[go: up one dir, main page]

WO2024133757A1 - Dérivés de cyclodextrine pour le traitement de la goutte et de l'hyperuricémie - Google Patents

Dérivés de cyclodextrine pour le traitement de la goutte et de l'hyperuricémie Download PDF

Info

Publication number
WO2024133757A1
WO2024133757A1 PCT/EP2023/087380 EP2023087380W WO2024133757A1 WO 2024133757 A1 WO2024133757 A1 WO 2024133757A1 EP 2023087380 W EP2023087380 W EP 2023087380W WO 2024133757 A1 WO2024133757 A1 WO 2024133757A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclodextrin
derivative
gout
hbcd
pol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2023/087380
Other languages
English (en)
Inventor
Adrián MATENCIO DURÁN
Francesco Trotta
Yousef KHAZAEI MONFARED
Fabrizio CALDERA
José Manuel LÓPEZ NICOLÁS
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.)
Universidad de Murcia
Universita degli Studi di Torino
Original Assignee
Universidad de Murcia
Universita degli Studi di Torino
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
Application filed by Universidad de Murcia, Universita degli Studi di Torino filed Critical Universidad de Murcia
Publication of WO2024133757A1 publication Critical patent/WO2024133757A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • the present invention relates to a cyclodextrin derivative complexes for the treatment of hyperuricemia or the gout.
  • Hyperuricemia is a metabolic disease caused by purine metabolism disorder. Hyperuricemia is clinically divided into primary hyperuricemia and secondary hyperuricemia. Primary hyperuricemia is mostly caused by congenital abnormal purine metabolism, and often accompanied by obesity, glucose/lipid metabolism disorder, atherosclerosis, coronary heart disease, hypertension and the like. Secondary hyperuricemia is caused by certain systemic diseases or drugs. When the serum uric acid (sUA) concentration is 6.8 mg/dl, the dissolution of uric acid reaches a saturation state. A concentration beyond this level is defined as hyperuricemia (HUA).
  • sUA serum uric acid
  • microcrystals In some patients with hyperuricemia, supersaturated sodium urate precipitates out as microcrystals with the increase of blood uric acid level.
  • the microcrystals are deposited on tissues or organs such as joints, synovium, tendons, kidneys and connective tissues (except the central nervous system) to form gout stones, causing acute and chronic inflammation and tissue damage, resulting in multiple system damages such as arthritis, urinary calculi and kidney disease.
  • the hyperuricemia in about 5% to 12% of patients will eventually develop into gout.
  • Febuxostat belongs to xanthine oxidase inhibitors (XOIs), which is a commonly used drug for treating gout.
  • XOIs xanthine oxidase inhibitors
  • the average range of the terminal elimination phase half-life of febuxostat in steady state is 5 to 6 hours, and the steady state can be substantially reached after one administration.
  • 40% to 70% of patients using febuxostat still cannot reach the clinically recommended sUA level.
  • the American Rheumatism Association recommends a combined treatment with uric acid excretion drugs.
  • Allopurinol can inhibit xanthine oxidase, so that hypoxanthine and xanthine cannot be converted into uric acid (i.e. uric acid synthesis is reduced), thereby reducing the uric acid concentration in blood and the deposition of urate in bones, joints and kidneys.
  • MSU monosodium urate
  • Gout is hence associated with elevated levels of uric acid that crystallize and deposit in joints, tendons, and surrounding tissues. Gout is marked by recurrent attacks of red, tender, hot, and/or swollen joints.
  • gout flares are associated with the reduction of uric acid levels.
  • Drugs such as colchicine can reduce the pain associated with gout flares while a patient's serum uric acid levels are being reduced, however, colchicine is associated with several undesired side effects, including gastrointestinal disorders.
  • Current guidelines recommend the use of non-steroidal anti-inflammatory drug or corticosteroids for acute inflammation (flare); while long-term management of the disease relies on a good lifestyle and the combination of different drugs such as allopurinol or probenecid, despite the associated adverse effects such as haematuria, constipation, or headaches.
  • the object of the present invention is hence to provide a treatment for hyperuricem ia or the gout.
  • CDs monosodium urate with cyclodextrins
  • HBCD-Pol Hyperbranched Cyclodextrin- based polymers
  • the invention relates to a cyclodextrin complex of uric acid, wherein the cyclodextrin is selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), methyl - cyclodextrin (M[3-CD) and an hyperbranched cyclodextrin-based polymer (HBCD- Pol).
  • HP[3-CD hydroxypropyl
  • SBE[3-CD sulfobutylether
  • M[3-CD methyl - cyclodextrin
  • HBCD- Pol hyperbranched cyclodextrin-based polymer
  • the hyperbranched cyclodextrin-based polymer is preferably a polymer obtainable by reacting a cyclodextrin with a compound having an electropositive carbon atom selected from the group consisting of citric acid, citric anhydride, pyromellitic dianhydride, pyromellitic acid, trimellitic acid, trimellitic anhydride, sulfosuccinic acid, sulfosuccinic anhydride, Trisodium trimetaphosphate (STMP), phytic acid and mellitic anhydride.
  • a compound having an electropositive carbon atom selected from the group consisting of citric acid, citric anhydride, pyromellitic dianhydride, pyromellitic acid, trimellitic acid, trimellitic anhydride, sulfosuccinic acid, sulfosuccinic anhydride, Trisodium trimetaphosphate (STMP), phytic acid and mellitic an
  • the invention relates to a cyclodextrin or its derivative for use in the treatment of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms an inclusion complex with uric acid.
  • the cyclodextrin or its derivative showed the effectiveness in the treatment of hyperuricemia or the gout, since when administered it forms an inclusion complex with uric acid, thus dissolving the already formed MSU.
  • hyperuricemia when used, it is intended primary and secondary hyperuricemia.
  • the diseases resulting from hyperuricemia are preferably selected from the group consisting of gout, tophi, kidney stones and uratic nephropathy.
  • cyclodextrin or its derivative any cyclodextrin compound selected from the group consisting of alphacyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and a derivative thereof.
  • the invention relates to a cyclodextrin selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3- cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) for use in the treatment of hyperuricemia or the gout.
  • a cyclodextrin selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3- cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) for use in the treatment of hyperuricemia or the gout.
  • the invention relates to a cyclodextrin or its derivative for use in the treatment of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid and the cyclodextrin or its derivative is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof.
  • the hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof is an active principle for use in the treatment of hyperuricemia or the gout.
  • the invention relates to a cyclodextrin, preferably selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) for use in the prevention of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms an inclusion complex with uric acid.
  • HP[3-CD hydroxypropyl
  • SBE[3-CD sulfobutylether
  • M[3-CD methyl
  • the cyclodextrin or its derivative forms an inclusion complex with uric acid.
  • the invention relates to a cyclodextrin or its derivative for use in the prevention of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid and the cyclodextrin or its derivative is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • the inventors found out that the presence of HP[3-CD or HBCD-Pol in condition of MSU formation was able to prevent and to reduce the crystal deposits by complexing the uric acid and so solubilizing the sodium urate, already present.
  • the prevention could be carried out not only in healthy subjects but also patients having both a predisposition to hyperuricemia. Preferably the prevention is addressed to an healthy subject.
  • mice model which was injected with MSU in the knee, was developed and HP[3-CD I HBCD-Pol samples were injected alone and in combination with different anti-gout drugs (Allopurinol, Probenecid, Colchicine and Febuxostat) and bioactive compounds (Resveratrol and Oxyresveratrol).
  • anti-gout drugs Allopurinol, Probenecid, Colchicine and Febuxostat
  • bioactive compounds Resveratrol and Oxyresveratrol
  • the results demonstrated a decrease of inflammation correlated to the use of cyclodextrins according to the invention, preferably HBCD-Poland higher effects in combination with drugs, thus obtaining a synergistic effect when administered with a compound acting against gout and/or hypouricemia.
  • the invention in another aspect relates to a combination of i) a cyclodextrin or its derivative, preferably the cyclodextrin hydroxypropyl [3- cyclodextrin (HP[3-CD), and ii) a compound acting against gout and/or hypouricemia for use in the treatment of hypouricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid.
  • a cyclodextrin or its derivative preferably the cyclodextrin hydroxypropyl [3- cyclodextrin (HP[3-CD)
  • HP[3-CD cyclodextrin hydroxypropyl
  • a compound acting against gout and/or hypouricemia for use in the treatment of hypouricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid.
  • the invention in a still another aspect relates to a combination of: i) a cyclodextrin or its derivative and ii) a compound acting against gout and/or hypouricemia for use in the treatment or in the prevention of hypouricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid and wherein the cyclodextrin or its derivative is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • a compound acting against gout and/or hypouricemia it is intended a drug, a nutraceutical, a food, a supplement known as capable to be used in the treatment or in the prevention of gout and/or hypouricemia.
  • the combination of the invention can advantageously be a drug, a supplement, a nutraceutical or a food.
  • the invention relates to a use of a nutraceutical product comprising a cyclodextrin or its derivative, preferably selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), and methyl [3-cyclodextrin (M[3-CD) in the improvement of the treatment of hyperuricemia or of the gout, by ameliorating its symptoms, preferably pain, swelling, redness, and joint tenderness and by leveling the characterizing biochemical parameters of a health subject.
  • a nutraceutical product comprising a cyclodextrin or its derivative, preferably selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), and methyl [3-cyclodextrin (M[
  • the invention relates to a use of a nutraceutical product comprising an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof in the improvement of the treatment of hyperuricemia or the gout, by ameliorating its symptoms, preferably pain, swelling, redness, and joint tenderness and by leveling the characterizing biochemical parameters of a health subject.
  • biochemical parameters can be referred to total antioxidant status, enzymes, and cytokines, usually altered for a patient having gout and hyperuricemia such as for example IL-6, TNF-alpha, IL1 [3.
  • biochemical levels and cytokines turned to normality in presence of all the medical and not medical treatments. These results encouraged the possibility to improve the current therapy of gout with these authorized excipients used as active principle and open the door of novel therapies.
  • Figure 1 shows the effect of 5mM of CDs of the invention on the solubility of 3mg/mL of UA (values related control) in 0.1 M disodium Phosphate buffer pH 7.4 at 25°C.
  • B Higuchi and Connors plot of increasing HP[3-CD concentrations on UA solubility at same conditions so demonstrating the formation of the complex.
  • Figure 2 shows (A) FTIR spectra of UA, HP[3-CD, physical mixture and inclusion complex. (B) TGA thermograms of UA, HP[3-CD, physical mixture and inclusion complex. (Ill) XRD pattern of UA, HP[3-CD, physical mixture and inclusion complex. Figure 2 demonstrated again the formation of the complex with uric acid.
  • FIG. 3 (A) The presence of HP[3-CD prevents the formation of MSU in vitro (0.1 M disodium Phosphate buffer pH 7.4 at 25°C). (B) Diffusion profile in vitro of UA in presence of HP[3-CD inside and outside membrane (Cut-off 1 KDa, (0.1 M disodium Phosphate buffer pH 7.4 at 37°C). (C) Schematic representation of MSU-UA- Complex equilibria in the diffusion experiment so demonstrating the prevention of hyperuricemia or the gout and the reduction of the monosodium urate deposits.
  • Figure 4 Effect of a 0.5% of
  • B Relative increase of solubility in different buffers of UA in presence of HBCD-Pol at increasing concentrations.
  • C Effect of different PMDA polymers at 1 % on UA solubility.
  • Figures 6A and 6B show the effect of different formulations on the ankle inflammation.
  • * is P ⁇ 0.05, ** ⁇ 0.01 , *** ⁇ 0.001 and # ⁇ 0.0001 , thus showing the effect of the use of the cyclodextrin according to the invention (better with HBCD- Pol) and in combination with a compound acting against gout and/or hypouricemia, giving a combinatorial effect.
  • FIG. 8 shows status of mice groups of example 7.
  • Figure 9 shows IL-6 response of mice groups of example 7.
  • the invention relates to a cyclodextrin complex of uric acid, wherein the cyclodextrin is selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) and an hyperbranched cyclodextrin-based polymer (HBCD-Pol).
  • HP[3-CD hydroxypropyl
  • SBE[3-CD sulfobutylether
  • M[3-CD methyl
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • the hyperbranched cyclodextrin-based polymer is preferably a polymer obtainable by reacting a cyclodextrin with a compound having an electropositive carbon atom selected from the group consisting of citric acid, citric anhydride, pyromellitic dianhydride (PMDA), pyromellitic acid, trimellitic acid, trimellitic anhydride, sulfosuccinic acid, sulfosuccinic anhydride, trisodium trimetaphosphate (STMP), phytic acid and mellitic anhydride.
  • a compound having an electropositive carbon atom selected from the group consisting of citric acid, citric anhydride, pyromellitic dianhydride (PMDA), pyromellitic acid, trimellitic acid, trimellitic anhydride, sulfosuccinic acid, sulfosuccinic anhydride, trisodium trimetaphosphate (STMP), phytic acid
  • the invention hence relates to a cyclodextrin or its derivative for use in the treatment of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms an inclusion complex with uric acid.
  • hyperuricemia when used, it is intended primary and secondary hyperuricemia.
  • the diseases resulting from hyperuricemia are preferably selected from the group consisting of gout, tophi, kidney stones and uratic nephropathy.
  • cyclodextrin or its derivative any cyclodextrin compound” selected from the group of alphacyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and a derivative thereof.
  • any derivative of cyclodextrin can be hydroxy derivative, methyl- or sulfobutyl-derivative.
  • the cyclodextrin or its derivative for use according to the invention can preferably be selected from the group of alpha-cyclodextrin, beta-cyclodextrin, gammacyclodextrin, hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) and an hyperbranched cyclodextrin- based polymer (HBCD-Pol) and a derivative thereof.
  • the invention relates to a cyclodextrin selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD) and methyl [3-cyclodextrin (M[3-CD) for use in the treatment of hyperuricemia or the gout.
  • a cyclodextrin selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD) and methyl [3-cyclodextrin (M[3-CD) for use in the treatment of hyperuricemia or the gout.
  • the invention relates to a cyclodextrin or its derivative for use in the treatment of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid and the cyclodextrin or its derivative is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • hyperbranched cyclodextrin-based polymer or a derivative thereof is an active principle for use in the treatment of hyperuricemia or the gout.
  • the hyperbranched cyclodextrin-based polymer is preferably a polymer obtainable by reacting a cyclodextrin with a compound having an electropositive carbon atom selected from the group consisting of citric acid, citric anhydride, pyromellitic dianhydride (PMDA), pyromellitic acid, trimellitic acid, trimellitic anhydride, sulfosuccinic acid, sulfosuccinic anhydride, trisodium trimetaphosphate (STMP), phytic acid and mellitic anhydridein a still another aspect the invention relates to a cyclodextrin for use in the prevention of gout or hyperuricemia, wherein the cyclodextrin or its derivative forms an inclusion complex with uric acid.
  • a compound having an electropositive carbon atom selected from the group consisting of citric acid, citric anhydride, pyromellitic dianhydride (PMDA), pyromelli
  • the cyclodextrin or its derivative for use in the prevention is selected from the group of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) and an hyperbranched cyclodextrin-based polymer (HBCD-Pol) and a derivative thereof.
  • the cyclodextrin or its derivative is selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD) and methyl [3-cyclodextrin (M[3-CD) for use in the prevention of hyperuricemia or the gout.
  • HP[3-CD hydroxypropyl
  • SBE[3-CD sulfobutylether
  • M[3-CD methyl [3-cyclodextrin
  • the invention relates to a cyclodextrin or its derivative for use in the prevention of hyperuricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid and the cyclodextrin or its derivative is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • the most effective cyclodextrin was HBCD-Pol that presented a combinatorial effect with the chelation of Na + ions.
  • HBCD-Pol not only formed the complex with uric acid, but contemporaneously it chelated Na + , thus influencing the solubility of the uric acid.
  • the highest effect was hence obtained with HBCD-Pol, the material which was able to chelate the sodium and complex UA at the same time, preventing the formation and mobilizing the MUS crystals.
  • the invention relates to a complex of hyperbranched cyclodextrin-based polymers (HBCD-Pol) and uric acid, wherein the hyperbranched cyclodextrin-based polymers (HBCD-Pol) chelates also sodium ions.
  • hyperbranched cyclodextrin-based polymers chelates also sodium ions
  • hyperbranched cyclodextrin-based polymers HBCD-Pol
  • This latter complex i.e. a complex with uric acid and sodium ions is preferred and efficacious when used in the treatment and in the prevention of hyperuricemia or the gout.
  • mice model which was injected with MSU in the knee was developed and HP[3-CD I HBCD-Pol samples were injected alone and in combination with different anti-gout drugs (Allopurinol, Probenecid, Colchicine and Febuxostat) and bioactive compounds (Resveratrol and Oxyresveratrol).
  • anti-gout drugs Allopurinol, Probenecid, Colchicine and Febuxostat
  • bioactive compounds Resveratrol and Oxyresveratrol
  • the invention in another aspect relates to a combination of i) a cyclodextrin or its derivative, preferably the cyclodextrin hydroxypropyl [3- cyclodextrin (HP[3-CD), and ii) a compound acting against gout and/or hypouricemia for use in the treatment of hypouricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid.
  • a cyclodextrin or its derivative preferably the cyclodextrin hydroxypropyl [3- cyclodextrin (HP[3-CD)
  • HP[3-CD cyclodextrin hydroxypropyl
  • a compound acting against gout and/or hypouricemia for use in the treatment of hypouricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid.
  • the invention in a still another aspect relates to a combination of: i) a cyclodextrin or its derivative and ii) a compound acting against gout and/or hypouricemia for use in the treatment or in the prevention of hypouricemia or the gout, wherein the cyclodextrin or its derivative forms a complex with uric acid and wherein the cyclodextrin or its derivative is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • a compound acting against gout and/or hypouricemia it is intended a drug, a nutraceutical, a food, a supplement known as capable to be used in the treatment or in the prevention of gout and/or hypouricemia.
  • the combination of the invention can advantageously be a drug, a supplement, a nutraceutical or a food.
  • the invention relates to a use of a nutraceutical product comprising a cyclodextrin or its derivative, preferably selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), and methyl [3-cyclodextrin (M[3-CD) in the improvement of the treatment of hyperuricemia or the gout, by ameliorating its symptoms, preferably pain, swelling, redness, and joint tenderness and by leveling the characterizing biochemical parameters of a health subject.
  • a nutraceutical product comprising a cyclodextrin or its derivative, preferably selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), and methyl [3-cyclodextrin (M[3
  • the invention relates to a use of a nutraceutical product comprising an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof in the improvement of the treatment of hyperuricemia or the gout, by ameliorating its symptoms, preferably pain, swelling, redness, and joint tenderness and by leveling the characterizing biochemical parameters of a health subject.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • biochemical parameters can be referred to total antioxidant status, enzymes, and cytokines, usually altered for a patient having gout and hyperuricemia such as for example IL-6, TNF-alpha, IL1 [3.
  • the cyclodextrin or its derivative is preferably selected from the group of alpha-cyclodextrin, betacyclodextrin, gamma-cyclodextrin, hydroxypropyl [3-cyclodextrin (HP[3-CD), sulfobutylether [3-cyclodextrin (SBE[3-CD), methyl [3-cyclodextrin (M[3-CD) and an hyperbranched cyclodextrin-based polymer (HBCD-Pol) and a derivative thereof.
  • the nutraceutical When the nutraceutical is used for the improvement of the treatment of hyperuricemia or the gout, by ameliorating its symptoms, preferably pain, swelling, redness, and joint tenderness and by leveling the characterizing biochemical parameters of a health subject and the cyclodextrin is an hyperbranched cyclodextrin-based polymer (HBCD-Pol) or a derivative thereof, then the nutraceutical may comprise also one or more other ingredients as active principles.
  • HBCD-Pol hyperbranched cyclodextrin-based polymer
  • mice model which was injected with MSU in the knee was developed and the cyclodextrin samples according to the invention were injected alone and in combination with different anti-gout drugs (Allopurinol, Probenecid, Colchicine and Febuxostat) and bioactive compounds (Resveratrol and Oxyresveratrol).
  • anti-gout drugs Allopurinol, Probenecid, Colchicine and Febuxostat
  • bioactive compounds Resveratrol and Oxyresveratrol
  • the cyclodextrin according to the invention selected from the group consisting of hydroxypropyl [3-cyclodextrin (HP[3-CD and hyperbranched cyclodextrin-based polymers (HBCD-Pol) showed a higher efficacy in the treatment and in the prevention according to the present invention.
  • the results demonstrated a decrease of inflammation correlated to the use of the cyclodextrin, preferably HBCD-Pol and in combination with drugs, giving a combinatorial effect.
  • UA inclusion complexes were prepared as follows: 25 mg of pure AU with 100 mg of HP[3-CD were added to 50 mL of milliQ water and stirred for 12 h. This suspension was lyophilized using a LyoQuest (Telstar) and the powder was conserved in a darkness dried environment.
  • Example 4 HPB-CD increase the release of UA from MSU in dialysis system.
  • the second was 1 -2% HP[3-CD (6.8-13.6mM) in the donor phase with the MSU (called “inside”) and the third comprised the addition of 1 % HP[3-CD in the receptor phase (called “outside”).
  • the results are presented in figure 3B: the presence of HP[3-CD inside (in the donor phase) increased the release of UA above all in the first times of the study, achieving more or less the same UA released at 24h.
  • the presence of HP[3-CD outside increased the release of UA due to the effect of the inclusion complex formation in the equilibria (Figure 3C).
  • the results corroborate the idea of the formation of the inclusion complex and its capacity to dissolve the MSU deposits.
  • the cut-off of the dialysis membrane suggested that a continuous administration (the stable presence in blood) of HP
  • Hyper-branched water-soluble [3-CD Polymers was prepared as reported [Trotta, F.; Caldera, F.; Cavalli, R.; Mele, A.; Punta, C.; Melone, L; Castiglione, F.; Rossi, B.; Ferro, M.; Crupi, V.; et al. Synthesis and Characterization of a Hyper-Branched Water-Soluble (3-Cyclodextrin Polymer. Beilstein J. Org. Chem. 2014, 10, 2586-2593, doi:10.3762/bjoc.10.271].
  • Novel HBCD-Pol of 1 :4 and 1 :8 (in this section HB1_4 and HB1_8) [3-CD:PMDA, and the classical 1 :12 but using HP
  • the mobile phase was pumped through the column at a flow rate of 1 ml/min and the samples (20 pl of a 1 mg/mL solution of prepared complexes as indicated in Example 2) were analyzed at 290 nm using a UV detector. While the sample with HBCD-Pol gave a value of 14.9 ⁇ 0.75 pg/mL, the complexes with HP[3-CD and SBE-CD gave 12.44 ⁇ 0.62 and 12.63 ⁇ 0.63 pg/mL respectively. As before, the differences between both commercial CDs are quite close (not statistically significative) although the polymer demonstrated higher complexation capacity.
  • HBCD-Pol of 1 :4 and 1 :8 (in this section HB1_4 and HB1_8), and 1 :12 using HP
  • Figure 4C the values of the increase of UA solubility were reported, it was clear a relationship between the crosslinker ratio, and the type of CD used.
  • Figure 4C showed the effect of different molar ratios (1 :4 and 1 :8 in comparison 1 :12, the used in HBCD-Pol) and the CD monomer (HP[3-CD instead of [3-CD).
  • mice model of gout was prepared according to bibliography (Torres, R.; Macdonald, L; Croll, S.D.; Reinhardt, J.; Dore, A.; Stevens, S.; Hylton, D.M.; Rudge, J.S.; Liu-Bryan, R.; Terkeltaub, R.A.; et al. Hyperalgesia, Synovitis and Multiple Biomarkers of Inflammation Are Suppressed by Interleukin 1 1nhibition in a Novel Animal Model of Gouty Arthritis. Ann. Rheum. Dis.
  • mice under isoflurane anesthesia acute gouty arthritis was caused by intra-articular injection of MSU crystals (0.5 mg) suspended in 20-pl endotoxin-free PBS into the tibio tarsal joint (ankle). Mice in the control group got a 20-pl intraarticular injection of sterile PBS.
  • HP[3-CD and HBCD-Pol different drugs and bioactive compounds with anti-gout effect were studied.
  • concentration of HP[3-CD was selected according to the highest value found in bibliography without toxicity (Tanaka, Y.; Yamada, Y.; Ishitsuka, Y.; Matsuo, M.; Shiraishi, K; Wada, K; Uchio, Y.; Kondo, Y.; Takeo, T.; Nakagata, N.; et al.
  • the tested drugs were Allopurinol (Xanthine oxidase inhibitor), colchicine (treat flares), Probenecid (increase renal excretion), Febuxostat (prevent damage to the joints, stop attacks of gout and reduce the size of gouty lumps) and bioactive compounds resveratrol and oxyresveratrol with Xanthine oxidase and ROS inhibitory effect were studied.
  • the dosages of the drugs were adopted from previous studies.
  • FIGS. 6A and 6B show the inflammation decrease at different times after the formulation administration. All the drugs tested decreased the inflammation in comparison with ankle control. In addition, each combination drug/cyclodextrin according to the invention increased noticeably the effectivity. Surprisingly, HP[3-CD and HBCD-Pol alone decreased the inflammation ratio after 24h of treatment, while at 6h was slightly increased. This behavior could be for the internal MSU mobilization, as our in vitro results suggested. At short times the blood UA concentration could be high and different pathways activate the inflammation; once the MSU deposit is clean, the inflammation would decrease.
  • liver enzymes AST (aspartate aminotransferase) and ALT (alanine aminotransferase), were evaluated as an indicator to illustrate the liver proper performance, so increased the level of these enzymes in the blood stream could be conducted as a liver damage (Nkosi, C.Z.; Opoku, A.R.; Terblanche, S.E. Effect of Pumpkin Seed (Cucurbita Pepo) Protein Isolate on the Activity Levels of Certain Plasma Enzymes in CCI4-lnduced Liver Injury in Low-Protein Fed Rats. Phytother.
  • the combination achieved the improvement of the values of these biochemical parameters, obtaining values similar to or close to the control values (healthy subjects).
  • colchicine toxicity was decreased with HP[3-CD and HBCD-Pol respectively, being the combination values near to control one.
  • all the combinations decreased the values obtained with free drug, being a proof of the combination reduced the toxicity at the same time that increased the efficacy of the drug.
  • Cytokines were the molecules responsible of the immune response and inflammation.
  • IL-1 is the principal agent in the flare cascade caused by MSU (Dalbeth, N.; Merriman, T.R.; Stamp, L.K. Gout. Lancet Lond. Engl. 2016, 388, 2039-2052, doi:10.1016/S0140-6736(16)00346-9.).
  • the final agent is the TNF-a, local mediator of the response.
  • the participation of IL-6 is generally admitted as a systemic agent in the immune response. For that reason, these 3 molecules were evaluated ( Figure 9,10,11 ).
  • the values of IL-1 [3 were always decreased in presence of the combinations. The same behavior happens for IL-6 and TNF-a. Surprisingly, the administration of free combinations seemed to increase the values of these cytokines in comparison with the healthy control.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un complexe cyclodextrine d'acide urique, la cyclodextrine étant choisie dans le groupe constitué par l'hydroxypropyl-β-cyclodextrine (HPβ-CD), la sulfobutyléther-β-cyclodextrine (SBEβ-CD), la méthyl-β-cyclodextrine (Mβ-CD) et les polymères à base de cyclodextrine hyper-ramifiés (HBCD-Pol). L'invention concerne également une cyclodextrine destinée à être utilisée dans la prévention et dans le traitement de l'hyperuricémie ou de la goutte.
PCT/EP2023/087380 2022-12-23 2023-12-21 Dérivés de cyclodextrine pour le traitement de la goutte et de l'hyperuricémie Ceased WO2024133757A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102022000026808 2022-12-23
IT102022000026808A IT202200026808A1 (it) 2022-12-23 2022-12-23 Derivati ciclodestrinici per il trattamento della gotta e della iperuricemia

Publications (1)

Publication Number Publication Date
WO2024133757A1 true WO2024133757A1 (fr) 2024-06-27

Family

ID=85461952

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/087380 Ceased WO2024133757A1 (fr) 2022-12-23 2023-12-21 Dérivés de cyclodextrine pour le traitement de la goutte et de l'hyperuricémie

Country Status (2)

Country Link
IT (1) IT202200026808A1 (fr)
WO (1) WO2024133757A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1256095C (zh) * 2004-12-13 2006-05-17 天津大学 环糊精－纤维素尿酸吸附剂的制备方法
CN113952327A (zh) * 2021-10-25 2022-01-21 大连理工大学 N-乙酰半胱氨酸、2-羟丙基-β-环糊精或开环葫芦脲在预防或治疗痛风方面的用途
CN115463109A (zh) * 2022-09-24 2022-12-13 重庆医科大学 一种仿生融合膜包裹尿酸酶和过氧化氢酶纳米粒及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1256095C (zh) * 2004-12-13 2006-05-17 天津大学 环糊精－纤维素尿酸吸附剂的制备方法
CN113952327A (zh) * 2021-10-25 2022-01-21 大连理工大学 N-乙酰半胱氨酸、2-羟丙基-β-环糊精或开环葫芦脲在预防或治疗痛风方面的用途
CN115463109A (zh) * 2022-09-24 2022-12-13 重庆医科大学 一种仿生融合膜包裹尿酸酶和过氧化氢酶纳米粒及其制备方法

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CHEN CHEN ET AL: "Monosodium urate crystals with controlled shape and aspect ratio for elucidating the pathological progress of acute gout", BIOMATERIALS ADVANCES, ELSEVIER, AMSTERDAM, NL, vol. 139, 25 June 2022 (2022-06-25), XP087141888, ISSN: 2772-9508, [retrieved on 20220625], DOI: 10.1016/J.BIOADV.2022.213005 *
DALBETH, N.MERRIMAN, T.R.STAMP, L.K, GOUT. LANCET LOND. ENGL., vol. 388, 2016, pages 2039 - 2052
DALBETH, N.MERRIMAN, T.R.STAMP, L.K. GOUT, LANCET LOND. ENGL, vol. 388, 2016, pages 2039 - 2052
LONGZHEN ZHENG ET AL: "Selective Determination of Uric Acid by Using a [beta]-Cyclodextrin Modified Electrode", ELECTROANALYSIS, VHC PUBLISHERS, INC, US, vol. 13, no. 16, 5 November 2001 (2001-11-05), pages 1351 - 1354, XP071934045, ISSN: 1040-0397, DOI: 10.1002/1521-4109(200111)13:16<1351::AID-ELAN1351>3.0.CO;2-F *
NKOSI, C.Z.OPOKU, A.R.TERBLANCHE, S.E.: "Effect of Pumpkin Seed (Cucurbita Pepo) Protein Isolate on the Activity Levels of Certain Plasma Enzymes in CCI4-Induced Liver Injury in Low-Protein Fed Rats", PHYTOTHER. RES. PTR, vol. 19, 2005, pages 341 - 345
TANAKA, Y.YAMADA, Y.ISHITSUKA, Y.MATSUO, M.SHIRAISHI, K.WADA, K.UCHIO, Y.KONDO, Y.TAKEO, T.NAKAGATA, N. ET AL.: "Efficacy of 2-Hydroxypropyl-β-Cyclodextrin in Niemann-Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease", BIOL. PHARM. BULL, vol. 38, 2015, pages 844 - 851
TORRES, R.MACDONALD, LCROLL, S.D.REINHARDT, J.DORE, A.STEVENS, S.HYLTON, D.M.RUDGE, J.S.LIU-BRYAN, R.TERKELTAUB, R.A. ET AL.: "Hyperalgesia, Synovitis and Multiple Biomarkers of Inflammation Are Suppressed by Interleukin 1 Inhibition", A NOVEL ANIMAL MODEL OF GOUTY ARTHRITIS. ANN. RHEUM. DIS, vol. 68, 2009, pages 1602 - 1608, XP055796891, DOI: 10.1136/ard.2009.109355
TREVISAN, G.HOFFMEISTER, C.ROSSATO, M.F.OLIVEIRA, S.M.SILVA, M.A.INEU, R.P.GUERRA, G.P.MATERAZZI, S.FUSI, C.NASSINI, R. ET AL.: "Transient Receptor Potential Ankyrin 1 Receptor Stimulation by Hydrogen Peroxide Is Critical to Trigger Pain during Monosodium Urate-Induced Inflammation in Rodents", ARTHRITIS RHEUM., vol. 65, 2013, pages 2984 - 2995
TROTTA, F.CALDERA, F.CAVALLI, R.MELE, A.PUNTA, C.MELONE, L.CASTIGLIONE, F.ROSSI, B.FERRO, M.CRUPI, V. ET AL.: "Synthesis and Characterization of a Hyper-Branched Water-Soluble (3-Cyclodextrin Polymer", BEILSTEIN J. ORG. CHEM., vol. 10, 2014, pages 2586 - 2593

Also Published As

Publication number Publication date
IT202200026808A1 (it) 2024-06-23

Similar Documents

Publication Publication Date Title
Bhosle et al. Mutual Prodrug Concept: F Mutual Prodrug Concept: Fundamentals and undamentals and Applications
JP4923144B2 (ja) スルホアルキルエーテルシクロデキストリン組成物
Koppisetti et al. Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review
JPH0370705B2 (fr)
JP2002507582A (ja) 鉄欠乏症の予防または治療のための治療組成物の成分として用いる鉄−デキストラン化合物、前記鉄−デキストラン化合物の製造法、および非経口投与可能な治療組成物の製造のための前記化合物の使用
EA020784B1 (ru) Комплекс включения пиноцембрина с циклодекстрином, способ его получения и применения
Wang et al. Pterostilbene: a potential therapeutic agent for fibrotic diseases
WO2024133757A1 (fr) Dérivés de cyclodextrine pour le traitement de la goutte et de l&#39;hyperuricémie
WO2023154939A2 (fr) Inhibition de gcpii pour le traitement de la sarcopénie et du vieillissement
RU2566065C2 (ru) Комплекс гарцинола и циклодекстрина и способ его применения
KR20250079143A (ko) 기능화된 폴리머의 의학적 용도
CN114558004B (zh) Qtx125药物制剂
Banerjee Beneficial role of Curcumin in preventing the aggregation of the amyloid-β peptide in Alzheimer’s disease
JP2017534687A (ja) 配合剤
Wu et al. Curcumin nanoparticles and the therapeutic potential of curcumin for musculoskeletal disorders.
CN112826796B (zh) 一种纳米粒在制备治疗胆囊相关疾病的药物中的应用
JP2016518422A (ja) 癌の治療および予防のための（＋）‐カテキンおよびアミノ酸の複合体を含む組成物
Oliveira N-Acetylcysteine (nac): impacts on human health
Nayak et al. Synthesis and evaluation of amide codrug of ibuprofen and amlodipine for dual inhibition of inflammation and hypertension
WO2011121645A1 (fr) Inhibiteur de formation de fibrilles amyloïdes
CN117551008B (zh) 一种去铁胺偶联物及其制备方法和应用
CA2561660C (fr) Compositions pharmaceutiques de pyrimidine-2,4,6-triones
Matencio et al. Commercial and non-commercial cyclodextrin derivatives as a novel therapy to improve gout’s disease and hyperuricemia
Abousamra et al. Effect of methyl-Β-cyclodextrin complexation on the hypoglycemic and hypolipidemic effects of khellin: Experimental study
JP2024013888A (ja) 慢性腎臓病進行抑制剤

Legal Events

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

Ref document number: 23838032

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23838032

Country of ref document: EP

Kind code of ref document: A1