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WO2025091065A1 - Composition de flavonoïde - Google Patents

Composition de flavonoïde Download PDF

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Publication number
WO2025091065A1
WO2025091065A1 PCT/AU2024/051100 AU2024051100W WO2025091065A1 WO 2025091065 A1 WO2025091065 A1 WO 2025091065A1 AU 2024051100 W AU2024051100 W AU 2024051100W WO 2025091065 A1 WO2025091065 A1 WO 2025091065A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
fatty acid
flavonoid
matrix
pinocembrin
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.)
Pending
Application number
PCT/AU2024/051100
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English (en)
Inventor
Alistair Cumming
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.)
Gretals Australia Pty Ltd
Original Assignee
Gretals Australia Pty Ltd
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 AU2023903533A external-priority patent/AU2023903533A0/en
Application filed by Gretals Australia Pty Ltd filed Critical Gretals Australia Pty Ltd
Publication of WO2025091065A1 publication Critical patent/WO2025091065A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K47/06—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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates generally to compositions for the delivery of a flavonoid to a human or other animal. More particularly, the compositions are used for application via routes that avoid first pass metabolism, such as via the buccal, sublingual, nasal, pharyngeal, routes.
  • Flavonoids a diverse class of polyphenolic compounds ubiquitously present in the plant kingdom, have garnered significant scientific interest due to their wide range of biological activities. Comprising over 6,000 identified structures, flavonoids can be further subdivided into several subclasses including flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones, based on variations in their central pyran ring.
  • flavonoids have been shown to modulate a multitude of signaling pathways, receptors, and enzymes. Their multifaceted interactions with the cellular machinery contribute to their antioxidative, anti-inflammatory, antiviral, and antitumoral properties.
  • the therapeutic utilization of flavonoids is not without challenges.
  • flavonoids Despite their promising in vitro activities, the in vivo bioavailability of flavonoids is often limited due to their extensive first-pass metabolism by the liver, leading to rapid conjugation, methylation, and excretion. Thus, while dietary consumption of flavonoids is associated with several health benefits, direct therapeutic applications often necessitate modifications to improve their pharmacokinetic profiles. In many cases, such modifications have an adverse effect on efficacy, or are otherwise not possible or practicable.
  • Flavonoids are typically obtained from low abundance natural sources, with the cost of isolating meaningful amounts of active often resulting in any therapeutic regime being prohibitively expensive.
  • the present invention provides a composition for delivering a flavonoid to a subject, the composition comprising: a flavonoid in combination with one or more of: a fatty acid, a solubility enhancer configured to increase the aqueous solubility of the fatty acid, and a matrix.
  • the fatty acid has a chain length of: between about 13 to 23 carbon atoms, or about 14 to 22 carbon atoms, or about 15 to 21 carbon atoms, or about 16 to 20 carbon atoms, or about 17 to 19 carbon atoms, or 18 carbon atoms.
  • the fatty acid is a dietary fatty acid.
  • the fatty acid is a monounsaturated fatty acid.
  • the fatty acid is a cis fatty acid
  • the double bond of the monounsaturated fatty acid is at or about midway along the carbon chain.
  • the fatty acid is an omega-9 fatty acid.
  • the omega-9 fatty acid is oleic acid.
  • the solubility enhancer is an emulsifier capable of emulsifying the fatty acid.
  • the solubility enhancer is a polymer.
  • the polymer is a polymer of ethylene oxide.
  • the solubility enhancer is polyethylene glycol
  • the PEG has a molecular weight or an average molecular weight of: between about 10 and 1000 Da, or between about 50 and 900 Da, or between about 100 and 800 Da, or between about 150 and 700 Da, between about 200 and 600 Da, or between about 300 and 500 Da, or about 400 Da.
  • the fatty acid and the solubility enhancer are provided as separate molecules, or combined in a single molecule.
  • the single molecule is formed by reaction of a fatty acid with a solubility enhancer at a ratio of about 1 : 1 , or another suitable ratio.
  • the single molecule is a PEG oleate.
  • the PEG oleate is PEG-7 oleate, PEG-8 oleate, PEG-9 oleate, PEG- 10 oleate, or PEG-11 oleate,
  • the matrix is a polymer or a biodegradable polymer.
  • the polymer or biodegradable polymer is an anionic or cationic polymer.
  • the matrix is stable under a physiological condition for less than about 20 minutes, including or absent any enzyme capable of breaking down the matrix.
  • the matrix is a gel or a hydrogel.
  • the matrix is positively charged at a physiological pH, including a pH between about 5.0 and 8.5. [031]. In one embodiment of the first aspect, the matrix is charged so as to bind a mucosal surface of a living animal or a cadaver animal, including the buccal, sublingual, pharyngeal, nasopharyngeal, pulmonary or nasal mucosa of an animal.
  • the matrix is configured to retain the flavonoid and the fatty acid therein and/or thereabout, and controllably release the flavonoid to a mucosa of an animal that is proximal to or in contact with the composition.
  • the matrix comprises an organic polymer.
  • the organic polymer is a polysaccharide.
  • the polysaccharide is a linear polysaccharide
  • the matrix is selected from a chitosan, an aminated cellulose, a starch, an alginate, a collagen, a gelatin, a chitin, a polylysine, a pollyallylamine, a polyethylenimine, a polyhydroxy alkanoate, a cellulose nanofiber, and a cellulose nanocrystal.
  • the flavonoid is a flavanone.
  • the flavanone has a chemical structure according to formula 1
  • R2’, R3, R3’, R4’, R5, R6, R7 are each independently: H,
  • O-CH3 a glucoside (including a rhamnosidoglucoside), or any other organic functional group.
  • R2’, R3, R3’, R4’, R5, R6, R7 are as follows:
  • the flavanone is dihydroxyflavanone and/or a (2S)-flavan-4-one, or a functional derivative thereof. [042]. In one embodiment of the first aspect, the flavanone is (2S)-5,7-dihydroxy-2- phenyl-2,3-dihydrochromen-4-one, or a functional derivative thereof.
  • the flavonoid is of the type naturally synthesized in a plant cell, although is not necessarily obtained from a plant cell.
  • the composition is formulated as a gel, a lozenge, a troche, a dragee, a viscous composition, a bioadhesive, a medication stick, a tablet, a capsule, a spray, or a slurry
  • the composition comprises a taste-masking agent, and/or a taste modifying agent, and/or a sweetener.
  • the present invention provides a method of administering a flavonoid to a subject in need thereof, or desirous thereof, the method comprising contacting the composition of any embodiment of the first aspect to a target issue of the body of the subject.
  • the target tissue is an external surface or an internal surface.
  • the external surface is a skin surface
  • the internal surface is a mucosal surface
  • the mucosal surface is a buccal, sublingual, pharyngeal, nasopharyngeal, pulmonary or nasal mucosal surface.
  • the step of contacting is for a period of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 minutes, or until the matrix of the composition has mostly or fully degraded. [051]. In one embodiment of the second aspect, the step of contacting comprises actuation of a dispenser about the surface, the dispenser comprising an outlet configured to direct the composition toward or onto the surface.
  • the method comprises causing the dispenser to release the composition via the outlet.
  • release of the composition is caused by decreasing the internal volume of a container holding the composition, compressing a flexible container holding the composition, or moving a plunger through a container holding the composition.
  • FIG. 2 shows chromatograms of (A) blank KBR, (B) pinocembrin spiked into KBR at 50 ng/mL (retention time: 3.8 min), and (C) a representative receptor chamber sample at 240.
  • FIG. 5 shows chromatograms of (A) blank plasma, (B) pinocembrin spiked into mouse plasma at 50 ng/mL (retention time: 3.8 min), and (C) a representative mouse plasma sample at 240 min post dose.
  • subject is used to refer to a member of an animal species of mammalian origin, including but not limited to, a mouse, a rat, a cat, a goat, sheep, horse, hamster, ferret, platypus, pig, a dog, a guinea pig, a rabbit and a primate, such as, for example, a monkey, ape, and human.
  • treat includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating clinical or symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms.
  • Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting recurrence of symptoms in patients that were previously asymptomatic for the disorder(s).
  • the present invention provides a composition for delivering a flavonoid to a subject, the composition comprising: a flavonoid in combination with one or more of: a fatty acid, a solubility enhancer configured to increase the aqueous solubility of the fatty acid, and a matrix.
  • the present invention is predicated at least in part on the inventors’ discovery that such a composition is useful for the delivery of a flavonoid across mucosal surfaces having a venous return that does not drain into the portal venous system.
  • the flavonoid may cross the mucosal surface and enter the general circulation without passing through the liver, thereby avoiding first pass metabolism.
  • avoidance of first pass metabolism allows for the use of lower amounts of flavonoid in a dosage form, or for less frequent dosing.
  • the need for less flavonoid to achieve useful plasma concentrations is advantageous where the cost of the active is a negative factor in a treatment decision.
  • the flavonoid of the present composition may be selected for any clinical, health, or lifestyle-related reason.
  • the aim of administration is to prevent or treat a condition, such as a disease or a disorder, in the subject.
  • the flavonoid is administered to improve function in an otherwise healthy subject.
  • Some subjects may seek administration of a flavonoid for reasons unrelated to health, and for some other perceived benefit.
  • flavonoid is intended to include flavanols, flavones, and flavanones.
  • the flavonoid is a flavanone, and in some embodiments a chiral flavanone existing as optical isomers, and in which case the flavanone may be either the D- isomeror the S-isomer.
  • an uneuqal mixture of the D-isomer and S-isomer is used, or a racemic mixture is used.
  • the S-isomer is used in the present compositions.
  • the flavonoid is the flavanone pinocembrin, or a modified form of pinocembrin.
  • pinocembrin is a naturally occurring compounding having a known safety profile.
  • the compound is not controlled to the extent that a medical practitioner must prescribe the compound.
  • the composition may comprise an effective amount of the flavonoid, having regard to the use of concern and the characteristics of the subject.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight of the subject to about 100 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.00001 mg/kg body weight to about 100 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.0001 mg/kg body weight to about 100 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.001 mg/kg body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound is of an amount from about 0.01 mg/kg body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.1 mg/kg (or 100 pg/kg) body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 1 mg/kg body weight to about 10 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 10 mg/kg body weight to about 100 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 2 mg/kg body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 3 mg/kg body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 4 mg/kg body weight to about 10 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 5 mg/kg body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 20, 30, 40, 50, or 60 mg/kg body weight to about 100 mg/kg body weight, including . According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 70 mg/kg body weight to about 100 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 80 mg/kg body weight to about 100 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 90 mg/kg body weight to about 100 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 90 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 80 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 70 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 60 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 50 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 40 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound is of an amount from about 0.000001 mg/kg body weight to about 30 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 20 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 10 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 1 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 0.1 mg/kg body weight.
  • the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 0.1 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 0.01 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 0.001 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 0.0001 mg/kg body weight. According to another embodiment, the effective amount of the flavonoid compound of the composition is of an amount from about 0.000001 mg/kg body weight to about 0.00001 mg/kg body weight.
  • the composition comprises flavonoid in an amount sufficient to achieve (in a single dosage form, or across multiple dosage forms) from 1 pg/kg/day to 25 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 1 pg/kg/day to 2 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 2 pg/kg/day to 3 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 3 pg/kg/day to 4 pg/kg/day.
  • the dose of the flavonoid compound of the pharmaceutical ranges from 4 pg/kg/day to 5 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 5 pg/kg/day to 6 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 6 pg/kg/day to 7 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 7 pg/kg/day to 8 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 8 pg/kg/day to 9 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 9 pg/kg/day to 10 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 1 pg/kg/day to 5 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 5 pg/kg/day to 10 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 10 pg/kg/day to 15 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 15 pg/kg/day to 20 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 25 pg/kg/day to 30 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 30 pg/kg/day to 35 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 35 pg/kg/day to 40 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 40 pg/kg/day to 45 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 45 pg/kg/day to 50 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 50 pg/kg/day to 55 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 55 pg/kg/day to 60 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 60 pg/kg/day to 65 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 65 pg/kg/day to 70 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 70 pg/kg/day to 75 pg/kg/day.
  • the dose of the flavonoid compound of the composition ranges from 80 pg/kg/day to 85 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 85 pg/kg/day to 90 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 90 pg/kg/day to 95 pg/kg/day. According to some other embodiments, the dose of the flavonoid compound of the composition ranges from 95 pg/kg/day to 100 pg/kg/day.
  • the amount flavonoid that can be included in the present composition generally ranges from generally about 0.001 mg/kg body weight to about 10 g/kg body weight.
  • dosage levels are based on a variety of factors, including the type of condition or disorder or other usage, the age, weight, sex, medical condition of the subject, the severity of the condition, the route and frequency of administration, and the particular flavonoid employed.
  • the dosage regimen may vary widely, but can be determined routinely by a physician or other health practitioner using standard methods, and having the benefit of the present specification. [072].
  • the fatty acid of the present composition is thought to function as a carrier, and possibly a permeation enhancer, which assists passage of the flavonoid through the relevant surface of the subject (such as the mucosa or the skin), and into the circulation.
  • the flavonoid may be simply mixed with the fatty acid to form a suspension and/or a solution.
  • this form of composition will be useful in delivery of flavonoid across the mucosa.
  • the flavonoid may be entrapped in fatty acid vesicles.
  • oleic acid vesicles may prepared using a film hydration method, whereby oleic acid and the flavonoid are dissolved or suspended in suitable solvent (such as methanol) followed by evaporation of solvent under vacuum using a rotary evaporator. The dried film is then hydrated at ambient temperature for several hours with phosphate buffer (pH 5.5). The prepared vesicular dispersion is sonicated to form the uniform size vesicular dispersion. Unentrapped flavonoid may be separated from the vesicle dispersion using gel chromatography (such as SephadexTM G-50). Vesicular compositions may be more applicable to transdermal applications.
  • the fatty acid is a dietary fatty acid.
  • dietary is used to mean that fatty acid is found in a food product such as fruits, vegetable oils, seeds, nuts, animal fats and fish oils.
  • dietary fatty acids may be subject to lower or no regulatory requirements for supply to the public.
  • Omega-9 fatty acids such as oleic acid
  • oleic acid are generally preferred given their natural abundance in plant sources such as olives. Consumers have a general familiarity with olive oil and similar products and may therefore more readily accept a flavonoid provided in that context.
  • the present composition may comprise a solubility enhancer to increase the aqueous solubility of the fatty acid.
  • the fatty acid which carries the flavonoid
  • the fatty acid will be exposed to an aqueous environment of the subject.
  • the composition is exposed the fluid bathing the mucosal cells, such fluid typically being a substantially aqueous solution of electrolytes, proteins, and carbohydrates.
  • the composition is for buccal or sublingual administration and in which case compatibility with the saliva is preferred.
  • the fatty acid (with flavonoid carried therein) may be rendered generally miscible with or dispersible within the saliva by way of the solubility enhancer.
  • the solubility enhancer has hydrophilic and hydrophobic regions and therefore able to interface with the fatty acid and an aqueous environment.
  • the solubility enhancer may be an emulsifier such as a polysorbate, carboxymethyl cellulose, sodium lauryl sulfate, glyceryl ester, and the like.
  • the solubility enhancer is “tunable” in so far as various forms are available so as to permit the selection of a species that is appropriate to the flavonoid and/or aqueous environment at hand.
  • Polymers having emulsification properties are useful in that regard given that shorter or longer forms of the polymer may be selected given the flavonoid and/or aqueous environment.
  • Polyethylene glycols are one genus of polymers with many available lengths that are useful in the present compositions.
  • compositions may further comprise a matrix.
  • a matrix may not be required given that the fatty acid (carrying the flavonoid) may rapidly absorb into at least the stratum comeum layer of the skin, and be retained therein.
  • the fluid overlaying the mucosal cells may undesirably wash away the composition thereby inhibiting contact of the flavonoid with the surface epithelium.
  • the matrix may mechanically retain the fatty acid and flavonoid, for example within voids or other structures. Alternatively, some type of physical force such as electrostatic attraction may be exploited to retain the fatty acid and flavonoid on or about the matrix.
  • the matrix will typically not function so as to sequester the flavonoid for an indefinite period given the need for the active to be released into the target tissue.
  • the fatty acid may be retained within the matrix, with the flavonoid being transported out of the fatty acid and into the target tissue along a concentration gradient.
  • a matrix may be poorly water soluble so as to avoid rapid degradation in the saliva or other aqueous fluid with which the composition contacts.
  • the matrix is water soluble to a limited extent so as to degrade over a predetermined time period. As will be appreciated, some degradation of the matrix may be desirable for the purpose of slowly releasing the fatty acid (with flavonoid) to provide a depot-effect.
  • the matrix may be configured to alter a pharmacokinetic parameter such as Tmax (time to peak plasma concentration), or AUC (area under the curve).
  • Degradation may also be desirable given that the composition should not remain in or on the body of the subject indefinitely.
  • the composition should dissolve much like a lozenge when the flavonoid has been effectively delivered to the mucosa. Absent any degradation, the subject would be forced to remove the spent matrix from the mouth, or to swallow it.
  • Degradation may be achieved by means other than dissolution.
  • the matrix may be configured to be susceptible to breakdown by resident enzymes.
  • the oral cavity comprises amylases, and in that context a starch-based matrix may be suitably susceptible to enzyme-based degradation.
  • the matrix may be generally inert in so far as no material leaches from it.
  • the matrix may also be generally biocompatible so as to not trigger any undesirable biological process such as an immune or an inflammatory response.
  • materials of a natural origin i.e. obtained from a plant or an animal or the earth may be preferable.
  • the present composition may be washed away by saliva or some other fluid when contacted with the target tissue.
  • the matrix may be configured to maintain contact with the target tissue.
  • the matrix may be positively charged under physiological conditions, for example, so as to be electrostatically attracted to a negatively charged buccal or sublingual epithelium.
  • the pH of buccal, nasal, pulmonary and pharyngeal cavities differ (varying between about 5.0 and 8.5) and accordingly, the matrix may be selected for an ability to be appropriately charged at the pH of the relevant cavity.
  • the matrix may consist of or comprise a bioadhesive configured to adhere to the target tissue, and in which case mucoadhesion may be employed.
  • Mucoadhesion arises from contact between mucins of the mucosa and the mucoadhesive (typically comprising polymers). Hydration (typically by the saliva) is important in consolidating the mucoadhesive joint. Formation of the joint involves the penetration of the polymer chains of the adhesive into the mucus layer and generation of polymer-mucin bonding arising from weak bonding, van der Waals forces, hydrogen bonding and electrostatic interactions.
  • the adhesive polymers typically possess a high number of functional groups, as hydroxyl groups or unionized carboxylate groups, capable of participating in weak bonding. The molecular weight of the polymers, and the polymer chain flexibility may be manipulated to facilitate penetration of polymer chains into the mucus, to provide a suitable level of hydration and entanglement with mucins.
  • Chitosan is a natural polysaccharide derived from the shell of crustaceans that has been found useful as a matrix where the target tissue is the buccal or sublingual mucosa.
  • the fatty acid and flavonoid are retained by the chitosan, with the overall complex having a net positive charge.
  • the amino group in chitosan has a pKb value of ⁇ 6.5, resulting significant protonation in solution, increasing according to a decrease in pH. This affords chitosan a bioadhesive property, allowing it to bind to negatively charged mucosal membranes.
  • the free amine groups on chitosan chains can form crosslinked polymeric networks with dicarboxylic acids to afford some mechanical properties which may give the composition some three-dimensional form as well as retaining any fatty acid and flavonoid.
  • the function of the matrix is fulfilled by pharmaceutical excipients such as binders, fillers, disintegrants and the like.
  • pharmaceutical excipients such as binders, fillers, disintegrants and the like.
  • Such compositions may be deposited in the buccal cavity, for example, with saliva causing the composition to decompose so as to expose and release the flavonoid into the cavity which in turn contacts the buccal mucosa.
  • compositions may take the form of a pharmaceutical composition or a single unit dosage form comprising a flavonoid.
  • Individual dosage forms of the invention may be suitable for mucosal (including sublingual, buccal, rectal, pulmonary, nasal, or vaginal), transdermal, or topical administration.
  • Pharmaceutical compositions and dosage forms of the invention typically also comprise one or more pharmaceutically acceptable excipients. Sterile dosage forms are also contemplated.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays, nebulizers or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; and solids that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-
  • the composition may comprise one or more compounds that control the rate by which the dosage form will decompose.
  • Such compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions of the invention that are suitable for oral administration (and be retained in the buccal cavity or sublingually) can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of flavonoid.
  • Typical oral dosage forms of the invention are prepared by combining the flavonoid in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous buccal and sublingual dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre -gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), macrocrystalline cellulose, and mixtures thereof.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre -gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AV1CEL-PH-101, AVTCEL-PH-103 AVICEL RC-581, AVICEL-PH- 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain an excess of disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre -gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, co oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • calcium stearate e.g., magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc
  • hydrogenated vegetable oil e.g., peanut oil, cottonseed oil
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O- SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
  • CAB-O- SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • the flavonoid used in the methods of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566.
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release. [102].
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.giller adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Transdermal dosage forms may be used. Such forms include "reservoir type” or
  • matrix type patches which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal and topical dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend oa the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl pal itate, mineral oil, and mixtures thereof.
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; ollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysoibate 80) and Span 60 (sorbitan monostearate).
  • Topical dosage forms may be used. Such forms include, but are not limited to, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art.
  • Mucosal dosage forms may be used which include, but are not limited to, ophthalmic solutions, sprays and aerosols.
  • Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • the flavonoid and/or the formulation and/or the dosage form is/are selected so as to limit or obviate first-pass metabolism of the flavonoid in the liver and/or facilitate passage (active or otherwise) across the blood-brain barrier.
  • the composition may be contacted to the target tissue in any appropriate manner. Where the composition is solid or semi-solid, the composition may be manually deposited into a relevant cavity (such as the mouth or the rectum) having the target tissue. Where the composition is flowable, the composition may be provided in a tube or a syringe-like contrivance and dispensed onto the target tissue. Where the composition is applied to the skin, the composition may be manually spread over the skin surface to facilitate absorption.
  • compositions may be administered to a subject for any reason, including in a method for treating or preventing a disease or a disorder, or for generally improving health.
  • a flavonoid can be used to treat or prevent a fibrotic condition, such as pulmonary fibrosis (including idiopathic pulmonary fibrosis, infection-induced pulmonary fibrosis, radiation-induced pulmonary fibrosis, progressive massive fibrosis, cystic fibrosis), pancreatic fibrosis (including cystic fibrosis), retropertinoneal fibrosis, hepatic fibrosis (including bridging fibrosis and cirrhosis), arterial fibrosis (including arterial stiffness), intestinal fibrosis (including Crohn’s disease), joint fibrosis (including athrofibrosis of the knee, shoulder and other joints, adhesive capsulitis), manual/digital fibrosis (including Dupuytren’s contracture), dermal fibrosis (including keloid, nephrogenic systemic fibrosis, scleroderma), penis (including Peyronie’s
  • pulmonary fibrosis including idiopathic
  • Pinocembrin is also effective in treating or preventing inflammatory conditions such as pulmonary inflammation (including COPD, asthma, rhinitis, bronchitis), dermal inflammation (including acne and scleroderma), gastrointestinal inflammation (including celiac disase, Crohn’s disease, colitis, diverticulitis), autoimmune diseases (such as SLE), urinary system diseases (including glomerulonephritis, cystitis, protastitis), sarcoidosis, transplant rejection, vasculitis, atherosclerosis, pelvic inflammatory disease, rheumatic fever, and otitis.
  • Flavonoids have known efficacy in many other conditions including cancer, cardiovascular conditions (such as ischemia), neurological conditions (such as Alzheimer’s disease, Parkinson’s disease, and motor neurone disease) and infectious diseases.
  • Flavonoids have also non-therapeutic applications, for example to improve cognition, memory, mood, general wellbeing, and the like.
  • Pinocembrin (S-isomer) obtained from a Eucalyptus species) was then added to gel formulations to give a final mass of 1 mg of pinocembrin in 33.3 mg of gel for use in vitro and 1 mg of pinocembrin in 8 mg of gel for use in vivo.
  • Plasma samples were taken at 15, 30, 60, 120, 240 and 480 min after buccal application and immediately centrifuged at 14,000 xg for 5 min, followed by plasma collection. Plasma samples were stored at -20°C and pinocembrin concentration quantified by HPLC-UV.
  • Standard solutions and samples were then vortexed and proteins precipitated by the addition of 100 pL of acetonitrile and then vortexed a second time before centrifugation at 14,000 xg for 5 min. The supernatant was then removed and an aliquot of 50 pL injected onto the HPLC column. [122].
  • six independently prepared quality control (QC) samples were prepared in KBR or blank mouse plasma at concentrations of 50, 500 and 5000 ng/mL and quantified against a calibration curve ranging from 50-5000 ng/mL.
  • LC-20AD pumps a SIL-20 AHT autoinjector, a DGU-20A3 degasser, a DPD-20A UV-Vis detector (Shimadzu, Kyoto, Japan) with a DiscoveryTM Cl 8 HPLC Column (5 pm, 15 cm x 4.6 mm, Sigma-Aldrich, St Louis, MO) and a DiscoveryTM Guard cartridge holder (5 pm, 2 cm x 4 mm, Sigma-Aldrich, St Louis, MO).
  • a gradient method was used to elute pinocembrin with a gradient program of 0.01 - 0.50 min: 20% B; 0.50 - 4.00 min: 20-60% B; 4.00 - 4.50 min: 60-95% B; 4.50 - 4.55 min: 95% B; 4.55 - 6.00 min: 95-20% B; and 6.00 - 7.50 min: 20% B, at a flow rate of 1.5 mL/min with mobile phase A being 0.1% (v/v) formic acid in water and mobile phase B being 0.1% (v/v) formic acid in acetonitrile.
  • the column oven temperature was 40°C and pinocembrin eluted at 3.8 min with a detection at 288 nm.
  • mice Given that it was not possible to dose every mouse with exactly 8 mg of gel, all plasma concentrations were normalised to a nominal dose of 40 mg/kg.
  • the average amount of pinocembrin administered to mice was 38.8 mg/kg with chitosan-only gels and 39.1 mg/kg with chitosan/oleic acid/PEG400 gels.
  • the assay was therefore considered suitable for the quantification of pinocembrin in KBR collected from the receptor chamber of Ussing chambers following application of pinocembrin gel formulations. Representative chromatograms are shown in Figure 2.
  • EXAMPLE 8 Development and validation of a HPLC-UV assay for pinocembrin quantification in mouse plasma
  • pinocembrin When pinocembrin was administered in a chitosan gel containing oleic acid and PEG400, plasma concentrations were detected as early as 30 min post-dose, which also peaked at 4 h post-dose with concentrations of 10801.5 ⁇ 2391.0 ng/mL (mean ⁇ SD). Importantly, statistical analysis demonstrated that the area under the pinocembrin plasma concentration vs time curve was significantly higher when pinocembrin was administered in a chitosan gel containing oleic acid and PEG400 relative to the chitosan-only gel.
  • the area under the pinocembrin plasma concentration vs time curve values increased 1.95-fold in the presence of oleic acid and PEG400 with values of 26856.6 ⁇ 2550.1 ng.h/mL and 52403.8 ⁇ 4118.4 ng.h/mL without and with oleic and PEG400, respectively.
  • the percentage of pinocembrin applied to the buccal mucosa that had permeated the mucosa was significantly (p ⁇ 0.05) increased when the chitosan gel contained oleic acid and PEG400 in combination, relative to chitosan alone.
  • Pinocembrin (40 mg/kg) was then applied to the buccal mucosa of anaesthetised C57BL/6 mice in a chitosan-based gel with or without oleic acid (5% w/w) and PEG400 (5% w/w), and plasma concentrations determined over 8 h post-application using a validated HPLC assay.
  • Plasma concentrations of pinocembrin were detected from 30 min post-dose and peaked at 4 h (mean plasma concentrations of 6114.2 ⁇ 1762.1 ng/mL (mean ⁇ SD)). Incorporation of oleic acid and PEG400 to the chitosan buccal gel led to a 1.95- fold increase in area under the pinocembrin plasma concentration curve, with peak plasma concentrations also detected at 4 hpost-dose (10801.5 ⁇ 2391.0 ng/mL, mean ⁇ SD). These studies demonstrate that the buccal mucosa represents a suitable application site for the systemic delivery of pinocembrin, with oleic acid and PEG400 significantly improving buccal permeability of pinocembrin.

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Abstract

L'invention concerne une composition permettant d'administrer un flavonoïde à un sujet animal humain ou non humain, la composition comprenant : un flavonoïde tel que la pinocembrine en combinaison avec un ou plusieurs parmi : un acide gras, un activateur de solubilité configuré pour augmenter la solubilité aqueuse de l'acide gras, et une matrice.
PCT/AU2024/051100 2023-11-03 2024-10-18 Composition de flavonoïde Pending WO2025091065A1 (fr)

Applications Claiming Priority (2)

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AU2023903533 2023-11-03
AU2023903533A AU2023903533A0 (en) 2023-11-03 Flavonoid composition

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102198126A (zh) * 2011-05-04 2011-09-28 刘布鸣 治疗口腔及牙齿疾病的涂抹剂及其涂抹器
US20160361257A1 (en) * 2015-06-10 2016-12-15 Michael Farber Composition for increasing testosterone levels and enhancing libido
WO2019110099A1 (fr) * 2017-12-06 2019-06-13 Qrumpharma Inc. Formulation de clofazimine inhalable
WO2020169425A1 (fr) * 2019-02-19 2020-08-27 Hedera D.O.O. Extrait de propolis liquide, sa préparation et son utilisation
WO2022160018A1 (fr) * 2022-02-03 2022-08-04 MCCAFFREY, Stephen, Mark Pulvérisation nasale antivirale

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102198126A (zh) * 2011-05-04 2011-09-28 刘布鸣 治疗口腔及牙齿疾病的涂抹剂及其涂抹器
US20160361257A1 (en) * 2015-06-10 2016-12-15 Michael Farber Composition for increasing testosterone levels and enhancing libido
WO2019110099A1 (fr) * 2017-12-06 2019-06-13 Qrumpharma Inc. Formulation de clofazimine inhalable
WO2020169425A1 (fr) * 2019-02-19 2020-08-27 Hedera D.O.O. Extrait de propolis liquide, sa préparation et son utilisation
WO2022160018A1 (fr) * 2022-02-03 2022-08-04 MCCAFFREY, Stephen, Mark Pulvérisation nasale antivirale

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