also be 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, or 13 or less, but is not limited thereto.

[0225] In one embodiment, in the above formula e, R may represent a branched alkylene group having 3 to 20 carbon atoms, more specifically a branched alkylene group having 3 to 17 carbon atoms, even more specifically a branched alkylene group having 3 to 15 carbon atoms, and even more specifically a branched alkylene group having 3 to 13 carbon atoms, but is not limited thereto.

[0226] In one embodiment, the hydrophobic block having a repeating unit of the structure represented by the formula e may be a biocompatible biodegradable polymer having a repeating unit of the structure selected from below, but is not limited thereto.

[0227]

[0228] In one embodiment, the repeating unit of the structure represented by the above formula e can be obtained by ring-opening polymerization of a lactone compound.

[0229] In addition, in one embodiment, the hydrophobic block having a repeating unit of the structure represented by the above formula e may be modified by chemically bonding tocopherol, cholesterol, or a fatty acid having 10 to 24 carbon atoms to the hydroxyl group at the end of the hydrophobic block in order to increase the hydrophobicity of the hydrophobic block and improve the stability of the nanoparticle.

[0230] A sixth aspect of the present invention provides a drug delivery composition comprising: an active ingredient selected from nucleic acids, polypeptides, viruses, or combinations thereof; a lipid of the present invention; and a lipid-polymer, an amphiphilic block copolymer, or a combination thereof.

[0231] The above nucleic acids, polypeptides, and viruses are as described above.

[0232] In one embodiment, the active ingredient is mRNA (messenger RNA).

[0233] The above mRNA may have its backbone, sugar, or base chemically modified or its terminals modified for purposes such as increasing blood stability or weakening the immune response.

[0234] In one embodiment, the content of the active ingredient may be 0.05 wt% or more, 0.1 wt% or more, 0.2 wt% or more, 0.3 wt% or more, 0.4 wt% or more, or 0.5 wt% or more, based on the dry weight of the total composition, and may also be 10 wt% or less, 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less, 5 wt% or less, 4 wt% or less, or 3 wt% or less. If the content of the active ingredient is excessively low, the amount of carrier used is too high compared to the active ingredient, so there may be side effects caused by the carrier, and conversely, if it is excessively high, there will be a large amount of active ingredient that is not encapsulated in the nanoparticles, and efficiency will decrease.

[0235] The above lipid-polymer is a polymer that has both hydrophilic and hydrophobic parts within the polymer molecule.

[0236] In one embodiment, the lipid-polymer may be a polymer in which one or more saturated and unsaturated hydrocarbon groups having 11 to 25 carbon atoms are introduced as hydrophobic portions into a hydrophilic block which is a hydrophilic portion.

[0237] The above hydrophilic block may be one or more selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, and derivatives thereof.

[0238] More specifically, the hydrophilic block may be one or more selected from the group consisting of monomethoxypolyethylene glycol, monoacetoxypolyethylene glycol, polyethylene glycol, copolymers of polyethylene and propylene glycol, and polyvinylpyrrolidone.

[0239] In one embodiment, the hydrophilic block may have a number average molecular weight (g / mol) of 200 or more, 500 or more, 1,000 or more, or 2,000 or more, and may also be 50,000 or less, 20,000 or less, 10,000 or less, or 5,000 or less, but is not limited thereto.

[0240] Additionally, if necessary, a functional group, a ligand capable of reaching specific tissues or cells, or a functional group capable of promoting intracellular delivery can be chemically attached to the end of the hydrophilic block to control the in vivo distribution of the nanoparticle delivery vehicle or increase the efficiency of the nanoparticle delivery vehicle being delivered into cells. The functional group or ligand may be one or more selected from the group consisting of monosaccharides, polysaccharides, vitamins, peptides, proteins, and antibodies against cell surface receptors. More specifically, the functional group or ligand may be one or more selected from the group consisting of anisamide, vitamin B9 (folic acid), vitamin B12, vitamin A, galactose, lactose, mannose, hyaluronic acid, RGD peptide, NGR peptide, transferrin, and antibodies against transferrin receptors.

[0241] In one embodiment, the saturated and unsaturated hydrocarbon group having 11 to 25 carbon atoms introduced as a hydrophobic portion into the hydrophilic block, which is a hydrophilic portion, may independently be selected from the group consisting of myristoyl, dimyristoyl, lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl, cerotyl, myristoleyl, palmitoleyl, sapienyl, oleyl, linoleyl, arachidonyl, eicosapentaenyl, erucyl, and docosahexaenyl.

[0242] In addition, in one embodiment, the compositional ratio of the hydrophilic portion to the hydrophobic portion in the lipid-polymer may be in the range of 10 to 90 weight% based on the weight of the polymer, specifically 20 to 80 weight%, more specifically 30 to 80 weight%, and even more specifically 40 to 80 weight%. If the proportion of the hydrophilic portion is excessively small, the solubility of the polymer in water is low, making it difficult to form nanoparticles; conversely, if it is excessively large, the hydrophilicity is too high, which may lower the stability of the nanoparticles.

[0243] In one embodiment of the present invention, the lipid-polymer may be a polyalkylene glycol (e.g., polyethylene glycol) into which saturated and unsaturated hydrocarbon groups having 11 to 25 carbon atoms (e.g., myristyl groups) have been introduced. For example, the lipid-polymer may be a PEGylated lipid. The PEG lipid refers to a polyethylene glycol (PEG)-modified lipid, which is a type of PEG derivative with a lipid moiety attached, such as DMG (dimyristoylglycerol) or DSPE (distearoylglycerophosphoethanolamine), and the PEG lipid may be used to improve the circulation time of active ingredients encapsulated in lipid nanoparticles and to reduce non-specific absorption. The above PEG lipid may be one or more combinations selected from the group consisting of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol. More specifically, the PEG lipid may include 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)](PEG-DSPE), PEG-distearyl glycerol (PEG-DSG), PEG-dipalmitoyl, PEG-dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), or PEG-1,2-dimyristyloxypropyl-3-amine (PEG-c-DMA).

[0244] The above amphiphilic block copolymer may be an AB-type block copolymer comprising a hydrophilic A block and a hydrophobic B block. The above AB-type block copolymer forms core-shell type polymer nanoparticles in an aqueous solution, wherein the hydrophobic B block forms the core (inner wall) and the hydrophilic A block forms the shell (outer wall).

[0245] The above hydrophilic A block and the above hydrophobic B block are as described above.

[0246] In one embodiment, the number average molecular weight (g / mol) of the hydrophilic A block may be 200 or more, 500 or more, 1,000 or more, or 2,000 or more, and may also be 50,000 or less, 20,000 or less, 10,000 or less, or 5,000 or less, but is not limited thereto.

[0247] In one embodiment, the number average molecular weight (g / mol) of the hydrophobic B block may be 200 or more, 500 or more, 1,000 or more, or 1,700 or more, and may also be 50,000 or less, 20,000 or less, 10,000 or less, or 6,000 or less, but is not limited thereto.

[0248] For example, the number average molecular weight combination of the hydrophilic A block-hydrophobic B block may be 2,000-6,000, 2,000-4,000, 2,000-3,000, 2,000-1,700, 2,000-1,300, etc., but is not limited thereto.

[0249] In one embodiment, in the amphiphilic block copolymer, the compositional ratio of the hydrophilic block (A) and the hydrophobic block (B) may be in the range of 20 to 70 weight% for the hydrophilic block (A) based on the total weight of the copolymer, and more specifically, in the range of 30 to 60 weight%. If the ratio of the hydrophilic block (A) is less than 20 weight% based on the total weight of the copolymer, the solubility of the polymer in water is low, making it difficult to form nanoparticles; therefore, it is preferable that the ratio of the hydrophilic block (A) be 20 weight% or more so that the copolymer has sufficient solubility in water to form nanoparticles. On the other hand, if the ratio of the hydrophilic block (A) exceeds 70 weight% based on the total weight of the copolymer, the hydrophilicity is too high, which lowers the stability of the polymer nanoparticles and makes it difficult to use as a solubilizing composition for an active ingredient / lipid complex; therefore, considering the stability of the nanoparticles, it is preferable that the ratio of the hydrophilic block (A) be 70 weight% or less.

[0250] In one embodiment, the amphiphilic block copolymer may be a biocompatible biodegradable polymer comprising the hydrophilic block described above; and a hydrophobic block having repeating units of the structure represented by the formula e.

[0251] In one embodiment, the number average molecular weight (g / mol) of the hydrophobic block having a repeating unit of the structure represented by the formula e may be 80 or more, 100 or more, 150 or more, 200 or more, 500 or more, 1,000 or more, or 1,700 or more, and may also be 50,000 or less, 20,000 or less, 10,000 or less, or 6,000 or less, but is not limited thereto.

[0252] For example, combinations of number average molecular weights of hydrophobic blocks having repeating units of a structure represented by chemical formula e can be 2,000-6,000, 2,000-4,000, 2,000-3,000, 2,000-1,700, 2,000-1,000, 2,000-800, 2,000-500, etc., but are not limited thereto.

[0253] In one embodiment, in an amphiphilic block copolymer comprising a hydrophobic block having a repeating unit of a structure represented by the formula e, the compositional ratio of the hydrophilic block to the hydrophobic block may be in the range of 25 to 95 weight% for the hydrophilic block based on the total weight of the copolymer, specifically 40 to 90 weight%, and more specifically 50 to 80 weight%. Since it is difficult to form nanoparticles due to the low solubility of the polymer in water if the ratio of the hydrophilic block is less than 25 weight% based on the total weight of the copolymer, it is preferable that the ratio of the hydrophilic block be 25 weight% or more so that the copolymer has sufficient solubility in water to form nanoparticles. Meanwhile, if the ratio of the hydrophilic block (A) exceeds 95% by weight based on the total weight of the copolymer, the hydrophilicity is too high and the stability of the polymer nanoparticles is lowered, making it difficult to use as a solubilizing composition for a composite containing active ingredients. Therefore, considering the stability of the nanoparticles, it is preferable that the ratio of the hydrophilic block be 95% by weight or less.

[0254] In one embodiment, the content of the lipid-polymer polymer, amphiphilic block copolymer, or a combination thereof in the drug delivery composition of the present invention may be 5 wt% or more, 7 wt% or more, 10 wt% or more, 12 wt% or more, 15 wt% or more, 17 wt% or more, 20 wt% or more, 25 wt% or more, 30 wt% or more, 35 wt% or more, 40 wt% or more, 45 wt% or more, 50 wt% or more, 55 wt% or more, or 60 wt% or more, based on the dry weight of the total composition, and may also be 90 wt% or less, 88 wt% or less, 86 wt% or less, 84 wt% or less, 82 wt% or less, 80 wt% or less, 75 wt% or less, 70 wt% or less, or 60 wt% or less. If the content of the above polymer is too low, the size of the nanoparticles becomes too large, which may reduce the stability of the nanoparticles and increase the loss rate during filter sterilization; conversely, if it is too high, there is a concern that the content of the active ingredient that can be incorporated will become too low.

[0255] In the drug delivery composition of the present invention, the active ingredient is maintained in a state of being encapsulated within a nanoparticle structure formed by the lipid-polymer polymer, the amphiphilic block copolymer or a combination thereof, and the lipid of Formula 1, thereby improving stability in blood or body fluids.

[0256] In one embodiment, the particle size of the nanoparticle may be defined by a Z-average value, for example, 800 nm or less, 600 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, 200 nm or less, or 150 nm or less, and may also be 10 nm or more, 50 nm or more, or 100 nm or more. In one embodiment, the particle size of the nanoparticle defined by a Z-average value may be, for example, 10 to 800 nm, 20 to 600 nm, 30 to 500 nm, 50 to 400 nm, or 80 to 300 nm.

[0257] In one embodiment, the particle size of the nanoparticle may be defined by a Z-average value and, for example, may be 800 nm or less, 600 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, 200 nm or less, or 150 nm or less, and may also be 10 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, 50 nm or more, 60 nm or more, 70 nm or more, 80 nm or more, 90 nm or more, or 100 nm or more. In one embodiment, the particle size of the nanoparticle defined by a Z-average value may be, for example, 10 to 800 nm, 20 to 600 nm, 30 to 500 nm, 40 to 400 nm, or 50 to 300 nm.

[0258] In one embodiment, the relative amount of the lipid-polymer, amphiphilic block copolymer, or a combination thereof polymer relative to the lipid of Formula 1 may be 0.01 parts by weight or more, 0.02 parts by weight or more, 0.03 parts by weight or more, 0.04 parts by weight or more, 0.05 parts by weight or more, 0.5 parts by weight or more, 1 part by weight or more, 1.5 parts by weight or more, 2 parts by weight or more, 2.5 parts by weight or more, 3 parts by weight or more, 3.5 parts by weight or more, or 3.7 parts by weight or more, based on 1 part by weight of the lipid of Formula 1, and may also be 50 parts by weight or less, 49 parts by weight or less, 47 parts by weight or less, 45 parts by weight or less, 43 parts by weight or less, 41 parts by weight or less, 40 parts by weight or less, 39 parts by weight or less, 37 parts by weight or less, 35 parts by weight or less, 30 parts by weight or less, 25 parts by weight or less, 20 parts by weight It may be less than or equal to 18 parts by weight, but is not limited thereto.

[0259] More specifically, the relative amount of the lipid-polymer polymer used relative to the lipid of Formula 1 may be 0.01 parts by weight or more, 0.02 parts by weight or more, 0.03 parts by weight or more, or 0.04 parts by weight or more based on 1 part by weight of the lipid of Formula 1, and may also be 5 parts by weight or less, 2 parts by weight or less, 1 part by weight or less, 0.5 parts by weight or less, or 0.1 parts by weight or less, but is not limited thereto.

[0260] More specifically, the relative amount of the amphiphilic block copolymer relative to the lipid of Formula 1 may be 0.1 parts by weight or more, 0.5 parts by weight or more, 1 part by weight or more, 1.5 parts by weight or more, or 2 parts by weight or more, based on 1 part by weight of the lipid of Formula 1, and may also be 50 parts by weight or less, 45 parts by weight or less, 40 parts by weight or less, 35 parts by weight or less, 30 parts by weight or less, 25 parts by weight or less, or 20 parts by weight or less, but is not limited thereto.

[0261] In one embodiment, the drug delivery composition of the present invention may further include a fused lipid to increase the efficiency of delivery of an active ingredient into the body.

[0262] In one embodiment, the fusion lipid may be one or more combinations selected from the group consisting of phospholipids, cholesterol, and tocopherol.

[0263] Specifically, the phospholipid may be one or more selected from the group consisting of phosphatidylethanolamin (PE), phosphatidylcholine (PC), and phosphatidic acid. The phosphatidylethanolamin (PE), phosphatidylcholine (PC), and phosphatidic acid may be in a form combined with one or two C10-24 fatty acids. The cholesterol and tocopherol include analogs, derivatives, and metabolites of cholesterol and tocopherol, respectively.

[0264] Specifically, the fused lipid is dilauroyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, dilinoleoyl phosphatidylethanolamine, 1-palmitoyl-2-oleoyl phosphatidylethanolamine, 1,2-diphytanoyl-3-sn-phosphatidylethanolamine, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dilinoleoyl phosphatidylcholine, 1-palmitoyl-2-oleoyl phosphatidylcholine, 1,2-diphytanoyl-3-sn-phosphatidylcholine, dilauroyl phosphatidic acid,It may be one or more combinations selected from the group consisting of dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, distearoyl phosphatidic acid, dioleoyl phosphatidic acid, dilinoleoyl phosphatidic acid, 1-palmitoyl-2-oleoyl phosphatidic acid, 1,2-diphytanoyl-3-sn-phosphatidic acid, cholesterol, and tocopherol.

[0265] More specifically, the fused lipid is dioleoyl phosphatidylethanolamine (DOPE), 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine (DPPC), distearoyl phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), It may be one or more combinations selected from the group consisting of 1,2-dioleoyl-3-dimethylammonium-propane (DODAP), 1,2-dioleoyl-sn-glycero-3-phosphate (18PA), cholesterol, and tocopherol.

[0266] In one embodiment of the present invention, the fusion lipid may be distearoyl phosphatidylcholine, cholesterol, or a combination thereof.

[0267] In one embodiment, the fused lipid content may be 1 wt% or more, 2 wt% or more, 3 wt% or more, 3.5 wt% or more, 4 wt% or more, 5 wt% or more, 5.5 wt% or more, or 5.7 wt% or more based on the dry weight of the total composition, and may also be 40 wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 19 wt% or less, 18 wt% or less, or 17 wt% or less.

[0268] In one embodiment, the relative amount of the fused lipid to the cationic lipid of Formula 1 may be 0.05 parts by weight or more, 0.06 parts by weight or more, 0.07 parts by weight or more, 0.08 parts by weight or more, 0.09 parts by weight or more, 0.1 parts by weight or more, 0.13 parts by weight or more, 0.2 parts by weight or more, 0.25 parts by weight or more, 0.3 parts by weight or more, 0.35 parts by weight or more, or 0.4 parts by weight or more, based on 1 part by weight of the cationic lipid of Formula 1, and may also be 6 parts by weight or less, 5.5 parts by weight or less, 5 parts by weight or less, 4.5 parts by weight or less, 4 parts by weight or less, 3.8 parts by weight or less, 3.5 parts by weight or less, or 3.2 parts by weight or less, but is not limited thereto.

[0269] In one embodiment, when a phospholipid is used as the fused lipid, the relative amount used may be 0.03 parts by weight or more, 0.04 parts by weight or more, 0.05 parts by weight or more, 0.06 parts by weight or more, 0.07 parts by weight or more, 0.09 parts by weight or more, or 0.1 parts by weight or more, based on 1 part by weight of the lipid of Formula 1, and may also be 4 parts by weight or less, 3.9 parts by weight or less, 3.7 parts by weight or less, 3.5 parts by weight or less, 3.3 parts by weight or less, 3.1 parts by weight or less, 3 parts by weight or less, 2.9 parts by weight or less, 2.7 parts by weight or less, or 2.2 parts by weight or less, but is not limited thereto.

[0270] In one embodiment, when cholesterol is used as the fused lipid, the relative amount used may be 0.02 parts by weight or more, 0.03 parts by weight or more, 0.04 parts by weight or more, 0.08 parts by weight or more, 0.1 parts by weight or more, or 0.2 parts by weight or more, based on 1 part by weight of the cationic lipid of Formula 1, and may also be 3 parts by weight or less, 2.7 parts by weight or less, 2.5 parts by weight or less, 2 parts by weight or less, 1.9 parts by weight or less, 1.7 parts by weight or less, 1.5 parts by weight or less, 1.3 parts by weight or less, or 1.1 parts by weight or less, but is not limited thereto.

[0271] In addition, in one embodiment, the drug delivery composition of the present invention may further include one or more additive components (hereinafter, “optional additive components”) that are typically included in drug delivery compositions.

[0272] In one embodiment, the optional additive component may be one or more selected from, for example, pH modifiers (e.g., acidifying agents, alkalizing agents, buffering agents), tonicity modifiers, bulking agents (e.g., sugars, polyols, amino acids, polymers, proteins, etc.), wetting agents, solubilizing agents, surfactants, antioxidants, antimicrobial agents, chelating agents, complexing agents, etc., but is not limited thereto.

[0273] In one embodiment, the pH adjuster may be one or more selected from acetate, citrate, tartrate, histidine, glutamate, phosphate, Tris, glycine, bicarbonate, succinate, sulfate, nitrate, etc., but is not limited thereto.

[0274] In one embodiment, the intestinal regulator may be one or more selected from mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, potassium chloride, glycerol, glycerin, propylene glycol, etc., but is not limited thereto.

[0275] In one embodiment, the bulking agent may be one or more selected from sugars and polyols including sucrose, trehalose, glucose, lactose sorbitol, mannitol, glycerol, etc.; amino acids including arginine, aspartic acid, glutamic acid, lysine, proline, glycine, histidine, methionine, alanine, etc.; polymers and proteins including gelatin, polyvinylpyrrolidone (PVP), polylactate-co-glycolate (PLGA), polyethylene glycol (PEG), dextran, cyclodextran, or derivatives thereof, starch derivatives, hydroxylamine sulfate (HAS), bovine serum albumin (BSA), etc., or combinations thereof, but is not limited thereto.

[0276] In one embodiment, the wetting agent and / or solubilizing agent is lecithin, PEG 300, PEG 600, PEG 1000, polyoxyethylene lauryl ether (e.g., Brij 30, Brij 35, Brij 56, Brij 76, Brij 97), polypropylene glycol (PPG) 2000, glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polysorbates 20, polysorbates 40, polysorbates 60, polysorbates 80, sorbitan monolaurate (Span It may be one or more selected from, but not limited to, sorbitan monooleate (Span 80), sorbitan trioleate (Span 85), cocamide monoethanolamine (cocamide MEA), cocamide diethanolamine (cocamide DEA), dodecyldimethylamine oxide, poloxamer, polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, etc.

[0277] In one embodiment, the antioxidant may be one or more selected from tocopherol (vitamin E), tocopherol alpha, alpha tocopherol hydrogen succinate, ascorbic acid, accorbyl palmitate, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, histamine, methionine, glutathione, poly(ethylamine), etc., but is not limited thereto.

[0278] In one embodiment, the antimicrobial agent may be one or more selected from benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimid, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, metacresol, ethyl alcohol, glycerin, hexatidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, propylene glycol, thimerosal, etc., but is not limited thereto.

[0279] In one embodiment, the chelating agent may be one or more selected from ethylenediaminetetraacetic acid (EDTA), disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, diethylenetriaminepentaacetic acid (DPTA), citric acid, hexaphosphate, thiolglycolic acid, zinc, etc., but is not limited thereto.

[0280] When any of the above additive components are used in the drug delivery composition of the present invention, the content of each additive may be, for example, 0.01 wt% or more, 0.05 wt% or more, or 0.1 wt% or more based on the dry weight of the total composition, and may also be 10 wt% or less, 5 wt% or less, or 1 wt% or less, but is not limited thereto.

[0281] The drug delivery composition according to the present invention is particularly useful for specifically delivering a drug to a target tissue or organ (e.g., liver, lung, spleen, brain, heart, etc.) and can be administered via routes of administration such as blood vessels, muscles, mucous membranes, subcutaneous, intradermal, oral, bone, transdermal, or local tissues, and can be formulated into various oral or parenteral formulations suitable for such routes of administration. Examples of oral formulations include tablets, capsules, powders, liquids, etc., and examples of parenteral formulations include ophthalmic drops, injections, etc. In one embodiment, the composition may be administered intramuscularly and may be an injectable formulation. For example, when the composition according to the present invention is freeze-dried, it may be reconstituted with injectable distilled water, 0.9% physiological saline, and a 5% aqueous dextrose solution to produce an injectable formulation.

[0282] Accordingly, the seventh aspect of the present invention provides a method for preparing a drug delivery composition comprising: (a) preparing a solution in which the lipid of the present invention and a lipid-polymer polymer, an amphiphilic block copolymer, or a mixture thereof are dissolved in a water-miscible organic solvent; and (b) adding and mixing an active ingredient selected from nucleic acids, polypeptides, viruses, or combinations thereof to the solution prepared in step (a).

[0283] In one embodiment, the water-miscible organic solvent of step (a) may be ethanol.

[0284] In one embodiment, step (b) may be performed in a solution under acidic conditions.

[0285] In one embodiment, the step (b) may include: (b-1) a step of preparing a buffer solution containing the active ingredient; and (b-2) a step of adding and mixing the buffer solution of the active ingredient prepared in step (b-1) to the solution prepared in step (a).

[0286] In one embodiment, the mixing ratio of the buffer solution of the active ingredient prepared in step (b-1) to the solution prepared in step (a) may be 1:1 to 1:5 in volume ratio, and more specifically, 1:2 to 1:4.

[0287] In another embodiment, the step (b) may include: (b-1) a step of adding the active ingredient to the solution prepared in step (a); and (b-2) a step of adding and mixing a buffer solution to the result of step (b-1).

[0288] In one embodiment, the method for preparing the drug delivery composition may further include the step of adding a pH adjusting buffer, water for injection, or a combination thereof to the product of step (b).

[0289] In another embodiment, the method for preparing the drug delivery composition may further include the step of removing the solvent from the product of step (b) and then adding a freeze-drying aid to freeze-dry.

[0290] The freeze-drying aid is added to help the freeze-dried composition maintain a cake shape or to help the composition melt uniformly within a short period of time during the reconstitution process after freeze-drying, and specifically, it may be one or more selected from the group consisting of sugars, amino acids, polymers, and proteins. For example, it may be one or more selected from the group consisting of lactose, mannitol, sorbitol, and sucrose. The content of the freeze-drying aid may be 1 to 90 weight% based on the total dry weight of the freeze-dried composition, and more specifically, 10 to 60 weight%.

[0291] The present invention will be explained in more detail below based on the following examples, but these are for the purpose of explaining the invention and do not limit the scope of the invention in any way.

[0292] [Example]

[0293] Example A: Preparation of lipid compounds and preparation of drug delivery composition Example I

[0294] Example A1

[0295] Compounds of the following chemical formulas A and B (compound A and compound B, respectively) were prepared according to the synthesis outline shown in Fig. 1.

[0296] [Chemical Formula A]

[0297]

[0298] [Chemical Formula B]

[0299]

[0300] 1,4,7-triazonane (100 mg, 0.774 mmol, 1 eq) and 2-hexyldecyl 5-(oxiran-2-yl)pentanoate (713.20 mg, 1.935 mmol, 2.5 eq) were placed in a 25 mL 1-neck round-bottom flask (RBF). Isopropanol (i-PrOH, 10 mL) was added to this mixture, and the mixture was stirred for 48 hours under reflux conditions. After the reaction of the mixture was complete, it was concentrated at 80°C, and the product was separated by silica column chromatography using a mixed solvent of dichloromethane (DCM), methanol (MeOH), and ammonium hydroxide (NH4OH) (DCM:MeOH:NH4OH = 100:10:1) as the developing solvent. The separated residue was further dried using a vacuum pump after vacuum evaporation. Finally, 232.2 mg of compound A (yield: 77.3%) and 132.3 mg of compound B (yield: 19.7%) in the form of a light yellow oil were obtained.

[0301] Compound A:

[0302] 1 H NMR (400 MHz, CHLOROFORM-d): δ3.96-3.95 (d, 6H), 3.62-3.60 (br, 3H), 2.80-2.33 (m, 18H), 2.32-2.29 (t, 6H), 1.64-1.61 (br, 11H), 1.53-1.49 (m, 3H), 1.43-1.30 (m, 82H), 0.90-0.86 (t, 18H)

[0303] Compound B:

[0304] 1 H NMR (400 MHz, CHLOROFORM-d): δ3.96-3.95 (d, 4H), 3.63-3.60 (br, 2H), 2.84-2.35 (m, 16H), 2.32-2.29 (t, 4H), 1.66-1.60 (br, 6H), 1.54-1.51 (m, 2H), 1.43-1.42 (m, 5H), 1.34-1.26 (m, 50H), 0.90-0.86 (t, 12H)

[0305] Example A2

[0306] A compound of the following chemical formula C (compound C) was prepared according to the synthesis outline shown in Figure 2.

[0307] [Chemical Formula C]

[0308]

[0309] 1,4,7-triazonan (100 mg, 0.774 mmol, 1 eq) and heptadecan-9-yl 5-(oxiran-2-yl)pentanoate (1332 mg, 3.483 mmol, 4.5 eq) were placed in a 25 mL 1-neck RBF. Isopropanol (i-PrOH, 5.0 mL) was added to this mixture, and the mixture was stirred for 24 hours under reflux conditions. After the reaction was complete, the mixture was vacuum concentrated at 80°C. The product was then separated by silica column chromatography using DCM:MeOH:NH4OH (100:10:1) as the developing solvent. The separated residue was vacuum evaporated and further dried using a vacuum pump. Finally, 453 mg of light yellow oil-form compound C (yield: 45.8%) was obtained.

[0310] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.88-4.83 (m, 3H), 3.63 (br, 3H), 2.82-2.30 (m, 18H), 2.28-2.27 (t, 6H), 1.66-1.60 (br, 6H), 1.50-1.26 (m, 86H) 0.90-0.86 (t, 18H)

[0311] Example A3

[0312] A compound of the following chemical formula D (compound D) was prepared according to the synthesis outline shown in Fig. 3.

[0313] [Chemical Formula D]

[0314]

[0315] 1,4,7,10-tetraazacyclododecane (50 mg, 0.290 mmol, 1 eq) and 2-hexyldecyl 5-(oxiran-2-yl)pentanoate (641.60 mg, 1.741 mmol, 6 eq) were placed in a 25 mL 1-neck RBF. Isopropanol (i-PrOH, 5.0 mL) was added to this mixture, and the mixture was stirred under reflux conditions for 24 hours. After the reaction was complete, the mixture was vacuum concentrated at 80°C. The product was then separated by silica column chromatography using DCM:MeOH:NH4OH (100:10:1) as the developing solvent. The separated residue was vacuum evaporated and further dried using a vacuum pump. Finally, 356.9 mg of compound D, a pale yellow oil, was obtained (yield: 74.7%).

[0316] 1 H NMR (400 MHz, CHLOROFORM-d): δ3.96-3.95 (d, 8H), 3.62-3.60 (br, 4H), 2.91-2.84 (m, 8H), 2.53-2.13 (m, 24H), 1.64-1.60 (m, 16H), 1.53-1.26 (m, 116H), 0.90-0.86 (t, 24H)

[0317] Example A4

[0318] Compounds of the following chemical formulas E and F (compound E and compound F, respectively) were prepared according to the synthesis outline shown in Fig. 4.

[0319] [Chemical Formula E]

[0320]

[0321] [Chemical Formula F]

[0322]

[0323] 1,4,7,10-tetraazacyclododecane (180.10 mg, 1.045 mmol, 1 eq) and heptadecan-9-yl 5-(oxiran-2-yl)pentanoate (1200.00 mg, 3.136 mmol, 3 eq) were placed in a 50 mL 1-neck RBF. Isopropanol (i-PrOH, 10.0 mL) was added to this mixture, and the mixture was stirred for 24 hours under reflux conditions. After the reaction was complete, the mixture was vacuum concentrated at 80°C. The product was then separated by silica column chromatography using DCM:MeOH:NH4OH (150:10:1) as the developing solvent. The separated residue was further dried using a vacuum pump after vacuum evaporation. Finally, 176.4 mg of compound E (yield: 44.1%) and 218.8 mg of compound F (yield: 54.7%) were obtained.

[0324] Compound E:

[0325] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.86-4.83 (m, 4H), 3.67 (br, 4H), 2.94-2.01 (m, 32H), 1.63 (br, 12H), 1.50 (br, 23H), 1.49-1.26 (m, 108H), 0.90-0.86 (t, 24H)

[0326] Compound F:

[0327] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.86-4.83 (m, 3H), 3.67 (br, 3H), 2.89-2.04 (m, 27H), 1.72-1.26 (m, 102H), 0.90-0.86 (t, 18H)

[0328] Example A5

[0329] A compound of the following chemical formula G (compound G) was prepared according to the synthesis outline shown in Fig. 5.

[0330] [Chemical Formula G]

[0331]

[0332] 1,4,8,11-tetraazacyclotetradecane (52.36 mg, 0.261 mmol, 1 eq) and heptadecan-9-yl 5-(oxiran-2-yl)pentanoate (600.00 mg, 1.568 mmol, 6 eq) were placed in a 25 mL 1-neck RBF. Isopropanol (i-PrOH, 2.6 mL) was added to this mixture, and the mixture was stirred under reflux conditions for 42 hours. After the reaction was complete, the solution was vacuum concentrated at 80°C. The resulting product was then separated by silica column chromatography using DCM:MeOH:NH4OH (150:10:1) as the developing solvent. The separated residue was vacuum evaporated and further dried using a vacuum pump. Finally, 328.7 mg of compound G (yield: 72.7%) in the form of a pale yellow oil was obtained.

[0333] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.88-4.83 (m, 4H), 3.58 (br, 4H), 3.21-2.01 (m, 30H), 1.68-1.26 (m, 142H), 0.90-0.86 (t, 24H)

[0334] Example A6

[0335] A compound of the following chemical formula H (compound H) was prepared according to the synthesis outline shown in Fig. 6.

[0336] [Chemical Formula H]

[0337]

[0338] Heptadecan-9-yl 6-(acryloyloxy)hexanoate (0.10 g, 2.14 mmol, 1 eq) and 1,5,9-triazcyclododecane (0.20 g, 713 μmol, 0.33 eq) were mixed in water (1 mL) and methanol (1 mL). After degassing, the mixture was purged three times with nitrogen (N2). Subsequently, the mixture was stirred at 110°C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by prep-HPLC. Finally, 0.20 g of the pale yellow oil-form compound H (yield: 19.4%) was obtained.

[0339] 1 HNMR (400 MHz, CHLOROFORM-d)δ4.87 (quin, 3 H) 4.06 (br t, 6 H) 2.67 (br dd, 6 H) 2.43 (br s, 12 H) 2.30 (t, 6 H) 1.63 - 1.70 (m, 12 H) 1.51 (br d, 18 H) 1.18 - 1.46 (m, 84 H) 0.83 - 0.95 (m, 18 H)

[0340] Example A7

[0341] A compound of the following chemical formula I (compound I) was prepared according to the synthesis outline shown in Fig. 7.

[0342] [Chemical Formula I]

[0343]

[0344] 1,5,9-triazcyclododecane (0.50 g, 2.41 mmol, 1 eq) was added to acetonitrile (ACN, 5 mL) at 25°C. Then, heptadecan-9-yl 6-(oxiran-2-yl)hexanoate (2.86 g, 7.22 mmol, 3 eq) was added to the mixture at 25°C. NaOH (0.48 g, 12.03 mmol, 5 eq) was added to this mixture at the same temperature. The mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the residue was filtered and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC. After removing ACN by concentrating under reduced pressure, the aqueous phase was neutralized with a saturated K₂CO₃ solution (10 mL) for 16 hours. Subsequently, the mixture was extracted with dichloromethane (5 mL × 2), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Finally, 0.19 g of compound I in the form of a pale yellow oil (yield: 5.80%) was obtained.

[0345] 1 HNMR: (400 MHz, CHLOROFORM-d)δ4.86 (br t, 3 H) 4.75 (br s, 3 H) 3.65-3.80 (m, 3 H) 2.86-3.22 (m, 3 H) 2.56-2.71 (m, 3 H) 2.05-2.46 (m, 12 H) 1.84-2.02 (m, 6 H) 1.65-1.72 (m, 6 H) 1.18-1.58 (m, 108 H) 0.88 (t, 18 H)

[0346] Example A8

[0347] A compound of the following chemical formula J (compound J) was prepared according to the synthesis outline shown in Fig. 8.

[0348] [Chemical Formula J]

[0349]

[0350] 1,5,9-triazcyclododecane (0.50 g, 2.41 mmol, 1 eq) was added to acetonitrile (5 mL) at 25°C. Subsequently, heptadecan-9-yl 8-bromooctanoate (3.33 g, 7.22 mmol, 3 eq) was added to the mixture at 25°C. Then, K₂CO₃ (1.33 g, 9.63 mmol, 4 eq) was added at the same temperature. The mixture was stirred at 90°C for 16 hours under a nitrogen (N₂) atmosphere. After the reaction was complete, the residue was filtered and concentrated under reduced pressure to obtain the residue. The product was purified by reverse-phase HPLC (mobile phase: [water (0.05% HCl)-ACN]). After removing ACN by concentrating under reduced pressure, the aqueous phase was neutralized with a saturated K₂CO₃ solution (10 mL) for 16 hours. Subsequently, the mixture was extracted with dichloromethane (5 mL × 2), dried with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. Finally, 0.30 g of compound J (yield: 9.30%) in the form of a pale yellow oil was obtained.

[0351] 1 HNMR: (400 MHz, CHLOROFORM-d)δ4.81 - 4.93 (m, 3 H) 2.44 (br s, 12 H) 2.28 (br t, 12 H) 1.48 - 1.60 (m, 24 H) 1.22 - 1.40 (m, 96 H) 0.89 (t, 18 H)

[0352] Example A9

[0353] A compound of the following chemical formula K (compound K) was prepared according to the synthesis outline shown in Fig. 9.

[0354] [Chemical Formula K]

[0355]

[0356] 1,4,8,12-tetraazacyclopentadecane (100 mg, 0.467 mmol, 1 eq), K₂CO₃ (112 mg, 0.866 mmol, 1.9 eq), Cs₂CO₃ (46 mg, 0.140 mmol, 0.3 eq), and KI (5.5 mg, 0.047 mmol, 0.1 eq) were placed in a 50 mL 1-neck RBF, 10 mL of THF was added, and the mixture was stirred. 2-butyloctyl 8-bromooctanoate (1096 mg, 2.799 mmol, 6 eq) was placed in a 20 mL vial, the vial was rinsed with 10 mL of THF, and the mixture was added to the RBF. The mixture was reacted under reflux conditions. After the reaction was complete, the mixture was cooled to room temperature and vacuum concentrated. Next, the mixture was diluted using Na2CO3 and methylene chloride (MC) and extracted using a saturated aqueous solution of Na2CO3. The extracted MC layer was dried with Na2SO4, filtered, and the filtrate was evaporated. The residue was separated by silica column chromatography using MC:MeOH:NH4OH (150:10:1) as the developing solvent. The separated portion was diluted with MC and further extracted using Na2CO3; the MC layer was dried with Na2SO4 and filtered. The filtrate was evaporated again, placed in a vial, and vacuum dried. Finally, 655 mg of compound K (96.3% yield), in the form of a pale yellow oil, was obtained.

[0357] 1 HNMR: (400 MHz, CHLOROFORM-d)δ3.97 - 3.96 (d, 8 H) 2.50-2.34 (m, 24 H) 2.31-2.28 (t, 8 H) 1.63-1.556 (m, 12 H) 1.41-1.29 (m, 8H) 1.29 - 1.27 (m, 90 H) 0.89 (t, 24 H)

[0358] Example A10

[0359] A compound of the following chemical formula L (compound L) was prepared according to the synthesis outline shown in Fig. 10.

[0360] [Chemical Formula L]

[0361]

[0362] 2-hexyldecyl 5-(oxiran-2-yl)pentanoate (510 mg, 1.40 mmol, 6 eq), 1,4,8,12-tetraazacyclopentadecane (50 mg, 0.23 mmol, 1 eq), and i-PrOH (20 mL) were placed in a 100 mL 1-neck RBF, and the reaction was started under reflux conditions. After 24 hours, the reaction was complete, the mixture was cooled to room temperature, and vacuum concentrated. Subsequently, silica column chromatography was performed on the product using MC:MeOH:NH4OH (150:10:1) as the developing solvent. The separated mixture was evaporated, diluted with MC (100 mL), and extracted using a saturated aqueous solution of Na2CO3. The extracted MC layer was dried with Na2SO4, filtered, and the filtrate was evaporated. Finally, 0.29 g of compound L in the form of a light yellow oil (yield: 74%) was obtained.

[0363] 1 HNMR: (400 MHz, Ethanol-d)δ4.02 - 4.01 (d, 8 H) 3.65 (br, 4 H) 2.70-2.38 (m, 24H) 2.36-2.33 (t, 8 H) 1.67-1.26 (m, 132 H) 0.89 (t, 24 H)

[0364] Example A11

[0365] A compound of the following chemical formula M (compound M) was prepared according to the synthesis outline shown in Fig. 11.

[0366] [Chemical Formula M]

[0367]

[0368] 1,4,8,12-tetraazacyclopentadecane (40 mg, 0.187 mmol, 1 eq) and 2-hexyldecyl 6-acrylamidohexanoate (458.66 mg, 1.120 mmol, 6 eq) were placed in a 25 mL 1-neck RBF. After adding n-butanol (n-BuOH, 10.0 mL) to this mixture, the mixture was stirred under reflux conditions for 48 hours. After the reaction was complete, the solution was concentrated under reduced pressure at 80°C. Subsequently, silica column chromatography was performed on the product using MC:MeOH:NH4OH (80:10:1) as the developing solvent. The separated mixture was vacuum-evaporated and further dried using a vacuum pump. Finally, 91.5 mg of compound M (yield: 26.5%) in the form of a pale yellow oil was obtained.

[0369] 1 HNMR: (400 MHz, CHLOROFORM-d)δ3.96 - 3.95 (d, 8 H) 3.26-2.20 (q, 8 H) 2.74-2.54 (m, 8 H) 2.49-2.32 (m, 14 H) 2.30-2.29 (t, 16 H) 1.65-1.60 (m, 18 H) 1.53-1.52 (m, 8H) 1.39 - 1.26 (m, 108 H) 0.89 (t, 24 H)

[0370] Example A12

[0371] A compound of the following chemical formula N (compound N) was prepared according to the synthesis outline shown in Fig. 12.

[0372] [Chemical Formula N]

[0373]

[0374] 1,4,8,12-tetraazacyclopentadecane (50 mg, 0.2 mmol, 1 eq) and isopropyl alcohol (10 mL) were placed in a 25 mL 1-neck RBF, and heptadecan-9-yl 5-(oxiran-2-yl)pentanoate (491 mg, 1.3 mmol, 5.5 eq) was added. The mixture was stirred at 110°C for 24 hours. After the reaction was complete, it was concentrated under vacuum. Subsequently, the product was separated by silica column chromatography using MC:MeOH:NH4OH (100:10:1) as the developing solvent. The separated mixture was vacuum dried. Finally, 274 mg of compound N (yield: 69.3%) in the form of a pale yellow oil was obtained.

[0375] 1 HNMR: (400 MHz, CHLOROFORM-d)δ4.88 - 4.83 (quin, 8 H) 3.60-3.58 (br, 4 H) 2.68-2.19 (m, 32 H) 1.64-1.26 (m, 146 H) 0.89 (t, 24 H)

[0376] Example A13

[0377] A compound of the following chemical formula O (compound O) was prepared according to the synthesis outline shown in Fig. 13.

[0378] [Chemical Formula O]

[0379]

[0380] 1,4,8,12-tetraazacyclopentadecane (100 mg, 0.466 mmol, 1 eq) and 2-hexyldecyl 6-(oxiran-2-yl)hexanoate (1070 mg, 2.799 mmol, 6 eq) were placed in a 25 mL 1-neck RBF. Isopropanol (i-PrOH, 10 mL) was added to this mixture, and the mixture was stirred under reflux conditions. After the reaction was complete, the mixture was vacuum concentrated at 80°C. The product was then separated by silica column chromatography using MC:MeOH:NH4OH (100:10:1) as the developing solvent. The separated residue was evaporated and further dried using a vacuum pump. Finally, 566 mg of compound O, in the form of a pale yellow oil, was obtained (yield: 69.6%).

[0381] 1 HNMR: (400 MHz, CHLOROFORM-d)δ3.96 - 3.95 (d, 8 H) 3.58 (br, 4 H) 2.68-2.20 (m, 32 H) 1.64-1.61 (m, 20 H) 1.49 (br, 6 H) 1.34-1.26 (m, 116 H) 0.89 (t, 24H)

[0382] [Preparation Example of a Drug Delivery Composition I]

[0383] 1. Preparation of raw materials

[0384] As shown in the table below, the substances required for formulation preparation were dissolved in each dilution solvent to the required concentrations. When dissolving, the substances were brought to room temperature before adding the solvent and dissolving them.

[0385]

[0386] 2. Mixing of raw materials

[0387] The required amounts of raw materials were taken and mixed according to the ratio of each compound A to O:DOPE:cholesterol:DMG-PEG = 50:10:38.5:1.5, with the NP ratio (amine group of lipid: phosphate group of mRNA) set to 6. Ethanol was added to the ethanol layer so that the sum of all raw materials was within 12.5 mM, and the aqueous phase and ethanol phase were mixed while maintaining a volume ratio of 3:1. Buffer exchange was performed as follows to lower the total ethanol content after mixing: the mixture was concentrated by centrifuging at 4,000 rpm using an Amicon-Ultra tube filter (Merk Millipore, UFC505096 or UFC805024, pore size: 50K or 100K, volume 0.5 mL or 4 mL or 15 mL), and then the process of diluting with PBS and centrifuging to concentrate was repeated to perform buffer exchange.

[0388] The specific process sequence is as follows.

[0389] 1) Two autoclaved tubes were prepared (tubes (A), (B)).

[0390] 2) Each compound of formulas A to O and DOPE, cholesterol, and DMG-PEG were added in sequence to Tube (A) in the number of moles calculated according to experimental conditions, and mixed by vortexing after addition.

[0391] 3) Ethanol was added as needed in the ethanol phase so that the total of all raw materials was within 6.25-12.5 mM.

[0392] 4) mRNA and 20 mM sodium acetate buffer (pH 4.6) were mixed in Tube (B). The ratio was calculated so that the volume of the aqueous phase was three times the volume of the ethanol phase.

[0393] 5) Mixing of tube (A) and tube (B) was performed using a Microfluidics (Ignite, Precision Nanosystem) instrument. The Microfluidics operating conditions were a Flow Rate Ratio (FRR) of C:R=3:1 and a Total Flow Rate (TRR) of 12 mL / min.

[0394] 6) The resulting mixture from step 5) was centrifuged at 4,000 rpm using an Amicon-Ultra tube filter (50K) to concentrate it, then diluted with PBS and centrifuged to concentrate it again to remove excess ethanol, and then concentrated to a final x mg / mL (theoretical concentration).

[0395] 7) Once concentrated to the desired concentration, it was sterilized using a 0.22 µm pore size filter.

[0396] 4. Evaluation of Physical Properties of the Formulation

[0397] 1) For the prepared formulations, particle characteristics (i.e., zeta-average particle size, polydispersity index (PDI), and zeta-potential) were determined using a particle size analyzer (Dynamic Light Scattering, DLS), and the results are shown in Table 1 below.

[0398] 2) For the prepared formulations, mRNA encapsulation efficiency was confirmed through a Ribo-green assay, and the results are shown in Table 1 below.

[0399]

[0400] Example B: Preparation Example II of a drug delivery composition using lipid compound A and drug delivery test

[0401] (1) Preparation of solutions by component

[0402] The components listed in Table 2 below were dissolved in each diluent solvent to prepare the formulations at the concentrations shown in Table 2. All components were brought to room temperature before use. Lipid compound A was mixed by vortexing after adding the diluent solvent. DSPC, Cholesterol, and DMG-PEG were incubated in a 60°C oven for at least 5 minutes after adding the diluent solvent, then brought to room temperature before use. mPEG-PLA (2K-4K) was treated with a bath sonicator for approximately 10 minutes after adding the diluent solvent. All components were used for formulation preparation after being visually confirmed to be completely dissolved.

[0403]

[0404] (2) Mixing of raw materials

[0405] According to Table 3 below, each component was taken and mixed in a glass vial to prepare the ethanol phase. If necessary, ethanol was added to ensure that the concentration of all mixed components ranged from 5.6 to 12.5 mM. The aqueous phase was prepared by adding 20 mM sodium acetate buffer (pH 4.6) to the mRNA to make the volume three times that of the ethanol phase. The ethanol and aqueous phases were mixed while maintaining a 3:1 ratio. Amicon Ultra Cnetrifugal Filter Units (Merk Milipore, UFC810024 or UFC910024) were used to reduce the ethanol content of the mixture. The buffer was exchanged by repeatedly concentrating and diluting the mixture in the Amicon Ultra Cnetrifugal Filter Units at 4,000 rpm.

[0406] The specific process sequence is as follows.

[0407] 1) Two autoclaved tubes were prepared (tubes (A), (B)).

[0408] 2) In tube (A), the moles of lipid compound A, DSPC, cholesterol, mPEG-PLA (2K-4K), or DMG-PEG calculated according to experimental conditions were added sequentially and mixed by vortexing.

[0409] 3) If necessary, ethanol was added and mixed by vortexing so that the concentration of all components contained in the ethanol phase was 5.6 to 12.5 mM.

[0410] 4) mRNA and 20 mM sodium acetate buffer (pH 4.6) were mixed in tube (B). The ratio was calculated so that the volume of the aqueous phase was three times the volume of the ethanol phase.

[0411] 5) Mixing of tube (A) and tube (B) was performed using a Microfluidics (Ignite, Precision Nanosystem) instrument. The mixing conditions were as follows: the Flow Rate Ratio (FRR) was C:R=3:1, and the Total Flow Rate (TFR) was 3–12 mL / min.

[0412] 6) The resulting mixture from step 5) was centrifuged at 4,000 rpm using Amicon Ultra Concentric Filter Units (100K), and the process of concentration and dilution was repeated to remove as much ethanol contained in the mixture as possible and the buffer was replaced. Afterwards, it was concentrated to the desired theoretical concentration.

[0413] 7) Once concentrated to the desired theoretical concentration, it was sterilized using a 0.22 µm pore size filter.

[0414] 8) The actual concentration was measured using a ribo-green assay and then used.

[0415]

[0416] (3) Evaluation of formulation

[0417] For the manufactured formulations, particle characteristics were confirmed using a dynamic light scattering (DLS) analyzer, and the results are shown in Table 4 below.

[0418]

[0419] (4) Administration of composition

[0420] 1) The prepared formulation was prepared at a concentration of 40 μg / mL based on mRNA, and 2 μg of mRNA was intramuscularly administered to one thigh of mice. Four hours after administration, protein expression in the body or in each organ was confirmed using the IVIS spectrum in vivo imaging system, and the results are shown in Table 5 below.

[0421]

[0422] 2) The prepared formulation was prepared at a concentration of 400 μg / mL based on mRNA, and 20 μg of mRNA was administered intramuscularly to mice. Seven days after administration, mouse splenocytes were isolated, and antigen-specific T cell immune responses induced in mice were confirmed using ELISpot. The results are shown in Table 6 below.

[0423]

Claims

1. Lipids having a structure represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, Each R is independently a substituted or unsubstituted alkylene group, and Each A independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one A is any one of (ii) to (iv), and R 11 , R 13 , R 14 and R 16 Each is independently a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and R 12 , R 15 and R 17 Each is independently a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and X is -OH or -SH, and n is an integer greater than or equal to 1.

2. In claim 1, a lipid having a structure represented by any one of the following chemical formulas: As mentioned above, R1 to R5 are each independently substituted or unsubstituted alkylene groups, and R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one of R6 to R8 is any one of (ii) to (iv), and R 11 , R 13 , R 14 and R 16 Each is independently a substituted or unsubstituted divalent saturated or unsaturated hydrocarbon group, and R 12 , R 15 and R 17 Each is independently a substituted or unsubstituted monovalent saturated or unsaturated hydrocarbon group, and L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-L'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, arylene groups, and heteroarylene groups, wherein L' is a directly bonded, substituted or unsubstituted alkylene group or substituted or unsubstituted alkenylene group, and R' is each independently selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted alkenyl group, and X is -OH or -SH.

3. In paragraph 2, the above R 11 ~R 17 A lipid, wherein one or more of the following are further substituted with one or more moieties selected from amino acids, sugars, vitamins, peptides, proteins, hormones, antibodies, neurotransmitters, pharmaceutically active small molecules, endosome-degrading agents, cell membrane permeability agents, charge blockers, drugs, nucleic acids, or derivatives thereof.

4. In Paragraph 2, R1 to R5 are each independently substituted or unsubstituted C 1-4 It is an alkylene group, and R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least one of R6 to R8 is any one of (ii) to (iv), and R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-20 It is a hydrocarbon group, and R 12 , R 15 and R 17 Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 2-20 It is a hydrocarbon group, and L1 and L2 are each independently -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -SS-, C 6-20 C having an arylene group and one or more heteroatoms selected from N, O, and S 3-20 Selected from the group consisting of heteroarylene groups, where L' is directly bonded, substituted, or unsubstituted C 1-13 alkylene group or substituted or unsubstituted C 1-13 It is an alkenylene group, and R' are each independently hydrogen atoms, substituted or unsubstituted C. 1-18 Alkyl groups and substituted or unsubstituted C 2-18 Selected from a group composed of alkenyl groups, and X is -OH or -SH, Geology.

5. In Paragraph 2, R1 to R5 are each independently substituted or unsubstituted C 2-4 It is an alkylene group, and R6 to R 10 Each independently (i) a hydrogen atom (H), (ii) , (iii) or (iv) However, at least two of R6 to R8 are any one of (ii) to (iv), and R 11 , R 13 , R 14 and R 16 Each is independently substituted or unsubstituted divalent saturated or unsaturated C 2-10 It is a hydrocarbon group, and R 12 , R 15 and R 17 Each is independently substituted or unsubstituted monovalent saturated or unsaturated C 10-20 It is a hydrocarbon group, and L1 and L2 are each independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, where R' is each independently a hydrogen atom, and a substituted or unsubstituted C 1-4 Selected from the group consisting of alkyl groups, and X is -OH, Geology.

6. In claim 1, a lipid having any one structure selected from compounds A to O below:

7. A drug delivery composition comprising a lipid according to any one of claims 1 to 6.

8. An active ingredient selected from nucleic acids, polypeptides, viruses, or combinations thereof; Geology of any one of paragraphs 1 to 6; and Lipid-polymer polymers, amphiphilic block copolymers, or combinations thereof; comprising Composition for drug delivery.

9. A drug delivery composition according to claim 8, wherein the active ingredient is mRNA.

10. A drug delivery composition according to claim 8, wherein the lipid-polymer polymer is a polymer in which one or more saturated and unsaturated hydrocarbon groups having 11 to 25 carbon atoms are introduced as hydrophobic portions into a hydrophilic block which is a hydrophilic portion.

11. A drug delivery composition according to claim 10, wherein the hydrophilic block is one or more selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and derivatives thereof.

12. A drug delivery composition according to claim 10, wherein the saturated and unsaturated hydrocarbon groups having 11 to 25 carbon atoms are independently selected from the group consisting of lauryl, myristoyl, dimyristoyl, myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl, cerotyl, myristoleyl, palmitoleyl, sapienyl, oleyl, linoleyl, arachidonyl, eicosapentaenyl, erucyl, and docosahexaenyl.

13. A drug delivery composition according to claim 8, wherein the amphiphilic block copolymer is an AB type diblock copolymer composed of a hydrophilic A block and a hydrophobic B block, wherein the hydrophilic A block is one or more selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and derivatives thereof, and the hydrophobic B block is one or more selected from the group consisting of polyester, polyanhydride, polyamino acid, polyorthoester and polyphosphazine.

14. A drug delivery composition according to claim 13, wherein the terminal hydroxyl group of the hydrophobic B block is modified by one or more selected from the group consisting of cholesterol, tocopherol, and fatty acids having 10 to 24 carbon atoms.

15. A drug delivery composition according to claim 8, further comprising a fused lipid.

16. A drug delivery composition according to claim 15, wherein the fusion lipid is one or more combinations selected from the group consisting of phospholipids, cholesterol, and tocopherol.

17. (a) a step of preparing a solution in which the lipid of any one of claims 1 to 6; and a lipid-polymer, an amphiphilic block copolymer, or a mixture thereof; is dissolved in a water-miscible organic solvent; and (b) a step of adding and mixing an active ingredient selected from nucleic acids, polypeptides, viruses, or combinations thereof to the solution prepared in step (a); comprising, Method for preparing a drug delivery composition.

18. A method for preparing a drug delivery composition, wherein the water-miscible organic solvent of step (a) in claim 17 is ethanol.

19. In Paragraph 17, step (b) is, (b-1) A step of preparing a buffer solution containing the above active ingredient; and (b-2) a step of adding the buffer solution of the active ingredient prepared in step (b-1) to the solution prepared in step (a) and mixing; comprising, Method for preparing a drug delivery composition.

20. In Paragraph 17, step (b) is, (b-1) A step of adding an active ingredient to the solution prepared in step (a); and (b-2) A step of adding a buffer solution to the product of step (b-1) and mixing; comprising, Method for preparing a drug delivery composition.

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