[go: up one dir, main page]

WO2018147710A1 - Nanoémulsion comprenant une matière à base d'imidazoquinoline et son utilisation - Google Patents

Nanoémulsion comprenant une matière à base d'imidazoquinoline et son utilisation Download PDF

Info

Publication number
WO2018147710A1
WO2018147710A1 PCT/KR2018/001891 KR2018001891W WO2018147710A1 WO 2018147710 A1 WO2018147710 A1 WO 2018147710A1 KR 2018001891 W KR2018001891 W KR 2018001891W WO 2018147710 A1 WO2018147710 A1 WO 2018147710A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
oil
nanoemulsion
agonist
imidazoquinoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2018/001891
Other languages
English (en)
Korean (ko)
Inventor
임용택
김선영
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HLB Science Inc
Original Assignee
Dandi Bioscience Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020180016726A external-priority patent/KR101996538B1/ko
Application filed by Dandi Bioscience Inc filed Critical Dandi Bioscience Inc
Priority to RU2019128380A priority Critical patent/RU2019128380A/ru
Priority to JP2019542161A priority patent/JP2020506938A/ja
Priority to AU2018218721A priority patent/AU2018218721A1/en
Priority to CN201880011728.0A priority patent/CN110430868A/zh
Priority to CA3052940A priority patent/CA3052940A1/fr
Priority to EP18750674.6A priority patent/EP3581170A4/fr
Priority to US16/485,544 priority patent/US20200046831A1/en
Publication of WO2018147710A1 publication Critical patent/WO2018147710A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention is directed to nanoemulsions comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and oil, and their use as adjuvants and vaccines.
  • Vaccine adjuvant is an adjuvant adjuvant and activates immune cells and plays an important role in the prevention and treatment of infectious diseases vaccines and chemotherapy.
  • Aluminum salts aluminum salt, alum
  • squalene nanoemulsions MF59, AS03, AF03, etc.
  • MF59, AS03, AF03, etc. humoral immune responses that contribute to antibody responses.
  • nanoemulsion-based adjuvants are limited to influenza vaccines.
  • an adjuvant composition comprising a complex of a negatively charged polymer and a toll-like receptor agonist, and a collagen-based or gelatin-based material. These adjuvant compositions are disclosed to have multi-stage phase transition properties with temperature changes.
  • imidazoquinoline-based drugs e.g., Imiquimod, Resiquimod, Dactolisib, Dactolisib, Gardiquimod) Quimod
  • Sumanirole sumanirol
  • imidazoquinoline-based materials have many difficulties in dispersing in aqueous solution due to their molecular structure.
  • imiquimod R837
  • DMSO dimethyl methoxysulfoxide
  • imiquimod has been commercialized in a cream formulation (product name: Aldara® from 3M) with various surfactants.
  • imidazoquinoline-based drugs in salt form eg, HCl
  • HCl salt form
  • the present inventors dissolve the imidazoquinoline toll-like receptor 7 or 8 agonist, which is difficult to solubilize in aqueous solution, into oil using a dispersion medium material and prepare the oil mixture in the form of nanoemulsion, thereby making it difficult to solubilize the imidazoquinoline series.
  • the present invention was developed by developing an immunoactivating substance having both the immunological properties and the immunological properties of oil-based nanoemulsions, and finding that it can be used not only for humoral immunity but also for adjuvant and vaccine for improving cellular immunity. Completed.
  • the present invention provides a nanoemulsion comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and an oil.
  • imidazoquinoline-based toll-like receptor 7 or 8 agonist may be dispersed in a nano-sized oil layer.
  • At least one selected from the group consisting of the surfactant and the immunoactivating material may be coated on the outside of the oil layer.
  • imidazoquinoline-based toll-like receptor 7 or 8 agonist may be immimod (Imiquimod), Resiquimod (Resiquimod), Dactolisib, Cardiquimod (Gardiquimod), Sumanirole (Sumanirole) ), Motolimod, 3M-052, S-34240, 852, 854-A from 3M, and their derivatives.
  • the oil may be selected from the group consisting of fish derived oil, animal derived oil, vegetable derived oil, tocopherol, mineral oil, and castor oil,
  • imidazoquinoline-based toll-like receptor 7 or 8 agonists and oil may be included in a weight ratio of 0.1: 100 to 1:50.
  • the imidazoquinoline-based toll-like receptor 7 or 8 agonist may further include a mediator to help the lipophilic interaction between the oil.
  • the mediator is myristic oleic acid, palmitoleic acid, sapienic acid (Sapienic acid), oleic acid, Elaidic acid (Elaidic acid), Vaccenic acid, linoleic acid, linoleicidic acid (Linoelaidic acid) , Alpha-linoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenonic acid, caprylic acid, capric acid, capric acid acid), Lauric acid, Myristic acid, Palmitic acid, Stearic acid, Arachidic acid, Behenic acid, Lignoceric acid, and It may be selected from the group consisting of cerotic acid.
  • the mediator material may be included in a weight ratio of 0.1: 10 to 10: 0.1 with the imidazoquinoline-based toll-like receptor 7 or 8 agonist.
  • the surfactant is a polyoxyethylene sorbitan ester surfactant (Tween), including polysorbate 20 and polysorbate 80; Copolymers comprising at least one of ethylene oxide (EO), propylene oxide (PO) and butylene oxide (BO); Octosinol including Triton X-100 and t-octylphenoxypolyethoxyethanol; (Octylphenoxy) polyethoxyethanol; Phosphatidylcholine (lecithin) phospholipids including phosphatidylethanolaniline, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, sphingomyelin and cardiolipin; Nonylphenol ethoxylate; Polyoxyethylene patty ethers derived from lauryl, cetyl and oleyl alcohols including triethyleneglycol monolauryl ethers; And sorbitan esters
  • the immunoactivator may be a toll-like receptor agonist (TLR), a saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a CDS ligand ( cytosolic DNA sensor ligands), stimulator of interferon genes (STING) ligands, and cationic lipids.
  • TLR toll-like receptor agonist
  • saponin a saponin
  • an antiviral peptide an antiviral peptide
  • an inflammasome inducer a NOD ligand
  • CDS ligand cytosolic DNA sensor ligands
  • STING stimulator of interferon genes
  • an adjuvant composition comprising the nanoemulsion is provided.
  • an adjuvant composition for enhancing cellular immunity as well as humoral immunity and a vaccine composition comprising an antigen.
  • a method for producing a nanoemulsion comprising a.
  • Nanoemulsions comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and an oil according to the present invention are useful for the prevention of infectious diseases, therapeutic vaccines and immune chemotherapy. It is possible to provide the vaccine adjuvant in the form of emulsion used for activation, and also to disperse imidazoquinoline-based materials stably in an oil such as squalene using a dispersion medium material, and finally to prepare the oil layer thus prepared in emulsion form. By the preparation, it is possible to provide a vaccine adjuvant using imidazoquinoline series material that is poorly soluble in most organic solvents and aqueous solutions.
  • the adjuvant in the form of a nanoemulsion of the present invention when used as a vaccine in combination with an antigen, has the effect of simultaneously improving humoral and cellular immunity.
  • the nanoemulsion comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and an oil according to the present invention is a lipophilic imidazoquinoline-based toll-like receptor agonist. Because of the controlled release behavior characteristics from the inner oil layer to the aqueous solution layer, it is released slowly in the body, thereby improving the cellular immune effect, while solving the systemic toxicity problem.
  • FIG. 1 is a schematic diagram showing the structure of a nanoemulsion adjuvant composition composed of an imidazoquinoline-based toll-like receptor agonist, a dispersion mediator material, an oil, a surfactant, and an immunoactivating agent component according to one embodiment of the invention.
  • FIG. 2A illustrates data obtained by measuring the size and size distribution of a nanoemulsion (NE-IQ) including a nanoemulsion (NE) and an imidazoquinoline-based toll-like receptor agonist according to an embodiment of the present invention.
  • Light Scattering Measurement data.
  • Figure 2b is a data measuring the size and size distribution of the nanoemulsion (NE-IQ) comprising a nanoemulsion (NE) and imidazoquinoline-based toll-like receptor agonist according to an embodiment of the present invention, TEM (Transmission) Electron Microscopy) image (NE-IQ).
  • Figure 3 shows the delivery and distribution in immune cells (BMDC: bone-marrow derived dendritic cell, BMMC: bone-marrow derived macrophage cell) of NE-IQ according to an embodiment of the present invention (NE-IQ (DID) , Lysotracker (FITC), where a is for BMDC and b is for BMMC.
  • BMDC bone-marrow derived dendritic cell
  • BMMC bone-marrow derived macrophage cell
  • Figure 4 shows the concentration dependence of imiquimod (R837) of the expression level of cytokines associated with the maturation of immune cells after the treatment of NE-IQ according to an embodiment of the invention
  • a is BMDC
  • b is BMMC
  • a is BMDC
  • b is BMMC
  • Figure 5 shows the concentration dependence of R837 of the surface marker expression rate survival rate associated with the maturation of immune cells after the treatment of NE-IQ according to an embodiment of the invention
  • a is a BMDC
  • b is a graph for BMMC.
  • Figure 6 shows the effect on immune cell survival after 24, 48 hours after treatment with NE-IQ according to an embodiment of the invention
  • a is a BMDC
  • b is a graph for BMMC.
  • Figure 7 shows the expression level of IFN-alpha, a type of Type I inteferon expressed after NE-IQ intramuscular injection.
  • Figure 8 shows the enzyme immunoassay-IgG titer (3, 6, 9 weeks) of NE and NE-IQ against OVA (Ovalbumin) antigen in accordance with an embodiment of the present invention.
  • Figure 9 shows the enzyme immunoassay-IgG1 titer (3, 6, 9 weeks) of NE and NE-IQ against OVA (Ovalbumin) antigen according to an embodiment of the present invention.
  • Figure 10 shows the enzyme immunoassay of NE and NE-IQ-IgG2a titer (3, 6, 9 weeks) against OVA (Ovalbumin) antigen in accordance with an embodiment of the present invention.
  • Figure 11 shows the enzyme immunoassay of NE and NE-IQ-IgG2a / IgG1 ratio (3, 6, 9 weeks) to the OVA (Ovalbumin) antigen according to an embodiment of the present invention.
  • Figure 12 shows the Immunization schedule for measuring the CTL immune response that is activated after intramuscular injection of NE-IQ.
  • Figure 13 shows the cellular immune-induced effects of NE and NE-IQ (IFN-gamma secretion by T cell activation) to the OVA (Ovalbumin) antigen according to an embodiment of the present invention.
  • Figure 16 shows the results of measuring activation of CD3 (+) CD8 (+) T cells after immunization of NE-IQ in mice transplanted with B16F10 cancer cells.
  • Fig. 17 shows the results of measuring activation of CD4 (+) IFN-gamma (+) cells after immunization of NE-IQ in mice transplanted with B16F10 cancer cells.
  • Fig. 19 shows the results of confirming that antigens specific to cancer cell growth are inhibited after administration of a vaccine consisting of NE-IQ and ovalbumin antigen to mice transplanted with B16F10-OVA cancer cells.
  • Figure 21 illustrates the cellular immune-induced effect (IFN-gamma secretion by T cell activation) of the NE-IQ series of vaccine adjuvant compositions for OVA (Ovalbumin) antigen in accordance with an embodiment of the present invention.
  • the term "combination of these" included in the expression of the mark of the form of the word means one or more mixtures or combinations selected from the group consisting of the components described in the mark of the form of the mark, It means to include one or more selected from the group consisting of components.
  • the present invention provides a nanoemulsion comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and an oil.
  • the imidazoquinoline-based toll-like receptor 7 or 8 agonist may be dispersed in a nanosized oil layer and coated with a surfactant, an immunoactivating material, or a combination thereof on the exterior of the emulsion. (FIG. 1).
  • FIG. 1 is a schematic diagram of a nanoemulsion of the present invention, wherein an imidazoquinoline-based toll-like receptor 7 or 8 agonist is dispersed in an oil layer, and a spherical surface having a surfactant and / or an immunoactivating material coated thereon Form.
  • the size of the nanoemulsion may be about 50 to 500 nm, for example about 50 to 300 nm, about 50 to 100 nm, about 70 to 500 nm, about 100 to 500 nm or about 100 to 200 nm.
  • the nanoemulsion is a) dissolving an imidazoquinoline-based toll-like receptor 7 or 8 agonist in oil to prepare an oil solution; b) mixing at least one selected from the group consisting of a surfactant and an immunoactivating substance with the oil solution; And c) dispersing the mixed solution obtained in step b in an aqueous solution.
  • the imidazoquinoline-based toll-like receptor 7 or 8 agonist may be dissolved in oil together with a mediator material to assist lipophilic interaction.
  • the immunoactivating material may be used in admixture with a surfactant in the nanoemulsion preparation process, or after the nanoemulsion is prepared, may be additionally attached to the surface.
  • the imidazoquinoline-based toll-like receptor 7 or 8 agonist and oil may be included in a weight ratio of 0.1: 100 to 1:50, for example, 1:20.
  • the imidazoquinoline-based toll-like receptor 7 or 8 agonist is an immunoactivating substance and includes imiquimod, Resiquimod, Dactolisib, Gardiquimod, and Sumani. It may be selected from the group consisting of Sumanirole, motolimod, 3M-052, S-34240, 852, 854-A, and analogs thereof of 3M, for example, imiqui May be a mode.
  • the oil may be selected from the group consisting of fish derived oils, animal derived oils, vegetable derived oils, tocopherols, mineral oils, castor oils and combinations thereof.
  • the fish oil may be used without limitation as long as it is a metabolizable oil, and includes, for example, cod liver oil, shark liver oil, whale oil and the like.
  • the shark liver oil contains squalene, a molecule known as 2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene, unsaturated terpene, squalene, Saturated analogs to squalane may also be included.
  • the animal derived oil may include lard, tallow oil, tallow, and the like.
  • the vegetable derived oil may be an oil derived from nuts, seeds, grains, and the like, and may include, for example, peanut oil, soybean oil, coconut oil, olive oil, and the like.
  • the tocopherol may be tocopherol containing vitamin E.
  • Various tocopherols are present ( ⁇ , ⁇ , ⁇ , ⁇ , ⁇ or ⁇ ), but ⁇ -tocopherol is generally used, for example DL- ⁇ -tocopherol can be used.
  • the imidazoquinoline-based toll-like receptor 7 or 8 agonists may be solubilized and dispersed in oil by a mediator that is poorly soluble and aids in lipophilic interaction with the oil.
  • the mediator may be, for example, myristic oleic acid, palmitoleic acid, sapienic acid, oleic acid, laidic acid, vacecic acid, linoleic acid, linoleicidic acid.
  • the mediator material may be used in a weight ratio of 0.1: 10 to 10: 0.1 with the imidazoquinoline-based toll-like receptor 7 or 8 agonist and oil, for example 1: 5 to 5: 1.
  • the surfactant is coated on the outside of the nanoemulsion so that the nanoemulsion can be dispersed in an aqueous solution, for example, polyoxyethylene sorbitan ester surfactant (Tween), in particular polysorbate 20 and polysorbate 80; Copolymers of ethylene oxide (EO), propylene oxide (PO), and / or butylene oxide (BO); Octosinol (eg, Triton X-100, or t-octylphenoxypolyethoxyethanol); (Octylphenoxy) polyethoxyethanol (IGEPAL CA-630 / NP-40); As phospholipid (phospholipid component), phosphatidylcholine (lecithin) phosphatidylethanolaniline, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, sphingomyelin and cardiolipin; Nonylphenol ethoxylates
  • the surfactant may be a mixture of these surfactants, such as a Tween 80 / Span 85 mixture, and a combination of polyoxyethylene sorbitan ester and octosinol. Other useful combinations may include laureth 9, polyoxyethylene sorbitan esters and / or octosinol.
  • the surfactant may be used in an amount of 0.001 to 20% by weight based on the total weight of the total nanoemulsion, for example, 0.01 to 1%, 0.001 to 0.1%, 0.005 to 0.02%; It may be used at a weight of 0.1 to 20%, 0.1 to 10%, 0.1 to 1% or about 0.5%.
  • the additional immunoactivating material coated on the outside of the nanoemulsion serves to stimulate the proliferation, differentiation and activity of dendritic cells, T cells and B cells, and thus activated T cells promote differentiation into cytotoxic T cells and And cytokines, such as interferon-gamma, are involved in cellular immune responses.
  • Such additional immunoactivating agents include, for example, toll-like receptor agonists (TLRs), saponins, antiviral peptides, inflammasome inducers, NOD ligands, CDS ligand (cytosolic DNA sensor ligand), stimulator of interferon genes (STING) ligand, cationic lipids (cationic lipids), and combinations thereof may include a material selected from the group consisting of, but is not limited thereto. have.
  • TLRs toll-like receptor agonists
  • saponins saponins
  • antiviral peptides antiviral peptides
  • inflammasome inducers NOD ligands
  • CDS ligand cytosolic DNA sensor ligand
  • STING stimulator of interferon genes
  • cationic lipids cationic lipids
  • combinations thereof may include a material selected from the group consisting of, but is not limited thereto. have.
  • the toll-like receptor agonist may be a natural toll-like receptor agonist or a synthetic toll-like receptor agonist.
  • the immunoactivating agent may comprise a combination of one or more toll-like receptor agonists, for example CL401 (dual TLR2 and TLR7 agonists) or CL429 (dual TLR2 and NOD2 agonists) alone or a combination thereof. It may include a combination, but is not limited thereto.
  • the toll-like receptor agonist may be one that can cause a signaling response through TLR-1, for example tri-acylated lipopeptide (LP); Phenol-soluble modulins; Cobacterium tuberculosis (Mycobacterium tuberculosis) lipopeptide; S- (2,3-bis (palmitoyloxy)-(2-RS) -propyl) -N-palmitoyl- (R) -Cys- (S) -Ser- (S) -Lys (4) -OH ; Bacterial lipopeptides from Borrelia burgdorfei; Trihydrochloride (Pam3Cys) lipopeptides that mimic the acetylated amino termini of OspA lipopeptides; And one or more materials selected from the group consisting of combinations thereof, but is not limited thereto.
  • LP tri-acylated lipopeptide
  • Phenol-soluble modulins Cobacterium tubercul
  • the toll-like receptor agonist may include a TLR-2 agonist, and may include, for example, Pam3Cys-Lip, but is not limited thereto.
  • the toll-like agonist may include a TLR-3 agonist, and may include, for example, Poly (I: C), Poly (ICLC), Poly (IC12U), Ampligen, or the like as a polyish family.
  • TLR-3 agonist may include, for example, Poly (I: C), Poly (ICLC), Poly (IC12U), Ampligen, or the like as a polyish family.
  • ICLC Poly
  • IC12U Poly (IC12U)
  • Ampligen or the like as a polyish family.
  • the present invention is not limited thereto.
  • the toll-like agonist may be one comprising a TLR-4 agonist, for example, Shigella flexineri outer membrane protein preparation, AGP, CRX-527, MPLA, PHAD, 3D-PHAD, GLA, And one or more materials selected from the group consisting of combinations thereof, but is not limited thereto.
  • TLR-4 agonist for example, Shigella flexineri outer membrane protein preparation, AGP, CRX-527, MPLA, PHAD, 3D-PHAD, GLA, And one or more materials selected from the group consisting of combinations thereof, but is not limited thereto.
  • the toll-like agonist may include a TLR-5 agonist, and may include, for example, flagellin or a fragment thereof, but is not limited thereto.
  • the toll-like agonist may be one comprising a TLR-7 agonist or a TLR-8 agonist, for example, an imidazoquinoline molecule such as imiquimod, R837, resquimod, or R848; VTX-2337; CRX642; Imidazoquinoline covalently bound to a phospholipid group or a phosphonolipid group; And one or more materials selected from the group consisting of combinations thereof, but is not limited thereto.
  • the toll-like agonist may be one containing a TLR-9 agonist, for example, may include an immunostimulatory oligonucleotide, but is not limited thereto.
  • the immunostimulatory oligonucleotides may include one or more CpG motifs, but are not limited thereto.
  • the saponin may be selected from the group consisting of QS21, Quil A, QS7, QS17, ⁇ -eskin, Digitonin, and combinations thereof, but is not limited thereto.
  • the antiviral peptide may include KLK, but is not limited thereto.
  • the influxome inducer may be trehalose-6,6-dibehenate (TDB), but is not limited thereto.
  • the NOD ligand may be M-TriLYS (NOD2 agonist-synthetic Muramil tripeptide) or NOD2 agonist (N-glycolylated muramyldipeptid), but is not limited thereto.
  • M-TriLYS NOD2 agonist-synthetic Muramil tripeptide
  • NOD2 agonist N-glycolylated muramyldipeptid
  • the CDS ligand may be Poly (dA: dT), but is not limited thereto.
  • the STING ligand may be cGAMP, di-AMP, or di-GMP, but is not limited thereto.
  • the immuno-activator is Pam3Cys-Lip, Poly (I: C), CRX-527, MPLA (monophosphoryl lipid A), flagellin (flagellin), imiquimod, resquimod, CpG, QS21, M
  • the cationic lipids are DC-cholesterol (3ß- [N- (N ', N'-dimethylaminoethane) -carbamoyl] cholesterol hydrochloride), DDA (dimethyldioctadecylammonium), DOTAP (1,2-dioleoyl-3-trimethylammonium-propane), DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane), EPC (1,2-dimyristoleoyl-sn-glycero-3-ethylphosphocholine), MVL5 (N1- [2-((1S) -1- [ (3-aminopropyl) amino] -4- [di (3-amino-propyl) amino] butylcarboxamido) ethyl] -3,4-di [oleyloxy] -benzamide), DODAP (lipids1,2-dioleoyl-3
  • the present invention also provides an adjuvant composition comprising the nanoemulsion according to the present invention and a vaccine composition comprising the adjuvant composition and the antigen according to the present invention.
  • the antigen may be selected from the group consisting of proteins, recombinant proteins, glycoproteins, genes, peptides, polysaccharides, lipopolysaccharides, polynucleotides, cells, viruses and combinations thereof.
  • the protein may include, for example, overalbumin, peptide, recombinant protein, subunit, split protein antigen.
  • the gene may comprise DNA or mRNA antigens, and the peptide may comprise peptide antigens specific for cancer cells or viruses.
  • the cells may include, for example, dendritic cells, cancer cells and cancer cell derived lysates, and the virus may include, for example, influenza, highly pathogenic influenza.
  • the adjuvant composition or vaccine composition may comprise one or more pharmaceutically acceptable carriers or diluents in addition to pharmaceutically effective amounts of nanoemulsions and / or antigens.
  • the term “pharmaceutically effective amount” refers to an amount sufficient to allow the physiologically active ingredient to be administered to an animal or human to exhibit the desired physiological or pharmacological activity. However, the pharmaceutically effective amount may be appropriately changed depending on the severity of symptoms, age, weight, health condition, sex, route of administration, and duration of treatment.
  • pharmaceutically acceptable refers to a physiologically acceptable and, when administered to a human, usually does not cause gastrointestinal disorders, allergic reactions such as dizziness or the like.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal, and can be formulated for various oral or parenteral administration. It may be formulated in a form.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • composition according to the invention can be administered via several routes including oral, transdermal, subcutaneous, intravenous or intramuscular, the dosage of the active ingredient being determined by several factors such as the route of administration, the age, sex, weight and severity of the patient. It may be appropriately selected depending on.
  • the composition of the present invention can be administered in parallel with known compounds that can enhance the desired effect.
  • Squalene comprising imiquimod prepared as in Example 1 (5% v / v, Sigma Aldrich, USA), Tween 80 (0.5% v / v, Sigma Aldrich, USA) and Span 85 (0.5% v / v, Sigma-Aldrich, USA) was dissolved in 2 mL of phosphate buffer solution (PBS, 0.0067M PO4) and released to disperse completely in phosphate buffer solution (PBS) for 1 minute using an ultrasonic tip sonicator. Thereafter, the mixture was stirred for about 2 hours using a tube revolve and then stored in a 4 ° C. refrigerator until use.
  • PBS phosphate buffer solution
  • the size of the emulsion was analyzed by DLS (Dynamic Light Scattering, Otsuga, Japan). As a result of measuring DLS (Dynamic Light Scattering, Otsuga, Japan), the diameters were 106.16 ⁇ 5.4 and 148.54 ⁇ 18.5m (Fig. 2, Table 1).
  • BMDCs Bone marrow-derived dendritic cells
  • BMMCs bone marrow-derived macrophage cells
  • NE-IQ squalene nanoemulsion
  • BMDCs bone marrow-derived dendritic cells
  • BMMCs bone marrow-derived macrophage
  • NE-IQ in Figure 4 When treated, it was confirmed that the secretion of IL-6 and IL-12, which induce Th1 response, was increased, and the secretion of TNF- ⁇ and inflammatory cytokine IL-1 ⁇ , which induce apoptosis and tumor suppression, was also increased. It can be seen that the increase is more significant than the case without including the mode (Imiquimod) (R837).
  • NE-IQ was applied to bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophage (BMMCs). After treatment, the cell proliferation rate was evaluated. In the proliferation rate of FIG. 6, an MTS assay kit (Cell Proliferation) assay for measuring mitochondrial activity was used. NE-IQ When treated, it was confirmed that both 24-hour and 48-hour increase in both types of immune cells was more than 10-fold higher than without imiquimod.
  • mice C57BL / 6 (female 5-6 weeks old, orient) mice were used, and 10 ⁇ g of ovalbumin (OVA) and 25 ⁇ g of imiquimod (R837) were dissolved in 50 ⁇ L in a single dose. 24 hours after the vaccine was injected into the mice, the secretion amount of IFN- ⁇ at the muscle and lymph node areas was analyzed by ELISA test method. NE-IQ The treated experimental group was confirmed to increase the cytokine secretion than other controls (control using NE and Alum adjuvant) (Fig. 7). Imiquimod (R837) is known to increase the secretion of interferon (IFN) cytokines through stimulation of toll like receptor 7.
  • IFN interferon
  • mice C57BL / 6 (female 5-6 weeks old, orient) mice were used, and 100 ⁇ g of ovalbumin (OVA) and 45.5 ⁇ g of imiquimod (R837) were used in one dose, as in Example 2 above.
  • OVA ovalbumin
  • R837 imiquimod
  • the prepared NE-IQ was dissolved in 100 ⁇ L and used.
  • Enzyme immunoassay was analyzed to increase the humoral immune response as mice were injected with the vaccine.
  • Humoral immune response was performed three times in total, and the orbital blood collection in the mice three weeks after the vaccination was completed to compare the production of immunoglobulin IgG and IgG subtypes IgG1 and IgG2a with the control (Fig. 8: IgG 9: IgG1, FIG. 10: IgG2a production amount).
  • the amount of antibody production was increased in all cases when the vaccine was inoculated, in particular, the highest effect was observed in the vaccine using NE-IQ containing imiquimod as an adjuvant.
  • the IgG2a / IgG1 value indicating the degree of cellular immune enhancement was found to be the highest value in the experimental group using NE-IQ as an adjuvant (FIG. 11). The reason seems to be due to the role of imiquimod loaded inside NE.
  • Example 8 Evaluate the effect of NE-IQ on cancer cell proliferation
  • Tumor healing ability was confirmed after administration of NE-IQ to intratumor injection using a C57BL / 6 mouse melanoma model.
  • 1x105 melanoma cells (B16F10) were injected subcutaneously into the right thigh of five female 6-week-old mice, and 100 ⁇ l of five injections were performed five days later, and the control group was injected with PBS. Then, tumor volume was measured 2-3 times a week for 19 days after cancer cell administration.
  • NE-IQ was administered after cancer cell injection, it was observed that tumor cell proliferation was significantly suppressed compared to the control group (FIG. 14).
  • T cell activated IFN-gamma-secreting CD8 + T cells in NE-IQ group compared with the control group. It was confirmed to promote (Fig. 17, Fig. 18).
  • a melanoma model (B16F10-OVA) expressing the peptide of obvalmin (Ovalbumin, OVA)
  • a vaccine consisting of NE-IQ and obalbumin antigen in the same manner as in Figure 12, the antigen-specific This confirmed that the cancer cell suppression (Fig. 19).
  • Another tumor model was used to confirm the cancer cell proliferation inhibitory effect of NE-IQ. Tumor healing ability was confirmed after administration of NE-IQ to intratumor injection using a lymphoma model (EG7-OVA) expressing C57BL / 6 mouse OVA antigen.
  • 1x105 lymphoma cells (EG7-OVA) were injected subcutaneously into the right thigh of five 6-week-old female females, and 100 ⁇ l were injected five times at three-day intervals after 5 days, and the control group was injected with PBS. Then, tumor volume was measured 2-3 times a week for 19 days after cancer cell administration. As a result, when NE-IQ was administered after cancer cell injection, it was observed that tumor cell proliferation was significantly suppressed compared to the control group (FIG. 20).
  • Example 9 Including one or more additional immunoactivating substances in NE-IQ Nano Emulsion Produce
  • Nanoemulsions comprising one or more additional immunoactivating substances, such as MPLA, DDA, QS21, etc. in the NE-IQ nanoemulsion were prepared in the composition shown in Table 2.
  • Example 9-1 NE-IQ-1 Adjuvant Manufacture: NE-IQ + DDA + MPLA
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma Aldrich, USA), DDA (dimethyldioctadecylammonium bromide, 1 mg / mL, Sigma Aldrich, USA), cholesterol (Cholesterol 0.25 mg / mL , Sigma-Aldrich, USA), MPLA [monophosphoryl lipid a, 0.2 mg / mL and yorki polar lipids (USA)] were dissolved in 1 mL of ethanol. After transferring the solution to a round flask, the ethanol was completely evaporated using a rotary evaporator to form a thin-film form.
  • the dispersion solution was transferred to a 4 mL vial and released using a sonicator for 1 minute to disperse the lipid membrane completely in phosphate buffer (PBS) for 1 minute. Then, the mixture was stirred for about 2 hours using a tube revolve and then stored in a 4 ° C. refrigerator until use.
  • PBS phosphate buffer
  • Example 9-2 NE-IQ-2 Adjuvant Manufacture: NE-IQ + MPLA + QS21
  • DOPC 1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma-Aldrich, USA
  • MPLA 0.2 mg / mL, yorki polar lipids (United States)
  • saponin QS21 , 0.2 mg / mL
  • cholesterol Choesterol 0.25 mg / mL, Sigma Aldrich, USA
  • Example 9-3 NE-IQ-3 Adjuvant Manufacture: NE-IQ + Pam3Cys -Lip + QS21
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma-Aldrich, USA), Pam3Cys-Lip (0.2 mg / mL, Invivo Gen, USA), QS21 (QS21, 0.2 mg / mL ) was dissolved in 1 mL of ethanol. The solution was transferred to a round flask and ethanol was completely evaporated using a rotary concentrator to form a thin lipid membrane. NE-IQ (Pam3Cys-Lip + QS21) adjuvant was then prepared using the same method as in Example 3.
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma Aldrich, USA), DDA (dimethyldioctadecylammonium bromide, 1 mg / mL, Sigma Aldrich, USA), c-di-AMP (2 mg, Invivo Gen, San Diego, USA), cholesterol (0.25 mg / mL, Sigma Aldrich, USA) were dissolved in 1 mL of ethanol. The solution was transferred to a round flask and ethanol was completely evaporated using a rotary concentrator to form a thin lipid membrane. NE-IQ (DDA + STING (cyclic DNA)) was then prepared using the same method as in Example 3.
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma Aldrich, USA), DDA (dimethyldioctadecylammonium bromide, 1 mg / mL, Sigma Aldrich, USA), cholesterol (0.25 mg / mL, Sigma-Aldrich, USA) was dissolved in 1 mL of ethanol. The solution was transferred to a round flask and ethanol was completely evaporated using a rotary concentrator to form a thin lipid membrane.
  • soybean oil (2.5% v / v, Sigma-Aldrich, USA) and Tween (1% v /) containing R837 prepared using the same preparation method as Example 1, except that soybean oil was used instead of squalene.
  • phosphate buffer solution PBS, 0.0067M PO4
  • the lipid membrane was dispersed in the solution at 600 rpm for 30 minutes at 60 ° C. using a stirrer.
  • the dispersed solution was transferred to a 4 mL vial and released using a sonicator for 1 minute to completely disperse the lipid membrane in phosphate buffer (PBS).
  • Poly (I: C) (2 mg / mL. Invivogen, USA) was dissolved in phosphate buffer solution (0.0067 M PO4), mixed with the nanoemulsion in a 1: 1 volume ratio, and then stirred for 2 hours. It was stored in a 4 °C refrigerator until.
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma Aldrich, USA), DDA (dimethyldioctadecylammonium bromide, 1 mg / mL, Sigma Aldrich, USA), cholesterol (0.25 mg / mL, Sigma-Aldrich, USA) was dissolved in 1 mL of ethanol. The solution was transferred to a round flask and ethanol was completely evaporated using a rotary concentrator to form a thin lipid membrane.
  • a phosphate buffer solution containing squalene (2.5% v / v, Sigma Aldrich, USA) and Tween (1% v / v) containing R837 prepared as in Example 1 (PBS, 0.0067M PO4)
  • PBS phosphate buffer
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma Aldrich, USA), DDA (dimethyldioctadecylammonium bromide, 1 mg / mL, Sigma Aldrich, USA), cholesterol (0.25 mg / mL, Sigma-Aldrich, USA) was dissolved in 1 mL of ethanol. The solution was transferred to a round flask and ethanol was completely evaporated using a rotary concentrator to form a thin lipid membrane.
  • phosphate buffer solution PBS, 0.0067M PO4 containing squalene (2.5% v / v, Sigma Aldrich, USA) and Tween (1% v / v) comprising R837 prepared in Example 1
  • the lipid membrane was dispersed in the solution at 600 rpm for 30 minutes at 60 ° C. using a stirrer.
  • the dispersed solution was transferred to a 4 mL vial, and then released using a sonicator for 1 minute to completely disperse the lipid membrane in phosphate buffer (PBS).
  • DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1 mg / mL, Sigma Aldrich, USA), DDA (dimethyldioctadecylammonium bromide, 1 mg / mL, Sigma Aldrich, USA), cholesterol (0.25 mg / mL, Sigma-Aldrich, USA) was dissolved in 1 mL of ethanol. The solution was transferred to a round flask and ethanol was completely evaporated using a rotary concentrator to form a thin lipid membrane.
  • the lipid membrane was dispersed in the solution at 600 rpm for 30 minutes at 60 ° C. using a stirrer.
  • the dispersed solution was transferred to a 4 mL vial and released using a sonicator for 1 minute to completely disperse lipids in phosphate buffer (PBS).
  • CpG (2 mg / mL. Invivogen, USA) is dissolved in phosphate buffer solution (0.0067 M PO4), mixed with the nanoemulsion in a 1: 1 volume ratio, stirred for about 2 hours, and then placed in a 4 ° C refrigerator until use. Stored.
  • the cellular immune response of T cells against the NE-IQ series vaccine adjuvant compositions prepared according to Examples 9-1 to 9-8 as described in Table 2 was measured using the same method as in Example 7. The results are shown in FIG. 21. As the additional immunoactivator was introduced, it was confirmed that the interferon-gamma (IFN- ⁇ ) secretion was rapidly improved.
  • IFN- ⁇ interferon-gamma
  • Nanoemulsions comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and an oil according to the present invention are useful for the prevention of infectious diseases, therapeutic vaccines and immune chemotherapy. It is possible to provide the vaccine adjuvant in the form of emulsion used for activation, and also to disperse imidazoquinoline-based materials stably in an oil such as squalene using a dispersion medium material, and finally to prepare the oil layer thus prepared in emulsion form. By the preparation, it is possible to provide a vaccine adjuvant using imidazoquinoline series material that is poorly soluble in most organic solvents and aqueous solutions.
  • the adjuvant in the form of a nanoemulsion of the present invention when used as a vaccine in combination with an antigen, has the effect of simultaneously improving humoral and cellular immunity.
  • the nanoemulsion comprising an oil layer comprising an imidazoquinoline-based toll-like receptor 7 or 8 agonist and an oil according to the present invention is an lipophilic imidazoquinoline-based toll-like receptor agonist. Because of the controlled release behavior from the inner oil layer to the aqueous solution layer, it is released slowly in the body, thereby improving cellular immune effects, while solving the systemic toxicity problem.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne une nanoémulsion comprenant une couche d'huile comprenant un agoniste du récepteur 7 ou 8 de type tol à base d'imidazoquinoline et une huile, et son utilisation en tant qu'adjuvant et vaccin. Selon la présente invention, il est possible de fournir un adjuvant de vaccin sous la forme d'une nanoémulsion qui peut se dissoudre une matière à base d'imidazoquinoline insoluble dans l'huile à l'aide d'une matière milieu de dispersion et disperser la solution huileuse facilement et de manière reproductible d'une manière soluble dans l'eau.
PCT/KR2018/001891 2017-02-13 2018-02-13 Nanoémulsion comprenant une matière à base d'imidazoquinoline et son utilisation Ceased WO2018147710A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
RU2019128380A RU2019128380A (ru) 2017-02-13 2018-02-13 Наноэмульсия, содержащая материал на основе имидазохинолина, и ее применение
JP2019542161A JP2020506938A (ja) 2017-02-13 2018-02-13 イミダゾキノリン系物質を含むナノエマルジョン及びその用途
AU2018218721A AU2018218721A1 (en) 2017-02-13 2018-02-13 Nanoemulsion comprising imidazoquinoline-based material and use thereof
CN201880011728.0A CN110430868A (zh) 2017-02-13 2018-02-13 包含基于咪唑并喹啉的材料的纳米乳液及其用途
CA3052940A CA3052940A1 (fr) 2017-02-13 2018-02-13 Nanoemulsion comprenant une matiere a base d'imidazoquinoline et son utilisation
EP18750674.6A EP3581170A4 (fr) 2017-02-13 2018-02-13 Nanoémulsion comprenant une matière à base d'imidazoquinoline et son utilisation
US16/485,544 US20200046831A1 (en) 2017-02-13 2018-02-13 Nanoemulsion comprising imidazoquinoline-based material and use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20170019330 2017-02-13
KR10-2017-0019330 2017-02-13
KR10-2018-0016726 2018-02-12
KR1020180016726A KR101996538B1 (ko) 2017-02-13 2018-02-12 이미다조퀴놀린계열 물질을 포함하는 나노에멀젼 및 이의 용도

Publications (1)

Publication Number Publication Date
WO2018147710A1 true WO2018147710A1 (fr) 2018-08-16

Family

ID=63107648

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/001891 Ceased WO2018147710A1 (fr) 2017-02-13 2018-02-13 Nanoémulsion comprenant une matière à base d'imidazoquinoline et son utilisation

Country Status (1)

Country Link
WO (1) WO2018147710A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022519705A (ja) * 2019-02-08 2022-03-24 リサーチ アンド ビジネス ファウンデーション ソンギュンクァン ユニバーシティ Ｔｏｌｌ－ｌｉｋｅ受容体７または８アゴニストとコレステロールの結合体およびその用途
US11433142B2 (en) 2020-03-23 2022-09-06 Hdt Bio Corp. Compositions and methods for delivery of RNA-lipid nanoparticle complexes encoding for viral RNA polymerase region and protein antigen
JP2022548733A (ja) * 2019-09-19 2022-11-21 ダンマルクス テクニスケ ウニベルシテット 免疫を刺激するミセル組成物
WO2023048760A1 (fr) * 2021-09-22 2023-03-30 Hdt Bio Corp. Vaccins à arn contre des maladies infectieuses
CN116162088A (zh) * 2022-12-14 2023-05-26 江苏省农业科学院 一种Toll样受体7激动剂纳米颗粒及其制备方法与应用
US11679163B2 (en) 2019-09-20 2023-06-20 Hdt Bio Corp. Compositions and methods for delivery of RNA
WO2024159157A3 (fr) * 2023-01-27 2024-09-06 Corner Therapeutics, Inc. Analogues phospholipidiques pour l'hyperactivation de cellules dendritiques de mammifères
US12233160B2 (en) 2021-09-22 2025-02-25 Hdt Bio Corp. Dried nanoparticle compositions
US12257299B2 (en) 2021-09-22 2025-03-25 Hdt Bio Corp. SARS-CoV-2 RNA vaccine compositions and methods of use
US12485163B2 (en) 2024-03-15 2025-12-02 Hdt Bio Corp. Cancer therapy compositions and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110009157A (ko) * 2008-04-16 2011-01-27 글락소스미스클라인 바이오로지칼즈 에스.에이. 백신

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110009157A (ko) * 2008-04-16 2011-01-27 글락소스미스클라인 바이오로지칼즈 에스.에이. 백신

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BACHELDER, ERIC M. ET AL.: "In Vitro Analysis of Acetalated Dextran Microparticles as a Potent Delivery Platform for Vaccine Adjuvants", MOLECULAR PHARMACEUTICS, vol. 7, no. 3, 2010, pages 826 - 835, XP055537339 *
CHEN, QIAN ET AL.: "Photothermal Therapy with Immune-adjuvant Nanoparticles Together with Checkpoint Blockade For Effective Cancer Immunotherapy", NATURE COMMUNICATIONS, vol. 7, 21 October 2016 (2016-10-21), pages 1 - 13, XP055537345 *
HEO, MIN BEOM ET AL.: "Programmed Nanoparticles for Combined Immunomodulation, Antigen Presentation and Tracking of imminunotherapeutic Cells", BIOMATERIALS, vol. 35, 2014, pages 590 - 600, XP028762522 *
LIN, WENJING ET AL.: "Co-delivery of Imiquimod and Plasmid DNA via an Amphiphilic pH-responsive Star Polymer that Forms Unimolecular Micelles in Water", POLYMERS, vol. 8, 2016, pages 1 - 1 7, XP055537349 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022519705A (ja) * 2019-02-08 2022-03-24 リサーチ アンド ビジネス ファウンデーション ソンギュンクァン ユニバーシティ Ｔｏｌｌ－ｌｉｋｅ受容体７または８アゴニストとコレステロールの結合体およびその用途
JP7287708B2 (ja) 2019-02-08 2023-06-06 プロジェニア インコーポレイテッド Ｔｏｌｌ－ｌｉｋｅ受容体７または８アゴニストとコレステロールの結合体およびその用途
US12318481B2 (en) 2019-09-19 2025-06-03 Danmarks Tekniske Universitet Immune stimulating micelle composition
JP2022548733A (ja) * 2019-09-19 2022-11-21 ダンマルクス テクニスケ ウニベルシテット 免疫を刺激するミセル組成物
JP7662206B2 (ja) 2019-09-19 2025-04-15 ダンマルクス テクニスケ ウニベルシテット 免疫を刺激するミセル組成物
US11679163B2 (en) 2019-09-20 2023-06-20 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11534497B2 (en) 2020-03-23 2022-12-27 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11648322B2 (en) 2020-03-23 2023-05-16 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11648321B2 (en) 2020-03-23 2023-05-16 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11654200B2 (en) 2020-03-23 2023-05-23 Hdt Bio Corp. Compositions and methods for delivery of RNA
US12433957B2 (en) 2020-03-23 2025-10-07 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11559584B2 (en) 2020-03-23 2023-01-24 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11458209B2 (en) 2020-03-23 2022-10-04 Hdt Bio Corp. Compositions and methods for delivery of nucleic acid-lipid nanoparticle complexes encoding for viral RNA polymerase region and protein antigen
US11752218B2 (en) 2020-03-23 2023-09-12 Hdt Bio Corp. Nucleic acid-small diameter and liquid core nanoparticle complexed compositions
US11896677B2 (en) 2020-03-23 2024-02-13 Hdt Bio Corp. Compositions and methods for delivery of RNA
US11433142B2 (en) 2020-03-23 2022-09-06 Hdt Bio Corp. Compositions and methods for delivery of RNA-lipid nanoparticle complexes encoding for viral RNA polymerase region and protein antigen
US12133894B2 (en) 2020-03-23 2024-11-05 Hdt Bio Corp. Compositions and methods for delivery of RNA
WO2023048760A1 (fr) * 2021-09-22 2023-03-30 Hdt Bio Corp. Vaccins à arn contre des maladies infectieuses
US12257299B2 (en) 2021-09-22 2025-03-25 Hdt Bio Corp. SARS-CoV-2 RNA vaccine compositions and methods of use
US12233160B2 (en) 2021-09-22 2025-02-25 Hdt Bio Corp. Dried nanoparticle compositions
US12350329B2 (en) 2021-09-22 2025-07-08 Hdt Bio Corp. RNA vaccines against infectious diseases
CN116162088A (zh) * 2022-12-14 2023-05-26 江苏省农业科学院 一种Toll样受体7激动剂纳米颗粒及其制备方法与应用
WO2024159157A3 (fr) * 2023-01-27 2024-09-06 Corner Therapeutics, Inc. Analogues phospholipidiques pour l'hyperactivation de cellules dendritiques de mammifères
US12485163B2 (en) 2024-03-15 2025-12-02 Hdt Bio Corp. Cancer therapy compositions and uses thereof

Similar Documents

Publication Publication Date Title
WO2018147710A1 (fr) Nanoémulsion comprenant une matière à base d'imidazoquinoline et son utilisation
KR101996538B1 (ko) 이미다조퀴놀린계열 물질을 포함하는 나노에멀젼 및 이의 용도
EP2341933B1 (fr) Dérivés d'imidazoquinoléine lipidés
CN112672763B (zh) 用于能够调节免疫应答的含金属制剂的组合物和方法
WO2013032207A1 (fr) Pré-concentré lipidique à libération modifiée d'une substance pharmacologiquement active et composition pharmaceutique la comprenant
CA2840079C (fr) Compositions et methodes pour traiter la grippe
CA2549114C (fr) Composition immunostimulante comprenant au moins un agoniste du recepteur toll-like 7 ou toll-like 8 et un agoniste du recepteur toll-like 4
RU2733124C1 (ru) Мультидоменная везикула, содержащая материал, контролирующий иммуносупрессивный фактор, способ её производства и содержащая её иммуномодулирующая композиция
WO2003000232A2 (fr) Procede de preparation de vesicules chargees d'oligodeoxynucleotides immunostimulateurs (iss-odn) et utilisations diverses de celles-ci
US10973900B2 (en) Dried composition
WO2021177679A1 (fr) Nanoparticules mimétiques d'agent pathogène vivant basées sur un squelette de paroi cellulaire d'agent pathogène, et leur procédé de production
KR0178422B1 (ko) 한탄 바이러스의 펩타이드 항원을 함유하는 리포좀
WO2025159614A1 (fr) Nanostructure comprenant des peptides d'antigène associé au cancer conjugués à de l'acide désoxycholique et son utilisation
WO2025028832A1 (fr) Adjuvant immunitaire et composition de vaccin contenant des nanoparticules de poly-bêta-hydroxybutyrate
CN120529901A (zh) 用于哺乳动物树突状细胞超活化的磷脂类似物
KR0173366B1 (ko) B형 간염 바이러스의 펩타이드 항원을 함유하는 리포좀

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18750674

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019542161

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 3052940

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018218721

Country of ref document: AU

Date of ref document: 20180213

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2018750674

Country of ref document: EP