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WO2024251923A1 - Compositions sans conservateur comprenant un complexe d'un corticostéroïde et d'une hpbcd pour le traitement ou la prévention d'une maladie inflammatoire par administration nasale - Google Patents

Compositions sans conservateur comprenant un complexe d'un corticostéroïde et d'une hpbcd pour le traitement ou la prévention d'une maladie inflammatoire par administration nasale Download PDF

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Publication number
WO2024251923A1
WO2024251923A1 PCT/EP2024/065683 EP2024065683W WO2024251923A1 WO 2024251923 A1 WO2024251923 A1 WO 2024251923A1 EP 2024065683 W EP2024065683 W EP 2024065683W WO 2024251923 A1 WO2024251923 A1 WO 2024251923A1
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WO
WIPO (PCT)
Prior art keywords
liquid composition
per day
treatment
prevention
hpbcd
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/EP2024/065683
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English (en)
Inventor
Paul Maes
William BIGAZZI
Natacha Rocks
Andreas Bilstein
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.)
Aquilon Pharmaceuticals
Original Assignee
Aquilon Pharmaceuticals
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Filing date
Publication date
Priority claimed from BE20235467A external-priority patent/BE1031693B1/fr
Priority claimed from BE20235466A external-priority patent/BE1031691B1/fr
Application filed by Aquilon Pharmaceuticals filed Critical Aquilon Pharmaceuticals
Publication of WO2024251923A1 publication Critical patent/WO2024251923A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K9/0043—Nose
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention relates to a liquid composition
  • a liquid composition comprising a complex of hydroxypropyl-beta-cyclodextrin (HPBCD) or derivatives thereof and a corticosteroid for use as a nasal spray in the treatment or prevention of inflammatory diseases.
  • HPBCD hydroxypropyl-beta-cyclodextrin
  • EP 1799231 to the University of Minnesota proposes the direct administration of cyclodextrins for the treatment of bronchial inflammatory diseases preferably asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • preservative-free nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • US2006120967 and US2006045850 to QPHARMA disclose nasal formulations of cyclodextrins comprising preservatives. However, the use of preservative-free nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • BE1029585 to Aquilon Pharmaceuticals discloses an inhalable composition comprising a complex of HPBCD and budesonide or ciclesonide for use in the topical prevention or topical treatment of viral respiratory diseases.
  • preservative free-nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • EP3151836 to the University of Minnesota and Paul Maes discloses the use of HPBCD in conjunction with the corticosteroid budesonide for the treatment and prevention of bronchial inflammatory diseases, preferably for chronic obstructive pulmonary disease, such as chronic bronchitis, obstructive bronchiolitis, emphysema, pulmonary fibrosis, cystic fibrosis and most preferably for tobacco-induced chronic obstructive pulmonary disease and cystic fibrosis disease.
  • preservative-free nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • EP 1894559 of Pari discloses several corticosteroids solubilized through cyclodextrins for the treatment of a long list of human diseases, comprising viral sinusitis.
  • EP1894559 teaches that the nasal administration requires a preservative to ensure its sterility after the withdrawal of a dose. Consequently, the use of preservative-free-nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • W02021001349 to Aquilon Pharmaceuticals discloses a liquid composition comprising one or more cyclodextrins or pharmaceutically acceptable derivatives thereof for use in the prevention or treatment of nasal inflammations, wherein the treatment or prevention of nasal inflammations is a topical treatment.
  • a preferred cyclodextrin is HPBCD.
  • preservative-free nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • WO2019067145 to ASDERA LLC discloses cyclodextrin compositions and methods that may be useful in the treatment and/or prevention of respiratory diseases, including, but not limited to the protection from virus or bacterial infections.
  • preservative- free-nasal sprays comprising HPBCD, and a corticosteroid is not disclosed.
  • a first aspect of the invention is a liquid composition for use as a nasal spray in the treatment or prevention of an inflammatory disease
  • liquid composition comprises a complex of a corticosteroid and hydroxypropyl-beta-cyclodextrin (HPBCD); and
  • preservative is selected from the group consisting of benzalkonium chloride, phenylethyl alcohol, benzyl alcohol, sodium benzoate, chlorbutanol, phenoxyethanol, cetrimide and 2- (ethylmercuriomercapto)benzoic acid sodium salt, sodium bisulfite, sodium bisulfate, sodium thiosulfate, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol hyaluronic acid, benzoic acid, potassium sorbate, and essential oils preferably from fruit extracts;
  • the composition comprises citric acid and/or natrium citrate as a pH buffer.
  • the composition has a pH from 2 to 8 , preferably from 3,5 to 6,5 and even more preferably from 4.0 to 5.5.
  • the viscosity of the liquid composition is in the range of about 0,01 mPa.s to about 10 mPa.s, preferably in the range of about 0,5 mPa.s to about 5 mPa.s and most preferably in the range from about 0,8 mPa.s to about 3 mPa.s at 20 °C as measured according to USP.
  • the corticosteroid is selected from the group consisting of ciclesonide, mometasone furoate, beclomethasone dipropionate, budesonide, and fluticasone propionate.
  • the liquid composition comprises HPBCD in an amount from 1 mg/ml to 100 mg/ml, preferably from about 5 mg/ml to about 80 mg/ml, even more preferably from 10 mg/ml to about 80 mg/ml.
  • the liquid composition comprises HPBCD in an amount from 8.00 mg/ml to 60 mg/ml.
  • the liquid composition comprises the corticosteroid in an amount from 0,20 mg/ml to 1 mg/ml, preferably from 0,020 mg/ml to 0,70 mg/ml, preferably from about 0,05 mg/ml to about 0,5 mg/ml and more preferably from about 0,1 mg/ml to 0,25 mg/ml.
  • the liquid composition comprises the corticosteroid in an amount f from 0,005 mg/ml to 1 mg/ml, preferably from 0,01 mg/ml to 0,09 mg/ml and more preferably from 0,02 mg/ml to 0,07 mg/ml.
  • the HPBCD is administered in an amount of 0.1 mg to 105 mg per day, or from 0.1 mg to 30 mg per day, preferably in the amount of 0.5 mg to 20 mg per day, even more preferably in the amount of 1 mg to 10 mg per day.
  • the HPBCD is administered in an amount of 0.1 mg to 105 mg per day, preferably from of 5 mg to 80 mg per day, preferably from 10 mg to 50 mg/day.
  • the HPBCD is administered in an amount of 10 mg to 50 mg per day.
  • the corticosteroid is administered in the amount of 0.020 mg to 1 mg per day, or of 0.020 mg to 0,700 mg per day, preferably in the amount of 0.05 mg to 0,5 mg per day, even more preferably in the amount of 0.05 mg to 0,40 mg per day, even more preferably in the amount of 0,07 mg to 0,30 mg per day.
  • the corticosteroid is administered in the amount of 0,07 mg/day to 0,4 mg/day.
  • the corticosteroid is administered in the amount of 50 pg/1 OOpI per dose.
  • the corticosteroid is administered in the amount of 400 pg/800 pl per day.
  • the liquid composition is administered to children aged from 2 to 6 years per inhalation, wherein the HPBCD is administered in the amount of 0,05 mg to 50 mg per day, or of 0,05 mg to 0,20 mg per day and wherein the corticosteroid, preferably budesonide or the ciclesonide, is administered per inhalation in an amount of 0,15 mg to 0,50 mg per day, or of 0,15 mg to 0,20 mg per day.
  • the liquid composition is administered to children aged from 6 to 14 years per inhalation, wherein the HPBCD is administered in the amount of 0,1 mg to 50 mg per day, or of 0,1 mg to 20 mg per day and wherein the corticosteroid is administered per inhalation in an amount of 0,25 mg to 1 mg per day, or of 0,25 mg to 0,5 mg per day.
  • a nasal spray device comprising the liquid composition for use as nasal spray in the treatment or prevention of an inflammatory disease
  • liquid composition comprises a complex of a corticosteroid and hydroxypropyl-beta-cyclodextrin (HPBCD); and
  • liquid composition is preservative-free.
  • Another aspect is a nasal spray device for delivering the liquid composition for use as nasal spray in the treatment or prevention of an inflammatory disease
  • liquid composition comprises a complex of a corticosteroid and hydroxypropyl-beta-cyclodextrin (HPBCD); and
  • Another aspect is a method of topical prevention or topical treatment of a nasal inflammatory disease, wherein a composition comprising a complex of HPBCD or a pharmaceutically acceptable derivative thereof and a corticosteroid is administered in a therapeutically effective amount without treatment-limiting side-effects to a subject in need thereof, wherein the liquid composition is preservative-free.
  • Another aspect is a method of nasal care which comprises intranasally spraying to a subject in need thereof a liquid composition:
  • liquid composition comprises a complex of a corticosteroid and hydroxypropyl-beta-cyclodextrin (HPBCD); and
  • liquid composition is preservative-free.
  • Liquid preservative free composition for use as nasal spray Liquid preservative free composition for use as nasal spray
  • the present invention concerns a liquid composition for use as a nasal spray in the treatment or prevention of an inflammatory disease
  • liquid composition comprises a complex of a corticosteroid and hydroxypropyl-beta-cyclodextrin (HPBCD); and
  • liquid composition is preservative-free.
  • prevention means any delay of the onset or any prevention of a disease.
  • the present invention concerns a liquid composition
  • a liquid composition comprising a complex of HPBCD (HPBCD) or a pharmaceutically acceptable derivative thereof and corticosteroid for use as a nasal spray in the treatment or prevention of an inflammatory disease.
  • HPBCD HPBCD
  • corticosteroid for use as a nasal spray in the treatment or prevention of an inflammatory disease.
  • the liquid composition is free of alpha or gamma-cyclodextrin.
  • the liquid composition comprises one or more further cyclodextrins, for example alpha-cyclodextrin, beta-cyclodextrins, gamma-cyclodextrin, and particularly 2-hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin, and methyl-beta- cyclodextrin.
  • cyclodextrins for example alpha-cyclodextrin, beta-cyclodextrins, gamma-cyclodextrin, and particularly 2-hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin, and methyl-beta- cyclodextrin.
  • liquid refers to a composition that may be administered by inhalation.
  • the term “liquid” means that the composition is capable of being micronized for inhalation purposes to an average particle size of 1 micrometer to 20 micrometers, preferably 1 micrometer to 10 micrometers and even more preferably 1 to 5 micrometers.
  • Suitable devices for micronization for inhalation include metered dose inhaler or nebulizers.
  • the liquid composition for use as a nasal spray in the treatment or prevention of an inflammatory disease is a liquid composition, ⁇ wherein no further active pharmaceutical ingredient is present in therapeutically effective amounts for which HPBCD is used to deliver an active pharmaceutical ingredient to other parts of the body than the respiratory system or the bronchial epithelium;
  • preservative is selected from the group consisting of benzalkonium chloride, phenylethyl alcohol, benzyl alcohol, sodium benzoate, chlorbutanol, phenoxyethanol, cetrimide and 2- (ethylmercuriomercapto)benzoic acid sodium salt, sodium bisulfite, sodium bisulfate, sodium thiosulfate, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol hyaluronic acid, benzoic acid, potassium sorbate, and essential oils preferably from fruit extracts;
  • Liquid aqueous composition Liquid aqueous composition
  • the composition of the invention is aqueous, which means that it is preferably a liquid composition comprising water as the predominant liquid constituent.
  • the liquid composition is a composition comprising HPBCD, water and optionally one or more other components suitable for use in pharmaceutical delivery such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients, and antimicrobial preservatives.
  • these components are present in very low amounts, typically in the range of 0,1 to 5 mg/ml.
  • the viscosity of the liquid aqueous composition is in the range of about 0,0, 1 mPa.s to about 10 mPa.s, preferably in the range of about 0,5 mPa.s to about 5 mPa.s and most preferably in the range from about 0,8 mPa.s to about 3 mPa.s at 20 °C as measured by the Ell or U.S. Pharmacopoeia (USP) 911 - Viscosity (Capillary Viscometer Methods).
  • the composition comprises an effective amount of HPBCD, salt or derivative thereof and a pharmaceutically acceptable carrier.
  • a preferred composition for nebulization comprises HPBCD, NaCI and water.
  • liquids for inhalation When administered in aerosol form, it is further preferred for safety and tolerability reasons that water is the only liquid present in the composition. However, in some cases it may be acceptable even for liquids for inhalation to comprise some amount of other liquids, in particular one or more organic solvents having a relatively low inhalation toxicity such as ethanol, propylene glycol, or glycerol. In one embodiment, these liquids are present in very low amounts, typically in the range of 0,1 to 5 mg/ml.
  • the pH of the composition is from 2 to 8 , preferably from 3,5 to 6,5 and even more preferably from 4.0 to 5.5.
  • the preferred pH may be obtained by adding a pH buffer.
  • Preferable pH buffers are citric acid/citrate/ascorbic acid or citric acid/citrate/EDTA.
  • the composition may comprise one or more excipients selected from pharmaceutically acceptable organic acids, salts of organic acids, inorganic acids, inorganic salts, bases, sugars, sugar alcohols, stabilizers, antioxidants, surfactants, and taste masking agents.
  • the composition of the present invention enables aqueous and dry powder formulations whose properties allow highly efficient and convenient aerosol or dry powder delivery using currently available aerosol generating devices, or dry powder inhalers.
  • Aerosolization in the sense of the present invention, means any spraying process that produces droplets.
  • the size of the droplets may vary. Typically, the size of the droplets is between 1 and 100 microns, preferably, between 1 ,5 and 10 microns and even more preferably between 2 and 7 microns.
  • Micronization in the sense of the present invention, means any process to decrease the particle size of dry powders or a suspension to between 1 and 100 microns, preferably, between 1 ,5 and 10 microns and even more preferably between 2 and 7 microns. pH of the liquid composition
  • composition of the present invention is preservative-free.
  • Preservatives are generally used to ensure the microbial stability of a liquid composition and increase its shelf life.
  • the preservative is selected from the group consisting of cetyl pyridinium chloride, phenol, benzethonium chloride, butylparaben, methyl paraben, ethyl paraben, propyl paraben, benzalkonium chloride, thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol, potassium sorbate, sodium benzoate, sorbic acid or combinations thereof.
  • the liquid composition of the present invention is free or organic solvents, such as alcohols.
  • the composition is free of flavonoids agents, such as Citrox. In another embodiment, the composition is free of oils. Topical treatment
  • composition of the present invention is for topical treatment, particularly by inhalation.
  • topical means that the composition of the invention is applied to the respiratory system, in particular to the nasal mucosa or the bronchial epithelium, for example by intranasal application or through inhalation of an aerosol generated by an aerosolgenerating device.
  • the treatment is a respiratory topical treatment in the sense that no other tissue or part of the body than the respiratory system, the nasal mucosa are targeted by the use of the invention.
  • active pharmaceutical ingredient refers to any substance or combination of substances used in a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.
  • active pharmaceutical ingredient refers to a molecule that is intended to be biologically active, for example for the purpose of treating inflammatory, autoimmune, or pulmonary disease, disorder, or condition.
  • active pharmaceutical ingredient refers to substances whose placing on the market requires a marketing authorization, for example as foreseen under directive 2001/83/EC of 6 November 2001 on the Community Code relating to medicinal products for human use.
  • the inflammatory disease may be any inflammatory disease independently of the cause.
  • the inflammatory disease may be any inflammatory disease independently of the cause.
  • the inflammatory disease may be any inflammatory disease independently of the cause.
  • Pathogen-induced such bacterial or viral inflammations, in particular respiratory viral disease.
  • Steroids are anti-inflammatory compounds which are commonly also referred to as steroids, corticoids, glucocorticoids, corticosteroids or cortisol analogues.
  • corticosteroids include aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluoromethoIone, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone paramethasone, mome
  • Preferred corticosteroids are beclomethasone, budesonide, flunisolide, fluticasone, ciclesonide, mometasone, or any compounds comprising the active moiety of any of these corticosteroids, such as salts, derivatives, and prodrugs thereof.
  • a preferred corticosteroid is budesonide.
  • Budesonide is also named (R,S)- 1 1 (3,16a, 17,21 -tetrahydroxypregna- 1 ,4-diene-3, 20- dione cyclic 16, 17-acetal with butyraidehyde or 16, 17-(butylidenebis(oxy))- 1 1 ,21 - dihydroxy-, (1 1 -[3,16-a)-pregna-l ,4-diene-3, 20-dione.
  • the chemical formula, molecular weight and CAS number for Budesonide are C25H34O6, MW: 430.5 and 51333-22-3, respectively.
  • Budesonide is a racemate consisting of a mixture of the two diastereomers 22 R and 22 S.
  • Budesonide is commercially available as a mixture of the two isomers (22R and 22 S). Commercial formulations of budesonide in solution are provided by AstraZeneca LP (Wilmington, Del.) under the trademark Pulmicort.
  • the molar ratio between the corticosteroid and the HPBCD may vary widely. In some embodiments, the molar ratio is from about 1 :1 to about 1 :400, preferably from about 1 :1 to about 1 :300 preferably from about 1 : 1 to about 1 : 100, preferably from about 1 : 1 to 1 :75 and even more preferably from about 1 :1 to about 1 : 50.
  • no further active pharmaceutical ingredient than a corticosteroid is present in the liquid composition in therapeutically effective amounts for which HPBCD is used to deliver an active pharmaceutical ingredient to other parts of the body than the respiratory system or the bronchial epithelium.
  • no further active pharmaceutical ingredient than a corticosteroid is present in the liquid composition in therapeutically effective amounts for which HPBCD is used to increase the solubility of the further active pharmaceutical ingredient in water.
  • HPBCD is an oligosaccharide composed of glucopyranose units.
  • the major unsubstituted cyclodextrins are usually prepared by the enzymatic degradation of starch.
  • HPBCD is a chemically modified cyclodextrin which may have increased water solubility over unmodified cyclodextrins.
  • HPBCD Also comprised are pharmaceutically acceptable derivatives of HPBCD as long as they are structurally and functionally similar to HPBCD.
  • the composition does not comprise any bronchodilators such as formoterol. In other embodiments, the composition further comprises bronchodilators such as formoterol.
  • an effective amount refers to an amount of an active agent as described herein that contributes to achieving one or more desirable clinical outcomes, such as those described in the "treatment” description above.
  • An appropriate “effective” amount in any individual case may be determined using standard techniques known in the art, such as a dose escalation study.
  • the term "therapeutically effective amount” is meant to refer to an amount of an active agent or combination of agents effective to ameliorate, delay, or prevent the symptoms. Determination of a therapeutically effective amount is well within the capabilities of the skilled person.
  • an effective amount of the liquid composition for use as nasal spray in the treatment or prevention of an inflammatory disease is administered.
  • the composition of the present invention is a liquid, preferably an aqueous composition.
  • the amount or content of the cyclodextrin in the composition is selected to ensure a sufficiently low viscosity at ambient temperature in view of inhalation.
  • the dynamic viscosity which may also be influenced by the choice and quantity of the further excipients, also has a clear influence on the particle size distribution of the aerosol formed by nebulization and on the efficiency of nebulization.
  • the viscosity may be adjusted to a range of about 0.8 to about 3 mPas at ambient temperature.
  • the dynamic viscosity of the composition is in the range of about 0.8 to about 2.5 mPas or even about 0.9 to about 1 .3 mPas at ambient temperature.
  • the HPBCD concentration in the composition according to the present invention is in the range from about 1 millimolar to about 100 millimolar, preferably from 5 millimolar to about 50 millimolar, and more preferably from about 7 millimolar to about 40 millimolar.
  • Other preferred concentrations range from about 10 millimolar to about 30 millimolar and from about 15 millimolar to about 25 millimolar.
  • the liquid composition comprises HPBCD in an amount from 1 mg/ml to 300 mg/ml, preferably from 1 mg/ml to 200 mg/ml, even more preferably from 1 mg/ml to 100 mg/ml.
  • the liquid composition comprises HPBCD in an amount from 1 mg/ml to 100 mg/ml, preferably from about 5 mg/ml to about 80 mg/ml and more preferably from about 8.00 mg/ml to 60 mg/ml.
  • the liquid composition comprises HPBCD in an amount from 1 mg/ml to 100 mg/ml, preferably from about 10 mg/ml to about 80 mg/ml, and more preferably from about 8.00 mg/ml to 60 mg/ml.
  • the HPBCD is administered per inhalation in the amount of 0.1 mg to 30 mg per day, preferably in the amount of 0.5 mg to 20 mg per day, even more preferably in the amount of 1 mg to 10 mg per day.
  • the HPBCD is administered in an amount of 0.1 mg to 105 mg per day, preferably from of 5 mg to 80 mg per day, preferably from 10 mg to 50 mg/day.
  • the HPBCD is administered in the amount of 0.1 mg to 30 mg per day. In another embodiment, the HPBCD is administered per inhalation in the amount of 0.5 mg to 20 mg per day. In another embodiment, the HPBCD is administered per inhalation in the amount of 1 mg to 10 mg per day.
  • the HPBCD is administered to children aged up to two years per inhalation in the amount of 0.1 mg to 0.5 mg per day.
  • the HPBCD is administered to children aged from two to 6 years per inhalation in the amount of 0.5 mg to 1 mg per day. In another embodiment, the HPBCD is administered to children aged from 6 years to 14 years per inhalation in the amount of 1 mg to 2 mg per day.
  • the HPBCD is administered to children aged up to two years per inhalation in the amount of 0.1 mg to 1 ,0 mg per day and wherein the corticosteroid, preferably the budesonide or the ciclesonide, is administered in an amount of 0,05 mg to 0,12 mg per day.
  • the HPBCD is administered to children aged from 2 to 6 years in the amount of 0,05 mg to 0,20 mg per day and wherein the corticosteroid is administered per inhalation in an amount of 0, 15 mg to 0,20 mg per day.
  • the HPBCD is administered to children aged from 6 to 14 years in the amount of 0,1 mg to 20 mg per day and wherein the corticosteroid is administered per inhalation in an amount of 0,25 mg to 0,5 mg per day.
  • the liquid composition is administered to children aged from 6 to 14 years per inhalation, wherein the HPBCD is administered in the amount of 0,1 mg to 50 mg per day, or of 0,1 mg to 20 mg per day and wherein the corticosteroid is administered per inhalation in an amount of 0,25 mg to 1 mg per day, or of 0,25 mg to 0,5 mg per day.
  • the liquid composition comprises a corticosteroid in an amount from 0,020 mg/ml to 0,70 mg/ml, preferably from about 0,05 mg/ml to about 0,5 mg/ml and more preferably from about 0,1 mg/ml to 0,25 mg/ml.
  • the liquid composition comprises a corticosteroid in an amount from 0,02 mg/ml to 2 mg/ml, preferably from 0,06 to 1 ,2 mg/ml and more preferably from 0,1 mg/ml to 0,8 mg/ml.
  • the liquid composition comprises the corticosteroid in an amount from 0,005 mg/ml to 1 mg/ml, preferably from 0,01 mg/ml to 0,09 mg/ml and more preferably from 0,02 mg/ml to 0,07 mg/ml.
  • the daily dosage of the steroid compound typically ranges from 1 microgram to 500 micrograms, preferably from about 30 micrograms to about 200 micrograms per day. In some embodiments, the daily dose of the steroid compound is from 50 micrograms to 150 micrograms and even more preferably from 75 micrograms to 125 micrograms. In another embodiment, the corticosteroid is administered per nasal spray in the amount of 0.020 mg to 0,700 mg per day, preferably in the amount of 0.05 mg to 0,5 mg per day, even more preferably in the amount of 0,07 mg to 0,25 per day.
  • the corticosteroid is administered per nasal spray in the amount of 0.020 mg to 1 mg per day, or of 0.020 mg to 0,700 mg per day, preferably in the amount of 0.05 mg to 0,5 mg per day, even more preferably in the amount of 0,07 mg to 0,30 mg per day.
  • the corticosteroid is administered in the amount of 0.020 mg to 1 mg per day, or of 0.020 mg to 0,700 mg per day, preferably in the amount of 0.05 mg to 0,5 mg per day, even more preferably in the amount of 0.05 mg to 0,4 mg per day, even more preferably in the amount of 0,07 mg to 0,30 mg per day.
  • the liquid composition preferably the aqueous liquid composition for use as nasal spray in the treatment or prevention of an inflammatory disease may comprise further ingredients, such as buffering agents; antioxidants; chelating agents and pH-adjusting agents.
  • Examples of further ingredients include PEG400, Citric acid monohydrate, Tri-Sodium citrate dihydrate, EDTA and NaCI.
  • liquid compositions of the present inventions are administered through an aerosol-generating device, in particular a nasal spray device.
  • the nasal spray device is a Rayleigh-jet based inhalers commercially available for example from Medspray. Such nozzle units are based on plain orifice nozzles, creating Rayleigh jets. A 2-micron hole creates a jet, breaking up into mono-disperse 4 micron droplet trains. The diameter of the droplets is twice the size of the orifice. The hole size can be engineered to meet specific requirements of devices. Spray nozzle chips are typically made with technologies generally seen in computer chips.
  • the present inventors have found that the nasal administration of a liquid composition comprising a complex of HPBCD, and a corticosteroid is particularly suitable for the prevention or treatment of an inflammatory disease without any need for preservatives.
  • the HPBCD acts as a stabilizer for the corticosteroid liquid composition.
  • the shelflife of the liquid composition is surprisingly increased, and the microbiological stability is surprisingly maintained similar to preservative-based formulations. This renders the use of preservatives unnecessary.
  • other compounds may be present, there is no need for administering further active pharmaceutical ingredients than the corticosteroid to obtain a positive effect in respect of the inflammatory disease.
  • no further active pharmaceutical ingredient than a corticosteroid is present in the composition of the present invention, wherein HPBCD is used as solubilizing excipient or as a drug delivery system.
  • Example 1 The following liquid compositions were tested:
  • Example 2 The following preservative-free (without benzalkonium chloride composition was tested:
  • Example 3 The composition of example 3 is as follows:

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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des compositions sans conservateur comprenant un complexe d'un corticostéroïde et d'une HPBCD pour le traitement ou la prévention d'une maladie inflammatoire par administration nasale.
PCT/EP2024/065683 2023-06-07 2024-06-06 Compositions sans conservateur comprenant un complexe d'un corticostéroïde et d'une hpbcd pour le traitement ou la prévention d'une maladie inflammatoire par administration nasale Pending WO2024251923A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
BEBE2023/5467 2023-06-07
BE20235467A BE1031693B1 (fr) 2023-06-07 2023-06-07 Compositions sans conservateur comprenant un complexe de corticostéroïde et d'hpbcd pour le traitement ou la prévention d'une maladie inflammatoire par administration nasale
BEBE2023/5466 2023-06-07
BE20235466A BE1031691B1 (fr) 2023-06-07 2023-06-07 Compositions sans conservateur comprenant un complexe de corticostéroïde et d'hpbcd pour le traitement ou la prévention d'une maladie inflammatoire par administration nasale

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0423240B1 (fr) 1988-07-07 1995-11-08 The Trustees Of The University Of Pennsylvania Modulation d interactions entre des cellules hotes et un virus par l utilisation d oligosaccharides cycliques
US20060045850A1 (en) 2004-08-30 2006-03-02 Qpharma, Llc Nasal delivery of cyclodextrin complexes of anti-inflammatory steroids
US20060120967A1 (en) 2004-12-07 2006-06-08 Qpharma, Llc Solution forms of cyclodextrins for nasal or throat delivery of essential oils
EP1799231A1 (fr) 2004-10-10 2007-06-27 Université de Liège Utilisation d'un composé de cyclodextrine pour le traitement et la prévention des maladies inflammatoires bronchiques.
EP1894559A1 (fr) 2006-09-01 2008-03-05 PARI Pharma GmbH Stabilisation de stéroides destinées à être inhalées
EP2923702A1 (fr) * 2014-03-28 2015-09-30 Universite De Liege Composition de cyclodextrine avec des dérivés de budésonide pour le traitement et la prévention d'une maladie inflammatoire pulmonaire
WO2019067145A1 (fr) 2017-08-28 2019-04-04 Asdera Llc Utilisation de cyclodextrines dans des maladies et des troubles impliquant un dérèglement des phospholipides
WO2021001349A1 (fr) 2019-07-01 2021-01-07 Aquilon Pharmaceuticals Composition inhalable comprenant de la cyclodextrine destinée à être utilisée dans le traitement d'inflammations nasales
WO2021048322A1 (fr) 2019-09-10 2021-03-18 Aquilon Pharmaceuticals Microparticules de type balle de golf destinées à être utilisées dans le traitement et la prévention de maladies pulmonaires
BE1029585B1 (fr) 2021-12-20 2023-02-03 Aquilon Pharmaceuticals Compositions inhalables comprenant un complexe de hpbcd et de budesonide ou ciclesonide pour le traitement ou la prevention d'une maladie virale respiratoire

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0423240B1 (fr) 1988-07-07 1995-11-08 The Trustees Of The University Of Pennsylvania Modulation d interactions entre des cellules hotes et un virus par l utilisation d oligosaccharides cycliques
US20060045850A1 (en) 2004-08-30 2006-03-02 Qpharma, Llc Nasal delivery of cyclodextrin complexes of anti-inflammatory steroids
EP1799231A1 (fr) 2004-10-10 2007-06-27 Université de Liège Utilisation d'un composé de cyclodextrine pour le traitement et la prévention des maladies inflammatoires bronchiques.
US20060120967A1 (en) 2004-12-07 2006-06-08 Qpharma, Llc Solution forms of cyclodextrins for nasal or throat delivery of essential oils
EP1894559A1 (fr) 2006-09-01 2008-03-05 PARI Pharma GmbH Stabilisation de stéroides destinées à être inhalées
EP2923702A1 (fr) * 2014-03-28 2015-09-30 Universite De Liege Composition de cyclodextrine avec des dérivés de budésonide pour le traitement et la prévention d'une maladie inflammatoire pulmonaire
EP3151836A2 (fr) 2014-03-28 2017-04-12 Université de Liège Composition de cyclodextrine avec des dérivés de budésonide pour le traitement et la prévention d'une maladie inflammatoire pulmonaire
WO2019067145A1 (fr) 2017-08-28 2019-04-04 Asdera Llc Utilisation de cyclodextrines dans des maladies et des troubles impliquant un dérèglement des phospholipides
WO2021001349A1 (fr) 2019-07-01 2021-01-07 Aquilon Pharmaceuticals Composition inhalable comprenant de la cyclodextrine destinée à être utilisée dans le traitement d'inflammations nasales
WO2021048322A1 (fr) 2019-09-10 2021-03-18 Aquilon Pharmaceuticals Microparticules de type balle de golf destinées à être utilisées dans le traitement et la prévention de maladies pulmonaires
BE1029585B1 (fr) 2021-12-20 2023-02-03 Aquilon Pharmaceuticals Compositions inhalables comprenant un complexe de hpbcd et de budesonide ou ciclesonide pour le traitement ou la prevention d'une maladie virale respiratoire

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