Composition containing cationic polyester and application thereof

Abstract

The invention discloses a composition containing cationic polyester and application thereof. The composition containing cationic polyester comprises cationic polyester, ionizable cationic lipid, steroidal lipid, neutral lipid and lipid polyethylene glycol. According to the composition containing the cationic polyester, spleen targeting and efficient delivery of active pharmaceutical ingredients such as mRNA (messenger Ribonucleic Acid) can be realized, especially during intravenous administration. According to the composition containing the cationic polyester, the delivery efficiency of lung injection, nasal administration and intramuscular injection can be remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field, in particular to a composition containing cationic polyester and application thereof. BACKGROUND

[0002] Nucleic acid drugs as a new emerging gene therapy have attracted extensive attention in the field of medicine and biological research. RNA drugs have advantages such as wide therapeutic applications, customizability and relatively short development period, and have wide application potential in various disease fields such as genetic diseases, cancers, infectious diseases and autoimmune diseases. However, the development of mRNA drugs still faces the bottleneck problem of in vivo delivery. The currently commercially successful delivery technology is mainly based on ionizable cationic lipid nanoparticle (LNP) technology. However, LNP still has many problems such as insufficient delivery efficiency, difficulty in extrahepatic targeting and poor stability, which greatly limit its application range. Therefore, developing an efficient and low-toxicity in vivo delivery system is still a bottleneck problem in the development of mRNA technology. SUMMARY

[0003] The present application aims to at least solve one of the above technical problems in the prior art. To this end, the purpose of the present application is to provide a composition containing cationic polyester and application thereof.

[0004] In order to achieve the above-mentioned purpose, the technical solution adopted by the present application is:

[0005] In a first aspect of the present application, a composition containing cationic polyester is provided, comprising cationic polyester, ionizable cationic lipid, steroidal lipid, neutral lipid, and lipid polyethylene glycol.

[0006] The cationic polyester comprises a copolymer of monomer C, monomer S and monomer M, and the copolymer is modified at the end with a group E;

[0007] Monomer C comprises cholesteryl;

[0008] Monomer S comprises an organic acid having at least two carboxyl groups at the end;

[0009] Monomer M comprises a compound containing two hydroxyl groups and at least one secondary or tertiary amine;

[0010] The compound modified with group E contains at least one primary, secondary or tertiary amine group.

[0011] In some embodiments of the present application, the copolymer comprises one end capped by monomer C and the other end modified with group E. In the present application, monomer C, monomer S and monomer M undergo linear polymerization, and cholesteryl contains a single hydroxyl group at one end, which is in the capping position after polymerization.

[0012] In some embodiments of the application, the copolymer is a non-branched copolymer.

[0013] In some embodiments of the application, the monomer S comprises a C3 to C40 aliphatic polycarboxylic acid having at least two carboxyl groups at the end groups.

[0014] In some embodiments of the application, the monomer S comprises at least one of succinic acid, adipic acid, azelaic acid, sebacic acid, dodecanedioic acid, dimer acid, 1,2,3-propanetricarboxylic acid, 1,3,5-pentanetricarboxylic acid, and the like aliphatic dicarboxylic acids.

[0015] In some embodiments of the application, the monomer M comprises a diol having a tertiary amine group.

[0016] In some embodiments of the application, the monomer M comprises a C3 to C40 diol having a tertiary amine group.

[0017] In some embodiments of the application, the monomer M comprises at least one of N-methyldiethanolamine, N-ethyldiethanolamine, N-n-propyldiethanolamine, N- isopropyldiethanolamine, N-n-butyldiethanolamine, N-tert-butyldiethanolamine, N- o-toluyldiethanolamine, N-octadecyldiethanolamine, 5-hydroxyindol-3-ethanol, 1,4- bis(2-hydroxyethyl)piperazine.

[0018] In some embodiments of the application, the compound provided is modified with a group E comprising:

[0019] (1 ) aliphatic, cycloaliphatic or araliphatic primary diamines, such as, in particular, ethylenediamine, 1,2-propylenediamine, 1,3-propylenediamine, 2-methyl-1,2- propylenediamine, 2,2-dimethyl-1,3-propylenediamine, 1,3-butylenediamine, 1,4- butylenediamine, 1,3-pentylenediamine (DAMP), 1,5-pentylenediamine, 1,5- diaminomethylpentane (MPMD), 2-butyl-2-ethyl-1,5-pentylenediamine (C1 1 - neodiamine), 1,6-hexylenediamine, 2,5-dimethyl-1,6-hexylenediamine, 2,2,4- and 2,4,4-trimethylhexamethylenediamine (TMD), 1,7-heptylenediamine, 1,8- octylenediamine, 1,9-nonylenediamine, 1,10-decanylenediamine, 1,1 1 - undecylenediamine, 1,12-dodecanylenediamine, 1,2-, 1,3- and 1,4-diaminocyclohexane, bis(4- aminocyclohexyl)methane (H12-MDA), bis-(4-amino-3-methylcyclohexyl)methane, bis-(4-amino-3-ethylcyclohexyl)methane, bis(4-amino-3,5-dimethylcyclohexyl)methane, bis(4-amino-3-ethyl-5-methylcyclohexyl)methane (M-MECA), 1 -amino-3- aminomethyl-3,5,5-trimethylcyclohexane (= isophoronediamine or IPDA), 2- and 4- methyl-1,3-diaminocyclohexane and mixtures thereof, 1,3- and 1,4-bis(aminomethyl)- cyclohexane, 2,5(2,6)-bis(aminomethyl)-bicyclo[2.2.1 ]heptane (NBDA), 3(4),8(9)- bis(aminomethyl)-tricyclo[5.2.1.02,6]decane, 1,4-diamino-2,2,6-trimethylcyclohexane (TMCDA), 1,8-methanediamine, 3,9-bis(3-aminopropyl)-2,4,8,10- tetraoxaspiro[5.5]undecane, and 1,3- and 1,4-xylylenediamine;

[0020] (2) aliphatic, cycloaliphatic or araliphatic primary triamines, such as, in particular, 4-aminomethyl-1,8-octanediamine, 1,3,5-tris(aminomethyl)benzene, 1,3,5- tris(aminomethyl)cyclohexane, tris-(2-aminoethyl)amine, tris(2-aminopropyl)amine, tris(3-aminopropyl)amine;

[0021] (3) ether group-containing aliphatic primary diamines, such as, in particular, bis(2- aminoethyl)ether, 3,6-dioxaoctane-1,8-diamine, 4,7-dioxadecane-1,10-diamine, 4,7- dioxadecane-2,9-diamine, 4,9-dioxadodecane-1,12-diamine, 5,8-dioxadodecane-3,10- diamine, 4,7,10-trioxatridecane-1,13-diamine;

[0022] (4) Polyamines having two aliphatic primary amine groups and tertiary amine groups, such as especially N,N'-bis(aminopropyl)piperazine, N,N-bis(3-aminopropyl)methylamine, N,N-bis(3-aminopropyl)ethylamine, N,N-bis(3-aminopropyl)propylamine, N,N-bis(3-aminopropyl)cyclohexylamine, N,N-bis(3-aminopropyl)-2-ethylhexylamine, and products obtained by double cyanoethylation and subsequent reduction of aliphatic amines derived from natural fatty acids, such as N,N-bis(3-aminopropyl)dodecylamine and N,N-bis(3-aminopropyl)tallow alkylamine;

[0023] (5) Polyamines having three aliphatic primary amine groups and tertiary amine groups, such as especially tri-(2-aminoethyl)amine, tri-(2-aminopropyl)amine and tri-(3-aminopropyl)amine;

[0024] (6) Polyamines having two aliphatic primary amine groups and secondary amine groups, such as, in particular, 3-(2-aminoethyl)aminopropylamine, bis(hexamethylenetriamine) (BHMT), diethylenetriamine (DETA), triethylenetetramine (TETA), tetraethylenepentamine (TEPA), pentaethylenehexamine (PEHA), and higher homologues of linear polyethylene amines, such as polyethylene polyamines having 5 to 7 ethylene amine units (so-called "higher ethylene polyamines", HEPA), products obtained by repeated cyanoethylation or cyanobutylation of primary diamines and primary polyamines having at least two primary amine groups and subsequent hydrogenation, such as dipropylenetriamine (DPTA), N-(2-aminoethyl)-1,3-propanediamine (N3-amine), N,N'-bis(3-aminopropyl)ethylenediamine (N4-amine), N,N'-bis-(3-aminopropyl)-1,4-diaminobutane, N... 5 -(3-aminopropyl)-2-methyl-1,5-pentanediamine, N 3 -(3-aminopentyl)-1,3-pentanediamine, N 5 -(3-amino-1-ethylpropyl)-2-methyl-1,5-pentanediamine and N,N'-bis(3-amino-1-ethylpropyl)-2-methyl-1,5-pentanediamine;

[0025] (7) Polyamines having an aliphatic primary amine group and at least one secondary amine group, such as, in particular, N-methyl-1,2-ethylenediamine, N-ethyl-1,2-ethylenediamine, N-butyl-1,2-ethylenediamine, N-hexyl-1,2-ethylenediamine, N-(2-ethylhexyl)-1,2-ethylenediamine, N-cyclohexyl-1,2-ethylenediamine, 4-aminomethylpiperidine, 3-(4-aminobutyl)piperidine, N-(2-aminoethyl)piperazine, N-(2-aminopropyl)piperazine, N... 1 -(3-(dimethylamino)propyl)-1,3-diaminopropane (DMAPAPA), N1 (2-(dimethylamino)ethyl)propane-1,3-diamine, the diamines obtained by cyanoethylation or cyanobutylation of primary monoamines and subsequent hydrogenation, such as N-methyl-1,3-propanediamine, N-ethyl-1,3-propanediamine, N-butyl-1,3-propanediamine, N-hexyl-1,3-propanediamine, N-(2-ethylhexyl)-1,3-propanediamine, N-dodecyl-1,3-propanediamine, N-cyclohexyl-1,3-propanediamine, 3-methylamino-1 -pentylamine, 3-ethylamino-1 -pentylamine, 3-butylamino-1 -pentylamine, 3-hexylamino-1 -pentylamine, 3-(2-ethylhexyl)amino-1 -pentylamine, 3-dodecylamino-1 -pentylamine, 3-cyclohexylamino-1 -pentylamine, and fatty diamines such as N-coconut alkyl-1,3-propanediamine, N-oleyl-1,3-propanediamine, N-soyalkyl-1,3-propanediamine, N-tallowalkyl-1,3-propanediamine or N-(C16-C22-alkyl)-1,3-propanediamine;

[0026] (8) Polyamines having an aliphatic primary amine group and at least one hydroxyl group, such as, in particular, 2-aminoethanol, 2-amino-1 -propanol, 1 -amino-2-propanol, 3-amino-1 -propanol, 1,3-diamino-2-propanol, 4-amino-1 -butanol, 4-amino-2-butanol, 2-amino-2-methylpropanol, 5-amino-1 -pentanol, 6-amino-1 -hexanol, 7-amino-1 -heptanol, 8-amino-1 -octanol, 10-amino-1 -decanol, 12-amino-1 -dodecanol and higher homologues thereof, aminopropyldiethanolamine (APDEA), 4-(2-aminoethyl)-2-hydroxyethylaniline, 3-aminomethyl-3,5,5-trimethyl-cyclohexanol, derivatives of diols such as diethylene glycol, dipropylene glycol, dibutylene glycol and higher oligomers and polymers of these diols with a primary amine group, in particular 2-(2-aminoethoxy)ethanol, 2-(2-(2-aminoethoxy)ethoxy)ethanol, alpha-(2-hydroxymethylethyl)-omega-(2-aminomethylethoxy)-poly(oxy(methyl-1,2-ethanediyl)); derivatives of polyalkoxylated tri- or higher-valent alcohols with a hydroxyl and a primary amine group; products of the single cyanoethylation of diols and subsequent hydrogenation, in particular 3-(2-hydroxyethoxy)propylamine, 3-(2-(2-hydroxyethoxy)ethoxy)propylamine and 3-(6-hydroxyhexyloxy)propylamine; and also aliphatic amines having primary and secondary amine groups and hydroxyl groups, such as N-hydroxyethyl-1,3-propanediamine, N-hydroxypropyl-1,3-propanediamine and N3-hydroxymethyl-1,3-pentanediamine;

[0027] (9) Compounds containing amino and guanidino groups, in particular guanidinobutylamine, N-(2-guanidinoethyl)guanidine, aminoguanidine, biguanide.

[0028] In some embodiments of the present application, the group E modified compound is at least one of 1,3-propanediamine, 1,2-propanediamine, 1,5-diamino-2-methylpentane, 1,3-diamino-2-propanol, polyethylene glycol diamine, 2,2'-diaminodiethylamine, N-methyl-2,2-diaminodiethylamine, triethylenetetramine, tetraethylenepentamine, 1,4-bis(3-aminopropyl)piperazine, tris(2-aminoethyl)amine, N-methylethylenediamine, N-(3-hydroxypropyl)ethylenediamine, N,N-dimethylethylenediamine, N,N-dimethyldipropylene triamine, 3-aminopyrrolidine, aminoethylpiperazine, guanidinobutylamine.

[0029] In some embodiments of the present application, the group E modified compound is at least one of 1,3-propanediamine, 1,2-propanediamine, 1,5-diamino-2-methylpentane, 1,3-diamino-2-propanol, polyethylene glycol diamine, 2,2'-diaminodiethylamine, N-methyl-2,2-diaminodiethylamine, triethylenetetramine, tetraethylenepentamine, 1,4-bis(3-aminopropyl)piperazine, tris(2-aminoethyl)amine, N-methylethylenediamine, N-(3-hydroxypropyl)ethylenediamine, N,N-dimethylethylenediamine, N,N-dimethyldipropylene triamine, 3-aminopyrrolidine, aminoethylpiperazine, guanidinobutylamine.

[0030]

[0031] In some embodiments of the present application, the molar ratio of monomer C to monomer S is 1:30 to 4:1.

[0032] In some embodiments of the present application, the molar ratio of monomer M to monomer S is 2:1 to 1:4.

[0033] In some embodiments of the present application, the cationic polyester has a number average molecular weight of 1 to 30 k, such as 2 to 20 k.

[0034] In some embodiments of the present application, the cationic polyester has a structure as shown in Formula I copolymer:

[0035]

[0036] wherein n is an integer from 0 to 200;

[0037] k is an integer from 0 to 30;

[0038] l, m are independently selected from an integer from 1 to 20;

[0039] R x is hydrogen, or substituted or unsubstituted alkyl containing 1 to 18 carbon atoms, or substituted or unsubstituted aromatic group containing at least 1 benzene ring, or substituted or unsubstituted heterocyclic group containing at least 1 heterocyclic ring, or substituted or unsubstituted alkoxy containing 1 to 18 carbon atoms and at least 1 oxygen atom;

[0040] R is group E.

[0041] In some embodiments of the present application, n is an integer from 1 to 150; k is an integer from 1 to 30, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29; l, m are independently selected from an integer from 1 to 20, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19; R is hydrogen, or a substituted or unsubstituted alkyl group containing 1-18 carbon atoms, or a substituted or unsubstituted aromatic group containing 1-3 benzene rings, or a substituted or unsubstituted heterocyclic group containing 1-5 heterocyclic rings, or a substituted or unsubstituted alkoxy group containing 1-18 carbon atoms and 1-5 oxygen atoms; R is group E. x R is hydrogen, or a substituted or unsubstituted alkyl group containing 1-18 carbon atoms, or a substituted or unsubstituted aromatic group containing 1-3 benzene rings, or a substituted or unsubstituted heterocyclic group containing 1-5 heterocyclic rings, or a substituted or unsubstituted alkoxy group containing 1-18 carbon atoms and 1-5 oxygen atoms; R is group E.

[0042] In some embodiments of the present application, the number average molecular weight of the polymer of formula I is 1-30 k, such as 2-20 k.

[0043] In some embodiments of the present application, when the group E-modified compound provided is E14, the structural formula of the polymer of formula I is denoted as ChPA-E14; correspondingly, when the group E-modified compound provided is E1-E13, E15-E18, the corresponding structural formula of the polymer of formula I is denoted as ChPA-E1-ChPA-E13, ChPA-E15-ChPA-E18, respectively; the polymer of formula I includes at least one of ChPA-E1-ChPA-E18.

[0044] In some embodiments of the present application, the preparation method of the cationic polyester refers to the preparation method described in patent CN118480173A, the entire contents of which are incorporated herein by reference.

[0045] In some embodiments of the application, the ionizable cationic lipid comprises at least one of 4-(N,N-dimethylamino)butanoic acid (dilinoleyl) methyl ester (Dlin-MC3-DMA), 2-dioctadecyloxy-3-trimethylammonium-propane (DOTAP), 1-octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]octanoate (SM-102), dimethylidioctadecylammonium bromide (DDAB), 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-chol), 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP), 1,2-di-(9Z-octadecenoyl)-3-dimethylammonium-propane (DODAP), 1,2-dioleoyl-c-(4'-trimethylammonium)-butanoyl-sn-glycerol (DOTB), dioctadecylamidoglycylspermine, SAINT-2, polycationic lipid 2,3-dioleoyloxy-N-[2( spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), ((4-hydroxybutyl)azabicyclo)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315), or a derivative thereof.

[0046] In some embodiments of the application, the sterol lipid comprises at least one of avenasterol, β-sitosterol, brassicasterol, ergocalciferol, campesterol, cholestanol, cholesterol, coprostanol, dehydrocholesterol, desmosterol, dihydroergocalciferol, dihydrocholesterol, dihydroergosterol, fecosterol, epicholesterol, ergosterol, fucosterol, hexahydrozearalenol, hydroxycholesterol; lanosterol, lumisterol, mycocerotic acid, phytostanol, sitostanol, stigmastanol, stigmasterol, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid.

[0047] In some embodiments of the application, the neutral lipid comprises at least one of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), sphingomyelin (SM).

[0048] In some embodiments of the application, the lipid polyethylene glycol comprises at least one of 1,2-dimyristoyl-sn-glycero-methoxy-polyethylene glycol (PEG-DMG), dimyristoylglycero-polyethylene glycol (PEG-c-DMG), polyethylene glycol-dimyristoylglycero (PEG-C14), PEG-1,2-dimyristoyloxypropyl-3-amine (PEG-c-DMA), 1,2-disteary-sn-glycero-3- phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE), PEGylated phosphatidylethanolamine (PEG-PE), PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, Tween-20, Tween-80, 1,2-dipalmitoyl-sn-glycero-methoxy polyethylene glycol PEG-DPG, 4-O-(2',3'-ditetradecanoyloxy)propyl-1-O-(ω-methoxy(polyethoxy)ethyl) butanedioate (PEG-s-DMG), methoxypolyethylene glycol ditetradecyl acetal (ALC-0159), PEG-dialkyloxypropyl (PEG-DAA), mPEG2000-1,2-di-O-alkyl-sn 3-carbamoylglycerol ester (PEG-c-DOMG), and N-acetylgalactosamine ((R)-2,3-bis(octadecyloxy)propyl-1-(methoxypoly(ethylene glycol) 2000) propyl carbamate)) (GalNAc-PEG-DSG). Preferably, the lipid polyethylene glycol comprises at least one of 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol 2000 (DMG-PEG2k), methoxypolyethylene glycol ditetradecyl acetal (ALC-0159), distearoylphosphatidyl ethanolamine-polyethylene glycol 2000 (DSPE-PEG2k).

[0049] wherein polyethylene glycol (PEG) is a PEG group having a degree of polymerization selected from 3 to 100; preferably PEG is a PEG group having a degree of polymerization selected from 3 to 50 or 50 to 100; more preferably PEG is a PEG group having a degree of polymerization selected from 3 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, or 90 to 100; more preferably PEG is a PEG group having a degree of polymerization selected from about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100.

[0050] In some embodiments of the application, the cationic polyester-containing composition comprises, in mole fraction, 0.1 to 80 parts (e.g., 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, 55 parts, 56 parts, 57 parts, 58 parts, 59 parts, 60 parts, 61 parts, 62 parts, 63 parts, 64 parts, 65 parts, 66 parts, 67 parts, 68 parts, 69 parts, 70 parts, 71 parts, 72 parts, 73 parts, 74 parts, 75 parts, 76 parts, 77 parts, 78 parts, 79 parts, 80 parts) of a cationic polyester containing ionizable N, 0 to 80 parts (e.g., 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, 55 parts, 56 parts, 57 parts, 58 parts, 59 parts, 60 parts, 61 parts, 62 parts, 63 parts, 64 parts, 65 parts, 66 parts, 67 parts, 68 parts, 69 parts, 70 parts, 71 parts, 72 parts, 73 parts, 74 parts, 75 parts, 76 parts, 77 parts, 78 parts, 79 parts, 80 parts) of an ionizable cationic lipid, 0 to 40 parts (e.g., 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts) of a sterol lipid, and 0 to 40 parts (e.g., 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts) of a phospholipid.37 parts, 38 parts, 39 parts, 40 parts) neutral lipid, 0-20 parts (e.g. 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts) lipid polyethylene glycol. Among them, 0 means that the lipid composition can not contain this ingredient, it can be understood that the four of neutral lipid, ionizable cationic lipid, steroidal lipid and lipid polyethylene glycol cannot be 0 at the same time; when using steroidal lipid, at least one of neutral lipid, ionizable cationic lipid and lipid polyethylene glycol is needed; when using lipid polyethylene glycol, at least one of neutral lipid, ionizable cationic lipid and steroidal lipid is also needed; when using steroidal lipid and lipid polyethylene glycol at the same time, at least one of neutral lipid and ionizable cationic lipid is also needed.

[0051] In some embodiments of the present application, the cationic polyester containing 0.1-80 parts of ionizable N refers to a corresponding molar fraction of cationic polyester that can provide 0.1-80 parts of ionizable N.

[0052] In a second aspect of the present application, a pharmaceutical composition is provided, comprising a pharmaceutical active ingredient and the composition containing cationic polyester.

[0053] In some embodiments of the present application, the pharmaceutical active ingredient comprises at least one of nucleic acid, protein, polypeptide, antibody, saccharide, and small molecule compound.

[0054] In some embodiments of the present application, the pharmaceutical active ingredient comprises at least one of antitumor drug, antibiotic, antiviral agent, antifungal drug, antitumor drug, antibiotic, antiviral agent, and antifungal drug.

[0055] In some embodiments of the present application, the nucleic acid comprises at least one of mRNA, circular RNA, saRNA, siRNA, microRNA, antisense oligonucleotide, shRNA, small activating RNA, and DNA.

[0056] In some embodiments of the present application, the molar fraction ratio of ionizable N of cationic polyester to P of nucleic acid in the composition containing cationic polyester is (0.1-10.0):1, such as (0.2-9.5):1, (0.3-9.0):1, (0.4-8.5):1, (0.5-8.0):1, (0.5-7.5):1, (0.5-7.0):1, (0.5-6.5):1, etc.

[0057] In some embodiments of the present application, the Dh of the pharmaceutical composition is 80-130 nm, such as 93-120 nm, 93-115 nm, etc. In the present application, Dh is measured by dynamic light scattering (DLS) using a particle size analyzer.

[0058] In some embodiments of the present application, the pharmaceutical composition can be administered by one of the following administration routes: oral, intranasal, intravenous, intraperitoneal, intramuscular, intra-articular, intra-lesional, intratracheal, subcutaneous, and intradermal.

[0059] In some embodiments of the present application, the pharmaceutical composition can be formulated into a preparation in solid, semi-solid, liquid, lyophilized, frozen or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0060] In a third aspect of the present application, a method for preparing the pharmaceutical composition is provided, comprising the following steps:

[0061] The cationic polyester-containing composition is dissolved in a solvent, and the active pharmaceutical ingredient is added for incubation to prepare the pharmaceutical composition.

[0062] In some embodiments of the present application, the solvent comprises at least one of ethanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0063] In some embodiments of the present application, the temperature for incubation is 10-40℃, such as 20-25℃; and the time for incubation is 5-60 min, such as 5-30 min, 10 min, 20 min, etc.

[0064] In a fourth aspect of the present application, the use of the cationic polyester-containing composition or the pharmaceutical composition in the preparation of a medicament for treating a disease is provided.

[0065] In some embodiments of the present application, the disease comprises at least one of cancer, inflammation, fibrotic disease, autoimmune disease, infection, congenital and genetic disease, connective tissue disease, digestive system disease, endocrine disease, eye disease, reproductive disease, cardiovascular disease, kidney and urinary disease, respiratory disease, metabolic disorder, musculoskeletal disease, nervous system disease, and hematological disease.

[0066] The beneficial effects of the present application are:

[0067] The cationic polyester-containing composition of the present application can achieve spleen targeting and efficient delivery of active pharmaceutical ingredients such as mRNA, especially when administered intravenously.

[0068] The cationic polyester-containing composition of the present application can significantly improve the delivery efficiency of pulmonary insufflation, nasal administration and intramuscular injection. BRIEF DESCRIPTION OF DRAWINGS

[0069] Figure 1 The pulmonary insufflation administration effect of each pharmaceutical composition in Example 12 of the present application.

[0070] Figure 2 The pulmonary insufflation administration effect of the pharmaceutical compositions in Example 11 and Comparative Example 2 in Example 12 of the present application.

[0071] Figure 3 The intravenous injection administration effect of the pharmaceutical compositions in Example 3 and 7 and Comparative Example 1 in Example 12 of the present application.

[0072] Figure 4 The nasal administration effect of the pharmaceutical compositions in Example 3 and 7 and Comparative Example 1 in Example 12 of the present application.

[0073] Figure 5 The intramuscular injection administration effect of the pharmaceutical compositions in Example 3 and 7 and Comparative Example 1 in Example 12 of the present application. DETAILED DESCRIPTION

[0074] The content of the present application is further described in detail through specific examples. The raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial channels or can be obtained by prior art methods, unless otherwise specified. Unless otherwise specified, the test or test method is a conventional method in the art.

[0075] Examples and Comparative Examples

[0076] Examples 1-11 and Comparative Examples 1-2 respectively prepared a pharmaceutical composition (composition of PLNP nanoparticles), the specific process is as follows:

[0077] The formula of the pharmaceutical compositions of Examples 1-11 and Comparative Examples 1-2 is shown in Table 1:

[0078] Table 1

[0079]

[0080] Among them, the mole fraction of each component respectively represents: ChPA-E14 is the mole fraction of ionizable N contained therein, mRNA is the mole fraction of P contained therein, and the rest of the components are the mole fraction of the molecules thereof.

[0081] The nucleic acid is Firefly Luciferase mRNA (N1-Me-Pseudo UTP, Nanjing Novozyme Biotech Co., Ltd.).

[0082] The preparation method of the pharmaceutical compositions of Examples 1-11 and Comparative Examples 1-2 is as follows:

[0083] The mRNA was configured into a 9 mM sodium acetate buffer, with the concentration of the mRNA being 33 μg / mL;

[0084] According to the composition of Table 1, the cationic polyester-containing composition was dissolved in ethanol to form a mixed solution of a specific concentration, which was mixed with the mRNA solution at a volume ratio of 1:3, incubated at room temperature (25°C) for 10 minutes, and the pharmaceutical composition was prepared.

[0085] The particle size of the prepared pharmaceutical composition was tested by a particle size analyzer (Malvern Panalytical Zetasizer Pro) at 25°C, and the test results Dh are shown in Table 1.

[0086] Example 12

[0087] In this example, the pharmaceutical composition was administered, and the specific process was as follows:

[0088] 4-6 week old C57 mice (body weight about 20 g) were purchased from Guangdong Medical Laboratory Animal Center and were monitored and raised in a specific pathogen-free (SPF) environment level.

[0089] The examples or comparative examples were injected into mice by pulmonary administration (administered by inserting a pulmonary spray needle into the trachea, 5 μg dose / mouse), and 24 hours later, 100 μL D-luciferin was injected intraperitoneally into the mice, and the luciferase expression effect in the lungs was observed and quantified by a small animal live fluorescence imaging instrument (Perkin Elmer).

[0090] The pharmaceutical compositions of Examples 1-11 or Comparative Examples 1-2 were injected into mice by intravenous administration (administered by inserting a 1 mL sterile syringe into the tail vein of the mice, 5 μg dose / mouse), and 24 hours later, 100 μL D-luciferin was injected intraperitoneally into the mice, and the luciferase expression effect in the heart, liver, spleen, lungs, and kidneys was observed and quantified by a small animal live fluorescence imaging instrument (Perkin Elmer).

[0091] The pharmaceutical compositions of Examples 1-11 or Comparative Examples 1-2 were injected into mice by intranasal administration (dropped into the nose with a pipette, 5 μg dose / mouse), and 24 hours later, 100 μL D-luciferin was injected intraperitoneally into the mice, and the luciferase expression effect in the nose was observed and quantified by a small animal live fluorescence imaging instrument (Perkin Elmer).

[0092] The pharmaceutical composition of Examples 1-11 or Comparative Examples 1-2 was injected into mice by intramuscular injection (inserting a 1 mL sterile syringe into the right lateral muscle of the thigh of the mouse, 5 μg dose per mouse), and 24 hours later, the mice were injected intraperitoneally with 100 μL of D-luciferin, and the luciferase expression effect at the injected muscle site was observed and quantified by a small animal live fluorescence imaging instrument (Perkin Elmer).

[0093] The results are shown in Table 1. Figures 1 to 5

[0094] It can be seen that when the PLNP nanoparticles prepared from the composition with different proportions of D-LIN-MC3-DMA components are administered in vivo by pulmonary administration, when the molar fraction of D-LIN-MC3-DMA is fixed, as the ChPA-E14 / D-LIN-MC3-DMA increases, the delivery efficiency first increases by 5 times, and the efficiency is highest when the ratio is 20 / 50; when the ChPA-E14 / D-LIN-MC3-DMA is fixed at 2 / 5, as the D-LIN-MC3-DMA decreases, the delivery efficiency first remains unchanged between 50 and 40.

[0095] When the SM-102 in the pharmaceutical composition is 50 and the ChPA-E14 is 20, the delivery efficiency is 5 times higher than that of LNP.

[0096] In vivo delivery effect and tissue distribution of intravenous administration of the pharmaceutical composition: when the SM-102 / ChPA-E14 is 40 / 14 and 50 / 20, the expression efficiency is higher than that of LNP.

[0097] Nasal administration delivery efficiency: when the SM-102 / ChPA-E14 is 40 / 14 and 50 / 20, the expression efficiency is 50 times higher than that of LNP.

[0098] Muscle administration delivery efficiency: when the SM-102 / ChPA-E14 is 40 / 14 and 50 / 20, the expression efficiency is 2 times higher than that of LNP.

[0099] The above examples are preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods and are included in the protection scope of the present application.​

Claims

1. A composition containing a cationic polyester, characterized in that: Including cationic polyesters, ionizable cationic lipids, steroidal lipids, neutral lipids, and lipid polyethylene glycol; The cationic polyester comprises a copolymer of monomer C, monomer S and monomer M, wherein the copolymer is end-modified with a group E; Monomer C includes cholesterol; Monomer S includes organic acids with at least two carboxyl groups at their end groups; Monomer M includes compounds containing two hydroxyl groups and at least one secondary or tertiary amine; The compound provided by the E group modification contains at least one primary, secondary, or tertiary amine group.

2. The composition containing cationic polyester according to claim 1, characterized in that: The cationic polyester has the structural formula of copolymer of formula I: Where n is an integer from 0 to 200; k is an integer from 0 to 30; l and m are independently selected from integers from 1 to 20; R x It is hydrogen, or a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, or a substituted or unsubstituted aromatic group containing at least one benzene ring, or a substituted or unsubstituted heterocyclic group containing at least one heterocycle, or a substituted or unsubstituted alkoxy group containing 1 to 18 carbon atoms and at least one oxygen atom; R is a group E.

3. The composition containing cationic polyester according to claim 1 or 2, characterized in that: The compound providing the E-group modification is selected from at least one of the following compounds:

4. The composition containing cationic polyester according to claim 3, characterized in that: When the compound providing the E-modified group is E14, the structural formula of the polymer of formula I is: It is denoted as ChPA-E14; correspondingly, when the compound provided with the E group modification is E1~E13, E15~E18, the polymer of formula I with the corresponding structure is denoted as ChPA-E1~ChPA-E13, ChPA-E15~ChPA-E18 in sequence; the polymer of formula I includes at least one of ChPA-E1~ChPA-E18.

5. The composition containing cationic polyester according to claim 1, characterized in that: The composition containing cationic polyester satisfies at least one of the following conditions: (I) The ionizable cationic lipids include methyl 4-(N,N-dimethylamino)butyrate (dilinoleyl) ester, 2-di-octadecyl-3-trimethylammonium-propane, 1-octylnonyl octanoate of 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]octanoate, dimethyl di-octadecylammonium bromide, 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol, 1,2-di-tetradecyl-3-trimethylammonium-propane, 1,2-di-(9Z-decadecyl)-carbamoyl]cholesterol, and 1,2-di-tetradecyl-3-trimethylammonium-propane. At least one of the following: (octaenoyl)-3-dimethylammonium-propane, 1,2-dioleoyl-c-(4'-trimethylammonium)-butyryl-sn-glycerol, di-octadecanoyl-alanylspermine, SAINT-2, polycationic lipid 2,3-dioleoyloxy-N-[2(spermine-carboxylamino)ethyl]-N,N-dimethyl-1-propanetrifluoroacetate, ((4-hydroxybutyl)azadialkyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), or a derivative thereof; (II) The steroidal lipids include at least one of the following: alfalfa sterol, β-sitosterol, brassosterol, ergocalciferol, campesterol, cholesterol, cocsterol, dehydrocholesterol, sterol, dihydroergocalciferol, dihydrocholesterol, dihydroergosterol, serotonol, epicholesterol, ergosterol, fucosterol, hexahydrophotosterol, hydroxycholesterol; lanosterol, photosterol, physcosterol, sitosterol, stigmasterol, stigmasterol, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid; (III) The neutral lipids include at least one of 1,2-distearate-sn-glycerol-3-phosphate choline, 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine, 1,2-dioleoyl-sn-glycerol-3-phosphate choline, 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline, 1,2-dimyristoyl-sn-glycerol-3-phosphate choline, 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline, and sphingomyelin; (IV) The lipid polyethylene glycols include 1,2-dimyristoyl-sn-glycerol methoxy-polyethylene glycol, dimyristoylglycerol-polyethylene glycol, polyethylene glycol-dimyristoylglycerol, PEG-1,2-dimyristoyloxypropyl-3-amine, 1,2-distearate-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)], PEGylated phosphatidylethanolamine, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, Tween-20, Tween-80, 1,2 At least one of the following: -dipalmityl-sn-glycerol-methoxy polyethylene glycol, 4-O-(2',3'-bis(tetradecanoyloxy)propyl-1-O-(ω-methoxy(polyethoxy)ethyl)succinate, methoxy polyethylene glycol bis(tetradecanoylacetamide), PEG-dialkoxypropyl, mPEG2000-1,2-bis-O-alkyl-sn3-carbamoylglycerol ester and N-acetylgalactosamine ((R)-2,3-bis(octadecanoyloxy)propyl-1-(methoxypoly(ethylene glycol)2000)propylcarbamate)).

6. The composition containing cationic polyester according to claim 1, characterized in that: The cationic polyester composition comprises, in molar amounts, 0.1 to 80 parts of cationic polyester containing ionizable N, 0 to 80 parts of ionizable cationic lipid, 0 to 40 parts of steroidal lipid, 0 to 40 parts of neutral lipid, and 0 to 20 parts of lipid polyethylene glycol.

7. A pharmaceutical composition, characterized in that: Compositions comprising the active pharmaceutical ingredient and the cationic polyester as described in any one of claims 1 to 6.

8. The pharmaceutical composition according to claim 7, characterized in that: The active pharmaceutical ingredient includes at least one of nucleic acid, protein, polypeptide, antibody, carbohydrate, and small molecule compound; preferably, the nucleic acid includes at least one of mRNA, circular RNA, saRNA, siRNA, microRNA, antisense oligonucleotide, shRNA, small activating RNA, and DNA; preferably, the molar ratio of ionizable N in the cationic polyester to P in the nucleic acid in the composition containing cationic polyester is (0.1-10.0):

1.

9. The pharmaceutical composition according to claim 7, characterized in that: The pharmaceutical composition is formulated into a solid, semi-solid, liquid, lyophilized, frozen, or gaseous form; preferably, the dosage form of the pharmaceutical composition includes any one of tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalers, gels, microspheres, and aerosols.

10. The use of a composition containing a cationic polyester according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 9 in the preparation of a medicament for treating diseases.

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