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WO2024229503A1 - Nanoémulsions d'huile de bois d'agar, procédés associés et leurs utilisations - Google Patents

Nanoémulsions d'huile de bois d'agar, procédés associés et leurs utilisations Download PDF

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Publication number
WO2024229503A1
WO2024229503A1 PCT/AU2023/050383 AU2023050383W WO2024229503A1 WO 2024229503 A1 WO2024229503 A1 WO 2024229503A1 AU 2023050383 W AU2023050383 W AU 2023050383W WO 2024229503 A1 WO2024229503 A1 WO 2024229503A1
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Prior art keywords
oil
water nanoemulsion
cancer
cells
cell
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English (en)
Inventor
Raniya MALIK
Yibei SHEN
Kamal Dua
Keshav Raj PAUDEL
Dinesh Kumar CHELLAPPAN
Thiagarajan MADHESWARAN
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Deaurora Pty Ltd
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Deaurora Pty Ltd
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Priority to AU2023447567A priority Critical patent/AU2023447567A1/en
Priority to PCT/AU2023/050383 priority patent/WO2024229503A1/fr
Publication of WO2024229503A1 publication Critical patent/WO2024229503A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/83—Thymelaeaceae (Mezereum family), e.g. leatherwood or false ohelo
    • A61K36/835—Aquilaria
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • Agarwood oil nanoemulsions methods pertaining to and uses thereof
  • This invention relates to an oil-in-water nanoemulsion comprising an extracted agarwood oil and a surfactant, wherein the oil-in-water nanoemulsion comprises particles comprising an extracted agarwood oil having specific size ranges.
  • This invention further relates to methods pertaining to and uses of the oil-in-water nanoemulsion comprising an extracted agarwood oil. Specifically, the ability to modulate several biological markers associated with diseases such as cancer, chronic inflammation and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Agarwood is an evergreen plant endemic to areas in south-east and subcontinental Asia.
  • An oil can be extracted from the plant, for example by various distillation methods.
  • the oil extracted from some agarwood pants has been previously described as biologically active but there are significant barriers to formulating this oil in a way suitable for administration to a patient and to be taken into biological tissues.
  • Inflammation refers to an evolutionarily conserved process that involves the activation of both immune and non-immune cells. It is characterized symptoms which can include redness, pain, swelling, heat, and loss of physiological function. The pathophysiological reasoning behind these signs and symptoms is modulated by complex biological processes that occur seconds to hours following exposure to causative factors that can be any external stimulus like pathogens, allergens, toxic materials, or foreign bodies, or it may be an internal stimulus due to some impairment in tissue functioning.
  • such an inflammatory response can help defend the host from viruses, bacteria, toxins (such as inhalants used to deliver pharmaceutically active material), and infections via the elimination of pathogens, thereby promoting tissue repair and healing.
  • the impending injury can be effectively minimized, thereby facilitating the restoration of tissue homeostasis, leading to the subsequent resolution of acute inflammatory processes.
  • inflammation if inflammation remains uncontrolled or unresolved, it may lead to chronic inflammatory responses that occur well beyond the presence of the causative stimuli and lead to development of conditions such as various cancers and chronic obstructive pulmonary inflammation disorder (COPD).
  • COPD chronic obstructive pulmonary inflammation disorder
  • Cancers such as lung cand breast cancers, are a diverse set of diseases with complex aetiologies. Patient prognosis is variable and remains poor for sub-sets of the population.
  • an oil-in-water nanoemulsion comprising an extracted agarwood oil and a surfactant where the oil-in-water nanoemulsion comprises particles comprising an extracted agarwood oil, where the particles have a specific ranges of diameter have significant activity for several biological markers associated with cancers and conditions associated with inflammation such as COPD.
  • the nanoemlustion of these specific parameters may improve cell permeation and uptake to enable delivery of the extracted agarwood oil. Without wishing to be bound by theory, this improvement may be due to improved water solubility, cellular uptake and possibly bioavailability and pharmacokinetic profile.
  • the extracted agarwood oil can be obtained from plant stock in a manner than can be considered sustainable.
  • the extraction is by a distillation process that does not involve the resources typically associated with complex synthetic biological or chemical processes.
  • the invention provides a n oil-in-water nanoemulsion comprising a continuous aqueous phase, a surfactant, and a particulate oil phase, wherein the particulate oil phase is dispersed within the aqueous phase, wherein the particulate oil phase comprises particles comprising extracted agarwood oil having a diameter in the range of about and including 160 nm to about 200 nm.
  • the particles have a diameter in the range of about and including 165 nm to about 195 nm. In some embodiments the particles have a diameter in the range of about and including 170 nm to about 190 nm. In some embodiments the particles have a diameter in the range of about and including 175 nm to about 185 nm. In some embodiments the particles have a diameter in the range of about and including 182 nm to about 178 nm. In some embodiments, the particles have a diameter of about 180 nm.
  • these particle sizes range may aid in the improvements of water solubility and cellular uptake.
  • the particles have a substantially spherical morphology.
  • the oil-in-water nanoemulsion has a polydispersity index in the range of about and including 0.30 to about 0.40. In some embodiments the oil-in-water nanoemulsion has a polydispersity index in the range of about and including 0.32 to about 0.38. In some embodiments the oil-in-water nanoemulsion has a polydispersity index of about 0.36.
  • the surfactant is a non-ionic surfactant.
  • the non-ionic surfactant is a Poloxomer.
  • the Poloxomer is Poloxomer 407.
  • the surfactant is present in a concentration of between and including about 1.5 to 3.5 mg/mL. In some embodiments the surfactant is present in a concentration of between and including about 2.0 mg/mL to 3.0 mg/mL. In some embodiments the surfactant is present in a concentration of between and including about 2.5 mg/mL.
  • the extracted agarwood oil is present in the nanoemulsion in a concentration of between and including about 5 mg/mL to about 15 mg/mL. In some embodiments the extracted agarwood oil is present in the nanoemulsion is present in the nanoemulsion in a concentration of about 7 mg/mL to about 13 mg/mL. In some embodiments the extracted agarwood oil is present in the nanoemulsion is present in the nanoemulsion in a concentration of about 10 mg/mL.
  • the an extracted agarwood oil comprises about 12.31 ⁇ 5 percentage weight valerianol, about 8.03 ⁇ 2 percentage weight gamma-eudesmol, about 3.71 ⁇ 1 percentage weight epi-cyclocolorenone, about 3.71 ⁇ 1 percentage weight nootkatone, about 3.69 ⁇ 1 percentage weight beta-eudesmol, about 3.02 ⁇ l percentage weight methyl phenethyl ketone, about 2.90 ⁇ l percentage weight 10-epi-gamma-eudesmol, about 1.74 ⁇ 0.5 percentage weight hinesol, about 1.6810.5 percentage weight dihydro-columellarin, about 0.8810.25 percentage weight alpha-curcumene, about 0.8510.25 percentage weight alpha- humulene, about 0.5610.1 percentage weight alpha-bulnesene, about 0.4510.1 percentage weight Selina-4, 11-diene, about 0.3810.1 percentage weight debromofiliformin, about 0.2610.05 percentage weight 4,5-di-epi-Aristolochene,
  • the invention provides a method of inhibiting transcription of a pro-inflammatory cytokine in at least one cell exposed to an inflammation inducer comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the pro-inflammatory cytokine is IL-8.
  • the invention provides a method of inhibiting protein expression of pro-inflammatory mediators and/or cytokines in at least one cell exposed to an inflammation inducer comprising administering to the cells an effective amount of the oil-in- water nanoemulsion hereinbefore described.
  • the pro-inflammatory mediators and/or cytokines are selected from the list consisting of IL-la, I L-ip, IL-IRa and GDF-15.
  • the invention provides a method of stimulating protein expression of anti-inflammatory mediators in at least one cell exposed to an inflammation inducer comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the anti-inflammatory mediators are selected from the list consisting of IL-10, IL-18Bpa, GH, VDBP, relaxin-2, 1 FN-y, PDGF-BB and TFF3.
  • the invention provides a method of stimulating transcription of antioxidant genes in at least one cell exposed to an inflammation inducer comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the antioxidant gene is GCLA or GSTP1.
  • the invention provides a pro-survival gene in at least one cell exposed to an inflammation inducer comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the pro-survival gene is PI3K.
  • the inflammation inducer is a respiratory drug deliverer.
  • the respiratory drug deliverer is cigarette smoke, vaporizer liquid or cigarette smoke extract (CSE).
  • the invention provides a method of suppressing cell proliferation and/or colony formation comprising administering to the cell an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the cell proliferation and/or colony formation is associated with lung cancer activity.
  • the cell proliferation associated with lung cancer activity is A549.
  • the invention provides a method of stimulating expression of a tumour suppressor gene in at least one cell comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • tumour suppressor gene is p53.
  • the invention provides a method of inhibiting expression of a protein involved in cancer cell migration in at least one cell comprising administering to the cells an effective amount of the oil-in-water nanoemulsion of hereinbefore described.
  • the cancer cell is A549.
  • the protein involved in cancer cell migration is selected from the list consisting of cathepsin B, cathepsin D, cathepsin S and cathepsin G.
  • the invention provides a method of inhibiting expression of a cancer associated gene in at least one cell comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the cancer associated gene is KRAS or EGFR.
  • the invention provides a method of inhibiting expression of a cancer associated protein in at least one cell comprising administering to the cells an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the cancer associated protein is selected from the list consisting of Dkk-1, vimentin, GM-CSF, survivin, amphiregulin and urokinase.
  • the methods hereinbefore described are performed in vivo or in vitro.
  • nanoemulsion hereinbefore described is administered to a human.
  • the invention provides a method for the treatment and/or prevention of a condition associated by chronic inflammation, comprising administering to a subject in need thereof an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • condition is associated with a change in expression or transcription are selected from the following list consisting of IL-8, IL-la, I L-ip, IL-IRa, GDF- 15, IL-10, IL-18Bpa, GH, VDBP, relaxin-2, IFN-y, PDGF-BB, TFF3, GCLA, GSTP1 and PI3K.
  • condition is COPD or a disease associated with chronic exposure to an inflammation inducer.
  • the invention provides a use of the oil-in-water nanoemulsion of hereinbefore described in the manufacture of a medicament for the treatment and/or prophylaxis for the treatment and/or prevention of a condition medicated by chronic inflammation.
  • condition is associated with a change in expression or transcription are selected from the following list consisting of L-8 IL-la, I L-ip, IL-IRA GDF-15 IL-10, IL-18Bpa, GH, VDBP, relaxin-2, IFN-y, PDGF-BB, TFF3, GCLC, GSTP1 and PI3K.
  • condition is COPD or a disease associated with chronic exposure to an inflammation inducer.
  • the invention provides a method for the treatment and/or prevention of cancer comprising administering to a subject in need thereof an effective amount of the oil-in-water nanoemulsion hereinbefore described.
  • the cancer is associated with a change in expression of the following list consisting of p53, KRAS and EGFR.
  • treatment of the cancer is associated with inhibition of expression of the proteins selected from the list consisting of casthespins B, casthespins D, casthespins S, casthespins G, Dkk-1, vimentin, GM-CSF, survivin, amphiregulin and urokinase.
  • the cancer is lung cancer or breast cancer.
  • the invention provides a use of the oil-in-water nanoemulsion hereinbefore described in the manufacture of a medicament for the treatment and/or prophylaxis for the treatment and/or prevention cancer.
  • cancer is associated with a change in expression or transcription of the following selected from the list consisting of p53, KRAS and EGFR.
  • the cancer is lung cancer or breast cancer.
  • the invention provides methods or uses hereinbefore described which are conducted using the oil-in-water nanoemulsion corresponding to less than and including about 100 pg/mL. In some embodiments the method or use is conducted using the oil-in-water nanoemulsion corresponding to up to and including about 50 pg/mL. In some embodiments the method or use is conducted using the oil-in-water nanoemulsion corresponding to between and including about 25 pg/mL to about 50 pg/mL. In some embodiments methods or uses hereinbefore described are conducted using the oil- in-water nanoemulsion at a concentration of about 25 pg/mL or about 50 pg/mL.
  • Figure 1 is a chart showing the that the oil-in-water nanoemulsion comprising an extracted agarwood oil is well tolerated in 5% CSE-induced BCi-NSl.l cells.
  • BCi-NSl.l cells were pre-incubated for 1 h in the presence of increasing concentrations of agarwood-NE (10, 50, 100, 500, or 1000 pg/mL), followed by exposure to 5% CSE for 24h.
  • MTT assay was used to measure cell viability.
  • Cell viability was normalised as a percentage compared to untreated control. The results are mean ⁇ SEM of 3 independent experiments (****; p ⁇ 0.0001).
  • Figure 2 is a chart showing Inhibition of transcription of pro-inflammatory cytokines by the oil-in-water nanoemulsion comprising an extracted agarwood oil in cells exposed to an inflammation inducer.
  • BCi-NSl.l cells were pre-incubated for 1 h in the presence of 25 and 50 pg/mL the oil-in-water nanoemulsion comprising an extracted agarwood oil, followed by exposure to 5% CSE for 24h.
  • Figure 3 is a chart showing inhibition of protein expression of pro-inflammatory cytokines and mediators by the oil-in-water nanoemulsion comprising an extracted agarwood oil in cells exposed to an inflammation inducer.
  • BCi-NSl.l cells were pre-incubated for 1 h in the presence of 25 and 50 pg/mL the oil-in-water nanoemulsion comprising an extracted agarwood oil, followed by exposure to 5% CSE for 24 h.
  • the protein levels of IL-la (A), I L-ip (B), IL-IRa (C), and GDF-15 (D) were determined via human cytokine protein array.
  • Figure 4 is a chart showing stimulation of protein expression of anti-inflammatory mediators by the oil-in-water nanoemulsion comprising an extracted agarwood oil in cells exposed to an inflammation inducer.
  • BCi-NSl.l cells were pre-incubated for 1 h in the presence of 25 and 50 pg/mL agarwood-NE, followed by exposure to 5% CSE for 24 h.
  • the protein levels of IL-10 (A), IL-18Bpa (B), GH (C), VDBP (D), relaxin-2 (E), I FN-y (F), PDGF-BB (G), and TFF3 (H) were determined via human cytokine protein array.
  • Figure 5 is a chart showing stimulation of transcription of antioxidant genes by the oil-in-water nanoemulsion comprising an extracted agarwood oil in cells exposed to an inflammation inducer.
  • BCi-NSl.l cells were pre-incubated for 1 h in the presence of 25 and 50 pg/mL the oil-in-water nanoemulsion comprising an extracted agarwood oil, followed by exposure to 5% CSE for 24 h.
  • Figure 6 is a chart showing stimulation of transcription of a pro-survival gene by the oil-in-water nanoemulsion comprising an extracted agarwood oil in cells exposed to an inflammation inducer.
  • BCi-NSl.l cells were pre-incubated for 1 h in the presence of 25 and 50 pg/mL the oil-in-water nanoemulsion comprising an extracted agarwood oil, followed by exposure to 5% CSE for 24 h.
  • Figure 7 is a photograph showing surpressed cell migration of A549 cells using the oil-in-water nanoemulsion comprising an extracted agarwood oil.
  • A549 cells were seeded at low density before adding the nanoemaulsion and growing for 10-14 days at 25 and 50 pg/mL. The sample were then stained with crystal violet to enable visualisation versus a control.
  • Figure 8 is a chart showing the effect of the oil-in-water nanoemulsion comprising an extracted agarwood oil on human lung adenocarcinoma cells (A549) cell proliferation.
  • A549 cells were seeded in a growth medium and the nanoemulsion was added at lpg/mL, 5, pg/mL 10 pg/mL, pg/mL 25 pg/mL and 50 pg/mL concentrations.
  • the oil-in-water nanoemulsion comprising an extracted agarwood oil significantly decreased A549 cell proliferation in a dose dependent manner versus a control.
  • Figure 9 is a chart showing the effect of the oil-in-water nanoemulsion comprising an extracted agarwood oil on mRNA gene expression was measured in A549 cells. This chart shows an increase in the suppressor p53 gene at 25 and 50 pg/mL concentrations versus a control.
  • Figure 10 is a chart showing the effect of the oil-in-water nanoemulsion comprising an extracted agarwood oil on mRNA gene expression was measured in A549 cells. This chart shows and decrease in the expression of KRAS and EGFR proteins at 25 and 50 pg/mL concentrations versus a control.
  • Figure 11 is a chart showing the effect A549 cells incubated with the oil-in-water nanoemulsion comprising an extracted agarwood oil 25 pg/mL and 50 pg/mL concentrations versus a control.
  • This chart shows a decrease in expression of casthespin B, casthespins D, casthespins S and casthespins G at 25 pg/mL and 50 pg/mL concentrations versus a control.
  • Figure 12 is a photograph showing that the nanoemulsion comprising an extracted agarwood oil was then added at 25 pg/mL and 50 pg/mL concentrations versus a control significantly decreases A549 cell migration over 24 to 48 hours.
  • Figure 13 is a chart showing inhibition of expression of the proteins Dkk-1, vimentin and CM-CSF using the nano emulsion comprising an extracted agarwood oil at 25 pg/mL and 50 pg/mL concentrations versus a control significantly decreases A549 cell migration over 24 to 48 hours.
  • Figure 14 is a chart showing a decrease in expression of Dkk-1, vimentin and GM- CSF in A459 cells at 25 pg/mL and 50 pg/mL concentrations versus a control.
  • Figure 15 is a chart showing a decrease in expression of survivin, amphiregulin and urokinase in A459 cells at 5 pg/mL and 50 pg/mL concentrations versus a control.
  • the present invention relates to an oil-in-water nanoemulsion comprising an extracted agarwood oil and a surfactant.
  • nanoemulsion relates to are relatively kinetically stable oil-in-water dispersions with droplet sizes on the order of 100s of nm. Specifically, the size range of about and including 160 nm to about 200 nm is to be understood to fall within the meaning of this term.
  • an extracted agarwood oil includes an oil extracted from plants of the Aquilaria genus, such as the species including Aquilaria Sinesis, Aquilaria Crassna, Aquilaria acuminata, Aquilaria apiculate, Aquilaria baillonii, Aquilaria banaensis, Aquilaria beccariana, Aquilaria brachyantha, Aquilaria cumingiana, Aquilaria filaria, Aquilaria grandiflora, Aquilaria hirta, Aquilaria khasiana, Aquilaria malaccensis, Aquilaria macrocarpa, Aquilaria rostrata and Aquilaria subintegra.
  • the term "subject” shall be taken to mean any mammalian animal, including a human.
  • the term "preventing”, “prevent” or “prevention” includes providing prophylaxis with respect to occurrence or recurrence of a specified disease.
  • An individual may be predisposed to or at risk of developing the disease or relapse but has not yet been diagnosed with the disease or the relapse.
  • an “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
  • the desired result may be a therapeutic or prophylactic result.
  • An effective amount can be provided in one or more administrations.
  • the term “effective amount” is meant an amount necessary to effect treatment or prevention of a disease as described herein.
  • the term “effective amount” is meant an amount necessary to treat or prevent a given disease. The effective amount may vary according to the disease to be treated or factor to be altered and according to the weight, age, racial background, sex, health and/or physical condition and other factors relevant to the subject being treated.
  • the effective amount will fall within a relatively broad range (e.g., a "dosage" range) that can be determined through routine trial and experimentation by a medical practitioner. Accordingly, this term is not to be construed to limit the disclosure to a specific quantity.
  • the effective amount can be administered in a single dose or in a dose repeated once or several times over a treatment period.
  • treating include administering a therapeutic agent, for example, to thereby reduce or eliminate at least one symptom of a specified disease or to slow progression of the disease.
  • a protein or gene associated with cancer or chronic inflammation is one where a change in transcription or expression has been correlated to the aetiology or manifestation of symptoms or progression of the disease in question.
  • the invention relates to an oil-in-water nanoemulsion.
  • a nanoemulsion of this type typically is comprised of a continuous aqueous phase and a particulate oil phase which is dispersed throughout the continuous phase.
  • the dispersed particulate oil phase is comprised of discrete particles comprising the extracted agarwood oil.
  • the particles are typically substantial spherical and have a diameter in the ranges of about and including 160 nm to about 200 nm.
  • a surfactant is often required to stabilise an emulsion where the continuous phase is aqueous and having dispersed within the nanoparticles comprising an oil.
  • Stabilisation by the surfactant reduces the likelihood of separation of the nanoemlusion into a discrete aqueous phase and a hydrophobic phase.
  • the surfactant can be a non-ionic surfactant.
  • the non-ionic surfactant is a poloxamer.
  • Poloxamers are non-ionic surfactants of copolymers.
  • the structure of this copolymer includes a central hydrophobic chain with hydrophilic chains extending therefrom.
  • the general formula can be represented as follows:
  • the poloxamer is poloxamer 407 which has a polyoxypropylene molecular mass of 4000 g/mol and a 70% polyoxyethylene content.
  • the surfacing is present in an amount to stabilise the emulsion, such as in the amounts described herein.
  • COPD is a slow-developing, irreversible disease and causing approximately 3 million deaths per year.
  • the principal features of COPD are chronic airway inflammation leading to irreversible damage of the lung parenchyma. This results in mucus retention and severe airflow limitation that leads to symptoms such as progressive and irreversible hyperresponsiveness of the airways.
  • COPD is characterized by acute worsening of the disease's symptoms.
  • inflammation inducer used herein includes a respiratory drug deliverer, endemic pollution, industrial and work-place pollutants for example.
  • Respiratory drug deliverer can be for example, vaporiser liquid, cigarette smoke extract (CSE), cigarette smoke (CS), smoke associated with other tobacco-based products such as cigars, cigarillos, pipe tobacco and shisha. Additionally, this can be the smoke and/or vapours inhaled when administering other medical products, such as medical cannabis where legal.
  • CSE cigarette smoke extract
  • CS cigarette smoke
  • smoke associated with other tobacco-based products such as cigars, cigarillos, pipe tobacco and shisha. Additionally, this can be the smoke and/or vapours inhaled when administering other medical products, such as medical cannabis where legal.
  • Exposure to an inflammation inducer as described, such as CS, can include the promotion of the release of pro-inflammatory cytokines and mediators such as the interleukins (IL) IL-la, IL-ip, IL-8, IL-18, and growth/differentiation factor-15 (GDF15).
  • IL interleukins
  • GDF15 growth/differentiation factor-15
  • exposure to an inflammation inducer as described, such as CS can include inhibition of the release of anti-inflammatory cytokines such as IL-10.
  • GDF-15 has also been previously described to be a biomarker for COPD, and circulating GDF-15 to be increased in COPD patients when compared to healthy subjects.
  • Additional anti-inflammatory mediators are impacted by exposure to an inflammation induce, such as CS, to an inflammation inducer can include IL-18 binding protein (IL-18BP), growth hormone (GH), and vitamin D binding protein (VDBP).
  • IL-18BP is a protein which can act as an IL-18 decoy, blocking the IL-18-mediated inflammatory response. Expression of this is reduced in the alveolar macrophages of rats exposed to second-hand smoke.
  • GH is also to reprogram macrophages towards an anti-inflammatory, reparative phenotype, and chronic exposure to exposure to an inflammation inducer has been described as reducing circulating GH levels.
  • VDBP is has cytokine-like activity and is an important mediator of inflammatory tissue injury. VDBP levels are downregulated in the plasma of people exposed to an inflammation induce, such as smokers compared to non-smokers.
  • Platelet-derived growth factor is a family of proteins regulating inflammation in the airways.
  • PDGF-BB has a complex immunomodulatory role in many conditions including asthma, where it was shown to orchestrate lung tissue remodelling. It has been described to inhibit inflammatory responses during sepsis through the inhibition of pro-inflammatory cytokines including tumour necrosis factor-a (TNF-a), IL-6, IL-13, and IL-8.
  • TNF-a tumour necrosis factor-a
  • IL-6 IL-6
  • IL-13 IL-8.
  • relaxin-2 Another anti-inflammatory protein with a relevant role in lung health is relaxin-2, which was recently shown, in a guinea pig model of exposure to an inflammation induce, such as CS exposure, to counteract CS-induced inflammation, remodelling, and tissue damage when administered exogenously.
  • TFF3 neuropeptide trefoil factor 3
  • CS tissue damage by exposure to an inflammation induces, such as CS is caused by the direct induction of airway epithelial cell death, which is mediated by many mechanisms including inhibition of the protein arginine methyltransferase 6 (PRMT6)-phosphatidylinositol 3-kinase (PI3K)-Akt cell survival signalling pathway.
  • PRMT6 protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyltransferase 6
  • PI3K protein arginine methyl
  • ROS reactive oxygen species
  • nanoemulsion herein described is active for many of these biological markers associated with inflammation, including those brought about by an inflammation inducer, such as CS, as well as associated with COPD.
  • the inventors have demonstrated that the nanoemulsion herein described is effective in preventing colony formation and cell proliferation of human lung adenocarcinoma cells (A549).
  • the cell proliferation assay was displayed dose dependent behaviour. Additionally, migration in a wound healing assay has been demonstrated to be reduced for A549 cells.
  • the nanoemulsion herein described has been shown to promote expression of the p53 tumour suppressor gene. This gene has been implicated in supressing cancers that develop as tumours.
  • Ki-ras2 Kirsten rat sarcoma viral oncogene homolog is a gene that leads to expression of proteins involved in cell signalling pathways which have been described as controlling cell growth, cell maturation, and apoptosis. It has been linked with lung cancers such as non-small cell lung cancer.
  • Epidermal growth factor receptor EGFR
  • EGFR epidermal growth factor receptor
  • the protein Dickkopf-related protein 1 (Dkk-1) has been described as promoting migration and/or invasion of non-small cell lung cancer via the p-catenin signalling pathway. Vimentin is required for lung adenocarcinoma metathesis via heterotypic cell-cancer- associated fibroblast interactions during collective invasion.
  • Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been implicated in the development of lung cancer tumour development.
  • the cathespins are a group of proteases that have been implicated in the degradation of the extracellular matrix as well as causing cancer metathesis.
  • Survivin expression inhibition aids in slowing tumor growth of non-small-cell lung cancer in cell both in vivo and in vitro.
  • Amphiregulin promotes resilience to cancer therapeutics such as gefitinib in cancers such as non-small-cell lung cancers.
  • Urokinase has been implicated in cancer invasion and metathesis mechanisms for lung cancers such as non- small-cell lung cancers.
  • nanoemulsion hereinbefore described is active in inhibiting expression of these cancer associated proteins.
  • the plant material was chopped and ground into power and left to air dry for 14 days to reduce moist contents.
  • the essential oil was extracted from the dry agarwood powder through supercritical fluid carbon dioxide extraction at 0.005-0.006% per kg of raw agarwood powder. The extraction was performed at a pressure of 22 MPa and a temperature of 47 °C for 2 h, with a carbon dioxide fluid flow rate of 2 L/h. The separation was performed at 8 MPa and 40 °C.
  • the essential oil obtained appeared as a transparent, slightly viscous liquid, with a brown colour and a deep woody aroma.
  • the essential oil was soluble in alcohol and fixed oils and had the following typical composition (Table 1)
  • Table 1 A typical composition of an extracted agarwood oil
  • the coarse emulsion formed was subjected to probe sonication for 15 min at 80% amplitude in a 1 Hz on/off cycle to minimize heating. This resulted in the formation of a homogenised oil-in-water nanoemulsion, which was made up to a final volume of 20 mL by adding purified water.
  • the obtained oil-in-water nanoemulsion was characterized for size and polydispersity index (dynamic light scattering), and morphology (transmission electron microscopy).
  • the nanoemulsion was composed of droplets with substantially spherical morphology, of 180 ⁇ 4.7 nm diameter and 0.36 ⁇ 0.03 polydispersity index.
  • the polydispersity index measures the relative homogeneity of the particle sizes present in a given analyte.
  • BCi-NSl.1 Minimally immortalized human airway epithelium-derived basal cells ( BCi-NSl.1) were purchased from R. G. Crystal (Weill Cornell Medical College, New York, NY, USA). These cells were grown in broncho-epithelial basal media (BEBM) (Lonza, New York, NY, USA) supplemented with various growth factors and other supplements, including bovine pituitary extract, insulin, GA-1000 (Gentamicin sulfate-Amphotericin), retinoic acid, transferrin, triiodothyronine, epinephrine, human epidermal growth factor (BEGM Single Quots, Lonza), at 37 °C under humidified condition in the presence of 5% CO2.
  • BEBM broncho-epithelial basal media
  • GA-1000 Genetamicin sulfate-Amphotericin
  • retinoic acid transferrin
  • triiodothyronine e
  • the cells were seeded onto a 96-well plate (Corning, New York, NY, USA) or a 6-well plate (Corning) at a density of 1 x 104/well and 2 x 105/well, respectively. After 80% confluency, the cells were pre-treated for 1 h with agarwood-NE at the concentrations indicated, followed by the treatment of with or without 5% cigarette-smoke extract (CSE) for 24 h.
  • CSE cigarette-smoke extract
  • RNA pellets were washed 2x with 1 mL 75% ethanol.
  • the tubes were centrifuged again at 8000x g, 4 °C, for 5 min. After the second round of centrifugation, the ethanol was removed, and the dry RNA pellets were dissolved in nuclease-free water. Nanodrop (Thermo Fisher Scientific, Waltham, MA, USA) was used to determine the concentration and purity of the RNA.
  • M-MLV buffer Thermo Fisher Scientific
  • random primers 0.5 pg/pL
  • dNTPs 10 mM
  • DTT 100 mM
  • a thermal cycler Eppendorf, Hamburg, Germany
  • Equal amounts (25 ng) of cDNA were then subjected to real-time qPCR with iTaq Universal SYBR green (BioRad, Hercules, CA, USA) and primers (forward and reverse, 0.5 pM each) using a CFX96 PCR system (BioRad).
  • the real-time qPCR involved thermal cycles of 95 °C for 30 s (1 cycle), 95 °C for 15 s (40 cycles), and 60 °C for 30 s (1 cycle).
  • Equal amounts (300 pg) of protein were loaded onto human cytokine arrays and incubated overnight at 4 °C. Further incubation with antibodies and reagents were conducted in accordance with the manufacturer's instructions. The protein spots in the array were photographed using the ChemiDoc MP (Bio-Rad, Hercules, CA, USA) and analysed using Image J. (version 1.53c, Bethesda, MD, USA).
  • FIG. 4 The protein levels of the investigated anti-inflammatory cytokines and mediators are shown in Figure 4.
  • Treatment of BCi-NSl.l cells with 5% CSE caused a significant reduction of the protein levels of the following cytokines compared to untreated control: IL- 10 (13.3%, Figure 4A), IL-18 Bpa (18.9%, Figure 4B), growth hormone (GH, 14.5%, Figure 4C), vitamin D binding protein (VDBP, 7.3%, Figure 4D), relaxin-2 (14.0%, Figure 4E), interferon-y (IFN-y, 15.9%, Figure 4F), platelet-derived growth factor (PDGF-BB, 13.3%, Figure 4G), and trefoil factor 3 (TFF3, 17.5%, Figure 4H).
  • A549 cells were seeded at low density in a growth medium and the nanoemulsion was added at 25 pg/mL to 50 pg/mL concentration. The cells were then grown for 10 - 14 days and images taken of the cells to assess the cell migration. After the growing period, the samples were stained with crystal violet to enable visualisation.
  • the oil- in-water nanoemulsion comprising an extracted agarwood oil significantly decreased A549 cell migration at 25 pg/mL and 50 pg/mL concentrations as can be seen in Figure 7.
  • the effect of the oil-in-water nanoemulsion comprising an extracted agarwood oil on human lung adenocarcinoma cells were conducted using a cell proliferation assay as described in the art.
  • A549 cells were seeded in a growth medium and the nanoemulsion was added at lpg/mL, 5, pg/mL 10 pg/mL, pg/mL 25 pg/mL and 50 pg/mL concentrations. After a period of growth, MTT was added and the absorbance was measured at 540 nm.
  • the oil-in-water nanoemulsion comprising an extracted agarwood oil significantly decreased A549 cell proliferation in a dose dependent manner versus a control as shown in Figure 8.
  • Statistical analysis was performed using 2-way ANOVA and Tukey multiple comparison.
  • mRNA gene expression was measured using qPCT in a manner similar to that already described.
  • A549 cells were seeded in 6 well plates with growth media. The cells were incubated for 24 hours with the oil-in-water nanoemulsion comprising an extracted agarwood oil and at 25 pg/mL and 50 pg/mL concentration. This was followed by RNA extraction, cDNA preparation and RT-CPR.
  • Figure 9 shows an increase in the p53 tumour suppression gene.
  • Figure 10 shows a decreased in both the KRAS and EGFR genes.
  • A549 cells were seeded in well plates and incubated with the oil-in-water nanoemulsion comprising an extracted agarwood oil 25 pg/mL and 50 pg/mL concentrations versus a control. After incubation for 24 hours, the proteins were extracted and quantified using an overnight incubation protein array blot. Chemidoc imaging of the blog was used to visualise the results.
  • Figure 11 shows a decrease in expression of casthespins B, casthespins D, casthespins S and casthespins G at 25 pg/mL and 50 pg/mL concentrations versus a control in A549 cells.
  • Figure 13 shows a decrease in expression of Dkk-1, vimentin and GM-CSF 25 pg/mL and 50 pg/mL concentrations versus a control in A549 cells.
  • Figure 14 shows a decrease in expression of survivin, amphiregulin and urokinase 25 pg/mL and 50 pg/mL concentrations versus a control in A549 cells.
  • A549 cell migration in a wound hearing / cell migration assay by the oil-in-water nanoemulsion comprising an extracted agarwood oil [0164] A549 cells were seeded in well plants in a growth media. A scraping tool was used to make wounds. The nanoemulsion comprising an extracted agarwood oil was then added at 25 pg/mL and 50 pg/mL concentrations versus a control. The cells were then allowed to migrate for 24 to 48 hours. Inspection was then performed using visual microscopy.
  • Figure 12 is a photograph showing that the nanoemulsion comprising an extracted agarwood oil was then added at 25 pg/mL and 50 pg/mL concentrations versus a control significantly decreases A549 cell migration over 24 to 48 hours.

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Abstract

Nanoémulsion huile dans eau comprenant une phase aqueuse continue, un tensioactif et une phase huileuse particulaire, la phase huileuse particulaire étant dispersée à l'intérieur de la phase aqueuse, la phase huileuse particulaire comprenant des particules comprenant de l'huile de bois d'agar extraite ayant un diamètre dans la plage d'environ et comprenant 160 nm à environ 200 nm.
PCT/AU2023/050383 2023-05-08 2023-05-08 Nanoémulsions d'huile de bois d'agar, procédés associés et leurs utilisations Pending WO2024229503A1 (fr)

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Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
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