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EP-4734962-A1 - NOVEL FORMULATIONS

EP4734962A1EP 4734962 A1EP4734962 A1EP 4734962A1EP-4734962-A1

Abstract

The present invention provides inter alia aqueous liquid pharmaceutical formulations comprising a surfactant component and a polynucleotide molecule. The formulations of the present invention are for use as medicaments, for example for use in the treatment or prevention of viral infection and disease associated with viral infection.

Inventors

  • ITO, KAZUHIRO
  • SHUR, Jagdeep
  • RAPEPORT, WILLIAM GARTH
  • IYER, RADHAKRISHNAN P.
  • SOBOLOV, Susan

Assignees

  • RIGImmune Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. Claims 1. An aqueous liquid pharmaceutical formulation, in the form of a stable colloidal emulsion, comprising (i) a surfactant component which is a mixture of a fatty acid or a pharmaceutically acceptable salt thereof and a non-ionic surfactant and (ii) a polynucleotide molecule.
  2. 2. The aqueous liquid pharmaceutical formulation according to claim 1, wherein the fatty acid is selected from the group consisting of arachidic acid, arachidonic acid, caprylic acid, lauric acid, linoleic acid, linolenic acid, myristic acid, myristoleic acid, oleic acid, palmitic acid, palmitoleic acid, sapienic acid, stearic acid, and vaccenic acid.
  3. 3. The aqueous liquid pharmaceutical formulation according to claim 2, wherein the fatty acid is selected from caprylic acid and oleic acid.
  4. 4. The aqueous liquid pharmaceutical formulation according to any one of claims 1 to 3, wherein the non-ionic surfactant is selected from the group consisting of polyoxyalkylenes, such as poloxamers, alkyl ethers of polyethylene glycol, alkylphenyl ethers of polyethylene glycol, and fatty acid esters, such as polyoxyethylene sorbitan fatty acid esters.
  5. 5. The aqueous liquid pharmaceutical formulation according to claim 4, wherein the non- ionic surfactant is selected from alkyl ethers of polyethylene glycol and polyoxyethylene sorbitan fatty acid esters.
  6. 6. The aqueous liquid pharmaceutical formulation according to claim 1, wherein the surfactant component is selected from the group consisting of mixtures of (a) oleic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (b) lauric acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (c) linoleic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (d) linolenic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (e) palmitic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (f) stearic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (g) oleic acid or a pharmaceutically acceptable salt thereof and a polyoxyalkylene, such as a poloxamer, (h) oleic acid or a pharmaceutically acceptable salt thereof and an alkyl ether of polyethylene glycol, (i) oleic acid or a pharmaceutically acceptable salt thereof and an alkylphenyl ether of polyethylene glycol, (j) caprylic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester, (k) caprylic acid or a pharmaceutically acceptable salt thereof and a polyoxyalkylene, such as a poloxamer, (l) caprylic acid or a pharmaceutically acceptable salt thereof and an alkyl ether of polyethylene glycol, and (m) caprylic acid or a pharmaceutically acceptable salt thereof and an alkylphenyl ether of polyethylene glycol. 130
  7. 7. The aqueous liquid pharmaceutical formulation according to claim 6, wherein the surfactant component is a mixture of oleic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester.
  8. 8. The aqueous liquid pharmaceutical formulation according to claim 7, wherein the surfactant component is a mixture of oleic acid or a pharmaceutically acceptable salt thereof and polysorbate 80.
  9. 9. The aqueous liquid pharmaceutical formulation according to claim 6, wherein the surfactant component is a mixture of caprylic acid or a pharmaceutically acceptable salt thereof and a polyoxyethylene sorbitan fatty acid ester.
  10. 10. The aqueous liquid pharmaceutical formulation according to claim 9, wherein the surfactant component is a mixture of caprylic acid or a pharmaceutically acceptable salt thereof and polysorbate 80.
  11. 11. The aqueous liquid pharmaceutical formulation according to claim 6, wherein the surfactant component is a mixture of oleic acid or a pharmaceutically acceptable salt thereof and an alkyl ether of polyethylene glycol.
  12. 12. The aqueous liquid pharmaceutical formulation according to claim 11, wherein the surfactant component is a mixture of oleic acid or a pharmaceutically acceptable salt thereof and Brij 35 (polyoxyethylene (23) lauryl ether).
  13. 13. The aqueous liquid pharmaceutical formulation according to claim 6, wherein the surfactant component is a mixture of caprylic acid or a pharmaceutically acceptable salt thereof and an alkyl ether of polyethylene glycol.
  14. 14. The aqueous liquid pharmaceutical formulation according to claim 13, wherein the surfactant component is a mixture of caprylic acid or a pharmaceutically acceptable salt thereof and Brij 35 (polyoxyethylene (23) lauryl ether).
  15. 15. The aqueous liquid pharmaceutical formulation according to any one of claims 1 to 14, wherein the fatty acid is in the form of the free acid.
  16. 16. The aqueous liquid pharmaceutical formulation according to any one of claims 1 to 15, wherein the concentration of the surfactant component in the formulation is 0.2 – 30000 µg/mL, for example 1 – 30000 µg/mL, for example 1 – 20000 µg/mL, 5 – 20000 µg/mL, 5 – 15000 µg/mL, 5 – 10000 µg/mL, or 5-5000 µg/mL.
  17. 17. The aqueous liquid pharmaceutical formulation according to any one of claims 1 to 16 wherein the ratio of the amount of fatty acid or a pharmaceutically acceptable salt thereof to non-ionic surfactant, wherein each is measured in µg/mL, is between about 5:1 and about 1:5, between about 5:1 and about 1:2, between about 4:1 and about 1:2, or between about 2:1 and about 1:2.
  18. 18. The aqueous liquid pharmaceutical formulation according to any one of claims 1 to 17, wherein the polynucleotide molecule is a ribonucleic acid (RNA) molecule. 131
  19. 19. The aqueous liquid pharmaceutical formulation according to claim 18, wherein the RNA molecule is an mRNA, miRNA, shRNA or siRNA molecule.
  20. 20. The aqueous liquid pharmaceutical formulation according to claim 19, wherein the RNA molecule is an shRNA molecule.

Description

Novel Formulations Related Applications This application claims the benefit of U.S. Provisional Application No.63/510,985, filed on June 29, 2023 and International Application No. PCT/US24/30546 filed on May 22, 2024. The entire teachings of the above applications are incorporated herein by reference. Sequence Listing The sequence listing submitted via EFS, in compliance with 37 CFR §1.52(e)(5), is incorporated herein by reference. The sequence listing XML file submitted via EFS contains the file “4329.3002 WO SEQ Listing.xml”, created on June 27, 2024, which is 13,174 bytes in size. Field This invention relates to aqueous liquid pharmaceutical formulations comprising a surfactant component and a polynucleotide molecule. The invention also relates inter alia to aqueous liquid pharmaceutical formulations for use as a medicament, for example for use in the treatment or prevention of viral infection and disease associated with viral infection, and related methods of treatment. Background of the Invention It is essential that a therapeutic agent is delivered to the target tissues and/or cells of a subject in an amount that allows said therapeutic agent to exert a therapeutic effect. Indeed, insufficient delivery of a therapeutic agent often impedes the ability of an otherwise efficacious therapeutic agent to achieve desired therapeutic outcomes. This problem is particularly pronounced for biologic therapeutics, such as immunoglobulins and polynucleotide molecules, in particular genomic DNA (gDNA), complementary DNA (cDNA), mRNA, siRNA, and shRNA, whose macromolecular nature and net ionic charge add additional complexities to targeted delivery. Unlike small molecule therapeutics, biologics do not undergo passive diffusion across cell membranes. Moreover, upon introduction intro a subject, polynucleotide molecules are susceptible to degradation by endonuclease and exonuclease enzymes which can hydrolyse the phosphodiester bonds of the polynucleotide backbone. Accordingly, the clinical value of polynucleotide therapeutics is dependent on delivery technologies that improve the stability of the polynucleotide, facilitate efficient internalisation, and increase target affinity (Kulkarni et al.2021). In view of the challenges associated with delivery of polynucleotide therapeutics, a number of platform delivery technologies have been developed, in particular in the context of gene 1    therapy products. These include chemically-modified antisense oligonucleotides (ASOs), N- acetylgalactosamine (GalNAc) conjugates, adeno-associated virus (AAV) vectors and lipid delivery systems, including lipid nanoparticles (LNPs) and liposomes (Kulkarni et al.2021). ASOs refer to polynucleotide molecules comprising a number of chemical modifications to the backbone, sugar moiety, or nitrogenous base to enhance affinity to target RNA, improve nuclease resistance and modulate the immunological profile of the polynucleotide (Khvorova and Watts, 2017). GalNAc conjugation facilitates accumulation of relevant polynucleotide therapeutics, particularly in the liver. Specifically, the GalNAc construct targets the asialoglycoprotein receptor which is predominantly expressed on liver hepatocytes. Subsequent internalisation via clathrin-mediated endocytosis, and endosomal escape by the polynucleotide molecule provides targeted delivery (Springer and Dowdy, 2018). These chemical modification technologies have significant utility but may complicate manufacturing processes and increase costs. Conversely, AAV vector systems are comparably simple and may provide efficient delivery of polynucleotide molecule to the nucleus. Moreover, different AAVs display different cell tropisms, such that the platform technology can be adapted to different target tissues or cells. However, lipid delivery systems, including lipid nanoparticles and liposomes, have increasingly become recognised as the most promising delivery system for polynucleotide molecules. In particular, the biocompatibility of lipid-based formulations and their respective ease of manufacturing, particularly at a large-scale, has made such formulations an attractive avenue for research and development. Moreover, lipid delivery systems are highly efficient in delivering a polynucleotide molecule into a target cell. Nevertheless, lipid delivery systems are associated with a number of problems. For example, lipid delivery systems, such as lipid nanoparticles and liposomes, frequently include a polyethylene glycol (PEG)-based compound which prevents the aggregation, and subsequent immune recognition and elimination, of lipid particles (Jokerst et al.2011). Indeed, PEGylated lipid particles appear to have an increased half-life in the circulation (Huang and Liu, 2011). However, PEGylated lipid nanoparticles have been reported to severely inhibit endosomal release of polynucleotide molecules (Song et al. 2002), as well as stimulating undesirable immune response, for example the raising of an antibody