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EP-4736848-A1 - PHARMACEUTICAL COMPOSITION CONTAINING CATIONIC LIPID AND USE THEREOF

EP4736848A1EP 4736848 A1EP4736848 A1EP 4736848A1EP-4736848-A1

Abstract

A pharmaceutical composition containing a cationic lipid and the use thereof. Specifically, provided are a pharmaceutical composition comprising a carrier, the carrier comprising a cationic lipid, and the molar percentage of the cationic lipid to the carrier being greater than or equal to 10% and less than 50%.

Inventors

  • LIU, Chongyi
  • LIAO, Cheng
  • TANG, Xiaojiao
  • SUN, HAIWEI
  • KUANG, JingWen
  • WANG, QIN
  • ZHU, Lingjian
  • JIANG, JUN
  • HUANG, JIAN
  • NING, Wei

Assignees

  • Shanghai Regenelead Therapies Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (19)

  1. A pharmaceutical composition, comprising a vector, wherein the vector comprises a cationic lipid, and the cationic lipid comprises the compound represented by formula I or a pharmaceutically acceptable salt thereof; a molar percentage of the cationic lipid to the vector is greater than or equal to 10% and less than 50%:
  2. The pharmaceutical composition according to claim 1, wherein the vector further comprises a non-cationic lipid, and the non-cationic lipid is selected from the group consisting of at least one of a phospholipid and cholesterol or a derivative thereof.
  3. The pharmaceutical composition according to claim 2, wherein the phospholipid is selected from the group consisting of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoyl phosphatidylglycerol (DPPG), palmitoyl oleoyl phosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-stearoylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyl oleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), and a mixture thereof, preferably from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).
  4. The pharmaceutical composition according to claim 2 or 3, wherein a content of the phospholipid accounts for 5-40%, preferably 10-20%, for example, 10%, of a molar amount of the vector.
  5. The pharmaceutical composition according to any one of claims 2-4, wherein cholesterol or the derivative thereof accounts for 30-60%, preferably 35-45%, for example, 40.5%, of the molar amount of the vector.
  6. The pharmaceutical composition according to any one of claims 1-5, wherein the vector further comprises a conjugated lipid; preferably, the conjugated lipid is PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, or PEG-modified dialkylglycerol; more preferably, the conjugated lipid is distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG2000), dimyristoylglycero-3-methoxypolyethylene glycol 2000 (DMG-PEG2000), and methoxypolyethylene glycol ditetradecylacetamide (ALC-0159).
  7. The pharmaceutical composition according to claim 6, wherein the conjugated lipid accounts for 0.5-4%, preferably 1.5-2.5%, for example, 1.5%, of the molar amount of the vector.
  8. The pharmaceutical composition according to any one of claims 1-7, comprising an active agent, wherein the active agent is selected from the group consisting of a nucleic acid, preferably from the group consisting of a ribonucleic acid and a deoxyribonucleic acid, and more preferably from the group consisting of a small interfering RNA, a microRNA, a small hairpin RNA, a messenger RNA (mRNA), a circular RNA, a self-replicating RNA, and a mixture thereof.
  9. The pharmaceutical composition according to claim 8, wherein the mRNA comprises an open reading frame (ORF), and the ORF encodes a protein or polypeptide; preferably, the mRNA further comprises any one or any combination of a 5' untranslated region element (5'UTR), a 3' untranslated region element (3'UTR), and a polyadenylic acid (poly-A) tail; preferably, the mRNA further comprises a 5'Cap structure.
  10. The pharmaceutical composition according to claim 9, wherein the protein or polypeptide is an antigen; preferably, the antigen is selected from the group consisting of a viral antigen, a bacterial antigen, and a cancer antigen; more preferably, the viral strain is selected from the group consisting of an influenza virus, a coronavirus, varicella zoster virus (VZV), and respiratory syncytial virus (RSV).
  11. The pharmaceutical composition according to claim 10, wherein the antigen is a varicella zoster virus (VZV) glycoprotein E (gE) protein whose amino acid sequence is set forth in any one of SEQ ID NO: 1 or SEQ ID NO: 21-SEQ ID NO: 25; preferably, a nucleotide sequence of the antigen is set forth in any one of SEQ ID NO: 3-SEQ ID NO: 8; more preferably, the nucleotide sequence of the mRNA is set forth in any one of SEQ ID NO: 13-SEQ ID NO: 20.
  12. The pharmaceutical composition according to claim 9, wherein the protein or polypeptide is hepatocyte growth factor (HGF), an antibody, or an antigen-binding fragment thereof.
  13. The pharmaceutical composition according to any one of claims 1-12, comprising: a) an active agent, preferably an mRNA; b) a cationic lipid comprising the compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein a molar percentage of the cationic lipid to the vector is greater than or equal to 10% and less than 50%: c) a non-cationic lipid selected from the group consisting of a phospholipid and cholesterol or a derivative thereof, wherein the phospholipid accounts for 5-40% of the molar amount of the vector, and cholesterol or the derivative thereof accounts for 30-60% of the molar amount of the vector; and d) a conjugated lipid, wherein a molar percentage content of the conjugate in the vector is 0.5-4%.
  14. The pharmaceutical composition according to any one of claims 1-13, wherein the pharmaceutical composition is a nanoparticle formulation, and the nanoparticle formulation has an average particle size of 10 nm-220 nm.
  15. A freeze-dried formulation, wherein the freeze-dried formulation is obtained by freeze-drying the pharmaceutical composition according to any one of claims 1-14.
  16. A reconstituted solution, wherein the reconstituted solution is obtained by a step of reconstituting the freeze-dried formulation according to claim 15, and a preferred solvent for the reconstitution is water for injection.
  17. A method for preparing the pharmaceutical composition according to any one of claims 1-14, comprising a step of mixing the cationic lipid, the non-cationic lipid, and the conjugated lipid in an organic solvent.
  18. Use of the pharmaceutical composition according to any one of claims 1-14, the freeze-dried formulation according to claim 15, or the reconstituted solution according to claim 16 in the manufacture of a medicament for inducing a protective immune response in a mammal, preferably in the manufacture of a vaccine.
  19. Use of the pharmaceutical composition according to any one of claims 1-14, the freeze-dried formulation according to claim 15, or the reconstituted solution according to claim 16 in the manufacture of a medicament for treating a disease or dysfunction in a mammal, wherein the disease is preferably a viral infection or cancer.

Description

TECHNICAL FIELD The present disclosure pertains to the field of pharmaceuticals and relates to a pharmaceutical composition comprising a cationic lipid and use thereof. BACKGROUND Nucleic acid-based drugs, such as messenger RNA (mRNA), antisense oligonucleotides, small interfering RNA (siRNA), and plasmids, have vast potential for application. A problem that hinders the advancement of this technology is how to safely and effectively deliver these drugs to target organs and cells within the body. Currently, nucleic acid drug delivery vectors are categorized into two main types: viral vectors and non-viral vectors. Lipid nanoparticle-mediated nucleic acid drug delivery is a primary method for non-viral delivery vectors. In gene therapy and vaccine applications, lipid nanoparticles have been shown to be excellent vectors for nucleic acids for treating various diseases. Lipid nanoparticles formed from cationic lipids and other auxiliary lipids such as cholesterol, phospholipids, and PEGylated lipids encapsulate nucleic acids, protecting them from degradation, promoting cellular uptake, and reducing immune responses. In addition, lipid nanoparticles offer other advantages for the delivery of bioactive ingredients into cells, including good targeting, minimal side effects, good stability, efficient transfection, etc. Although lipid nanoparticles have demonstrated advantages in delivery, their safety, efficacy, and specificity remain to be improved. There remains a need to develop improved cationic lipid compositions that facilitate the delivery of therapeutic agents and/or prophylactic agents, such as nucleic acids, to cells. SUMMARY The present disclosure provides a pharmaceutical composition comprising a vector, wherein the vector comprises a cationic lipid, and the cationic lipid comprises the compound represented by formula I or a pharmaceutically acceptable salt thereof; a molar percentage of the cationic lipid to the vector is greater than or equal to 10% and less than 50%: In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 15-49%, including but not limited to 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or a value between any two of these numbers, of a molar amount of the vector. In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 42-49% of the molar amount of the vector. In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 45% of the molar amount of the vector. In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 46% of the molar amount of the vector. In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 47% of the molar amount of the vector. In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 48% of the molar amount of the vector. In some embodiments, the cationic lipid in the pharmaceutical composition accounts for 49% of the molar amount of the vector. In some other embodiments, the vector in the pharmaceutical composition further comprises a non-cationic lipid, and the non-cationic lipid is selected from the group consisting of at least one of a phospholipid and cholesterol or a derivative thereof. In some embodiments, the non-cationic lipid in the pharmaceutical composition is selected from the group consisting of a mixture of a phospholipid and cholesterol or a derivative thereof. A content of the phospholipid in the pharmaceutical composition provided in some embodiments accounts for 5-40%, including but not limited to 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or a value between any two of these numbers, of the molar amount of the vector. In some embodiments, the content of the phospholipid in the pharmaceutical composition accounts for 15% of the molar amount of the vector. In some embodiments, the content of the phospholipid in the pharmaceutical composition accounts for 20% of the molar amount of the vector. In some embodiments, the content of the phospholipid in the pharmaceutical composition accounts for 10-20% of the molar amount of the vector. In some embodiments, the content of the phospholipid in the pharmaceutical composition accounts for 10% of the molar amount of the vector. The phospholipid in the pharmaceutical composition provided in some other embodiments is selected from the group consisting of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-gly