Nanoparticle composition for drug delivery

Abstract

The present invention relates to a composition for drug delivery and a preparation method thereof and, more specifically, to: a composition for drug delivery in which a drug is encapsulated inside a nanoparticle structure formed by a specific polymer and a cationic compound; and a preparation method thereof.

Description

Composition of nanoparticles for drug delivery

[0001] The present invention relates to a drug delivery composition and a method for producing the same, and more particularly, to a drug delivery composition in which a drug is encapsulated inside a nanoparticle structure formed by a specific polymer and a cationic compound, and a method for producing the same.

[0002] Safe and efficient drug delivery technologies for the treatment of anionic drugs, including nucleic acids, have long been studied, and various carriers and delivery technologies have been developed. Carriers are broadly divided into viral carriers, such as those using adenoviruses or retroviruses, and nonviral carriers, such as those using cationic lipids and cationic polymers. Viral carriers are known to be susceptible to risks such as nonspecific immune responses. Therefore, recent research is focused on improving these drawbacks by utilizing nonviral carriers. While nonviral carriers are less efficient than viral carriers, they offer the advantage of fewer side effects in terms of in vivo safety.

[0003] Among non-viral delivery systems, the most representative ones are complexes of cationic lipids and nucleic acids (lipoplexes) and polycationic polymers and nucleic acids (polyplexes). These cationic lipids or polycationic polymers have been extensively studied for their ability to stabilize anionic drugs and enhance intracellular delivery by forming complexes with them through electrostatic interactions. However, when administered intravenously at the doses necessary to achieve sufficient efficacy, they induce significant toxicity, although less than viral vectors, making them unsuitable for pharmaceutical use. Therefore, the development of anionic drug delivery technologies that minimize the use of potentially toxic cationic polymers or cationic lipids, thereby reducing toxicity while maintaining stability in vivo and enabling intracellular delivery for sufficient efficacy is needed.

[0004] Accordingly, anionic drug delivery compositions and various manufacturing methods have been disclosed, which form a complex through electrostatic interaction between a nucleic acid and a cationic lipid, and encapsulate the complex within the nanoparticle structure of an amphiphilic block copolymer. For example, Korean Patent Publication No. 2017-0032858 discloses an anionic drug delivery composition and a manufacturing method thereof, which comprises an anionic drug as an active ingredient; a cationic compound; an amphiphilic block copolymer; and a polylactic acid salt, 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 salt. However, existing nanoparticle drug delivery systems, including those disclosed in the above-mentioned patent, still lack the efficiency of delivering drugs (particularly, mRNA) such as nucleic acids, polypeptides, or viruses into the body.

[0005] The present invention aims to provide a drug delivery composition and a method for producing the same, which have significantly improved delivery efficiency of drugs (particularly, mRNA) such as nucleic acids, polypeptides or viruses into the body compared to existing known nanoparticle drug delivery vehicles.

[0006] A first aspect of the present invention provides a drug delivery composition comprising: an active ingredient selected from a nucleic acid, a polypeptide, a virus, or a combination thereof; an amphiphilic block copolymer comprising a hydrophilic block and a hydrophobic block; and a cationic compound; wherein the hydrophobic block is a biocompatible, biodegradable polymer having repeating units of a structure represented by the following chemical formula 1:

[0007] [Chemical Formula 1]

[0008]

[0009] In the above chemical formula 1,

[0010] R represents a branched alkylene group having 3 or more carbon atoms.

[0011] A second aspect of the present invention provides a method for producing a composition for drug delivery, comprising the steps of: (a) preparing a solution in which an amphiphilic block copolymer including a hydrophilic block and a hydrophobic block and a cationic compound are dissolved in a water-miscible organic solvent; and (b) adding and mixing an active ingredient selected from a nucleic acid, a polypeptide, a virus, or a combination thereof to the solution prepared in step (a), wherein the hydrophobic block is a biocompatible, biodegradable polymer having repeating units of a structure represented by the above chemical formula 1.

[0012] The drug delivery composition according to the present invention can significantly improve the delivery efficiency of drugs (particularly, mRNA) such as nucleic acids, polypeptides or viruses into the body compared to existing nanoparticle drug delivery vehicles.

[0013] Hereinafter, the present invention will be described in more detail.

[0014] Active ingredients

[0015] The active ingredient included in the drug delivery composition of the present invention is selected from nucleic acids, polypeptides, viruses, or a combination thereof.

[0016] The above “nucleic acid” may be, for example, but is not limited to, DNA, RNA, siRNA, shRNA, miRNA, mRNA, aptamer, antisense oligonucleotide, or a combination thereof.

[0017] The above “polypeptide” may mean a protein that is active in the body, such as an antibody or a fragment thereof, a cytokine, a hormone or an analog thereof, or a polypeptide sequence of an antigen, an analogue or precursor thereof, which can be recognized as an antigen through a series of processes in the body.

[0018] The above “virus” may be an oncolytic virus, and may be, for example, one or more selected from the group consisting of adenovirus, AAV, vaccinia virus, herpes simplex virus (HSV), and vesicular stomatitis virus (VSV). In one specific embodiment, the oncolytic virus is an adenovirus. The adenovirus used in a specific embodiment of the present invention comprises a luciferase gene, which can be detected by imaging.

[0019] The above virus can express various therapeutic genes in a subject's body, and is not limited to a specific molecular weight, protein, bioactivity, or therapeutic area. The prophylactic virus can induce immunity in a subject's body against the target disease. A composition containing the disease-preventing virus has the advantages of reducing the immune induction caused by the virus itself, targeting or expanding target cells, and reducing hyperimmune responses to the virus upon re-administration, allowing for effective effects with multiple vaccinations.

[0020] In one specific embodiment of the present invention, the active ingredient is messenger RNA (mRNA).

[0021] The mRNA may have its backbone, sugars or bases chemically modified or its ends modified for purposes such as increasing blood stability or weakening the immune response.

[0022] In one specific example, 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, 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, based on the dry weight of the entire composition. If the content of the active ingredient is too small, the amount of carrier used is too large compared to the drug, which may cause side effects due to the carrier, and conversely, if it is too large, the amount of drug that is not encapsulated in the nanoparticles increases, which reduces the efficiency.

[0023] Amphiphilic block copolymer

[0024] The drug delivery composition of the present invention comprises an amphiphilic block copolymer comprising a hydrophilic block and a hydrophobic block as polymer components, wherein the hydrophobic block is a biocompatible biodegradable polymer having repeating units of a structure represented by the following chemical formula 1:

[0025] [Chemical Formula 1]

[0026]

[0027] In the above chemical formula 1,

[0028] R represents a branched alkylene group having 3 or more carbon atoms.

[0029] In one specific example, the number of repeating units (degree of polymerization) of the hydrophobic block 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, but is not limited to, 25 or less, 24 or less, 23 or less, 22 or less, 21 or less, or 20 or less.

[0030] In one specific example, the amphiphilic block copolymer may be an AB type block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B). The AB type block copolymer forms core-shell type polymer nanoparticles in an aqueous solution, in which the hydrophobic block (B) forms a core (inner wall) and the hydrophilic block (A) forms a shell (outer wall).

[0031] In one specific example, the hydrophilic block may be at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and derivatives thereof.

[0032] More specifically, the hydrophilic block may be at least one selected from the group consisting of monomethoxypolyethylene glycol (mPEG), monoacetoxypolyethylene glycol, polyethylene glycol, copolymers of polyethylene and propylene glycol, and polyvinylpyrrolidone.

[0033] In one specific example, the number average molecular weight (g / mol) of the hydrophilic 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.

[0034] In addition, if necessary, a functional group, ligand, or functional group capable of promoting intracellular delivery that can reach a specific tissue or cell can be chemically bonded to the terminal of the hydrophilic block to control the distribution of the polymer nanoparticle carrier formed of the amphiphilic block copolymer and polylactic acid salt in the body or to increase the efficiency of delivery of the nanoparticle carrier into cells. In one specific example, the functional group or ligand includes any molecule such as an amino acid, sugar, vitamin, peptide, protein, hormone, antibody, neurotransmitter, pharmaceutically active small molecule, endosomolytic agent, cell membrane permeabilizer, charge blocker, drug, nucleic acid, or derivative thereof that can directly or indirectly interact with other compounds such as receptors. The sugar may include, but is not limited to, galactose, galactosamine, N-acetylgalactosamine, or a combination 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, but is not limited to, growth factors such as VEGF, EGF, NGF, and PDGF; cholesterol; bile acids; GABA, glutamate, acetylcholine, or combinations thereof. In one embodiment, the functional group or ligand may be attached to the end of the hydrophilic block using a linker molecule. The above linker molecules may include, but are 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, and the like.

[0035] The hydrophobic block is a biocompatible biodegradable polymer having repeating units of a structure represented by the chemical formula 1.

[0036] In one specific example, the number of carbon atoms of R in the above chemical formula 1 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.

[0037] In one specific example, R in the above chemical formula 1 may represent a branched alkylene group having 3 to 20 carbon atoms, more specifically, may represent a branched alkylene group having 3 to 17 carbon atoms, even more specifically, may represent a branched alkylene group having 3 to 15 carbon atoms, and even more specifically, may represent a branched alkylene group having 3 to 13 carbon atoms, but is not limited thereto.

[0038] In one specific example, the hydrophobic block may be a biocompatible biodegradable polymer having repeating units of a structure selected from, but not limited to:

[0039] , , , , , , , , , , , , , , , ,

[0040] In one specific example, the repeating unit of the structure represented by the above chemical formula 1 can be obtained by ring-opening polymerization of a lactone compound.

[0041] In one specific example, the number average molecular weight (g / mol) of the hydrophobic block 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.

[0042] For example, the number average molecular weight combination of the hydrophilic block-hydrophobic block may be, but is not limited to, 2,000-6,000, 2,000-4,000, 2,000-3,000, 2,000-1,700, 2,000-1,300, 2000-1000, 2000-800, 2000-500, etc.

[0043] Additionally, in one specific example, the hydrophobic block may be modified by chemically bonding tocopherol, cholesterol, or a fatty acid having 10 to 24 carbon atoms to a hydroxyl group at the end of the hydrophobic block to increase the hydrophobicity of the hydrophobic block and thereby improve the stability of the nanoparticle.

[0044] In one specific example, in the amphiphilic block copolymer, the composition ratio of the hydrophilic block and the hydrophobic block may be in the range of 25 to 95 wt% of the hydrophilic block, specifically 40 to 90 wt%, and more specifically 50 to 80 wt%, based on the total weight of the copolymer. If the proportion of the hydrophilic block is less than 25 wt% based on the total weight of the copolymer, the polymer has low solubility in water, making it difficult to form nanoparticles. Therefore, it is preferable that the proportion of the hydrophilic block is 25 wt% or more in order for the copolymer to have sufficient solubility in water to form nanoparticles. On the other hand, if the proportion of the hydrophilic block (A) exceeds 95 wt% based on the total weight of the copolymer, the hydrophilicity is too high, lowering the stability of the polymer nanoparticles, making it difficult to use it as a solubilizing composition of a complex containing an active ingredient. Therefore, it is preferable that the proportion of the hydrophilic block is 95 wt% or less in consideration of nanoparticle stability.

[0045] In one specific example, the content of the amphiphilic block copolymer in the drug delivery composition of the present invention may be 5 wt% or more, 6 wt% or more, 7 wt% or more, 10 wt% or more, 12 wt% or more, 15 wt% or more, 17 wt% or more, or 18 wt% or more, and may also be 90 wt% or less, 80 wt% or less, 70 wt% or less, 60 wt% or less, 50 wt% or less, 40 wt% or less, or 30 wt% or less, based on the dry weight of the entire composition. If the content of the polymer is too low, the size of the nanoparticles may become too large, which may lower the stability of the nanoparticles and increase the loss rate during filter sterilization. Conversely, if the content is too high, the content of the active ingredient that can be incorporated may become too low.

[0046] According to one specific example, within the scope that can achieve the purpose of the present invention, the hydrophobic block may further include additional hydrophobic repeating units other than the repeating units of the structure represented by the chemical formula 1.

[0047] In one specific embodiment, the additional hydrophobic repeating unit may be at least one selected from the group consisting of polyester, polyanhydride, polyamino acid, polyorthoester and polyphosphazine, and more specifically, may be at least one selected from the group consisting of polylactide (PLA), polyglycolide, polydioxan-2-one, copolymers of polylactide and glycolide and copolymers of polylactide and polydioxan-2-one, but is not limited thereto.

[0048] cationic compounds

[0049] The drug delivery composition of the present invention comprises a cationic compound.

[0050] In one embodiment, the cationic compound may be a cationic lipid, a cationic polymer, or a combination thereof, and more specifically, may be a cationic lipid.

[0051] For example, the cationic lipids include N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride (DOTAP), N,N-dimethyl-(2,3-dioleoyloxy)propylamine (DODMA), N,N,N-trimethyl-(2,3-dioleoyloxy)propylamine (DOTMA), 1,2-diacyl-3-trimethylammonium-propane (TAP), 1,2-diacyl-3-dimethylammonium-propane (DAP), 3beta-[N-(N',N',N'-trimethylaminoethane)carbamoyl]cholesterol (TC-cholesterol), 3beta-[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-cholesterol), 3beta-[N-(N'-monomethylaminoethane)carbamoyl]cholesterol (MC-cholesterol), 3beta-[N-(aminoethane)carbamoyl]cholesterol (AC-cholesterol), cholesteryloxypropan-1-amine (COPA), N-(N'-aminoethane)carbamoylpropanoic tocopherol (AC-tocopherol) and N-(N'-methylaminoethane)carbamoylpropanoic tocopherol (MC-tocopherol), and more specifically, 3beta-[N-(N',N',N'-trimethylaminoethane)carbamoyl]cholesterol (TC-cholesterol), It may be at least one selected from the group consisting of 3beta[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-cholesterol), 3beta[N-(N'-monomethylaminoethane)carbamoyl]cholesterol (MC-cholesterol), 3beta[N-(aminoethane)carbamoyl]cholesterol (AC-cholesterol), N-(1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride (DOTAP), N,N-dimethyl-(2,3-dioleoyloxy)propylamine (DODMA), and N,N,N-trimethyl-(2,3-dioleoyloxy)propylamine (DOTMA).

[0052] In one specific example, the cationic lipid may be a lipid having a structure represented by the following chemical formula 2 or an ionized form thereof:

[0053] [Chemical Formula 2]

[0054]

[0055] In the above chemical formula 2,

[0056] M1 and M2 are each independently a divalent linker group,

[0057] R1 and R2 are each independently a substituted or unsubstituted carbon cyclic group or heterocyclic group,

[0058] R3 is a hydrogen atom or a substituted or unsubstituted organic group optionally containing one or more heteroatoms,

[0059] R4 to R 11 are each independently a hydrogen atom, or a substituted or unsubstituted saturated or unsaturated hydrocarbon group,

[0060] Me is a methyl group,

[0061] a, b, c and d are each independently integers from 1 to 20.

[0062] In the above chemical formula 2, the expression that any group is “substituted or unsubstituted” means that the group is unsubstituted or is a hydroxyl group or C, unless otherwise specified. 1-6 This means that it is substituted with an alkyl group.

[0063] According to one specific example, in the above chemical formula 2, M1 and M2 are each independently -C(O)O-, -OC(O)-, -OC(O)-M'-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 (more specifically, C 6-20 Arylene, more specifically C6-10 arylene), and heteroarylene (more specifically, C having one or more (e.g., 1 to 3) heteroatoms selected from N, O and S 3-20 Heteroarylene, more specifically C 3-10 heteroarylene), wherein M' is a direct bond, C 1-13 Alkylene (more specifically C 1-6 alkylene) or C 2-13 Alkenylene (more specifically C 2-6 alkenylene), and R' is each independently a hydrogen atom, C 1-18 Alkyl (more specifically C 1-10 Alkyl, more specifically C 1-6 alkyl) and C 2-18 Alkenyl (more specifically C 2-10 Alkenyl, more specifically C 2-6 It can be selected from the group consisting of alkenyl).

[0064] According to one specific example, in the above chemical formula 2, R1 and R2 are each independently substituted or unsubstituted C 3-20 Cycloalkyl (more specifically C 3-10 Cycloalkyl, more specifically C 3-6 cycloalkyl), substituted or unsubstituted C 3-20 Cycloalkenyl (more specifically C 3-10 Cycloalkenyl, more specifically C 3-6 cycloalkenyl), substituted or unsubstituted C 6-20 Aryl (more specifically C 6-10 Aryl, more specifically C6 aryl), substituted or unsubstituted C 3-20 Heterocycloalkyl (more specifically C 3-10 Heterocycloalkyl, more specifically C 3-6 heterocycloalkyl), substituted or unsubstituted C 3-20 Heterocycloalkenyl (more specifically C 3-10Heterocycloalkenyl, more specifically C 3-6 heterocycloalkenyl), and substituted or unsubstituted C 3-20 Heteroaryl (more specifically C 3-10 Heteroaryl, more specifically C 3-6 may be selected from the group consisting of heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein each of the heterocycloalkyl, heterocycloalkenyl and heteroaryl may independently have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S.

[0065] According to one specific example, in the above chemical formula 2, R3 is a hydrogen atom, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclic group, -(CH2) n Q, - (CH2) n may be selected from the group consisting of CHQR, -CHQR and -CQ(R)2, wherein each R is independently a hydrogen atom, C 1-3 Alkyl and C 2-3 may be selected from the group consisting of alkenyl; Q is a carbocyclic group, a heterocyclic group, -OR, -O(CH2) n N(R)2, -C(O)OR, -OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R 12 , N(R)S(O)2R 12 , -O(CH2) n OR, -N(R)C(=NR 13 )N(R)2, -N(R)C(=CHR 13 )N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2, -N(OR)C(=NR 13)N(R)2, -N(OR)C(=CHR 13 )N(R)2, -C(=NR 13 )N(R)2, - C(=NR 13 )R, -C(O)N(R)OR and -C(R)N(R)2C(O)OR, wherein each n is independently an integer from 1 to 5, and R 12 is C 3-6 Selected from the group consisting of carbon cyclic groups and heterocyclic groups, R 13 Silver H, CN, NO2, C 1-6 Alkyl, -OR, -S(O)2R, -S(O)2N(R)2, C 2-6 Alkenyl, C 3-6 Selected from the group consisting of a carbon cyclic group and a heterocyclic group, each R is independently a hydrogen atom, C 1-3 Alkyl and C 2-3 is selected from the group consisting of alkenyl, each X is independently selected from the group consisting of F, CI, Br and I, provided that R3 is -(CH2) n Q, -(CH2) n When CHQR, -CHQR or -CQ(R)2, (i) if n is 1, 2, 3, 4 or 5, Q is not -N(R)2, or (ii) if n is 1 or 2, Q is not a 5-, 6- or 7-membered heterocycloalkyl.

[0066] According to one specific example, in the above chemical formula 2, R4 to R 11 are each independently a hydrogen atom, C 1-3 Alkyl and C 2-3 It can be selected from the group consisting of alkenyl.

[0067] According to one specific example, in the chemical formula 2, a, b, c and d can each independently be an integer from 1 to 15.

[0068] More specifically, in the above chemical formula 2, M1 and M2 can each independently be -C(O)O- or -OC(O)-.

[0069] More specifically, in the above chemical formula 2, R1 and R2 are each independently substituted or unsubstituted C 3-6 It may be cycloalkyl.

[0070] More specifically, in the above chemical formula 2, R3 is a hydrogen atom or a substituted or unsubstituted C 1-3 It may be alkyl, and more specifically unsubstituted C 1-3 C substituted with alkyl or hydroxy groups 1-3 It could be an alkyl.

[0071] More specifically, in the above chemical formula 2, R4 to R 11 can be a hydrogen atom.

[0072] More specifically, in the above chemical formula 2, a, b, c and d can each independently be an integer from 3 to 11, and even more specifically, an integer from 5 to 9.

[0073] More specifically, the lipid of the above chemical formula 2 may have any one structure selected from the following chemical formulas 2-A to 2-O:

[0074]

[0075]

[0076] In another embodiment, the cationic lipid may be a lipid having any one of the structures shown in Chemical Formula 3 below, or an ionized form thereof:

[0077] [Chemical Formula 3]

[0078] ;

[0079] ;

[0080] ;

[0081] In each of the structures shown in the above chemical formula 3, at least two (more specifically, 2 to 7) of the R groups are Rx, and the remaining R groups are Ry,

[0082] Rx are each independently , , and , wherein a, b and c are each independently an integer from 2 to 20, R1 is a substituted or unsubstituted saturated or unsaturated divalent hydrocarbon group, R2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, represents a substituted or unsubstituted methylene group,

[0083] Ry is independently H or a substituted or unsubstituted alkyl group, and two Ry other than H can be linked to each other to form a ring structure together with the nitrogen atom to which they are attached.

[0084] L is each independently a substituted or unsubstituted alkylene group, and may optionally have an ether bond (-O-), a thioether bond (-S-), or a disulfide bond (-S-S-) within its structure.

[0085] In the above chemical formula 3, the expression that any group is “substituted or unsubstituted” means that the group is unsubstituted or is substituted with -OH, a halogen atom, C, unless otherwise specified. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl 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 It means that it is substituted with one or more substituents selected from among heteroaryl groups.

[0086] According to one specific example, in the above chemical formula 3, each Rx is independently , , and , wherein a, b and c can each independently be an integer from 2 to 20 or from 2 to 15, and R1 is a substituted or unsubstituted saturated or unsaturated divalent C 1-12 It may be a hydrocarbon group, and R2 is a substituted or unsubstituted unsaturated monovalent C 2-24 It may be a hydrocarbon group, represents a substituted or unsubstituted methylene group.

[0087] According to one specific example, in the chemical formula 3, a, b, and c may each independently be an integer from 2 to 15, and more specifically, may each independently be an integer from 3 to 12. Even more specifically, a may be an integer from 5 to 7, and b and c may each independently be an integer from 3 to 11, but are not limited thereto.

[0088] According to one specific example, in the chemical formula 3, each Ry is independently H, or C 1-20 It may be an alkyl group, wherein the alkyl group is each independently unsubstituted or -OH, C 1-20 Alkyl, C 1-20 Alkoxy, -NH2, -NH(C 1-20 alkyl), -N(C 1-20 alkyl)2, optionally substituted C 3-20 Carbocyclic group (e.g., C 3-20 Cycloalkyl group or C 6-20 aryl group) and optionally substituted C 3-20 Heterocyclic group (e.g., C 3-20 Heterocycloalkyl group or C 3-20wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S, and two Ry other than H may be connected to each other together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O. In addition, the alkyl group or alkoxy group here is more specifically C 1-10 An alkyl group or an alkoxy group, more specifically C 1-6 It may be an alkyl group or an alkoxy group, but is not limited thereto.

[0089] According to one specific example, in the above chemical formula 3, each L is independently C 1-20 Alkylene group (more specifically C 1-10 Alkylene group, more specifically C 1-6 alkylene group), which may be independently unsubstituted or -OH, C 1-20 Alkyl, C 1-20 Alkoxy, -NH2, -NH(C 1-20 alkyl), -N(C 1-20 alkyl)2, optionally substituted C 3-20 Carbocyclic group (e.g., C 3-20 Cycloalkyl group or C 6-20 aryl group) and optionally substituted C 3-20 Heterocyclic group (e.g., C 3-20 Heterocycloalkyl group or C 3-20 wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S. In addition, the alkyl group or alkoxy group is more specifically C 1-10 An alkyl group or an alkoxy group, more specifically C 1-6 It may be an alkyl group or an alkoxy group, but is not limited thereto.

[0090] More specifically, in the above chemical formula 3, each Ry is independently H, or C 1-10 It may be an alkyl group, wherein the alkyl group is each independently unsubstituted or -OH, C 1-10 Alkyl, C 1-10 Alkoxy, -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, optionally substituted C 3-10 Carbocyclic group and optionally substituted C 3-10 It may be substituted by one or more selected from a heterocyclic group, wherein said heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S, and two Ry, other than H, may be linked to each other together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0091] More specifically, in the above chemical formula 3, each L is independently C 1-10 It can be an alkylene group, which is independently unsubstituted or -OH, C 1-10 Alkyl, C 1-10 Alkoxy, -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, optionally substituted C 3-10 Carbocyclic group and optionally substituted C 3-10 It may be substituted by one or more selected from a heterocyclic group, wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S.

[0092] More specifically, in the above chemical formula 3, each Rx is independently , and , wherein a, b and c can each independently be an integer from 3 to 12, and R1 is a substituted or unsubstituted C1-12 alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C 2-12 It may be an alkynylene group, and R2 is substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 It can be an alkynyl group, represents a substituted or unsubstituted methylene group.

[0093] More specifically, in the above chemical formula 3, each Ry is independently H, or C 1-6 It may be an alkyl group, wherein said alkyl group may be independently unsubstituted or substituted by one or more selected from -OH and -NH2, and two Ry, other than H, may be linked to each other together with the nitrogen atom to which they are attached, to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0094] More specifically, in the above chemical formula 3, each L independently represents an unsubstituted C 1-6 It may be an alkylene group.

[0095] Specifically, the lipid of the above chemical formula 3 may have any of the following structures:

[0096]

[0097] In each of the above structures, R1 to R7 are each independently , , and , wherein a, b and c are each independently an integer from 2 to 20, R1 is a substituted or unsubstituted saturated or unsaturated divalent hydrocarbon group, R2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, represents a substituted or unsubstituted methylene group.

[0098] More specifically, the lipid of the above chemical formula 3 may have any one structure selected from the following chemical formulas 3-A to 3-V:

[0099]

[0100]

[0101]

[0102] In another specific example, the cationic lipid may be a lipid having a structure represented by the following chemical formula 4 or an ionized form thereof:

[0103] [Chemical Formula 4]

[0104]

[0105] In the above chemical formula 4,

[0106] M1 and M2 are each independently a divalent linker group,

[0107] R1 and R2 are each independently a substituted or unsubstituted carbon cyclic group or heterocyclic group,

[0108] R3 is a hydrogen atom or a substituted or unsubstituted organic group optionally containing one or more heteroatoms,

[0109] R4 to R7 are each independently a hydrogen atom or a substituted or unsubstituted saturated or unsaturated hydrocarbon group,

[0110] a and b are each independently an integer from 1 to 20.

[0111] In the following chemical formula 4, the expression that any group is “substituted or unsubstituted” means that the group is unsubstituted or is substituted with -OH, a halogen atom, C, unless otherwise specified. 1-8 Alkyl group (more specifically C 3-7 alkyl group) or C 1-8 Halogenated alkyl group (more specifically C 3-7It means that it is substituted with one or more substituents selected from among halogenated alkyl groups.

[0112] According to one specific example, in the above chemical formula 4, M1 and M2 are each independently -C(O)O-, -OC(O)-, -OC(O)-M'-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 (more specifically, C 6-20 Arylene, more specifically C 6-10 arylene), and heteroarylene (more specifically, C having one or more (e.g., 1 to 3) heteroatoms selected from N, O and S 3-20 Heteroarylene, more specifically C 3-10 heteroarylene), wherein M' is a direct bond, C 1-13 Alkylene (more specifically C 1-6 alkylene) or C 2-13 Alkenylene (more specifically C 2-6 alkenylene), and R' is each independently a hydrogen atom, C 1-18 Alkyl (more specifically C 1-10 Alkyl, more specifically C 1-6 alkyl) and C 2-18 Alkenyl (more specifically C 2-10 Alkenyl, more specifically C 2-6 It can be selected from the group consisting of alkenyl).

[0113] According to one specific example, in the above chemical formula 4, R1 and R2 are each independently substituted or unsubstituted C 3-20 Cycloalkyl (more specifically C 3-15 Cycloalkyl, more specifically C 6-15 cycloalkyl), substituted or unsubstituted C 3-20 Cycloalkenyl (more specifically C 3-15Cycloalkenyl, more specifically C 6-15 cycloalkenyl), substituted or unsubstituted C 6-20 Aryl (more specifically C 6-14 Aryl), substituted or unsubstituted C 3-20 Heterocycloalkyl (more specifically C 3-15 heterocycloalkyl), substituted or unsubstituted C 3-20 Heterocycloalkenyl (more specifically C 3-15 heterocycloalkenyl), and substituted or unsubstituted C 3-20 Heteroaryl (more specifically C 3-15 may be selected from the group consisting of heterocycloalkyl, heterocycloalkenyl and heteroaryl, wherein each of the heterocycloalkyl, heterocycloalkenyl and heteroaryl may independently have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S.

[0114] According to one specific example, in the above chemical formula 4, R3 is a hydrogen atom, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclic group, -(CH2) n Q, - (CH2) n may be selected from the group consisting of CHQR, -CHQR and -CQ(R)2, wherein each R is independently a hydrogen atom, C 1-3 Alkyl and C 2-3 may be selected from the group consisting of alkenyl; Q is a carbocyclic group, a heterocyclic group, -OR, -O(CH2) n N(R)2, -C(O)OR, -OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R 12 , N(R)S(O)2R 12 , -O(CH2) n OR, -N(R)C(=NR 13)N(R)2, -N(R)C(=CHR 13 )N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2, -N(OR)C(=NR 13 )N(R)2, -N(OR)C(=CHR 13 )N(R)2, -C(=NR 13 )N(R)2, - C(=NR 13 )R, -C(O)N(R)OR and -C(R)N(R)2C(O)OR, wherein each n is independently an integer from 1 to 5, and R 12 is C 3-6 Selected from the group consisting of carbon cyclic groups and heterocyclic groups, R 13 Silver H, CN, NO2, C 1-6 Alkyl, -OR, -S(O)2R, -S(O)2N(R)2, C 2-6 Alkenyl, C 3-6 Selected from the group consisting of a carbon cyclic group and a heterocyclic group, each R is independently a hydrogen atom, C 1-3 Alkyl and C 2-3 is selected from the group consisting of alkenyl, each X is independently selected from the group consisting of F, CI, Br and I, provided that R3 is -(CH2) n Q, -(CH2) n When CHQR, -CHQR or -CQ(R)2, (i) if n is 1, 2, 3, 4 or 5, Q is not -N(R)2, or (ii) if n is 1 or 2, Q is not a 5-, 6- or 7-membered heterocycloalkyl.

[0115] According to one specific example, in the above chemical formula 4, R4 to R7 are each independently a hydrogen atom, C 1-3 Alkyl and C 2-3 It can be selected from the group consisting of alkenyl.

[0116] According to one specific example, in the chemical formula 4, a and b can each independently be an integer from 1 to 15, and more specifically, an integer from 3 to 13.

[0117] More specifically, in the above chemical formula 4, M1 and M2 can each be independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(R')-, and -N(R')C(O)-, wherein R' is as defined above.

[0118] More specifically, in the above chemical formula 4, R1 and R2 are each independently substituted or unsubstituted C 3-15 It may be cycloalkyl.

[0119] More specifically, in the above chemical formula 4, R3 is a hydrogen atom, or a substituted or unsubstituted C 1-3 It could be an alkyl.

[0120] More specifically, in the above chemical formula 4, R4 to R7 may be hydrogen atoms.

[0121] More specifically, in the above chemical formula 4, a and b can each independently be an integer from 5 to 11, and more specifically, an integer from 5 to 9.

[0122] According to one specific example, in the chemical formula 4, R1 and R2 are different from each other, and at this time, R1 is substituted or unsubstituted C 6-15 It may be cycloalkyl, and R2 is substituted or unsubstituted C 3-6 It may be cycloalkyl.

[0123] More specifically, the lipid of the above chemical formula 4 may have any one structure selected from the following chemical formulas 4-A to 4-R:

[0124]

[0125] In another specific example, the cationic lipid may be a lipid having a structure represented by the following chemical formula 5:

[0126] [Chemical Formula 5]

[0127]

[0128] In the above chemical formula 5,

[0129] R1 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,

[0130] R2, R3 and R4 are each independently a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,

[0131] R5, R6 and R7 are each independently a substituted or unsubstituted saturated or unsaturated monovalent hydrocarbon group,

[0132] R8 and R9 are each independently a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group or carbon cyclic group, or each independently -R 10 -(L4) n -R 11 And,

[0133] R 10 are each independently a substituted or unsubstituted alkylene group,

[0134] R 11 are each independently a substituted or unsubstituted saturated or unsaturated monovalent hydrocarbon group,

[0135] L1, L2, L3 and L4 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-, alkenylene, alkynylene, arylene, and heteroarylene, wherein L' is a direct bond, alkylene, alkenylene or alkynylene, and R' is each independently selected from the group consisting of a hydrogen atom, alkyl, alkenyl and alkynyl,

[0136] n is 0 or 1,

[0137] X - is a pharmaceutically acceptable monovalent anion.

[0138] In the above chemical formula 5, the expression that any group is “substituted or unsubstituted” means that the group is unsubstituted or is substituted with -OH, a halogen atom, C, unless otherwise specified. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl 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 It means that it is substituted with one or more substituents selected from among heteroaryl groups.

[0139] In the above chemical formula 5, the expression that any group (e.g., heteroaryl, heterocycloalkyl, etc.) is a “hetero” group means that the group has one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S, unless otherwise specified.

[0140] In the above chemical formula 5, the “monovalent hydrocarbon group” may be branched or unbranched, cyclic or acyclic, or aromatic.

[0141] According to one specific example, in the chemical formula 5,

[0142] The above R1 is substituted or unsubstituted C 1-6 alkylene group, C 2-6 Alkenylene group or C 2-6 It may be an alkynylene group,

[0143] The above R2, R3 and R4 are each independently substituted or unsubstituted C 3-12 alkylene group, C 3-12 Alkenylene group or C 3-12 It may be an alkynylene group,

[0144] The above R5, R6 and R7 are each independently a substituted or unsubstituted saturated or unsaturated monovalent C 3-20 It may be a hydrocarbon group,

[0145] The above R8 and R9 are each independently substituted or unsubstituted C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 3-6 A carbon cyclic group, or each independently -R 10 -(L4) n -R 11 It can be,

[0146] The above R 10 are independently substituted or unsubstituted C 3-12 It may be an alkylene group,

[0147] The above R 11 are independently substituted or unsubstituted saturated or unsaturated monovalent C 3-20 It may be a hydrocarbon group,

[0148] The above L1, L2, L3 and L4 are each independently -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-, C 2-6 Alkenylene, C 2-6 Alkynylene, C 6-20 Arylene, and C 3-20 may be selected from the group consisting of heteroarylene, wherein L' is a direct bond, C 1-13 Alkylene, C 2-13 Alkenylene or C 2-13 It can be alkynylene, and R' is each independently a hydrogen atom, C 1-18 Alkyl, C 2-18 Alkenyl and C 2-18 may be selected from the group consisting of alkynyl,

[0149] n is 0 or 1,

[0150] X - may be a monovalent anion of a pharmaceutically acceptable inorganic acid or organic acid.

[0151] More specifically, in the chemical formula 5,

[0152] The above R1 is substituted or unsubstituted C 3-4 alkylene group, C 3-4 Alkenylene group or C 3-4 It may be an alkynylene group,

[0153] The above R2, R3 and R4 are each independently substituted or unsubstituted C 6-8 alkylene group, C 6-8 Alkenylene group or C 6-8 It may be an alkynylene group,

[0154] The above R5, R6 and R7 are each independently a substituted or unsubstituted saturated or unsaturated monovalent C 5-15 It may be a hydrocarbon group,

[0155] The above R8 and R9 are each independently substituted or unsubstituted C 1-2 Alkyl group, C 2-3 Alkenylene group or C 2-3 Alkynylene group, or each independently -R 10 -(L4) n -R 11 It can be,

[0156] R 10 are independently substituted or unsubstituted C 6-8 It may be an alkylene group,

[0157] R 11 are independently substituted or unsubstituted saturated or unsaturated monovalent C 5-15 It may be a hydrocarbon group,

[0158] The above L1, L2, L3 and L4 are each independently -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -P(O)(OR')O-, -SS-, C 2-5 Alkenylene and C 2-5may be selected from the group consisting of alkynylene, wherein R' is each independently a hydrogen atom, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 may be selected from the group consisting of alkynyl,

[0159] n is 0 or 1,

[0160] X - is a halide (F - , Cl - , Br - , I - ), nitrate anion (NO3 - ), benzoic acid anion (C6H5COO - ), methanesulfonic acid anion, acetate anion (CH3COO - )(=AcO - ), or trihaloacetate anion (CF3COO - ) may be.

[0161] More specifically, in the chemical formula 5,

[0162] The above R1 is substituted or unsubstituted C 3-4 It may be an alkylene group,

[0163] The above R2, R3 and R4 are each independently substituted or unsubstituted C 6-8 It may be an alkylene group,

[0164] The above R5, R6 and R7 are each independently a substituted or unsubstituted saturated or unsaturated monovalent C 5-15 It may be a hydrocarbon group,

[0165] The above R8 and R9 are each independently substituted or unsubstituted C 1-2 An alkyl group, or each independently -R 10 -(L4) n -R 11 It can be,

[0166] R 10 are independently substituted or unsubstituted C 6-8 It may be an alkylene group,

[0167] R 11 are independently substituted or unsubstituted saturated or unsaturated monovalent C 5-15 It may be a hydrocarbon group,

[0168] The above L1, L2, L3 and L4 are each independently -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -P(O)(OR')O-, -SS-, and C 2-5 may be selected from the group consisting of alkenylene, wherein R' is each independently a hydrogen atom and C 1-6 may be selected from the group consisting of alkyl,

[0169] n is 0 or 1,

[0170] X - is Cl - , Br - , or acetate anion (CH3COO - )(=AcO - ) may be.

[0171] More specifically, the cationic lipid may have any one structure selected from the following chemical formulae 5-A to 5-Q:

[0172]

[0173]

[0174] In another specific example, the cationic lipid may be a lipid having a structure represented by the following chemical formula 6 or an ionized form thereof:

[0175] [Chemical Formula 6]

[0176]

[0177] In the above chemical formula 6,

[0178] R1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,

[0179] R2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,

[0180] R3 is an unsubstituted alkylene group,

[0181] R is a hydrogen atom (H) or , wherein R4 is a substituted or unsubstituted alkyl group, alkenyl group, or alkynyl group, R5 is a substituted or unsubstituted alkylene group, alkenylene group, or alkynylene group, and * represents a point of attachment to a nitrogen atom.

[0182] In the above chemical formula 6, the expression that any group is “substituted or unsubstituted” means that the group is unsubstituted or is a halogen atom, -OH, C, unless otherwise specified. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl 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 It means that it is substituted with one or more substituents selected from among heteroaryl groups.

[0183] In the above chemical formula 6, “alkyl”, “alkenyl”, “alkynyl”, “alkylene”, “alkenylene” and “alkynylene” can each independently be branched or unbranched, or cyclic or acyclic.

[0184] According to one specific example, in the chemical formula 6,

[0185] R1 and R4 are each independently substituted or unsubstituted C 1-30 Alkyl group, substituted or unsubstituted C 2-30 Alkenyl group, or substituted or unsubstituted C 2-30 It can be an alkynyl group,

[0186] R2 and R5 are each independently substituted or unsubstituted C 1-15 alkylene group, substituted or unsubstituted C 2-15 Alkenylene group, or substituted or unsubstituted C 2-15 It may be an alkynylene group,

[0187] R3 is unsubstituted C 2-9 It may be an alkylene group.

[0188] More specifically, in the chemical formula 6,

[0189] R1 and R4 are each independently substituted or unsubstituted C 1-20 Alkyl group, substituted or unsubstituted C 2-20 Alkenyl group, or substituted or unsubstituted C 2-20 It can be an alkynyl group,

[0190] R2 and R5 are each independently substituted or unsubstituted C 1-12 alkylene group, substituted or unsubstituted C 2-12 Alkenylene group, or substituted or unsubstituted C 2-12 It may be an alkynylene group,

[0191] R3 is unsubstituted C 2-7 It may be an alkylene group.

[0192] More specifically, in the chemical formula 6,

[0193] R1 and R4 are each independently substituted or unsubstituted C 5-20 Alkyl group, substituted or unsubstituted C 5-20 Alkenyl group, or substituted or unsubstituted C 5-20 It can be an alkynyl group,

[0194] R2 and R5 are each independently substituted or unsubstituted C 3-12 alkylene group, substituted or unsubstituted C 3-12 Alkenylene group, or substituted or unsubstituted C 3-12 It may be an alkynylene group,

[0195] R3 is unsubstituted C 2-5 It may be an alkylene group.

[0196] More specifically, the lipid of the above chemical formula 6 may have any one structure selected from the following chemical formulas 6-A to 6-L:

[0197]

[0198]

[0199] In another specific example, the cationic lipid may be a lipid having a structure represented by the following chemical formula 7:

[0200] [Chemical Formula 7]

[0201]

[0202] In the above chemical formula 7,

[0203] R1, R2 and R3 are each independently a substituted or unsubstituted alkyl group,

[0204] R4 is a substituted or unsubstituted divalent hydrocarbon group,

[0205] R5, R6, R7 and R8 are each independently a substituted or unsubstituted saturated or unsaturated divalent hydrocarbon group,

[0206] R9 and R 10 are each independently a substituted or unsubstituted saturated or unsaturated monovalent hydrocarbon group,

[0207] L1, L2, L3 and L4 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- and -S(O)2-, wherein L' is a direct bond, alkylene, alkenylene or alkynylene, and R' is each independently selected from the group consisting of a hydrogen atom, alkyl, alkenyl and alkynyl,

[0208] X - is a monovalent anion.

[0209] In the above chemical formula 7, the expression that any group is “substituted or unsubstituted” means that the group is unsubstituted or is a halogen atom, -OH, C, unless otherwise specified. 1-6 Alkyl group, C 1-6 Alkoxy group, C1-6 Halogenated alkyl 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 It means that it is substituted with one or more substituents selected from among heteroaryl groups.

[0210] In the above chemical formula 7, the expression that any group (e.g., heteroaryl, heterocycloalkyl, etc.) is a “hetero” group means that the group has one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S, unless otherwise specified.

[0211] In the above chemical formula 7, the “monovalent hydrocarbon group” and the “divalent hydrocarbon group” may be branched or unbranched, cyclic or acyclic.

[0212] In the above chemical formula 7, “alkyl”, “alkenyl”, “alkynyl”, “alkylene”, “alkenylene” and “alkynylene” can each independently be branched or unbranched, or cyclic or acyclic.

[0213] According to one specific example, in the chemical formula 7,

[0214] R1, R2 and R3 are each independently substituted or unsubstituted C 1-6 It can be an alkyl group,

[0215] R4 is substituted or unsubstituted divalent C 2-6 It may be a hydrocarbon group,

[0216] R5, R6, R7 and R8 are each independently a substituted or unsubstituted saturated or unsaturated divalent C 2-20 It may be a hydrocarbon group,

[0217] R9 and R 10 are independently substituted or unsubstituted saturated or unsaturated monovalent C 2-20 It may be a hydrocarbon group,

[0218] L1, L2, L3 and L4 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- and -S(O)2-, wherein L' is a direct bond, C 1-13 Alkylene, C 2-13 Alkenylene or C 2-13 Alkynylene, and R' is each independently a hydrogen atom, C 1-18 Alkyl, C 2-18 Alkenyl and C 2-18 Selected from the group consisting of alkynyl,

[0219] X - It can be a monovalent anion of an inorganic acid or an organic acid.

[0220] More specifically, in the above chemical formula 7,

[0221] R1, R2 and R3 are each independently substituted or unsubstituted C 1-3 It can be an alkyl group,

[0222] R4 is substituted or unsubstituted C 2-4 It may be an alkylene group,

[0223] R5, R6, R7 and R8 are each independently substituted or unsubstituted C 2-13 Alkylene group or C 2-13 It may be an alkenylene group,

[0224] R9 and R 10 are independently substituted or unsubstituted C 6-20 Alkyl group, C 6-20 Alkenyl group or C 6-20 It can be an alkynyl group,

[0225] L1, L2, L3 and L4 can each be independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)- and -P(O)(OR')O-, wherein R' is each independently a hydrogen atom and C 1-6 may be selected from the group consisting of alkyl,

[0226] X - is F - , Cl - , Br - , I - , nitrate anion, benzoate anion, methanesulfonic acid anion, acetate anion (CH3COO - )(=AcO - ), or trihaloacetate anion (CF3COO - ) may be.

[0227] More specifically, the lipid of the above chemical formula 7 may have any one structure selected from the following chemical formulas 7-A and 7-B:

[0228]

[0229] Meanwhile, in one specific example, the cationic polymer may be selected from the group consisting of chitosan, glycol chitosan, protamine, polylysine, polyarginine, polyamidoamine (PAMAM), polyethylenimine, dextran, hyaluronic acid, albumin, high molecular weight polyethyleneimine (PEI), polyamine, and polyvinylamine (PVAm), and more specifically, may be at least one selected from the group consisting of polyethyleneimine (PEI), polyamine, and polyvinylamine (PVAm).

[0230] In one specific embodiment, the content of the cationic compound in the drug delivery composition of the present invention may be 5 wt% or more, 10 wt% or more, 15 wt% or more, 20 wt% or more, 25 wt% or more, 30 wt% or more, or 35 wt% or more, and may also be 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 75 wt% or less, 70 wt% or less, or 65 wt% or less, based on the dry weight of the entire composition. If the content of the cationic compound is too low, it may not be sufficient to form nanoparticles, and conversely, if it is too high, the size of the nanoparticles may become too large, which may lower the stability of the nanoparticles and increase the loss rate during filter sterilization.

[0231] 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 a polymer component including the amphiphilic block copolymer and the cationic compound, thereby improving stability in blood or body fluid.

[0232] In one embodiment, the particle size of the nanoparticles can be defined by the Z-average value and can be, 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 can also be 10 nm or more, 50 nm or more, or 100 nm or more. In one embodiment, the particle size of the nanoparticles defined by the Z-average value can be, for example, 10 to 800 nm, 20 to 600 nm, 30 to 500 nm, 50 to 400 nm, or 80 to 300 nm.

[0233] In one specific example, the relative amount of the polymer component including the amphiphilic block copolymer relative to the cationic compound 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, or 0.05 parts by weight or more, based on 1 part by weight of the cationic compound, 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, or 37 parts by weight or less, but is not limited thereto.

[0234] Any additional ingredients

[0235] In one specific embodiment, the drug delivery composition of the present invention may further comprise a fusible lipid to increase the delivery efficiency of the active ingredient into the body.

[0236] In one specific embodiment, the fusion lipid may be one or a combination of two or more selected from the group consisting of phospholipids, PEGylated lipids, cholesterol, and tocopherol.

[0237] Specifically, the phospholipid may be at least one selected from the group consisting of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidic acid. The phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidic acid may be in a form bound to one or two C10-24 fatty acids. The cholesterol and tocopherol include analogs, derivatives, and metabolites of cholesterol and tocopherol, respectively.

[0238] Specifically, the PEG lipid refers to a polyethylene glycol (PEG)-modified lipid, which is a type of PEG derivative having a lipid moiety such as DMG or DSPE attached thereto. PEG lipids have been widely used to improve the circulation time of active ingredients encapsulated in lipid nanoparticles and reduce nonspecific absorption. The PEG lipid may be a combination of one or more 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. For example, the PEG lipids include 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), or PEG-1,2-dimyristyloxolpropyl-3-amine (PEG-c-DMA).

[0239] Specifically, the above-mentioned fusion lipids are 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 a combination of two or more 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.

[0240] More specifically, the fusion lipids are dioleoyl phosphatidylethanolamine (DOPE), 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine (DPPC), distearoyl phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-octadecanoyl-sn-glycero-3-phosphocholine (18:0 Lyso PC), 1-9z-octadecenoyl-sn-glycero-3-phosphocholine (1-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine, 18:1 Lyso PC). 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-oleoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine (18:1 Lyso PE), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (18:0-18:1 PE), 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphoethanolamine (18:0-18:2 PE), 1,2-Dilinoleoyl-sn-glycero-3-phosphoethanolamine (1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 18:2 PE), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-(1'-rac-glycerol), 18:0 Lyso PG), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-rac-glycerol), 18:1 Lyso PG), dipalmitooleoylphosphoethanolamine (1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine, DPPE), It may be one or a combination of two or more selected from the group consisting of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-dioleoyl-3-dimethylammonium propane (DODAP), 1,2-dioleoyl-sn-glycero-3-phosphate (18PA), cholesterol and tocopherol.

[0241] In one embodiment of the present invention, the fusion lipid may be distearoyl phosphatidylcholine, cholesterol, or a combination thereof.

[0242] In one specific embodiment, the content of the fusion lipid may be at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, or at least 5 wt%, and may also be at most 40 wt%, at most 35 wt%, at most 30 wt%, at most 25 wt%, or at most 20 wt%, based on the dry weight of the entire composition.

[0243] In one specific example, the relative amount of the fusion lipid used compared to the cationic compound 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, or 0.1 parts by weight or more, based on 1 part by weight of the cationic compound, 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, or 3.8 parts by weight or less, but is not limited thereto.

[0244] In one specific example, when a phospholipid is used as the fusion 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, or 0.06 parts by weight or more, based on 1 part by weight of the cationic compound, 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, or 2.7 parts by weight or less, but is not limited thereto.

[0245] In one specific example, when cholesterol is used as the fusion lipid, the relative amount used may be 0.02 parts by weight or more, 0.03 parts by weight or more, or 0.04 parts by weight or more, and may also be 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, based on 1 part by weight of the cationic compound, but is not limited thereto.

[0246] In addition, in one specific embodiment, the drug delivery composition of the present invention may additionally include one or more additive components (hereinafter, “optional additive components”) that are typically included in drug delivery compositions.

[0247] In one specific embodiment, the optional additive component may be, but is not limited to, one or more selected from, for example, a pH modifier (e.g., an acidifying agent, an alkalizing agent, a buffering agent), a tonicity modifier, a bulking agent (e.g., a sugar, a polyol, an amino acid, a polymer, a protein, etc.), a wetting agent, a solubilizing agent, a surfactant, an antioxidant, an antimicrobial agent, a chelating agent, a complexing agent, etc.

[0248] In one specific example, the pH adjusting agent may be one or more selected from acetate, citrate, tartrate, histidine, glutamate, phosphate, Tris, glycine, bicarbonate, succinate, sulfate, nitrate, and the like, but is not limited thereto.

[0249] In one specific example, the tonicity regulator may be one or more selected from, but is not limited to, mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, potassium chloride, glycerol, glycerin, propylene glycol, and the like.

[0250] In one embodiment, the bulking agent may be one or more selected from, but is not limited to, sugars and polyols including sucrose, trehalose, glucose, lactose sorbitol, mannitol, glycerol, and the like; amino acids including arginine, aspartic acid, glutamic acid, lysine, proline, glycine, histidine, methionine, alanine, and the like; 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), and the like; or combinations thereof.

[0251] In one embodiment, the humectant and / or solubilizer is selected from the group consisting of lecithin, PEG 300, PEG 600, PEG 1000, polyoxyethylene lauryl ethers (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, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), sorbitan trioleate (Span 85), cocamide monoethanolamine (cocamide MEA), cocamide diethanolamine (cocamide DEA), dodecyldimethylamine oxide, poloxamer, polyvinyl pyrrolidone 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., but are not limited thereto.

[0252] In one specific example, the antioxidant may be one or more selected from, but is not limited to, tocopherol (vitamin E), alpha tocopherol, alpha tocopherol hydrogen succinate, ascorbic acid, acorbyl 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), and the like.

[0253] In one specific example, the antimicrobial agent may be one or more selected from benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, macresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, thimerosal, and the like, but is not limited thereto.

[0254] In one specific example, 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, and the like, but is not limited thereto.

[0255] When any of the above additive components is 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, and may also be 10 wt% or less, 5 wt% or less, or 1 wt% or less, based on the dry weight of the entire composition, but is not limited thereto.

[0256] Composition and method for producing the same

[0257] The drug delivery composition according to the present invention 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 administration preparations suitable for such routes of administration. Examples of the oral administration preparations include tablets, capsules, powder preparations, and liquid preparations, and examples of the parenteral administration preparations include various preparations such as eye drops and injections. In one specific example, the composition may be an injectable preparation. For example, when the composition according to the present invention is lyophilized, it can be reconstituted with distilled water for injection, 0.9% saline solution, and 5% dextrose aqueous solution, and thus can be prepared in the form of an injectable preparation.

[0258] The present invention also provides a method for producing a drug delivery composition, comprising the steps of: (a) preparing a solution in which an amphiphilic block copolymer including a hydrophilic block and a hydrophobic block and a cationic compound are dissolved in a water-miscible organic solvent; and (b) adding and mixing an active ingredient selected from a nucleic acid, a polypeptide, a virus, or a combination thereof to the solution prepared in step (a), wherein the hydrophobic block is a biocompatible, biodegradable polymer having repeating units of a structure represented by the above chemical formula 1.

[0259] In one specific example, the water-miscible organic solvent of step (a) may be ethanol.

[0260] In one specific embodiment, the step (b) may be performed in a solution under acidic conditions.

[0261] In one specific example, the step (b) may include: (b-1) preparing a buffer solution containing the active ingredient; and (b-2) adding and mixing the buffer solution of the active ingredient prepared in step (b-1) to the solution prepared in step (a).

[0262] In one specific example, 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 by volume, and more specifically, 1:2 to 1:4.

[0263] In another specific example, the step (b) may include: (b-1) adding the active ingredient to the solution prepared in step (a); and (b-2) adding and mixing a buffer solution to the resultant product of step (b-1).

[0264] In one specific example, the method for preparing the drug delivery composition may further include a step of adding a pH adjusting buffer, water for injection, or a combination thereof to the resultant product of step (b).

[0265] In another specific example, the method for preparing the drug delivery composition may further include a step of removing the solvent from the resultant product of step (b) and then adding a freeze-drying aid to freeze-dry the product.

[0266] The freeze-drying aid is added to enable the freeze-dried composition to maintain a cake shape or to help the composition melt evenly within a short period of time during the reconstitution process after freeze-drying, and specifically, may be at least one selected from the group consisting of sugars, amino acids, polymers, and proteins. For example, it may be at least one selected from the group consisting of lactose, mannitol, sorbitol, and sucrose. The content of the freeze-drying aid may be 1 to 90 wt%, and more specifically, 10 to 60 wt%, based on the total dry weight of the freeze-dried composition.

[0267] Hereinafter, the present invention will be described in more detail based on the following examples, but these are only for explaining the present invention and the scope of the present invention is not limited in any way by these examples.

[0268] [Example]

[0269] Example 1 of preparing cationic lipids

[0270] A compound of the following chemical formula 2-A was prepared.

[0271] [Chemical Formula 2-A]

[0272]

[0273] (1) Synthesis of 1-cyclopropylnonan-1-ol

[0274] In a 2000 mL 3-neck round-bottom flask (RBF), cyclopropanecarbaldehyde (35.0 g, 499 mmol, 1.00 eq) and tetrahydrofuran (THF) (700 mL) were added under a nitrogen atmosphere, cooled to -65°C, octylmagnesium bromide (2 M, 375 mL, 1.50 eq) was added, and the mixture was stirred at -65°C for 2 h. The reactor was warmed to 15°C, poured into a saturated NH4Cl aqueous solution (500 mL), and the organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate (EtOAc) (450 mL) (150 mL each three times). The organic layers were collected, concentrated in vacuo, and purified using a silica column with petroleum ether:EtOAc = 50:1→0:1 to obtain 1-cyclopropylnonan-1-ol (87.5 g, 73.1%).

[0275] 1 H NMR (400 MHz, CHLOROFORM-d):δ2.93 - 2.81 (m, 1H), 1.61 (br d, 2H), 1.52 - 1.27 (m, 12H), 0.95 - 0.86 (m, 4H), 0.60 - 0.45 (m, 2H), 0.34 - 0.19 (m, 2H)

[0276] (2) Synthesis of 1-cyclopropylnonyl 8-bromooctanoate

[0277] A 1000 mL 3-neck RBF was charged with 1-cyclopropylnonan-1-ol (30.0 g, 163 mmol, 1.00 eq), 8-bromooctanoic acid (72.6 g, 326 mmol, 2.00 eq), methylene chloride (DCM) (300 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (31.2 g, 163 mmol, 1.00 eq), and 4-dimethylaminopyridine (DMAP) (19.9 g, 163 mmol, 1.00 eq) and stirred at 25°C for 16 h. After concentrating the mixture in the reactor in vacuo, silica powder was added and purified using a silica column with petroleum ether:EtOAc = 10:1→50:1 to obtain 1-cyclopropylnonyl 8-bromooctanoate (22.8 g, 36.0%).

[0278] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.29 (td, 1H), 3.59 - 3.31 (m, 2H), 2.32 (t, 2H), 1.94 - 1.75 (m, 2H), 1.73 - 1.60 (m, 4H), 1.49 - 1.25 (m, 18H), 1.03 - 0.93 (m, 1H), 0.90 (t, 3H), 0.61 - 0.24 (m, 4H)

[0279] (3) Synthesis of the compound of chemical formula 2-A

[0280] In a 100 mL 3-neck flask, methylamine hydrochloride (173 mg, 2.57 mmol, 1.00 eq), ethanol (EtOH) (30 mL), N,N-diisopropylethylamine (DIEA) (1.66 g, 12.8 mmol, 5.00 eq), and 1-cyclopropylnonyl 8-bromooctanoate (3.00 g, 7.70 mmol, 3.00 eq) were sequentially added and stirred at 80°C for 72 hours. The mixture in the reactor was concentrated in vacuo, silica powder was added, and the mixture was purified using a silica column with a ratio of petroleum ether:EtOAc = 10:1 → 1:1 to obtain a compound of chemical formula 2-A (660 mg, 38.9%).

[0281] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.29 (td, 2H), 2.32 (br t, 8H), 2.22 (s, 3H), 1.74 - 1.60 (m, 8H), 1.54 - 1.42 (m, 4H), 1.39 - 1.23 (m, 36H), 1.02 - 0.87 (m, 8H), 0.61 - 0.23 (m, 8H)

[0282] Example 2 of preparing cationic lipids

[0283] A compound of the following chemical formula 4-A was prepared.

[0284] [Chemical Formula 4-A]

[0285]

[0286] (1) Synthesis of 4-pentylcyclohexyl 8-bromooctanoate

[0287] 8-Bromooctanoic acid (2.00 g, 8.96 mmol, 1.00 eq), dichloromethane (DCM) (40 mL), and dimethylformamide (DMF) (0.5 mL) were placed together in a 250 mL 3-neck round bottom flask (RBF), and oxalyl chloride (2.28 g, 17.9 mmol, 2.00 eq) was added thereto at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for 4 h under a nitrogen atmosphere, then 4-pentylcyclohexan-1-ol (2.29 g, 13.5 mmol, 1.50 eq) and triethylamine (TEA) (1.36 g, 13.5 mmol, 1.50 eq) were added, and the mixture was stirred at 25°C for an additional 12 h under a nitrogen atmosphere. The mixture in the reactor was concentrated in vacuo, and the concentrated residue was purified using a silica column with petroleum ether:ethyl acetate (EtOAc) = 1:0→50:1 to obtain 4-pentylcyclohexyl 8-bromooctanoate (2.46 g, 6.55 mmol, 73.1% yield) as a pale yellow oil.

[0288] 1 H NMR (400 MHz, CHLOROFORM-d):δ0.76 - 0.86 (m, 3 H) 0.88 - 1.94 (m, 28 H) 2.21 (dt, 2 H) 3.33 (td, 2 H) 4.52 - 4.66 (m, 1 H) 4.87 - 4.95 (m, 1 H)

[0289] (2) Synthesis of 4-pentylcyclohexyl 8-((2-hydroxyethyl)amino)octanoate

[0290] A 100 mL 3-neck RBF was charged with 4-pentylcyclohexyl 8-bromooctanoate (2.46 g, 6.55 mmol, 1.00 eq), 2-aminoethan-1-ol (2.00 g, 32.8 mmol, 5.00 eq), and ethanol (EtOH) (50 mL) and stirred at 80°C for 16 h under a nitrogen atmosphere. The mixture in the reactor was concentrated under vacuum, and the concentrated residue was purified using a silica column with a ratio of petroleum ether:EtOAc = 1:0→50:1 to obtain 4-pentylcyclohexyl 8-((2-hydroxyethyl)amino)octanoate (2.00 g, 5.62 mmol, 85.8% yield) as a yellow solid.

[0291] 1 H NMR (400 MHz, CHLOROFORM-d):δ0.76 - 0.86 (m, 3 H) 0.88 - 1.94 (m, 27 H) 2.32 (t, 2 H) 2.51 (t, 2 H) 2.71 (t, 2H), 3.54 (d, 2 H) 3.91 - 4.00 (m, 1 H) 4.11 - 4.31 (m, 1 H)

[0292] (3) Synthesis of cyclopentadecyl 8-bromooctanoate

[0293] A 250 mL 3-neck RBF was charged with cyclopentadecanol (5.00 g, 22.1 mmol, 1.00 eq), 8-bromooctanoic acid (4.93 g, 22.1 mmol, 1 eq), sulfuric acid (H2SO4) (217 mg, 2.21 mmol, 0.10 eq), and toluene (100 mL) and stirred at 120°C for 16 h under a nitrogen atmosphere. The solvent was evaporated, and the residue was purified using a silica column with a ratio of petroleum ether:EtOAc = 1:0→50:1 to obtain cyclopentadecyl 8-bromooctanoate (2.60 g, 6.03 mmol, 27.3% yield) as a colorless oil.

[0294] 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.89 (quin, 1H), 3.41 (dt, 2H), 2.28 (t, 2H), 1.85 (quin, 2H), 1.73 - 1.16 (m, 36H)

[0295] (4) Synthesis of the compound of chemical formula 4-A

[0296] A 100 mL 3-neck RBF was charged with cyclopentadecyl 8-bromooctanoate (1.60 g, 3.71 mmol, 1.00 eq), 4-pentylcyclohexyl 8-((2-hydroxyethyl)amino)octanoate (1.32 g, 3.71 mmol, 1.00 eq), N,N-diisopropylethylamine (DIEA) (527 mg, 4.08 mmol, 1.10 eq), and EtOH (30 mL) and stirred at 80°C for 48 h. The solvent was evaporated, and the residue was purified using a silica column with a ratio of petroleum ether:EtOAc = 10:1→1:1. Subsequently, the mixture was purified again by prep-HPLC (Folic Acid condition), washed with NaHCO3 aqueous solution (300 mL), concentrated the organic layer, and extracted with DCM (200 mL x 2). The organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated to obtain the compound of chemical formula 4-A (0.240 g, 340 μmol, 9.16% yield) as a yellow oil.

[0297] 1 H NMR (400 MHz, CHLOROFORM-d): δ4.91 (br s, 1H), 4.82 (quin, 1H), 3.46 (br t, 2H), 2.51 (br d, 2H), 2.37 (br t, 4H), 2.21 (td, 4H), 1.58 - 1.42 (m, 14H), 1.33 - 1.17 (m, 52H), 0.83 - 0.80 (m, 3H).

[0298] Preparation Example 1 of an Amphiphilic Block Copolymer (mPEG-PNL)

[0299] An amphiphilic block copolymer of the following chemical formula was prepared.

[0300]

[0301] Monomethoxy PEG (5.00 g, 2.5 mmol, 1.0 eq) was added to a 100 mL 2-neck RBF and dried at 120°C for 2 h. δ-Nonalactone and 1,5,7-triazabicyclo[4.4.0]dec-5-ene, which had been vacuum-dried at room temperature for 2 h, were sequentially added to the polymerization reactor containing monomethoxy PEG and stirred at 50°C for 1 h. After completion of the reaction, the reactant was added dropwise to cold diethyl ether to perform primary precipitation. The precipitate was recovered using a centrifuge, and the reaction mixture was dissolved in methylene chloride (DCM) and then added dropwise to cold diethyl ether to perform secondary precipitation. The precipitate was collected using a centrifuge, and the reaction mixture was dissolved in DCM, then dropped into cold hexane to perform a third precipitation. The precipitate was collected using a centrifuge, and the reaction mixture was dissolved in DCM, then dropped into cold hexane to perform a fourth precipitation, thereby obtaining an amphiphilic block copolymer.

[0302] 1 H-NMR (400 MHz, CDCl3)δ4.88-4.87 (CH-O-CO, m), 4.22-4.20 (CH2-O-CO, m), 3.83-3.54 (CH-OH, O-CH2-CH2-O, m), 3.34 (O-CH3, s), 2.34-2.28 (O-CO-CH2, m), 1.72-1.25 (CH2-CH2-CH2-CH3, m), 0.91-0.87 (CH2-CH3, m)

[0303] Comparative Example 1

[0304] According to the composition shown in Table 1 below, a drug delivery composition was prepared as follows. A solution of 11.4 mg of Lipid5(8-[(2-hydroxyethyl)[8-(nonyloxy)-8-oxooctyl]amino]-octanoic acid, 1-octylnonyl ester) dissolved in 570 μl of ethanol, a solution of 2.5 mg of DSPC (distearoylphosphatidylcholine) dissolved in 250 μl of ethanol, a solution of 4.8 mg of cholesterol dissolved in 480 μl of ethanol, and a solution of 1.2 mg of DMG-PEG (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000) dissolved in 120 μl of ethanol were sequentially mixed, and then vortexed to evenly mix, thereby preparing an ethanol solution. Luciferase mRNA 1 mg was mixed with 20 mM sodium acetate buffer (pH 4.6) to prepare an aqueous solution of the active ingredient, which was then added to the prepared ethanol solution so that the volume ratio of the aqueous phase to the ethanol phase was 3:1. After mixing, the solution was centrifuged at 4000 rpm using an Amicon Ultra centrifugal Filter and concentrated to 1 / 3 of the initial volume. After concentration, the solution was diluted with additional PBS (phosphate buffer) equivalent to the initial volume, and centrifuged again at 4000 rpm to concentrate to 1 / 3 of the initial volume. This process was repeated 6 times to remove ethanol, exchange the buffer with PBS, and concentrate. After concentration to the desired concentration, it was sterilized using a 0.22 μm pore size filter.

[0305]

[0306] Examples 1-18

[0307] According to the composition shown in Table 2 below, a drug delivery composition was prepared as follows. The lipid compound of Chemical Formula 2-A of the cationic lipid preparation example 1 or the lipid compound of Chemical Formula 4-A of the cationic lipid preparation example 2 was dissolved in ethanol at a concentration of 20 mg / mL, DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) at a concentration of 10 mg / mL, cholesterol at a concentration of 10 mg / mL, and mPEG-PNL (monomethoxypolyethyleneglycol-polynonalactone) of the amphiphilic block copolymer preparation example 1 was dissolved in ethanol at a concentration of 25 mg / mL. For each of the above components, an amount of each prepared solution corresponding to the amount shown in Table 2 was taken and added, and then vortexed to evenly mix, thereby preparing an ethanol solution. Luciferase mRNA 1 mg was mixed with 20 mM sodium acetate buffer (pH 4.6) to prepare an aqueous solution of the active ingredient, which was then added to the prepared ethanol solution so that the volume ratio of the aqueous phase to the ethanol phase was 3:1. After mixing, it was vortexed for about 5 seconds to mix well, and then centrifuged at 4000 rpm using an Amicon Ultra centrifugal Filter to concentrate to 1 / 3 of the initial volume. After concentration, it was diluted with additional PBS (phosphate buffer) equivalent to the initial volume, and centrifuged again at 4000 rpm to concentrate to 1 / 3 of the initial volume. This process was repeated 6 times to remove ethanol, exchange the buffer with PBS, and concentrate. After concentration to the desired concentration, it was sterilized using a 0.22 μm pore size filter.

[0308]

[0309] (3) Evaluation of physical properties of the formulation

[0310] For each formulation of Comparative Example 1 and Examples 1 to 18, particle characteristics were confirmed using a particle size analyzer (dynamic light scattering, DLS), and the results are shown in Table 3 below.

[0311]

[0312] (4) Administration of the composition

[0313] Each formulation of Comparative Example 1 and Examples 1 to 10, 13, 14 and 16 and 18 was prepared at a concentration of 10 μg / mL and administered intravascularly to mice so that 2 μg of mRNA was administered per mouse. Four hours after administration, luciferin dissolved in sterile water was prepared at a concentration of 15 μg / μL and administered intraperitoneally so that 3 mg of luciferin was administered per 20 g mouse. Fifteen minutes after intraperitoneal administration of luciferin, the results of protein expression by organ were measured using a luminescence measurement imaging system and are shown in Table 4 below.

[0314] As confirmed from Table 4, the drug delivery formulation according to the present invention had excellent selective drug delivery efficiency to the liver during intravenous administration.

[0315]

Claims

1. An active ingredient selected from nucleic acids, polypeptides, viruses or a combination thereof; An amphiphilic block copolymer comprising a hydrophilic block and a hydrophobic block; and cationic compounds; Here, the hydrophobic block is a biocompatible biodegradable polymer having a repeating unit of a structure represented by the following chemical formula 1. Compositions for drug delivery: [Chemical Formula 1] In the above chemical formula 1, R represents a branched alkylene group having 3 or more carbon atoms.

2. A composition for drug delivery in claim 1, wherein the hydrophilic block is at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, and derivatives thereof.

3. A composition for drug delivery in claim 1, wherein in the chemical formula 1, R represents a branched alkylene group having 3 to 20 carbon atoms.

4. A drug delivery composition in the first paragraph, wherein the hydrophobic block is a biocompatible biodegradable polymer having repeating units of a structure selected from the following: , , , , , , , , , , , , , , , , 5. A composition for drug delivery in claim 1, wherein the repeating unit of the structure represented by the chemical formula 1 is obtained by ring-opening polymerization of a lactone compound.

6. A drug delivery composition according to claim 1, wherein the cationic compound is a cationic lipid, a cationic polymer, or a combination thereof.

7. A drug delivery composition according to claim 1, wherein the effective ingredient is mRNA.

8. A drug delivery composition according to any one of claims 1 to 7, further comprising a fusion lipid.

9. A composition for drug delivery in claim 8, wherein the fusion lipid is one or a combination of two or more selected from the group consisting of phospholipids, PEG lipids, cholesterol, and tocopherol. 10.(a) a step of preparing a solution in which an amphiphilic block copolymer including a hydrophilic block and a hydrophobic block and a cationic compound are dissolved in a water-miscible organic solvent; and (b) a step of adding and mixing an effective ingredient selected from a nucleic acid, a polypeptide, a virus or a combination thereof to the solution prepared in step (a); Here, the hydrophobic block is a biocompatible biodegradable polymer having a repeating unit of a structure represented by the following chemical formula 1. Method for preparing a composition for drug delivery: [Chemical Formula 1] In the above chemical formula 1, R represents a branched alkylene group having 3 or more carbon atoms.

11. A method for producing a drug delivery composition in claim 10, wherein the water-miscible organic solvent of step (a) is ethanol.

12. In paragraph 10, step (b) (b-1) a step of preparing a buffer solution containing the above effective ingredient; and (b-2) a step of adding and mixing the buffer solution of the effective ingredient prepared in step (b-1) to the solution prepared in step (a); A method for preparing a composition for drug delivery.

13. In paragraph 10, step (b) (b-1) a step of adding an effective ingredient to the solution prepared in step (a); and (b-2) a step of adding a buffer solution to the result of step (b-1) and mixing; including; A method for preparing a composition for drug delivery.

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