Nanoparticle compositions for drug delivery

Abstract

The present invention relates to a nanoparticle composition for drug delivery, and more specifically to a drug delivery composition that comprises an amphiphilic block copolymer and a lipid having a specific structure that can easily form a complex with an anionic drug, and that can easily form drug-containing nanoparticles, and is therefore useful for drug delivery, particularly for delivering drugs specifically to the lungs.

Description

[Technical Field]

[0001] The present invention relates to a nanoparticle composition for drug delivery, and more specifically, to a drug delivery composition that comprises an amphiphilic block copolymer and a lipid of a specific structure that can easily form a complex with an anionic drug, and that can easily form drug-containing nanoparticles and is useful for drug delivery, particularly for delivering drugs specifically to the lungs. [Background technology]

[0002] Safe and efficient drug delivery technologies for treatment using anionic drugs, including nucleic acids, have long been studied, and various delivery vehicles and delivery technologies have been developed. Delivery vehicles are mainly divided into viral delivery vehicles using adenoviruses, retroviruses, etc., and non-viral delivery vehicles using cationic lipids, cationic polymers, etc. Viral delivery vehicles are known to pose many problems for commercialization due to risks such as non-specific immune responses and complex manufacturing processes. Therefore, recent research has been conducted toward improving these drawbacks by using non-viral delivery vehicles. Non-viral delivery vehicles have the advantages of fewer side effects in terms of safety in the body and lower manufacturing costs compared to viral delivery vehicles.

[0003] Representative non-viral delivery vehicles for delivering nucleic acid substances include cationic lipid-nucleic acid complexes (lipoplexes) and polycationic polymer-nucleic acid complexes (polyplexes). Such cationic lipids and polycationic polymers form complexes with anionic drugs through electrostatic interactions, stabilizing the anionic drugs and increasing their intracellular delivery, and thus have been the subject of extensive research (Non-Patent Documents 1 and 2).

[0004] However, polycationic polymers have cytotoxicity due to their multivalent cationic charge, making their practical application problematic. Furthermore, nucleic acid-cationic lipid complexes have low stability in the blood, making their in vivo use difficult. Furthermore, ionic liposomes containing cationic lipids, neutral lipids, and fusogenic lipids have drawbacks, such as the complex synthesis of the cationic lipids used, cytotoxicity, and low efficiency of intracellular nucleic acid delivery.

[0005] Meanwhile, in order to provide a mixed polymer nanoparticle composition that solubilizes a large amount of poorly soluble drugs and has good stability in an aqueous solution, Patent Document 1 discloses a mixed polymer nanoparticle composition that contains an amphiphilic block copolymer consisting of a hydrophilic block and a hydrophobic block and a polylactic acid derivative containing a carboxylic acid end group, and that can form polymer nanoparticles in body fluids or aqueous solutions, and a pharmaceutical composition in which a poorly soluble drug is contained in polymer nanoparticles made of the mixed polymer nanoparticle composition. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Korea Patent No. 2003-0032897 [Non-patent literature]

[0007] [Non-Patent Document 1] De Paula D, Bentley MV, Mahato RI, Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting, RNA 13 (2007) 431-56 [Non-patent document 2] 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 Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present invention to provide compositions useful for drug delivery, particularly compositions useful for delivering drugs specifically to the lung. [Means for solving the problem]

[0009] A first aspect of the present invention provides a drug delivery composition comprising a drug as an active ingredient; and a structure selected from the following or an ionized form thereof: [ka] wherein in each of the structures, at least two of the R groups are Rx and the remaining R groups are Ry; where Rx is independently [ka] is selected from wherein a, b, and c each independently represent an integer of 2 to 20; R1 represents a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group; and R2 represents a substituted or unsubstituted, unsaturated monovalent hydrocarbon group. [ka] represents a substituted or unsubstituted methylene group, each Ry is independently H or a substituted or unsubstituted alkyl group, and two Ry groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently a substituted or unsubstituted alkylene group, and the structure may optionally contain an ether bond (-O-), a thioether bond (-S-), or a disulfide bond (-SS-).

[0010] According to one embodiment of the present invention, each Ry is independently H or C. 1-20 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —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 groups and optionally substituted C 3-20 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S, and two R groups that are not H may be linked 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.

[0011] According to one embodiment of the present invention, each L is independently C 1-20 alkylene groups, each independently unsubstituted or substituted with —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 groups and optionally substituted C 3-20 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S. The heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S. More specifically, each Rx is independently [ka] wherein a, b, and c may each independently be an integer of 2 to 20 or 2 to 15; R1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 R2 may be a substituted or unsubstituted unsaturated monovalent C 2-24 may be a hydrocarbon group, [ka] represents a substituted or unsubstituted methylene group.

[0012] More specifically, each Ry is independently H or C. 1-10 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group consisting of —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 groups and optionally substituted C 3-10 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S, and two R groups that are not H may be linked 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.

[0013] More specifically, each L is independently C 1-10 alkylene groups, each independently unsubstituted or selected from the group consisting of —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 groups and optionally substituted C 3-10 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S. The heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S.

[0014] More specifically, each Rx is independently [ka] wherein a, b, and c may each independently be an integer from 3 to 12; and R1 is selected from the group consisting of substituted or unsubstituted C 1-12 Alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C2 -12 R2 may be a substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 may be an alkynyl group, [ka] represents a substituted or unsubstituted methylene group.

[0015] More specifically, each Ry is independently H or C. 1-6 and alkyl groups, wherein the alkyl groups are independently unsubstituted or substituted with one or more selected from -OH and -NH, and two R groups that are not H may be joined 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.

[0016] More specifically, each L is independently an unsubstituted C 1-6 It may also be an alkylene group.

[0017] More specifically, the lipid may have a structure selected from the following formulas (A-V):

[0018] [Table 1-1]

[0019] [Table 1-2]

[0020] [Table 1-3]

[0021] In one embodiment, the drug may be complexed with the lipid. In one embodiment, the composition of the first aspect of the present invention may further comprise an amphiphilic block copolymer. In one embodiment, the drug may form a complex with the lipid, and the complex may be encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer. In one embodiment, the composition according to the first aspect of the present invention may be in the form of a kit comprising a first chamber containing the lipid; and a second chamber containing the drug. In one embodiment, the first chamber may further comprise an amphiphilic block copolymer.

[0022] A second aspect of the present invention is a drug delivery composition comprising nanoparticles, A drug delivery composition is provided, wherein the nanoparticles comprise a lipid having a structure selected from the following or an ionized form thereof, and the nanoparticles do not contain a drug:

[0023] [ka] (In the formula, R and L are as defined above.)

[0024] In one embodiment, the nanoparticles may further comprise an amphiphilic block copolymer. In one embodiment, the drug delivery composition of the present invention may be for delivering a drug to the lungs. In one embodiment, the composition for delivering an antibacterial agent of the present invention may further comprise polylactate. [Effects of the Invention]

[0025] The compositions according to the present invention are highly useful for the specific pulmonary delivery of drugs encapsulated within nanoparticles formed by amphiphilic block copolymers. [Brief explanation of the drawings]

[0026] [Figure 1] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 1. [Figure 2] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 2. [Figure 3] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 3. [Figure 4] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 4. [Figure 5] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 5. [Figure 6] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 6. [Figure 7] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 7. [Figure 8] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 8. [Figure 9] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 9. [Figure 10] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 10. [Figure 11] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 11. [Figure 12] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 12. [Figure 13] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 13. [Figure 14] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 14. [Figure 15] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 15. [Figure 16] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 16. [Figure 17] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 17. [Figure 18] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 18. [Figure 19] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 19. [Figure 20] 1 is a reaction scheme for the lipid synthesis process carried out in Example 20. [Figure 21] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 21. [Figure 22] 1 is a reaction scheme for the lipid synthesis process carried out in Production Example 22. [Figure 23] 1 shows the results of a drug delivery experiment carried out in a test example of the present invention, and photographs of the results measured with a luminescence measurement imaging system. BEST MODE FOR CARRYING OUT THE INVENTION

[0027] The present invention will now be described in further detail. [Lipids and their manufacturing methods] The lipids used in the present invention have a structure selected from the following, or in their ionized form: [ka]

[0028] (wherein in each of the structures, at least two (more specifically, 2 to 7) of the R groups are Rx and the remaining R groups are Ry; Rx is independently [ka] wherein a, b, and c are each independently an integer of 2 to 20; R1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group; and R2 is a substituted or unsubstituted, unsaturated monovalent hydrocarbon group; [ka] represents a substituted or unsubstituted methylene group, each Ry is independently H or a substituted or unsubstituted alkyl group, and two Ry groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently a substituted or unsubstituted alkylene group, and the structure may optionally contain an ether bond (-O-), a thioether bond (-S-), or a disulfide bond (-SS-).

[0029] In this specification, the expression "substituted or unsubstituted" for any group means that the group is not substituted or is substituted with an -OH, halogen atom, C, or C, unless otherwise specified. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 3-20 Cycloalkyl groups, C 3-20 Heterocycloalkyl groups, C 6-20 Aryl group or C 3-20 It means that the group is substituted with one or more substituents selected from heteroaryl groups.

[0030] According to one embodiment of the present invention, each Rx is independently [ka] wherein a, b, and c may each independently be an integer of 2 to 20 or 2 to 15; R1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 R2 may be a substituted or unsubstituted unsaturated monovalent C 2-24 may be a hydrocarbon group, [ka] represents a substituted or unsubstituted methylene group.

[0031] According to one embodiment of the present invention, a, b, and c may each independently be an integer of 2 to 15, more specifically, may each independently be an integer of 3 to 12. Even more specifically, a may each independently be an integer of 5 to 7, and b and c may each independently be an integer of 3 to 11, but are not limited thereto.

[0032] According to one embodiment of the present invention, each Ry is independently H or C. 1-20 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —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 groups (e.g., C 3-20 Cycloalkyl group or C 6-20 aryl groups) and optionally substituted C 3-20 Heterocyclic groups (e.g., C 3-20 Heterocycloalkyl group or C 3-20 heteroaryl groups), wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S, and two R groups that are not H may be linked 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 may more specifically be C 1-10 Alkyl or alkoxy groups, more specifically C 1-6 It may be, but is not limited to, an alkyl group or an alkoxy group.

[0033] According to one embodiment of the present invention, each L is independently C 1-20 Alkylene groups (more specifically, C 1-10 Alkylene groups, more specifically C 1-6alkylene groups), each independently unsubstituted or 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 groups (e.g., C 3-20 Cycloalkyl group or C 6-20 aryl groups) and optionally substituted C heterocyclic groups (e.g., C 3-20 Heterocycloalkyl group or C 3-20 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S (e.g., 1 to 3). The alkyl or alkoxy group may be, more specifically, C 1-10 Alkyl or alkoxy groups, more specifically C 1-6 It may be, but is not limited to, an alkyl group or an alkoxy group.

[0034] More specifically, each Ry is independently H or C. 1-10 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —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 groups and optionally substituted C 3-10 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S, and two R groups that are not H may be linked 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.

[0035] More specifically, each L is independently C 1-10alkylene groups, each independently unsubstituted or selected from the group consisting of —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 groups and optionally substituted C 3-10 It may be substituted with one or more heterocyclic groups, wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S.

[0036] More specifically, each Rx is independently [ka] wherein a, b, and c may each independently be an integer from 3 to 12; and R1 is selected from the group consisting of substituted or unsubstituted C 1-12 Alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C 2-12 R2 may be a substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 may be an alkynyl group, [ka] represents a substituted or unsubstituted methylene group.

[0037] More specifically, each Ry is independently H or C. 1-6 and R may be an alkyl group, wherein the alkyl groups are independently unsubstituted or substituted with one or more selected from -OH and -NH, and two R groups that are not H may be joined 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.

[0038] More specifically, each L is independently an unsubstituted C1-6 It may also be an alkylene group.

[0039] Specifically, the lipid may have a structure selected from the following: [ka]

[0040] In each of the above structures, R1 to R7 are each independently [ka] wherein a, b, and c are each independently an integer of 2 to 20; R1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group; and R2 is a substituted or unsubstituted, unsaturated monovalent hydrocarbon group; [ka] represents a substituted or unsubstituted methylene group.

[0041] More specifically, the lipid may have a structure selected from the following formulas (A-V):

[0042] [Table 2-1]

[0043] [Table 2-2]

[0044] [Table 2-3]

[0045] As one embodiment of the lipid used in the present invention, a lipid having a structure represented by the following formula (1-1) can be produced by a method comprising the following steps: (1) reacting a compound of formula (a) with a compound of formula (b) to obtain a compound of formula (c); (2) reacting a compound of formula (c) with a compound of formula (d) to obtain a compound of formula (e); and (3) reacting a compound of formula (e) with a compound of formula (f) and deprotecting the reaction product

[0046] H2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2(1-1) H2N-(CH2) a -C(=O)OH (a) OH-R' (b) H2N-(CH2) a -C(=O)O-R' (c) [ka] H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R' (e) H2N-(CH2) 1-20 -NH-C(=O)OC(CH3)3(f) (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, a, b, and c each independently represent an integer of 2 to 20; X is selected from the group consisting of F, CI, Br and I.

[0047] In one embodiment of the method for producing a lipid having a structure represented by formula (1-1), the reaction of step (1) can be carried out in a solvent (e.g., cyclohexane) in the presence of a catalyst (e.g., p-toluenesulfonic acid monohydrate (p-TsOH)) under reflux, the reaction of step (1) can be carried out in a solvent (e.g., methylene chloride (MC)) in the presence of a catalyst (e.g., triethylamine (TEA)) at low temperature (e.g., -10 ° C to 10 ° C) or room temperature (e.g., 20 ° C to 30 ° C). The reaction of step (3) can be carried out in a solvent (e.g., N-butanol (n-BuOH)) under reflux, and the deprotection of step (3) can be carried out in a solvent (e.g., methylene chloride (MC)) in the presence of an acid (e.g., trifluoroacetic acid (TFA)) at room temperature (e.g., 20 ° C to 30 ° C). However, the present invention is not limited thereto.

[0048] As one embodiment of the lipid used in the present invention, a lipid having a structure represented by the following formula (1-2) can be produced by a method comprising a step of reacting a compound of formula (e) obtained by the method for producing a lipid having a structure represented by formula (1-1) with a compound of formula (g):

[0049] (C 1-20 alkyl)2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2(1-2) H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R' (e) H2N-(CH2) 1-20 -N(C 1-20 alkyl)2(g) (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, and a, b, and c are each independently an integer of 2 to 20.

[0050] In one embodiment of the method for producing lipids according to the third aspect of the present invention, the reaction can be carried out under reflux in a solvent (for example, n-butanol (n-BuOH)), but is not limited thereto.

[0051] In one embodiment of the method for producing a lipid having a structure represented by the following formula (1-3) used in the present invention, there is provided a method comprising the steps of reacting a compound of formula (e) obtained by the method for producing a lipid having a structure represented by formula (1-1) with a compound of formula (h):

[0052] AN(C 1-10 alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A (1-3) H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R' (e) (C 1-10 alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl) (h) (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, A is -CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R', a, b, and c each independently represent an integer of 2 to 20; X is selected from the group consisting of F, CI, Br and I.

[0053] In one embodiment of the method for producing a lipid having a structure represented by formula (1-3), the reaction can be carried out under reflux in a solvent (e.g., n-butanol (n-BuOH)), but is not limited thereto.

[0054] As an embodiment of the lipid used in the present invention, a lipid having a structure represented by the following formula (1-4) can be produced by a method comprising the following steps: (1) reacting a compound of formula (a) with a compound of formula (b') to obtain a compound of formula (c'); (2) reacting a compound of formula (c') with a compound of formula (d) to obtain a compound of formula (e'); and (3) reacting the compound of formula (e') with the compound of formula (h)

[0055] A'-N(C 1-10 alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A' (1-4) H2N-(CH2) a -C(=O)OH (a) OH-R2(b') H2N-R1-C(=O)O-R2(c') [ka] H2C=CH-C(=O)-HN-R1-C(=O)O-R2(e') (C 1-10 alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl) (h) (In the formula, A' is -CH2-CH2-C(=O)-HN-R1-C(=O)O-R2, R1 is independently a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group, R2 is independently a substituted or unsubstituted, unsaturated monovalent hydrocarbon group, a is an integer of 2 to 20, and X is selected from the group consisting of F, CI, Br, and I.)

[0056] In one embodiment of the method for producing a lipid having a structure represented by the formula (1-4), the reaction in step (1) is carried out in a solvent (e.g., cyclohexane) in the presence of a catalyst (e.g., p-toluenesulfonic acid monohydrate (p-TsOH)) under reflux, the reaction in step (2) is carried out in a solvent (e.g., methylene chloride (MC)) in the presence of a catalyst (e.g., triethylamine (TEA)) at low temperature (e.g., −10° C. to 10° C.) or room temperature (e.g., 20° C. to 30° C.), and the reaction in step (3) can be carried out in a solvent (e.g., N-butanol (n-BuOH)) under reflux, but is not limited thereto.

[0057] The lipid having the specific structure used in the present invention can easily form a complex with an anionic drug, and is therefore useful for drug delivery.

[0058] [Drug delivery composition] A first aspect of the present invention relates to a drug delivery composition comprising a drug as an active ingredient and a lipid having the specific structure described above or in its ionized form. In one embodiment, the drug may be complexed with the lipid.

[0059] In one embodiment, the composition of the first aspect of the present invention may further comprise an amphiphilic block copolymer. In one embodiment, the drug may form a complex with the lipid, and the complex may be encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer. In one embodiment, the composition according to the first aspect of the present invention may be in the form of a kit comprising: a first chamber containing the lipid; and a second chamber containing the drug. In one embodiment, the first chamber may further comprise an amphiphilic block copolymer.

[0060] A second aspect of the present invention relates to a drug delivery composition comprising nanoparticles, wherein the nanoparticles comprise a lipid having the specific structure described above or in its ionized form; and the nanoparticles do not contain a drug. In one embodiment, the nanoparticles may further comprise an amphiphilic block copolymer.

[0061] The drug delivery composition according to the second aspect of the present invention is not subject to storage or transportation environments, and when used, the end user can quickly produce drug-containing nanoparticles by simply mixing the composition with the drug without going through complicated processes, even if the type of drug (e.g., mRNA) changes. Therefore, for example, in the case of personalized vaccines or pandemic situations, there is no need to optimize the mRNA production process in the hospital, and once the complete mRNA is produced, it can be quickly administered to the human body by simply mixing it with the composition of the present invention. In one embodiment, the drug delivery composition of the present invention may be for delivering a drug to the lungs.

[0062] In one embodiment, the drug delivery composition of the present invention may further comprise a polylactate. In one embodiment, the drug may be complexed with a lipid, and the complex may be encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer and polylactate. In the nanoparticles, in an aqueous environment, the hydrophilic portion of the amphiphilic block copolymer forms the outer wall of the nanoparticle, and the hydrophobic portion of the amphiphilic block copolymer (and polylactate, if present) forms the inner wall of the nanoparticle, and the drug-lipid complex can be encapsulated inside the nanoparticles thus formed. This nanoparticle structure improves the stability of the active ingredient in blood or body fluids.

[0063] In one embodiment, the drug may be selected from a nucleic acid, a polypeptide, a virus, or a combination thereof. The "nucleic acid" may be, for example, but is not limited to, DNA, RNA, siRNA, shRNA, miRNA, mRNA, an aptamer, an antisense oligonucleotide, or a combination thereof. The term "polypeptide" may refer to a protein that has 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 the polypeptide sequence of an antigen, an analog thereof, or a precursor thereof.

[0064] In one embodiment, the particle size of the nanoparticles is defined by the Z-average value and may 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, or 10 nm or more, 50 nm or more, or 100 nm or more. In a specific embodiment, the particle size of the nanoparticles defined by the 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.

[0065] The "Z-average" refers to the average hydrodynamic diameter of a particle distribution measured using dynamic light scattering (DSL). The nanoparticles have a monodisperse particle distribution, and the polydispersity index may be, for example, 0.01 to 0.50, 0.05 to 0.455, or 0.1 to 0.40.

[0066] In one embodiment, the surface charge of the nanoparticles may be, for example, 0 mV or more, 1 mV or more, 5 mV or more, or 10 mV or more, or 80 mV or less, 70 mV or less, or 60 mV or less. In a specific embodiment, the surface charge of the nanoparticles may be, for example, 0 to 80 mV, 1 to 70 mV, or 5 to 60 mV. The surface charge may be measured in an environment similar to a biological environment, for example, in 8 to 12 mM HEPES buffer (pH 7.0 to 7.5).

[0067] Maintaining the particle size and surface charge of the nanoparticles at these levels is preferable in terms of the stability of the nanoparticle structure, the amount of ingredients, absorbability in the body, and ease of sterilization as a pharmaceutical composition. For example, when the active ingredient is a nucleic acid, one or more ends of the nucleic acid may be modified with one or more selected from the group consisting of cholesterol, tocopherol, and fatty acids having 10 to 24 carbon atoms. The cholesterol, tocopherol, and fatty acids having 10 to 24 carbon atoms include analogs, derivatives, and metabolites of cholesterol, tocopherol, and fatty acids, respectively.

[0068] In one embodiment, when the active ingredient is RNA, the amount of the active ingredient may be, for example, 0.05-30 wt %, 0.1-25 wt %, 0.25-20 wt %, 0.5-15 wt %, 1-10 wt %, or 1-5 wt % based on the total weight of the nanoparticles. If the content of the active ingredient is less than this range, the amount of delivery carrier is too high compared to the drug, which may result in side effects caused by the delivery carrier. If the amount of the nucleotide is more than this range, the size of the nanoparticles may become too large, reducing their stability and increasing the loss rate during filter sterilization.

[0069] In one embodiment, the amount of the lipid may be, for example, 500 parts by weight or less, 400 parts by weight or less, 300 parts by weight or less, 200 parts by weight or less, 100 parts by weight or less, 80 parts by weight or less, or 60 parts by weight or less, or 1 part by weight or more, 2 parts by weight or more, 23 parts by weight or more, 4 parts by weight or more, or 5 parts by weight or more, per part by weight of the active ingredient. In one embodiment, the amount of the lipid may be 1 to 500 parts by weight, 2 to 400 parts by weight, 3 to 300 parts by weight, 4 to 200 parts by weight, or 5 to 80 parts by weight per part by weight of the active ingredient. If the amount of the lipid is less than the above range, it may not be possible to form a stable complex with the active ingredient. If the amount of the lipid is greater than the above range, the size of the nanoparticles may become too large, reducing the stability of the nanoparticles and increasing the loss rate during filter sterilization.

[0070] When the active ingredient is a nucleic acid, the lipid and nucleic acid bind to each other through electrostatic interaction to form a complex. In one embodiment, the charge ratio between the nucleic acid (P) and the lipid (N) (N / P; the ratio of the positive charge of the lipid to the negative charge of the nucleic acid) may be 0.5 or more, 1 or more, 2 or more, or 5 or more, or 200 or less, 150 or less, 100 or less, or 60 or less, for example, 0.5 to 200, 1 to 150, 2 to 100, or 5 to 60. If the ratio (N / P) is below the above range, it may be difficult to form a complex containing a sufficient amount of nucleic acid. On the other hand, if the ratio (N / P) is above the above range, toxicity may be induced. Furthermore, the N / P ratio may play an important role in spleen-specific expression of the active ingredient.

[0071] In one embodiment, the lipids of the present invention are complexed with a drug, and the complex is encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer. In one embodiment, the amphiphilic block copolymer may be an AB type block copolymer comprising a hydrophilic A block and a hydrophobic B block, which in an aqueous environment forms core-shell polymeric nanoparticles in which the hydrophobic B block forms the core (inner wall) and the hydrophilic A block forms the shell (outer wall).

[0072] 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. More specifically, the hydrophilic A block may be one or more selected from the group consisting of monomethoxypolyethylene glycol (mPEG), monoacetoxypolyethylene glycol, polyethylene glycol, a copolymer of polyethylene and propylene glycol, and polyvinylpyrrolidone.

[0073] In one embodiment, the number average molecular weight (g / mol) of the hydrophilic A block may be, but is not limited to, 200 or more, 500 or more, 1,000 or more, or 2,000 or more, and 50,000 or less, 20,000 or less, 10,000 or less, or 5,000 or less.

[0074] Furthermore, if necessary, functional groups, ligands, or functional groups capable of targeting specific tissues or cells, or functional groups capable of promoting intracellular delivery, can be chemically bonded to the ends of the hydrophilic A block to control the biodistribution of polymeric nanoparticle delivery vehicles formed from amphiphilic block copolymers and polylactic acid salts or to enhance the intracellular delivery efficiency of the nanoparticle delivery vehicles. 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, antibodies against transferrin receptors, and the like.

[0075] The hydrophobic B block is a biocompatible, biodegradable polymer, which in one embodiment may be one or more selected from the group consisting of polyesters, polyanhydrides, polyamino acids, polyorthoesters, and polyphosphazines. More specifically, the hydrophobic B block may be one or more selected from the group consisting of polylactide (PLA), polyglycolide, polycaprolactone, polydioxane-2-one, a copolymer of polylactide and glycolide, a copolymer of polylactide and polydioxane-2-one, a copolymer of polylactide and polycaprolactone, and a copolymer of polyglycolide and polycaprolactone.

[0076] In one embodiment, the number average molecular weight (g / mol) of the hydrophobic B block may be, but is not limited to, 200 or more, 500 or more, 1,000 or more, or 1,700 or more, and 50,000 or less, 20,000 or less, 10,000 or less, or 6,000 or less.

[0077] For example, the combination of the number average molecular weight of the hydrophilic A block and the hydrophobic B block may be, but is not limited to, 2,000 to 6,000, 2,000 to 4,000, 2,000 to 3,000, or 2,000 to 1,700.

[0078] In one embodiment, in order to increase the hydrophobicity of the hydrophobic B block and thereby improve the stability of the nanoparticles, the hydrophobic B block may be modified by chemically bonding tocopherol, cholesterol, or a fatty acid having 10 to 24 carbon atoms to the hydroxy group at the end of the hydrophobic B block.

[0079] In one embodiment, the polylactate is distributed in the core (inner wall) of the nanoparticle, strengthening the hydrophobicity of the core to stabilize the nanoparticle and effectively evading the reticuloendothelial system (RES) in the body. That is, the carboxylate anion of polylactate binds to cationic complexes more effectively than polylactic acid, lowering the surface potential of the polymeric nanoparticles. This reduces the positive charge on the surface compared to polymeric nanoparticles without polylactate, making them less likely to be captured by the reticuloendothelial system and more efficiently delivered to target sites (e.g., cancer cells, inflammatory cells, etc.).

[0080] In one embodiment, the number average molecular weight (g / mol) of the polylactate is 500 to 50,000, more specifically 1,000 to 10,000. If the number average molecular weight of the polylactate is less than 500, the hydrophobicity may be too low, and the core (inner wall) of the nanoparticles may not exist. If the number average molecular weight of the polylactate is more than 50,000, the size of the polymer nanoparticles may become too large.

[0081] In one embodiment, the end opposite to the end of the metal carboxylate (e.g., sodium carboxylate) of the polylactic acid salt (e.g., sodium salt of polylactic acid) may be substituted with one selected from the group consisting of hydroxy, acetoxy, benzoyloxy, decanoyloxy, palmitoyloxy, and alkoxy having 1 to 2 carbon atoms.

[0082] In one embodiment, the polylactate may be one or more selected from the group consisting of compounds of the following formulas (2) to (7) (wherein "COO" represents a carboxyl group, i.e., "C(=O)O"):

[0083] RO-CHZ-[A] m -[B] n -COOM (2) (In the formula, A is -COO-CHZ-; B is -COO-CHY-, -COO-CHCHCHCHCH-, or -COO-CHCHOCH-; R is a hydrogen atom, or an acetyl, benzoyl, decanoyl, palmitoyl, methyl, or ethyl group; Z and Y each is a hydrogen atom, or a methyl or phenyl group; M is Na, K, or Li; n is an integer of 1 to 30; and m is an integer of 0 to 20.)

[0084] RO-CHZ-[COO-CHX] p -[COO-CHY'] q -COO-CHZ-COOM (3) (In the formula, X is a methyl group; Y' is a hydrogen atom or a phenyl group; p is an integer of 0 to 25, q is an integer of 0 to 25, with the proviso that p+q is an integer of 5 to 25; R is a hydrogen atom, or an acetyl, benzoyl, decanoyl, palmitoyl, methyl, or ethyl group; M is Na, K, or Li; and Z is a hydrogen atom, methyl, or phenyl group.)

[0085] RO-PAD-COO-W-M' (4) (Wherein W-M' is [ka] wherein PAD is selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymers of D,L-lactic acid and glycolic acid, copolymers of D,L-lactic acid and mandelic acid, copolymers of D,L-lactic acid and caprolactone, and copolymers of D,L-lactic acid and 1,4-dioxane-2-one; R is a hydrogen atom, or an acetyl, benzoyl, decanoyl, palmitoyl, methyl, or ethyl group; and M is independently Na, K, or Li.

[0086] SO-PAD-COO-Q (5) (Wherein, S is [ka] L is -NR1- or -O-, where R1 is a hydrogen atom or C 1-10 Q is CH3, CH2C3, CH2CH2CH3, CH2CH2CH2CH3, or CH2C6H5; a is an integer of 0 to 4; b is an integer of 1 to 10; M is Na, K, or Li; and PAD is one or more selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxane-2-one.

[0087] [ka] (wherein R' represents -PAD-OC(O)-CHCH-C(O)-OM, where PAD is selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxane-2-one, M represents Na, K, or Li, and a represents an integer of 1 to 4.)

[0088] YO-[-C(O)-(CHX) a -O-] m -C(O)-R-C(O)-[-O-(CHX’) b -C(O)-] n -OZ (7) (wherein X and X’ are independently hydrogen, alkyl having 1 to 10 carbon atoms or aryl having 6 to 20 carbon atoms; Y and Z are independently Na, K, or Li; m and n are independently integers from 0 to 95, provided that 5 < m + n < 100; a and b are independently integers from 1 to 6; R is -(CH2) k -, divalent alkenyl having 2 to 10 carbon atoms, divalent aryl having 6 to 20 carbon atoms or a combination thereof, where k is an integer from 0 to 10.)

[0089] In one embodiment, the polylactate may be the compound of the formula (2) or formula (3).

[0090] In one embodiment, the composition of the present invention may further contain a fusogenic lipid in order to enhance the intracellular delivery efficiency of a drug (for example, mRNA). When the fusogenic lipid is mixed with a complex of a drug (for example, mRNA) and the lipid, it forms a complex of drug (for example, mRNA) / lipid / fusogenic lipid by hydrophobic interaction, and the complex containing the fusogenic lipid is encapsulated within the nanoparticle structure of an amphiphilic block copolymer.

[0091] More specifically, the phospholipid may be one or more 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 bonded to one or two C 10-24 fatty acids. The cholesterol and tocopherol include each analog, derivative and metabolite of cholesterol and tocopherol.

[0092] More specifically, the fusogenic lipid is selected from the group consisting of dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE), dilinoleoylphosphatidylethanolamine, 1-palmitoyl-2-oleoylphosphatidylethanolamine, 1,2-diphytanoyl-3-sn-phosphatidylethanolamine, 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dioleo ... The phosphatidylcholine may be one or a combination of two or more selected from the group consisting of dilauroylphosphatidic acid, dimyristoylphosphatidic acid, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dilinoleoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1,2-diphytanoyl-3-sn-phosphatidylcholine, dilauroylphosphatidic acid, dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid, distearoylphosphatidic acid, dioleoylphosphatidic acid, dilinoleoylphosphatidic acid, 1-palmitoyl-2-oleoylphosphatidic acid, 1,2-diphytanoyl-3-sn-phosphatidic acid, cholesterol, and tocopherol.

[0093] More specifically, the fusogenic lipid may be one or more selected from the group consisting of dioleoylphosphatidylethanolamine (DOPE), 1,2-dipalmitoleyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), distearoylphosphatidylcholine (DSPC), and 1,2-dipalmitoleyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0094] In one embodiment, the amount of the amphiphilic block copolymer used may be 1 to 500 parts by weight, 1 to 400 parts by weight, 1 to 300 parts by weight, 2 to 500 parts by weight, 2 to 400 parts by weight, 2 to 300 parts by weight, 3 to 500 parts by weight, 3 to 400 parts by weight, 3 to 300 parts by weight, 4 to 500 parts by weight, 4 to 400 parts by weight, or 4 to 300 parts by weight, relative to 1 part by weight of the lipid.

[0095] In one embodiment, the amount of the polylactate used may be 0.1 to 100 parts by weight, 0.1 to 80 parts by weight, 0.1 to 50 parts by weight, 0.1 to 30 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, 0.5 to 100 parts by weight, 0.5 to 80 parts by weight, 0.5 to 50 parts by weight, 0.5 to 30 parts by weight, 1 to 100 parts by weight, 1 to 80 parts by weight, 1 to 50 parts by weight, 1 to 30 parts by weight, 2 to 100 parts by weight, 2 to 80 parts by weight, 2 to 50 parts by weight, or 2 to 30 parts by weight, relative to 1 part by weight of the lipid.

[0096] In one embodiment, the composition of the present invention may further comprise an aqueous solution, a water-miscible organic solvent, or a combination thereof. The term "aqueous solution" is used in the same sense as an aqueous solution, and examples thereof include water, sterile water, buffer solutions, and injection solutions, and may also include buffer solutions further containing an organic acid. The aqueous solution may be, for example, a citrate buffer solution, a PBS buffer solution, and the like, but is not limited to these. The "water-miscible organic solvent" may include, but is not limited to, a C1-C4 lower alcohol, acetone, acetonitrile, an aqueous mixture thereof, or a mixture thereof.

[0097] In one embodiment, the composition of the present invention may further comprise a stabilizer suitable for improving the stability of the active ingredient. Examples of the stabilizer include, but are not limited to, pH adjusters, inorganic salts, sugars, surfactants, chelating agents, etc. The term "saccharides" refers to monosaccharides, disaccharides, their reduced sugars, sugar alcohols, and polymers of single or mixed polysaccharides, while the term "polysaccharides" refers to polysaccharides of three or more sugars. Examples of the monosaccharides include mannose, glucose, arabinose, fructose, and galactose; examples of the disaccharides include sucrose, trehalose, maltose, lactose, cellobiose, gentiobiose, isomaltose, and melibiose; examples of the sugar alcohols include mannitol, sorbitol, xylitol, erythritol, and maltitol; and examples of the polysaccharides include, but are not limited to, raffinose, dextran, starch, hydroxyethyl starch, cyclodextrin, cellulose, hetastarch, and oligosaccharides. Examples of the "pH adjuster" include, but are not limited to, Tris, glycine, histidine, glutamate, succinate, phosphate, acetate, aspartate, or a combination thereof. Examples of the "surfactant" include, but are not limited to, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, chenodeoxycholic acid, N-lauroyl sarcosine sodium salt, lithium dodecyl sulfate, 1-octanesulfonic acid sodium salt, sodium cholate hydrate, sodium deoxycholate, glycodeoxycholic acid sodium salt, benzalkonium chloride, Triton X-100, Triton X-114, lauromacrogol 400, polyoxyl 40 stearate, polysorbate 20, 40, 60, 65, and 80, or a combination thereof. Examples of the "chelating agent" include, but are not limited to, citric acid, polyphenolic acid, EDTA, DTPA, EDDHA, or a combination thereof. The "inorganic salt" refers to a salt of a monovalent or divalent metal, and includes, but is not limited to, NaCl, KCl, MgCl2, CaCl2, MgSO4, CaSO4, CaCO3, MgCO3, and the like.

[0098] The present invention will be described in more detail below with reference to examples. However, these examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any way. [Example]

[0099] [Lipid production] Manufacturing Example 1 1-1. The compound of formula (A) below was produced according to the synthesis scheme shown in FIG. [ka]

[0100] 1-2. Synthesis of undecyl 6-acrylamidohexanoate A 250 mL three-neck round-bottom flask (RBF) was charged with 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 eq), undecan-1-ol (11.94 g, 69.30 mmol, 1 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred at reflux. After 24 h, the reaction mixture was concentrated under vacuum and extracted with methylene chloride (MC) and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give low-purity undecyl 6-aminohexanoate. Without further purification, the previously obtained undecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (TEA) (15.43 g, 152.46 mmol, 2.2 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After that, acryloyl chloride (6.90 g, 76.23 mmol, 1.1 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 4 h, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified using a silica column with ethyl acetate:hexane (1:1) to obtain undecyl 6-acrylamidohexanoate (17.22 g, yield: 73%).

[0101] 1 H-NMR (400 MHz, CDCl3) δ 6.25 (dd, 1H), 6.01-6.08 (m, 1H), 5.61-5.68 (m, 2H), 4.01 (t, 2H), 3.31 (q, 2H), 2.28 (t, 2H), 1.43-1.68 (m, 6H), 1.30-1.45 (m, 18H), 0.89 (t, 3H)

[0102] 1-3. Synthesis of undecyl 2,2-dimethyl-4,11-dioxo-8-(3-oxo-3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)-3-oxa-5,8,12-triazaoctadecane-18-oate A 100 mL single-neck RBF was charged with undecyl 6-acrylamidohexanoate (3 g, 8.83 mmol, 3 eq), tert-butyl (2-aminoethyl)carbamate (0.47 g, 2.94 mmol, 1 eq), and n-butanol (n-BuOH) (40 mL) and stirred at reflux. After 4 days, the mixture was concentrated under vacuum at 70 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give undecyl 2,2-dimethyl-4,11-dioxo-8-(3-oxo-3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)-3-oxa-5,8,12-triazaoctadecane-18-oate (1.34 g, 54% yield).

[0103] 1 H-NMR (400 MHz, CDCl3) δ 4.06 (t, 4H), 3.49 (q, 4H), 3.26-3.16 (br, 2H), 2.71 (q, 4H), 2.48-2.41 (br, 2H), 2.32-2.85 (m, 8H), 1.67-1.26 (m, 48H), 1.44 (s, 9H), 0.87 (t, 6H)

[0104] 1-4. Synthesis of Compound of Formula (A) To a 100 mL single-neck RBF, undecyl 2,2-dimethyl-4,11-dioxo-8-(3-oxo-3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)-3-oxa-5,8,12-triazaoctadecane-18-oate (1 g, 1.19 mmol) and methylene chloride (20 mL) were added, and trifluoroacetic acid (TFA) (2 mL) was added dropwise. After stirring at room temperature for 4 hours, the mixture in the reactor was extracted with saturated aqueous sodium bicarbonate, and the methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound of formula (A) (0.31 g, 35%).

[0105] 1H-NMR (400 MHz, CDCl3) δ 6.86 (t, 2H), 4.06 (t, 4H), 3.25 (t, 4H), 2.89 (t, 2H), 2.68 (t, 4H), 2.58 (t, 2H), 2.36 (t, 4H), 2.31 (t, 2H), 1.65 - 1.26 (m, 48H), 0.89 (t, 6H)

[0106] Manufacturing Example 2 2-1. The compound of formula (B) below was produced according to the synthesis scheme shown in FIG. [ka]

[0107] Synthesis of 2-2,2-hexyldecyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 eq), 2-hexyldecan-1-ol (16.80 g, 69.30 mmol, 1 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-hexyldecyl 6-aminohexanoate. Without further purification, the previously obtained 2-hexyldecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (TEA) (15.43 g, 152.46 mmol, 2.2 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After that, acryloyl chloride (6.90 g, 76.23 mmol, 1.1 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 4 h, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using ethyl acetate:hexane (1:1) to obtain 2-hexyldecyl 6-acrylamidohexanoate (14.25 g, yield: 50%).

[0108] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.07-6.12 (m, 1H), 5.62-5.64 (m, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.54-1.68 (m, 5H), 1.26-1.41 (m, 26H), 0.87 (t, 6H)

[0109] Synthesis of 2-3,2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate

[0110] 2-Hexyldecyl 6-acrylamidohexanoate (4 g, 9.76 mmol, 3 eq), tert-butyl (2-aminoethyl)carbamate (0.52 g, 3.25 mmol, 1 eq), and n-butanol (n-BuOH) (40 mL) were added to a 100 mL single-neck RBF and stirred at reflux. After 4 days, the mixture was concentrated under vacuum at 70 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give 2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate (2.23 g, 70% yield).

[0111] 1 H-NMR (400 MHz, CDCl3) δ 7.09 (br, 2H), 3.96 (d, 4H), 3.35 (q, 4H), 3.26 (q, 4H), 3.06 (br, 4H), 2.88 (t, 4H), 2.50 (br, 4H), 2.32 (t, 4H), 1.67-1.35 (m, 62H), 1.44 (s, 9H), 0.89 (t, 12H)

[0112] 2-4. Synthesis of Compound of Formula (B) To a 100 mL single-neck RBF, 2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate (2 g, 2.04 mmol) and methylene chloride (40 mL) were added, and trifluoroacetic acid (TFA) (4 mL) was added dropwise. After stirring at room temperature for 4 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound of formula (B) (1.21 g, 67%).

[0113] 1 H-NMR (400 MHz, CDCl3) δ 6.96 (t, 2H), 3.96 (t, 4H), 3.21 - 3.13 (m, 6H), 2.71 (t, 2H), 2.64 (t, 4H), 2.37 (t, 4H), 2.31 (t, 4H), 1.65 - 1.33 (m, 62H), 0.89 (t, 6H)

[0114] Manufacturing Example 3 3-1. A compound of the following formula (C) was produced according to the synthesis scheme shown in FIG. [ka]

[0115] 3-2. Synthesis of Compound of Formula (C) 2-Hexyldecyl 6-acrylamidohexanoate (3 g, 7.32 mmol, 3 eq) synthesized in Example 2-2, N,N-dimethylethylenediamine (0.22 g, 2.44 mmol, 1 eq), and N-butanol (n-BuOH) (30 mL) were added to a 100 mL single-neck RBF and refluxed with stirring. After 3 days, the mixture was concentrated under vacuum at 70 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain the compound of formula (C) (0.95 g, 43% yield).

[0116] 1 H-NMR (400 MHz, CDCl3) δ 4.05 (t, 4H), 3.15 (q, 4H), 2.77 (br, 4H), 2.69 (t, 4H), 2.53 (br, 6H), 2.12 (t, 4H), 2.28 (t, 4H), 1.66 - 1.26 (m, 62H), 0.89 (t, 6H)

[0117] Manufacturing Example 4 4-1. A compound of the following formula (D) was produced according to the synthesis scheme shown in FIG. [ka]

[0118] Synthesis of 4-2,2-butyloctyl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (5.03 g, 38.32 mmol, 1.20 eq), 2-butyl-1-n-octanol (5.95 g, 31.93 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (10.93 g, 57.48 mmol, 1.80 eq), and cyclohexane (200 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-butyloctyl 6-aminohexanoate. Without further purification, the previously obtained 2-butyloctyl 6-aminohexanoate, methylene chloride (170 mL), and triethylamine (7.11 g, 70.28 mmol, 2.20 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (3.18 g, 35.12 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using ethyl acetate (EtOAc):hexane (1:2) to obtain 2-butyloctyl 6-acrylamidohexanoate (5.0 g, yield: 44%).

[0119] 1 H-NMR (400 MHz, CDCl3) δ 6.47 (dd, 1H), 6.09-6.15 (m, 1H), 5.63 (dd, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.54-1.68 (m, 6H), 1.27-1.40 (m, 20H), 0.87-0.91 (m, 6H)

[0120] 4-3. Synthesis of Compound of Formula (D) 2-Butyloctyl 6-acrylamidohexanoate (1000.00 mg, 2.83 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (111.16 mg, 1.09 mmol, 1.00 eq), and n-BuOH (11 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound (D) (712.60 mg, 81% yield).

[0121] 1 H-NMR (400 MHz, CDCl3) δ 7.87 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.61 (t, 4H), 2.41 (t, 4H), 2.36 (t, 4H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.70 (m, 8H), 1.48-1.54 (m, 4H), 1.25-1.39 (m, 37H), 0.90 (t, 3H)

[0122] Production Example 5 5-1. The compound of formula (E) below was produced according to the synthesis scheme shown in FIG. [ka]

[0123] Synthesis of 5-2,2-hexyloctyl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (1.84 g, 13.99 mmol, 1.20 eq), 2-hexyl-1-n-octanol (2.50 g, 11.66 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (3.99 g, 20.99 mmol, 1.80 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-hexyloctyl 6-aminohexanoate. Without further purification, the previously obtained 2-hexyloctyl 6-aminohexanoate, methylene chloride (60 mL), triethylamine (2.60 g, 25.65 mmol, 2.20 eq), and methylene chloride (60 mL) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (1.16 g, 12.83 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain 2-hexyloctyl 6-acrylamidohexanoate (3.63 g, 82% yield).

[0124] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.11 (m, 1H), 5.63 (dd, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.41-1.68 (m, 6H), 1.21-1.41 (m, 20H), 0.85-0.90 (m, 6H)

[0125] 5-3. Synthesis of Compound of Formula (E) 2-Hexyloctyl 6-acrylamidohexanoate (660.27 mg, 1.73 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (68.00 mg, 0.67 mmol, 1.00 eq), and n-BuOH (7 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound (E) (375.60 mg, 65% yield).

[0126] 1 H-NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.71 (m, 8H), 1.48-1.54 (m, 4H), 1.20-1.40 (m, 45H), 0.90 (t, 12H)

[0127] Manufacturing Example 6 6-1. A compound of the following formula (F) was produced according to the synthesis scheme shown in FIG. [ka]

[0128] 6-2. Synthesis of butyl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (6.37 g, 48.57 mmol, 1.20 eq), butan-1-ol (3.00 g, 40.47 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (15.40 g, 80.95 mmol, 2.00 eq), and cyclohexane (200 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure butyl 6-aminohexanoate. Without further purification, the previously obtained butyl 6-aminohexanoate, methylene chloride (200 mL), and triethylamine (9.01 g, 89.04 mmol, 2.20 eq) were added to a 500 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (4.03 g, 44.52 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:1) to give butyl 6-acrylamidohexanoate (3.58 g, yield: 37%).

[0129] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.01-6.11 (m, 1H), 5.62-5.67 (m, 2H), 4.07 (t, 2H), 3.34 (q, 2H), 2.31 (t, 2H), 1.41-1.62 (m, 6H), 1.34-1.39 (m, 4H), 0.93 (t, 3H)

[0130] 6-3. Synthesis of Compound of Formula (F) A 100 mL three-necked RBF was charged with butyl 6-acrylamidohexanoate (700.00 mg, 2.90 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (113.99 mg, 1.12 mmol, 1.00 eq), and N-BuOH (11 mL) and stirred under reflux. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound (F) (479.00 mg, 73% yield). 1 H-NMR (400 MHz, CDCl3) δ 7.89 (s, 2H), 4.06 (t, 4H), 3.22 (q, 4H), 2.61 (t, 4H), 2.46 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.31 (s, 6H), 1.60-1.70 (m, 10H), 1.41-1.60 (m, 4), 1.32-1.39 (m, 8H), 0.90 (t, 6H)

[0131] Manufacturing Example 7 7-1. The compound of formula (G) below was produced according to the synthesis scheme shown in FIG. [ka]

[0132] Synthesis of 7-2,2-octyldodecyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (1.05 g, 8.04 mmol, 1.20 eq), 2-octyldodecan-1-ol (2.00 g, 6.70 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (2.29 g, 12.06 mmol, 1.80 eq), and cyclohexane (100 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-octyldodecyl 6-aminohexanoate. Without further purification, the previously obtained 2-octyldodecyl 6-aminohexanoate, methylene chloride (33 mL), and triethylamine (1.49 g, 14.74 mmol, 2.20 eq) were added to a 100 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (0.67 g, 7.37 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain 2-octyldodecyl 6-acrylamidohexanoate (1928.20 mg, yield: 62%).

[0133] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.10 (m, 1H), 5.59-5.64 (m, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.54-1.68 (m, 4H), 1.26-1.41 (m, 36H), 0.89 (t, 6H)

[0134] 7-3. Synthesis of Compound of Formula (G) 2-Octyldodecyl 6-acrylamidohexanoate (592.57 mg, 1.27 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (50.00 mg, 0.49 mmol, 1.00 eq), and n-BuOH (5 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give compound (G) (346.8 mg, 69% yield).

[0135] 1 H-NMR (400 MHz, CDCl3) δ 7.83 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.69 (m, 8H), 1.48-1.54 (m, 4H), 1.25-1.39 (m, 69H), 0.90 (t, 3H)

[0136] Manufacturing Example 8 8-1. The compound of formula (H) below was produced according to the synthesis scheme shown in FIG. [ka]

[0137] Synthesis of 8-2,2-hexyl octyl 8-acrylamido octanoate A 250 mL three-neck RBF was charged with 8-aminooctanoic acid (1.78 g, 11.19 mmol, 1.20 eq), 2-hexyloctan-1-ol (2.00 g, 9.33 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (3.19 g, 16.79 mmol, 1.80 eq), and cyclohexane (100 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure 2-hexyloctyl 8-aminooctanoate. Without further purification, the previously obtained 2-hexyloctyl 8-aminooctanoate, methylene chloride (100 mL), and triethylamine (2.08 g, 20.52 mmol, 2.20 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (0.93 g, 10.26 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:1) to obtain 2-hexyloctyl 8-acrylamidooctanoate (2838.70 mg, 74% yield).

[0138] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.10 (m, 1H), 5.55-5.64 (m, 2H), 3.97 (d, 2H), 3.32 (q, 2H), 2.29 (t, 2H), 1.51-1.65 (m, 4H), 1.27-1.35 (m, 27H), 0.85-0.90 (m, 6H)

[0139] 8-3. Synthesis of Compound of Formula (H) 2-Hexyloctyl 8-acrylamidooctanoate (703.42 mg, 0.76 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (30.00 mg, 0.29 mmol, 1.00 eq), and n-BuOH (5 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 h, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give compound (H) (218.90 mg, 81% yield).

[0140] 1 H-NMR (400 MHz, CDCl3) δ 7.78 (s, 2H), 3.96 (d, 4H), 3.21 (q, 4H), 2.64 (t, 4H), 2.44 (t, 4H), 2.38 (t, 4H), 2.28-2.32 (m, 4H), 2.26 (s, 6H), 1.66-1.72 (m, 2H), 1.40-1.63 (m, 10H), 1.20-1.40 (m, 54H), 0.90 (t, 12H)

[0141] Manufacturing Example 9 9-1. The compound of formula (I) below was produced according to the synthesis scheme shown in FIG. [ka]

[0142] Synthesis of 9-2,2-decyltetradecyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (887.70 mg, 6.77 mmol, 1.20 eq), 2-decyltetradecane-1-ol (2.00 g, 5.64 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (1.93 g, 10.15 mmol, 1.80 eq), and cyclohexane (100 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-decyltetradecyl 6-aminohexanoate. Without further purification, the previously obtained 2-decyltetradecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (1.26 g, 12.41 mmol, 2.20 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (561.44 mg, 6.20 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain 2-decyltetradecyl 6-acrylamidohexanoate (1.29 g, yield: 44%).

[0143] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.10 (m, 1H), 5.62-5.64 (m, 2H), 3.97 (d, 2H), 3.34 (q, 2H) 2.31 (t, 2H), 1.54-1.68 (m, 5H), 1.26-1.41 (m, 44H), 0.88-0.89 (m, 6H)

[0144] 9-3. Synthesis of Compounds of Formula (I) 2-Decyltetradecyl 6-acrylamidohexanoate (306.44 mg, 0.59 mmol, 2.40 eq), N,N'-dimethyl-1,3-propanediamine (25.00 mg, 0.24 mmol, 1.00 eq), and n-BuOH (2.5 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 h, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give the compound of formula (I) (209.2 mg, 75% yield).

[0145] 1 H-NMR (400 MHz, CDCl3) δ 7.86 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.60 (t, 4H), 2.41 (t, 4H), 2.35 (t, 4H), 2.30 (t, 4H), 2.24 (s, 6H), 1.61-1.69 (m, 11H), 1.48-1.53 ​​(m, 4H), 1.20-1.40 (m, 87H), 0.9 (t, 12H)

[0146] Manufacturing Example 10 10-1. The compound of formula (J) below was produced according to the synthesis scheme shown in FIG. [ka]

[0147] 10-2. Synthesis of Compound of Formula (J) 2-Hexyldecyl 6-acrylamidohexanoate (2000.00 mg, 4.88 mmol, 3.00 eq) synthesized in Example 2-2, N,N'-dimethyl-1,3-propanediamine (170.00 mg, 1.63 mmol, 1.00 eq), and N-BuOH (20 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain the compound of formula (J) (934.00 mg, yield: 62%).

[0148] 1 H-NMR (400 MHz, CDCl3) δ 7.88 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.60 (t, 4H), 2.40 (t, 4H), 2.35 (t, 4H), 2.30 (t, 4H), 2.27 (s, 6H), 1.61-1.70 (m, 8H), 1.40-1.54 (m, 4H), 1.20-1.40 (m, 52H), 0.90 (t, 12H)

[0149] Manufacturing Example 11 11-1. The compound of formula (K) below was produced according to the synthesis scheme shown in FIG. [ka] 11-2. Synthesis of nonyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 eq), nonan-1-ol (21.58 g, 69.30 mmol, 1 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was concentrated in vacuo and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give low-purity nonyl 6-aminohexanoate. Without further purification, the previously obtained nonyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (15.43 g, 152.46 mmol, 2.2 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. Acryloyl chloride (6.90 g, 76.23 mmol, 1.1 eq) was then added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 4 h, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:1) to give nonyl 6-acrylamidohexanoate (15.66 g, yield: 66%).

[0150] 1 H-NMR (400 MHz, CDCl3) δ 6.28 (d, 1H), 6.11 (m, 1H), 5.64 (d, 2H), 4.07 (t, 2H), 3.63 (q, 2H), 2.32 (t, 2H), 1.68 - 1.26 (m, 20H), 0.90 (t, 3H)

[0151] 11-3. Synthesis of Compound of Formula (K) Nonyl 6-acrylamidohexanoate (1000.00 mg, 3.21 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (126.18 mg, 1.23 mmol, 1.00 eq), and N-BuOH (10 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound (K) (770.10 mg, 86% yield).

[0152] 1 H-NMR (400 MHz, CDCl3) δ 7.87 (s, 2H), 4.05 (t, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.42 (t, 4H), 2.36 (t, 2H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.69 (m, 10H), 1.40-1.60 (m, 4H), 1.27-1.38 (m, 28H), 0.87 (t, 6H)

[0153] Manufacturing Example 12 12-1. The compound of formula (L) below was produced according to the synthesis scheme shown in FIG. [ka]

[0154] 12-2. Synthesis of Compound of Formula (L) 2-Butyloctyl 6-acrylamidohexanoate (850.65 mg, 2.43 mmol, 2.60 eq) synthesized in Example 4-2, tert-butyl N-(2-aminoethyl)carbamate (150.00 mg, 0.94 mmol, 1.00 eq), and n-BuOH (10 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to obtain impure 2-butyloctyl 8-(3-((6-((2-butyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate. The compound of formula (L) was then synthesized without further purification. 2-Butyloctyl 8-(3-((6-((2-butyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate (143.20 mg, 0.16 mmol) and methylene chloride (2 mL) were added to a 25 mL single-neck RBF, and trifluoroacetic acid (0.2 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to obtain the compound of formula (L) (85.1 mg, 67%).

[0155] 1 H-NMR (400 MHz, CDCl3) δ 6.38 (t, 2H), 3.96 (d, 4H), 3.18 (q, 4H), 2.93 (t, 2H), 2.67 (t, 4H), 2.58 (t, 2H), 2.29-2.36 (m, 8H), 1.61-1.66 (m, 6H), 1.48-1.60 (m, 4H), 1.27-1.38 (m, 38H), 0.90-0.92 (m, 12H) Manufacturing Example 13

[0156] 13-1. The compound of formula (M) below was produced according to the synthesis scheme shown in FIG. [ka]

[0157] 13-2. Synthesis of Compound of Formula (M) To a 100 mL three-neck RBF, 2-hexyloctyl 6-acrylamidohexanoate (1429.07 mg, 3.74 mmol, 2.40 eq) synthesized in Example 5-2, tert-butyl N-(2-aminoethyl)carbamate (250.00 mg, 1.56 mmol, 1.00 eq), and n-BuOH (10 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give impure 2-hexyloctyl 8-(3-((6-((2-hexyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate, which was then used for the synthesis of the compound of formula (M) without further purification steps. 2-Hexyloctyl 8-(3-((6-((2-hexyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate and methylene chloride (3 mL) were added to a 25 mL single-neck RBF, and trifluoroacetic acid (0.3 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (8:1:0.1) to give the compound of formula (M) (116.6 mg, 9.1% yield for two steps).

[0158] 1H-NMR (400 MHz, CDCl3) δ 6.94 (t, 2H), 3.96 (d, 4H), 3.12-3.20 (m, 6H), 2.73 (t, 2H), 2.62 (t, 4H), 2.29-2.37 (m, 8H), 1.59-1.65 (m, 6H), 1.47-1.52 (m, 4H), 1.20-1.39 (m, 46H), 0.90 (t, 12H)

[0159] Manufacturing Example 14 14-1. The compound of formula (N) below was produced according to the synthesis scheme shown in FIG. [ka]

[0160] 14-2. Synthesis of Compound of Formula (N) To a 100 mL three-neck RBF, 2-octyldodecyl 6-acrylamidohexanoate (1200.00 mg, 2.58 mmol, 2.40 eq) synthesized in Example 7-2, tert-butyl N-(2-aminoethyl)carbamate (171.99 mg, 1.07 mmol, 1.00 eq), and n-BuOH (10 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give impure 2-octyldodecyl 2,2-dimethyl-8-(3-((6-((2-octyldodecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate, which was then used for the synthesis of compound of formula (N) without further purification. 2-Octyldodecyl 2,2-dimethyl-8-(3-((6-((2-octyldodecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate and methylene chloride (10 mL) were added to a 100 mL single-neck RBF, and trifluoroacetic acid (1.0 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give the compound of formula (N) (137.8 mg, two steps 12.9%).

[0161] 1 H-NMR (400 MHz, CDCl3) δ 6.86 (t, 2H), 3.96 (d, 4H), 3.17 (q, 4H), 2.98 (t, 2H), 2.61-2.67 (m, 6H), 2.29-2.37 (m, 8H), 1.60-1.66 (m, 7H), 1.20-1.38 (m, 72H), 0.90-0.95 (m, 12H)

[0162] Manufacturing Example 15 15-1. The compound of formula (O) below was produced according to the synthesis scheme shown in FIG. [ka]

[0163] 15-2. Synthesis of Compound of Formula (O) To a 100 mL three-neck RBF, 2-hexyloctyl 8-acrylamidooctanoate (1130.14 mg, 2.76 mmol, 2.60 eq) synthesized in Example 8-2, tert-butyl N-(2-aminoethyl)carbamate (170.00 mg, 1.06 mmol, 1.00 eq), and n-BuOH (11 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give impure 2-hexyloctyl 8-(3-((8-((2-hexyloctyl)oxy)-8-oxooctyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaicosan-20-oate, which was then used for the synthesis of compound of formula (O) without further purification steps. 2-Hexyloctyl 8-(3-((8-((2-hexyloctyl)oxy)-8-oxooctyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaicosan-20-oate and methylene chloride (4.4 mL) were added to a 25 mL single-neck RBF, and trifluoroacetic acid (0.4 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give the compound of formula (O) (225.5 mg, 24.2% yield for two steps).

[0164] 1H-NMR (400 MHz, CDCl3) δ 6.81 (t, 2H), 3.96 (d, 4H), 3.15 (q, 4H), 3.03 (t, 2H), 2.63-2.66 (m, 6H), 2.35 (t, 4H), 2.29 (t, 4H), 1.59-1.62 (m, 6H), 1.46-1.50 (m, 4H), 1.27-1.39 (s, 55H), 0.87-0.92 (m, 12H)

[0165] Manufacturing Example 16 16-1. The compound of formula (P) below was produced according to the synthesis scheme shown in FIG. [ka]

[0166] 16-2. Synthesis of Compound of Formula (P) To a 100 mL three-neck RBF, 2-decyltetradecyl 6-acrylamidohexanoate (891.15 mg, 1.71 mmol, 2.40 eq) synthesized in Example 9-2, tert-butyl N-(2-aminoethyl)carbamate (114.00 mg, 0.71 mmol, 1.00 eq), and n-BuOH (6.2 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (20:1:0.1) to give impure 2-decyltetradecyl 8-(3-((6-((2-decyltetradecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate, which was then used for the synthesis of compound (P) without further purification. To a 25 mL single-neck RBF was added 2-decyltetradecyl 8-(3-((6-((2-decyltetradecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate and methylene chloride (6.0 mL), and trifluoroacetic acid (0.6 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound of formula (P) (157.9 mg, 20.1% yield for two steps).

[0167] 1 H-NMR (400 MHz, CDCl3) δ 6.98 (t, 2H), 3.96 (d, 4H), 3,16 (q, 4H), 3.01 (t, 2H), 2.65 (t, 6H), 2.36 (t, 4H), 2.30 (t, 4H), 1.60-1.66 (m, 7H), 1.48-1.54 (m, 5H), 1.20-1.40 (m, 83H), 0.90-0.95 (m, 12H)

[0168] Manufacturing Example 17 17-1. The compound of formula (Q) below was produced according to the synthesis scheme shown in FIG. [ka]

[0169] 17-2. Synthesis of Compound of Formula (Q) Nonyl 6-acrylamidohexanoate (3000.00 mg, 9.63 mmol, 2.60 eq) synthesized in Example 11-2, N,N-dimethylpropanediamine (378.53 mg, 1.00 mmol, 1.00 eq), and N-BuOH (18 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to obtain the compound of formula (Q) (1257.6 mg, yield: 47%).

[0170] 1 H-NMR (400 MHz, CDCl3) δ 4.05 (t, 4H), 3.22 (q, 4H), 2.73 (t, 4H), 2.50 (t, 2H), 2.25-2.47 (m, 10H), 2.23 (s, 6H), 1.60-1.67 (m, 10H), 1.48-1.58 (m, 4H), 1.27-1.38 (m, 28H), 0.88 (t, 6H)

[0171] Manufacturing Example 18 18-1. The compound of the following formula (R) was produced according to the synthesis scheme shown in FIG. [ka]

[0172] 18-2. Synthesis of compounds of formula (R) 2-Hexyldecyl 6-acrylamidohexanoate (1500.00 mg, 3.67 mmol, 2.60 eq) synthesized in Example 2-2, N,N-dimethylpropanediamine (143.90 mg, 1.41 mmol, 1.00 eq), and N-BuOH (7 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain the compound of formula (R) (476.10 mg, yield: 37%).

[0173] 1 H-NMR (400 MHz, CDCl3) δ 6.88 (t, 2H), 3.97 (d, 4H), 3.21 (q, 4H), 2.72 (t, 4H), 2.49 (t, 2H), 2.29-2.35 (m, 10H), 2.22 (s, 6H), 1.61-1.67 (m, 9H), 1.49-1.55 (m, 4H), 1.27-1.40 (m, 50H), 0.88 (t, 12H)

[0174] Manufacturing Example 19 19-1. The compound of formula (S) below was produced according to the synthesis scheme shown in FIG. [ka]

[0175] 19-2. Synthesis of Compound of Formula (S) 2-Hexyldecyl 6-acrylamidohexanoate (2000.00 mg, 4.88 mmol, 3.00 eq) synthesized in Example 2-2, 2-morpholinoethan-1-ol (210.00 mg, 1.63 mmol, 1.00 eq), and n-BuOH (20 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to obtain the compound of formula (S) (596.00 mg, yield: 39%).

[0176] 1 H-NMR (400 MHz, CDCl3) δ 6.82 (t, 2H), 3.96 (d, 4H), 3.69 (t, 4H), 3.22 (q, 4H), 2.76 (t, 3H), 2.58 (t, 2H), 2.43-2.49 (m, 6H), 2.29-2.34 (m, 7H), 1.61-1.67 (m, 6H), 1.38-1.54 (m, 4H), 1.27-1.38 (m, 52H), 0.88 (t, 12H)

[0177] Manufacturing Example 20 20-1. The compound of formula (T) below was produced according to the synthesis scheme shown in FIG. [ka] Synthesis of 20-2.dec-3-yn-1-yl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (3.06 g, 23.34 mmol, 1.20 eq), dec-3-yn-1-ol (3.00 g, 19.45 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (5.55 g, 29.17 mmol, 1.50 eq), and cyclohexane (130 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and aqueous NaOH. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure dec-3-yn-1-yl 6-aminohexanoate. Without further purification, the previously obtained dec-3-yn-1-yl 6-aminohexanoate, methylene chloride (130 mL), and triethylamine (4.33 g, 42.79 mmol, 2.20 eq) were added to a 500 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (1.94 g, 21.39 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to give dec-3-yn-1-yl 6-acrylamidohexanoate (765.60 mg, 12% yield).

[0178] 1 H-NMR (400 MHz, CDCl3) δ 6.29 (d, 1H), 6.11 (m, 1H), 5.64 (d, 2H), 4.15 (t, 2H), 3.36 (t, 2H), 2.49 (m, 2H), 2.35 (t, 2H), 2.15 (t, 2H), 1.67 - 1.26 (m, 14H), 0.88 (t, 3H)

[0179] 20-3. Synthesis of Compound of Formula (T) To a 100 mL three-necked RBF, dec-3-yn-1-yl 6-acrylamidohexanoate (300.00 mg, 0.94 mmol, 2.20 eq), N,N'-dimethyl-1,3-propanediamine (43.80 mg, 0.43 mmol, 1.00 eq), and n-BuOH (5 mL) were added and stirred under reflux. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain compound (T) (165.3 mg, 52% yield).

[0180] 1 H-NMR (400 MHz, CDCl3) δ 7.90 (s, 2H), 4.13 (t, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.48 (m, 4H), 2.42 (m, 4H), 2.36 (t, 4H), 2.32 (t, 4H), 2.25 (s, 6H), 2.15 (m, 4H), 1.63-1.79 (m, 7H), 1.40-1.60 (m, 9H), 1.25-1.38 (m, 8H), 0.90 (t, 6H)

[0181] Manufacturing Example 21 21-1. The compound of formula (U) below was produced according to the synthesis scheme shown in FIG. [ka]

[0182] 21-2. Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate

[0183] A 100 mL three-neck RBF was charged with 6-aminohexanoic acid (295.37 mg, 2.25 mmol, 1.20 eq), (9Z,12Z)-octadeca-9,12-dien-1-ol (500.00 mg, 1.88 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (642.47 mg, 3.38 mmol, 1.80 eq), and cyclohexane (20 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and aqueous NaOH. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure (9Z,12Z)-octadeca-9,12-dien-1-yl 6-aminohexanoate. Without further purification, the previously obtained (9Z,12Z)-octadeca-9,12-dien-1-yl 6-aminohexanoate, methylene chloride (20 mL), and triethylamine (417.72 mg, 4.13 mmol, 2.20 eq) were added to a 100 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (186.82 mg, 2.06 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate (579.9 g, 71% yield).

[0184] 1 H NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.11 (m, 1H), 5.62-5.64 (m, 2H), 5.34-5.38 (m, 4H), 4.05 (t, 2H), 3.33 (q, 2H), 2.76 (t, 2H), 2.29 (t, 2H), 2.05 (q, 4H), 1.56-1.67 (m, 6H), 1.28-1.39 (m, 18H), 0.89 (t, 3H)

[0185] 21-3. Synthesis of Compounds of Formula (U) (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate (305.258 mg, 0.70 mmol, 2.40 eq), N,N'-dimethyl-1,3-propanediamine (30.00 mg, 0.29 mmol, 1.00 eq), and n-BuOH (3 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 h, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give compound (U) (185.10 mg, 65% yield).

[0186] 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 5.34-5.38 (m, 8H), 4.05 (s, 4H), 3.22 (q, 4H), 2.80 (t, 4H), 2.60 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.28 (t, 4H), 2.03 (s, 6H), 2.05 (q, 8H), 1.60-1.68 (m, 10H), 1.49-1.60 (m, 4H), 1.27-1.37 (m, 36H), 0.89 (t, 3H)

[0187] Manufacturing Example 22 22-1. The compound of formula (V) below was produced according to the synthesis scheme shown in FIG. [ka]

[0188] Synthesis of 22-2,1-cyclopropylnonyl 6-(((benzoyloxy)carbonyl)amino)hexanoate

[0189] 1-Cyclopropylnonan-1-ol (8.68 g, 47.1 mmol, 1.00 eq) and methylene chloride (170 mL) were added to a 500 mL three-neck RBF at 25 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (11.7 g, 61.3 mmol, 1.30 eq) and triethylamine (EtN) (9.54 g, 94.2 mmol, 2.00 eq) were added to the mixture. 6-(((benzyloxy)carbonyl)amino)hexanoic acid (15.0 g, 56.5 mmol, 1.20 eq) and 4-dimethylaminopyridine (DMAP) (1.15 g, 9.42 mmol, 0.20 eq) were added. The mixture was purged with nitrogen (N) three times. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with 600 mL of methylene chloride (200 mL x 3). The methylene chloride layer was collected, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether (PE) / ethyl acetate (EtOAc) = 10 / 1 to 1 / 100). 1-Cyclopropylnonyl 6-(((benzoyloxy)carbonyl)amino)hexanoate (9.00 g, 20.9 mmol, 44.3% yield) was obtained as a colorless oil.

[0190] 1 H NMR (400 MHz, CDCl3) δ 4.27 (td, 1H), 3.41 (t, 2H), 2.31 (t, 2H), 1.89 - 1.74 (m, 2H), 1.68 - 1.60 (m, 4H), 1.43 (s, 2H), 1.38 - 1.25 (m, 16H), 0.99 - 0.92 (m, 1H), 0.89 (t, 3H), 0.59 - 0.51 (m, 1H), 0.49 - 0.42 (m, 1H), 0.38 (qd, 1H), 0.31 - 0.21 (m, 1H)

[0191] Synthesis of 22-3.1-cyclopropylnonyl 6-aminohexanoate Under an argon (Ar) atmosphere, palladium catalyst (Pd / C) (2.22 g, 2.09 mmol, 10% purity, 0.10 eq) was added to a 35 mL portion of a cylindrical flask. Tetrahydrofuran (THF) (90 mL) was added to the upper portion of the cylindrical flask. 1-Cyclopropylnonyl 6-(((benzoyloxy)carbonyl)amino)hexanoate (9.00 g, 20.9 mmol, 1.00 eq) was added to the mixture. Hydrogen (H) was charged to 50 psi. The mixture was stirred at 50 °C for 16 h. The Pd / C filter cake was safely filtered and collected. The filtrate was concentrated under pressure to give a residue. The residue was purified by column chromatography (SiO2, methylene chloride / methanol = 10 / 1 to 1 / 100) to obtain 1-cyclopropylnonyl 6-aminohexanoate (6.00 g, 20.2 mmol, yield 96.7%) as a yellow oil.

[0192] 1 H NMR (400 MHz, CDCl3) δ 4.27 (td, 1H), 2.71 (t, 2H), 2.32 (t, 2H), 1.71 - 1.60 (m, 5H), 1.53 - 1.43 (m, 2H), 1.42 - 1.18 (m, 15H), 1.00 - 0.92 (m, 1H), 0.89 (t, 3H), 0.59 - 0.50 (m, 1H), 0.49 - 0.42 (m, 1H), 0.38 (qd, 1H), 0.33 - 0.18 (m, 1H)

[0193] Synthesis of 22-4.1-cyclopropylnonyl 6-acrylamidohexanoate To a 100 mL three-neck RBF, methylene chloride (30 mL) and 1-cyclopropylnonyl 6-aminohexanoate (3.00 g, 10.1 mmol, 1.00 eq) were added. Triethylamine (TEA) (4.59 g, 45.4 mmol, 4.50 eq) was added to the mixture at 0 °C. Acryloyl chloride (1.37 g, 15.1 mmol, 1.50 eq) was added dropwise to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h and then gradually cooled to room temperature. The reaction mixture was neutralized with water (40 mL) at 20 °C and extracted with methylene chloride (50 mL x 3). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 to 1 / 100). 1-Cyclopropylnonyl 6-acrylamidohexanoate (2.60 g, 7.40 mmol, 73.3% yield) was obtained as a yellow oil.

[0194] 1 H NMR (400 MHz, CDCl3) δ6.34 - 6.21 (m, 1H), 6.15 - 5.98 (m, 1H), 5.64 (br dd, 1H), 4.27 (td, 1H), 3.41 - 3.08 (m, 2H), 2.40 - 2.22 (m, 2H), 1.72 - 1.61 (m, 4H), 1.58 (s, 6H), 1.45 - 1.35 (m, 2H), 1.27 (br s, 9H), 1.00 - 0.91 (m, 1H), 0.89 (t, 3H), 0.61 - 0.51 (m, 1H), 0.50 - 0.41 (m, 1H), 0.37 (qd, 1H), 0.30 - 0.20 (m, 1H)

[0195] 22-5. Synthesis of Compound of Formula (V) A 50 mL three-neck RBF was charged with a mixture of dimethyl sulfoxide (DMSO) (3.5 mL) and water (3.5 mL) and 1-cyclopropylnonyl 6-acrylamidohexanoate (0.70 g, 1.99 mmol, 1.00 eq). To the mixture was added TEA (134 mg, 1.33 mmol, 0.67 eq). To the mixture was added N1,N3-dimethylpropane-1,3-diamine (67.8 mg, 663 μmol, 0.33 eq). The mixture was purged with N2 three times. The mixture was stirred at 100 °C for 48 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, methylene chloride / methanol = 10 / 1) to give 0.3 g of compound of formula (V) with relatively low purity. This was purified by reverse-phase HPLC (column: Phenomenexluna C18 15025 mm 10 μm; mobile phase: [water (FA)-ACN]; gradient: 40%-70% B, 10 min) to give the compound of formula (V) (0.15 g, 186 μmol, yield 28.1%, purity 96.1%) as a yellow oil.

[0196] 1 H NMR (400 MHz, CDCl3) δ7.91 (br s, 2H), 4.26 (td, 2H), 3.31 - 3.17 (m, 4H), 2.61 (t, 4H), 2.41 (t, 4H), 2.38 - 2.33 (m, 4H), 2.33 - 2.27 (m, 4H), 2.25 (s, 6H), 1.72 - 1.62 (m, 10H), 1.56 - 1.48 (m, 4H), 1.41 - 1.25 (m, 28H), 1.01 - 0.92 (m, 2H), 0.89 (t, 6H), 0.59 - 0.50 (m, 2H), 0.49 - 0.41 (m, 2H), 0.36 (qd, 2H), 0.31 - 0.21 (m, 2H)

[0197] [Composition Preparation and Pulmonary Delivery Testing] Example 1: Preparation of a drug delivery composition using the lipid of Preparation Example 2 and drug delivery test (1) Preparation of solutions of each component The components shown in Table 1 below were dissolved in each dilution solvent to prepare the concentrations shown in Table 1 below. Dissolution was performed using an ultrasonic generator (bathsonicator) for approximately 5 to 10 minutes, and the absence of undissolved particles was confirmed visually before use. For dioleoylphosphatidylethanolamine (DOPE) and cholesterol, the solutions were incubated in a 65°C oven for approximately 5 minutes, and the absence of precipitation was confirmed visually before use in the test.

[0198] [Table 3]

[0199] (2) Preparation of the composition The necessary amounts of components were mixed to achieve an N / P ratio (amine groups in lipid components / phosphate groups in mRNA) of 20, with the lipids of Preparation Example 2:mPEG-PLA (2K-4K):DOPE:cholesterol = 5:5:1:4. Ethanol was added to the ethanol layer to adjust the total molecular weight of all components to 6.25-12.5 mM, and the aqueous and ethanol phases were mixed at a 3:1 ratio. After mixing, the total volume was diluted 20-fold with 1X PBS to reduce the total ethanol content, and the mixture was concentrated using an Amicon-Ultra tube filter (Merck Millipore, UFC505096 or UFC805024, pore size: 50K or 100K, volume: 0.5 mL, 4 mL, or 15 mL). The buffer used for the aqueous phase was 20 mM sodium acetate buffer (pH 4.6) (prepared by diluting 3 M sodium acetate buffer to 20 mM and titrating to pH 4.6 with 1 M HCl).

[0200] More specifically, the composition manufacturing process is as follows: 1) Two autoclaved tubes were prepared (tubes (A) and (B)). 2) The lipid of Production Example 2, DOPE, cholesterol, and mPEG-PLA (2K-4K) in molar amounts calculated according to the experimental conditions were added in that order to tube (A), and mixed by vortexing. 3) In the ethanol phase, ethanol was added as necessary so that the total molecular weight of all components was within the range of 6.25 to 12.5 mM. 4) In the case of mPEG-PLA, at least 3% water was required for complete dissolution, so water was added so that the total ethanol phase became 95% ethanol. 5) In tube (B), mRNA and 20 mM sodium acetate buffer (pH 4.6) were mixed, with the aqueous phase being added in a volume three times the total volume of the ethanol phase. 6) The solution in tube (B) was transferred to tube (A) and mixed as shown in the figure below. At this time, mixing was carried out as quickly as possible to obtain a uniform formulation, and then vortexing was performed to mix (Figure 24). 7) The prepared formulation was diluted with PBS so that the ethanol content was 5% or less.

[0201] (3) Concentration and sterilization 1) The diluted formulation was centrifuged using an Amicon Ultra centrifugal filter and concentrated to a desired volume depending on the purpose. 2) The formulation was concentrated to the desired concentration and then sterilized using a filter with a pore size of 0.22 μm.

[0202] (4) Administration of the composition The formulation prepared according to the above method was adjusted to 10 μg / mL and administered intravenously to mice at 2 μg of mRNA per mouse. Four hours later, luciferin dissolved in sterile water was adjusted to 15 μg / μL and administered intraperitoneally to give 3 mg of luciferin per 20 g of mouse. Fifteen minutes after intraperitoneal administration of luciferin, protein expression in the whole body and in each organ was measured using a luminescence imaging system. The results are shown in Table 2 below and Figure 23.

[0203] As can be seen from FIG. 23, the drug delivery formulation according to the present invention had excellent pulmonary delivery efficiency when administered intravenously. On the other hand, as a comparative example, LNPs were prepared using SM102 (heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate, purchased from SINOPEG) and D-Lin-MC3-DMA (dilinoleylmethyl-4-dimethylaminobutyric acid, purchased from MedChemExpress), and the same amount of mRNA (2 μg / 200 μL) as in the example was administered intravenously to mice. After 4 hours, imaging was performed using the same method as in the previous example, and the results are shown in Table 2 and Figure 23. As can be seen from Figure 23, the comparative formulation was delivered to the liver when administered intravenously.

[0204] Examples 2 to 12: Preparation of drug delivery compositions using the lipids of Preparation Examples 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, and 16, and pulmonary delivery tests Drug delivery compositions were prepared in the same manner as in Example 1, using the lipids of Preparation Examples 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, and 16, respectively, instead of the lipid of Preparation Example 2, at the N / P ratios shown in Table 2 below. Drug delivery tests were performed using these compositions in the same manner as in Example 1, and the results are shown in Table 2 below and Figure 23. As can be seen from FIG. 23, the drug delivery formulations of Examples 2 to 12, when administered intravenously as in Example 1, had very high pulmonary delivery efficiency.

[0205] [Table 4]

Claims

1. a drug as the active ingredient; and A lipid having a structure selected from the following or an ionized form thereof: A drug delivery composition comprising: 【Chemistry 1】 wherein in each of the structures, at least two of the R groups are R and the remaining R groups are R; wherein each Rx is independently 【Chemistry 2】 is selected from where a, b, and c are each independently an integer from 2 to 20; 1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, 【Transformation 3】 represents a substituted or unsubstituted methylene group, each R is independently H or a substituted or unsubstituted alkyl group, and two R groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is 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—) in its structure.

2. Each Rx is independently 【Chemistry 4】 is selected from where a, b, and c are each independently an integer from 2 to 20; 1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 is a hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent C 2-24 is a hydrocarbon group, 【Transformation 5】 represents a substituted or unsubstituted methylene group, Each R is independently H or C 1-20 alkyl groups, wherein the alkyl groups are independently unsubstituted or —OH, C 1-20 Alkyl, C 1-20 Alkoxy, —NH 2 , —NH(C 1-20 alkyl), -N(C 1-20 alkyl) 2 , optionally substituted C 3-20 Carbocyclic groups and optionally substituted C 3-20 two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently C 1-20 alkylene groups, each independently unsubstituted or —OH, C 1-20 Alkyl, C 1-20 Alkoxy, —NH 2 , —NH(C 1-20 alkyl), -N(C 1-20 alkyl) 2 , optionally substituted C 3-20 Carbocyclic groups and optionally substituted C 3-20 The drug delivery composition of claim 1 , substituted with one or more heterocyclic groups.

3. Each Rx is independently 【Transformation 6】 is selected from where a, b, and c are each independently an integer from 2 to 15; 1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 is a hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent C 2-24 is a hydrocarbon group, 【Transformation 7】 represents a substituted or unsubstituted methylene group, Each R is independently H or C 1-10 alkyl groups, wherein the alkyl groups are independently unsubstituted or —OH, C 1-10 Alkyl, C 1-10 Alkoxy, —NH 2 , —NH(C 1-10 alkyl), -N(C 1-10 alkyl) 2 , optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently C 1-10 alkylene groups, each independently unsubstituted or —OH, C 1-10 Alkyl, C 1-10 Alkoxy, —NH 2 , —NH(C 1-10 alkyl), -N(C 1-10 alkyl) 2 , optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 The drug delivery composition of claim 2 , which is substituted with one or more heterocyclic groups.

4. Each Rx is independently 【Transformation 8】 wherein a, b, and c are each independently an integer from 3 to 12; 1 is a substituted or unsubstituted C 1-12 Alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C 2-12 is an alkynylene group, and R 2 is a substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 is an alkynyl group, 【Chemistry 9】 represents a substituted or unsubstituted methylene group, Each R is independently H or C 1-6 alkyl groups, wherein the alkyl groups are independently unsubstituted or selected from the group consisting of -OH and -NH 2 and two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently unsubstituted C 1-6 The drug delivery composition according to claim 3 , wherein the alkylene group is an alkylene group.

5. The drug delivery composition according to claim 4, wherein the lipid has a structure selected from the following formulas (A to V): Table 1-1 Table 1-2 Table 1-3

6. The drug delivery composition of claim 1 , wherein the drug forms a complex with the lipid.

7. The drug delivery composition of claim 1 , further comprising an amphiphilic block copolymer.

8. The drug delivery composition according to claim 7, wherein the amphiphilic block copolymer forms a complex with the lipid, and the complex is encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer.

9. a first chamber containing the lipid; and a second chamber containing the drug; The drug delivery composition according to claim 1, which is in the form of a kit comprising:

10. The drug delivery composition of claim 9 , wherein the first chamber further comprises an amphiphilic block copolymer.

11. A drug delivery composition comprising nanoparticles, The nanoparticles comprise a lipid having a structure selected from the following or an ionized form thereof: The nanoparticles do not contain a drug, and the drug delivery composition: 【Chemistry 10】 wherein in each of the structures, at least two of the R groups are R and the remaining R groups are R; wherein each Rx is independently 【Chemistry 11】 is selected from where a, b, and c are each independently an integer from 2 to 20; 1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, 【Chemistry 12】 represents a substituted or unsubstituted methylene group, each R is independently H or a substituted or unsubstituted alkyl group, and two R groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is 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—) in its structure.

12. The drug delivery composition of claim 11 , wherein the nanoparticles further comprise an amphiphilic block copolymer.

13. The drug delivery composition according to any one of claims 1 to 12, which is for delivering a drug to the lungs.

14. The drug delivery composition according to any one of claims 1 to 12, further comprising a polylactate.

Images