WO2016171656A1 - Préparations à base de diacéréine et procédés de réduction des taux d'acide urique sanguins grâce à l'utilisation de cette dernière - Google Patents

Préparations à base de diacéréine et procédés de réduction des taux d'acide urique sanguins grâce à l'utilisation de cette dernière Download PDF

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Publication number
WO2016171656A1
WO2016171656A1 PCT/US2015/026678 US2015026678W WO2016171656A1 WO 2016171656 A1 WO2016171656 A1 WO 2016171656A1 US 2015026678 W US2015026678 W US 2015026678W WO 2016171656 A1 WO2016171656 A1 WO 2016171656A1
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WO
WIPO (PCT)
Prior art keywords
release layer
rhein
diacerein
weight
formulation
Prior art date
Application number
PCT/US2015/026678
Other languages
English (en)
Inventor
Carl Oscar BROWN III
Hanpin Lim
Wei-Shu Lu
Tien-Kuen Chung
Chi-Kuang Chen
Original Assignee
Twi Biotechnology, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA2983394A priority Critical patent/CA2983394A1/fr
Application filed by Twi Biotechnology, Inc. filed Critical Twi Biotechnology, Inc.
Priority to KR1020177032849A priority patent/KR20180013880A/ko
Priority to BR112017022509A priority patent/BR112017022509A2/pt
Priority to RU2017140079A priority patent/RU2690372C2/ru
Priority to JP2017555702A priority patent/JP2018513203A/ja
Priority to EP15890063.9A priority patent/EP3285754A4/fr
Priority to MX2017013489A priority patent/MX2017013489A/es
Priority to AU2015392441A priority patent/AU2015392441A1/en
Priority to PCT/US2015/026678 priority patent/WO2016171656A1/fr
Priority to CN201580081063.7A priority patent/CN107708681A/zh
Publication of WO2016171656A1 publication Critical patent/WO2016171656A1/fr
Priority to IL255073A priority patent/IL255073A0/en
Priority to CONC2017/0011722A priority patent/CO2017011722A2/es

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a diacerein formulation, especially to a method of lowering blood levels of uric acid using this formulation.
  • rhein is 9, 10-dihydro-4, 5-dihydroxy-9, lO-dioxo-2-anthracene carboxylic acid having a structure of Formula (I), and one of its prodrugs, diacerein, is 4, 5-bis (acetyloxy) 9, 10-dihydro-4, 5-dihydroxy-9, lO-dioxo-2-anthracenecarboxylic acid having a structure of Formula (II).
  • Diacerein is entirely converted into rhein before reaching the systemic circulation, and exerts its physiological function in form of rhein within the body.
  • Diacerein is an anti-inflammatory agent widely used in the treatment of osteoarthritis, which has been demonstrated to inhibit interleukin- 1 (IL-1) signaling.
  • diacerein capsules are available in 50 mg strength and are marketed under various trade names in different countries, including Art 50 ® , Artrodar ® , etc.
  • diacerein can also be used as an adjunctive treatment for type II diabetes mellitus.
  • diacerein can be administered by oral route, it cannot be completely absorbed by the digestive tract, and the oral bioavailability of diacerein has been estimated to be approximately 40% to 60%. The incomplete absorption of diacerein may result in undesirable side effects such as diarrhea or soft stools.
  • diacerein As disclosed in US patent No. 8,865,689, diacerein was found to be effective in reducing the blood uric acid levels, and can be used for treating hyperuricemia or a metabolic disorder associated with hyperuricemia. However, no diacerein formulations specific for lowering the blood uric acid levels have been developed so far.
  • the present invention provides a diacerein formulation having improved properties, as well as its uses in treating diseases including, but not limited to, hyperuricemia, a metabolic disorder associated with hyperuricemia, osteoarthritis and type 2 diabetes mellitus.
  • the invention provides a controlled-release formulation with reduced adverse side effects and/or higher bioavailability, comprising an immediate-release layer and an extended-release layer.
  • this invention provides a method of lowering blood levels of uric acid in a subject, comprising administering the above controlled-release formulation to the subject in need thereof.
  • this invention provides a method of lowering blood levels of uric acid in a subject, comprising administering to the subject in need thereof a formulation containing a therapeutically effective amount of a compound selected from the group consisting of diacerein, rhein, monoacetylrhein, a prodrug and a pharmaceutically acceptable salt thereof, wherein when the formulation is administered to said subject it provides at least one of the following pharmacokinetic parameters: (i) a maximum plasma concentration C ma x of rhein above 5.0 ⁇ g/ml; (ii) an area under the concentration time curve AUCo-t or AUCo- ⁇ of rhein above 35.0 ⁇ g ⁇ hr/ml; (iii) T max of about 3 to 4.5 hours after oral administration to the subject under a fed condition; and (iv) a plasma concentration of rhein above 2.8 ⁇ g/ml for at least 4 hours.
  • this invention provides a method of lowering blood levels of uric acid in a subject, comprising administering to the subject in need thereof a formulation containing at least about 75 mg of a compound selected from the group consisting of diacerein, rhein, monoacetylrhein, a prodrug and a pharmaceutically acceptable salt thereof.
  • FIG. 1 shows the dissolution profiles of the controlled-release formulations A and F of the present invention, measured by the United States Pharmacopeia (USP) Apparatus II (Paddle) at 50 rpm in 900 ml of pH 6.8 PBS at 37°C;
  • USP United States Pharmacopeia
  • FIG. 2 is a statistical bar graph showing inhibition of uric acid uptake by different doses of rhein
  • FIG. 3 shows the average plasma concentration-time profiles of rhein after subjects received treatment with different diacerein formulations
  • FIG. 4 is a statistical bar graph showing the serum uric acid concentrations before and after the treatment with different diacerein formulations.
  • IR immediate-Release
  • Controlled-Release or "CR” and “Extended-Release” or “ER,” as used herein, refers to the gradual release of a drug at a predetermined rate other than an immediate release manner over a period of time.
  • terapéuticaally effective amount refers to an amount that alleviates or reduces one or more symptoms of a disease.
  • C max refers to the maximum observed plasma concentration, calculated as the mean of the individual maximum blood plasma concentrations.
  • average plasma concentration refers to the arithmetic mean blood plasma concentration.
  • T max refers to the time at which the peak (maximum) observed blood plasma drug concentration for each individual participating in the bioavailability study.
  • AUCo- ⁇ or "AUCinf,” as used herein, refers to the mean area under the plasma/serum/blood concentration-time curve extrapolated to infinity. It is calculated as the arithmetic mean of the area under the plasma concentration-time curve from time zero extrapolated to infinity, calculated for each individual participating in the bioavailability study.
  • AUCo-t refers to the area under the plasma/serum/blood concentration-time curve from time zero to time t, where "t" is the last sampling time point with measurable concentration for individual formulation.
  • diacerein or its analogs refers to diacerein, rhein, monoacetylrhein, or a pharmaceutically acceptable salt or a prodrug thereof.
  • the terms "a (an)”, “the” or the like used in this specification shall be understood to encompass both the singular form and the plural form.
  • the present invention provides a controlled-release formulation, comprising an immediate-release layer and an extended-release layer.
  • the immediate-release layer comprises a therapeutically effective amount of a compound selected from the group consisting of diacerein, rhein, monoacetylrhein, a prodrug and a pharmaceutically acceptable salt thereof (hereinafter referred to as "diacerein or its analogs"); a filler; a binder; a disintegrant; and a lubricant; and the extended-release layer comprises a therapeutically effective amount of diacerein or its analogs, a controlled-release polymer, a filler, and a lubricant; and wherein the weight ratio of diacerein or its analogs in the immediate-release layer to that in the extended-release layer is about 2: 1 to about 1 :9.
  • the formulation further comprises a cosmetic coating.
  • the immediate-release layer comprises about 5% to about 60% by weight, preferably about 5% to about 50% by weight of diacerein or its analogs; about 30% to about 95% by weight, preferably about 40% to about 85% by weight of a filler; about 0.1% to about 20% by weight, preferably about 1% to about 10% by weight of a binder; about 0.1% to about 20% by weight, preferably about 1% to about 10% by weight of a disintegrant; and about 0.01% to about 5% by weight, preferably about 0.1% to about 2.5% by weight of a lubricant, based on the total weight of the immediate-release layer; and the extended-release layer comprises about 5% to about 60% by weight, preferably about 5% to about 50% by weight of diacerein or its analogs; about 1% to about 60% by weight, preferably about 10% to about 50% by weight of a controlled-release polymer; about 1% to about 70% by weight, preferably about 10% to about 55% by weight of a filler;
  • fillers include, but are not limited to, lactose monohydrate, lactose anhydrous, and starches.
  • the filler is lactose monohydrate.
  • binders include, but are not limited to, povidone, starch, gelatin, tragacanth, methylcellulose, hypromellose, and hydroxypropylcellulose.
  • the binder is povidone.
  • Suitable disintegrants include, but are not limited to, sodium carboxymethylcellulose, L-hydroxypropylcellulose, cropovidone, corn starch, sodium starch glycolate, starch, croscarmellose sodium, and alginic acid or its sodium salt.
  • the disintegrant is croscarmellose sodium.
  • Suitable lubricants include, but are not limited to, light anhydrous silicic acid, talc, stearic acid and its zinc, magnesium, or calcium salt, and polyethyleneglycol.
  • the lubricant is magnesium stearate.
  • Controlled-release polymers that can be used in the present invention may be, for instance, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and its derivatives, polyanhydrides, polyaminoacids, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, carboxymethylamide, potassium methacrylate/divinylbenzene copolymer, starches and their derivatives, ⁇ -cyclodextrin, dextrin derivatives with linear or branched chains, ethyl cellulose, methyl cellulose, meth
  • the formulation of the invention can deliver a higher dose of diacerein without increasing the side effects like diarrhea.
  • it can be administered to patients with a higher dose compared to the commercial diacerein drugs (e.g., Artrodar ® , 50 mg Q.D. or B.I.D, 50 or 100 mg daily in total), and may contain at least about 75 mg, preferably about 75 to 200 mg, more preferably about 75 to 100 mg of diacerein or its analogs, thereby enhancing the treatment effect in a single dose.
  • the commercial diacerein drugs e.g., Artrodar ® , 50 mg Q.D. or B.I.D, 50 or 100 mg daily in total
  • the commercial diacerein drugs e.g., Artrodar ® , 50 mg Q.D. or B.I.D, 50 or 100 mg daily in total
  • the commercial diacerein drugs e.g., Artrodar ® , 50 mg Q.D. or B.I.D, 50 or 100 mg daily in
  • the inventors of the present application found that the formulation containing at least about 75 mg of diacerein is more effective in reducing blood levels of uric acid than Artrodar ® (an immediate-release formulation containing 50 mg of diacerein).
  • the formulation of the invention comprises preferably at least about 75 mg, more preferably about 75 to 200 mg, most preferably about 75 to 100 mg of diacerein or its analogs.
  • the controlled-release formulation preferably has an in vitro dissolution rate when measured by the United States Pharmacopeia (USP) Apparatus II (Paddle) at 50 rpm in 900 ml of pH 6.8 PBS at 37°C, between about 30% and about 45%, preferably about 35% and about 40%, diacerein released after 1 hour; between about 50% and about 60% diacerein released after 4 hours; between about 60% and about 75%, preferably about 65% and about 75%, diacerein released after 8 hours; and not less than about 80% diacerein released after 16 hours, by weight.
  • USP United States Pharmacopeia
  • the controlled-release formulation of the invention when administered to a subject, may provide at least one of the following pharmacokinetic parameters: (i) a maximum plasma concentration C max of rhein above 5.0 ⁇ g/ml; (ii) an area under the concentration time curve AUCo-t or AUCo- ⁇ of rhein above 35.0 ⁇ g ⁇ hr/ml; (iii) T max of about 3 to 4.5 hours after oral administration to a subject under a fed condition; and (iv) a plasma concentration of rhein above 2.8 ⁇ g/ml for at least 4 hours.
  • a formulation exhibiting the above pharmacokinetic parameters shows reduced adverse side effects, reduced food effect, higher bioavailability, and/or better effect in reducing the blood uric acid levels as compared to the conventional immediate-release formulation.
  • the formulation is a once-daily (i.e., taken once per day) controlled-release formulation.
  • the formulation of the invention has the above-mentioned advantages, it is beneficial when used for treating all the diseases to which diacerein is therapeutically effective.
  • diseases include, but are not limited to, hyperuricemia, a metabolic disorder associated with hyperuricemia, osteoarthritis and type 2 diabetes mellitus.
  • the metabolic disorder associated with hyperuricemia includes, but is not limited to, acute gout, chronic gout, gout arthritis, gout flares, uric acid nephrolithiasis, gouty nephropathy, cardiovascular diseases (e.g., hypertension and atherosclerosis), obesity, chronic kidney disease, and insulin resistance.
  • the formulation can be used for decreasing inflammatory effects of gout arthritis and gout flares induced by hyperuricemia; and/or dissolving kidney stones; and/or reducing the recurrence rate of acute inflammatory arthritis induced by hyperuricemia; and/or slowing down the progression of urate nephropathy in a subject.
  • the formulation may further comprise one or more additional therapeutic agent, such as an anti-inflammatory agent or a urate-lowering agent to enhance the therapeutic effect of diacerein.
  • additional therapeutic agent such as an anti-inflammatory agent or a urate-lowering agent to enhance the therapeutic effect of diacerein.
  • anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs ( SAIDs), corticosteroids, and colchicines.
  • urate-lowering agents include, but are not limited to, xanthine oxidase inhibitors, uricosuric agents, urate oxidases, urinary alkalinizers, and fenofibrate.
  • the present invention also provides a method of lowering blood levels of uric acid in a subject, comprising administering to the subject in need thereof a formulation containing diacerein or its analogs.
  • the formulations that can be used in this method may have the structure, composition and other properties as those defined above for the formulation of the present invention.
  • the formulations suitable for this method may have different structure and composition as long as when administered to a subject they can provide at least one of the following pharmacokinetic parameters: (i) a maximum plasma concentration C max of rhein above 5.0 ⁇ g/ml; (ii) an area under the concentration time curve AUCo-t or AUCo- ⁇ of rhein above 35.0 ⁇ g ⁇ hr/ml; (iii) T max of about 3 to 4.5 hours after oral administration to the subject under a fed condition; and (iv) a plasma concentration of rhein above 2.8 ⁇ g/ml for at least 4 hours.
  • the formulation used in the method contains at least about 75 mg, preferably about 75 to 200 mg, more preferably about 75 to 100 mg of diacerein or its analogs.
  • Total Coated Tablet Weight 368.84 100 368.83 100 368.83 100 368.83 100 368.83 100 368.83 100 368.83 100
  • Table 2 summarizes the raw data of the dissolution of Tablets A and F of the present invention, and FIG. 1 shows the dissolution profiles.
  • Uric acid is mainly eliminated through urinary excretion and up to 90% of filtered urate is re-absorbed. A decrease in an excretion rate of urate is considered to elevate serum uric acid, resulting in hyperuricemia.
  • URAT1 urate transporter 1, the SLC22A12 gene
  • URAT1 has been genetically associated with urate levels, and inhibition of URAT1 may decrease serum uric acid.
  • the transfected HEK293T cells After 24h to 72h incubation of the transfected HEK293T cells, they were reseeded in a microplate. At least 12 hours after the cell plated, the culture medium was removed and the cells were washed and then incubated in a 100 ⁇ Cl-free HBSS Buffer for 5 to 10 mins. The buffer was removed and 50 ⁇ per well of Cl-free HBSS Buffer containing 50 ⁇ uric acid [ 8"14 C] ( ⁇ . ⁇ ) was added with or without rhein (under four doses, 30, 10, 3.3 and 1.1 ⁇ ) to the cells incubated for 5 mins at 37°C. At the end of the incubation, uric acid [ 8 14 C] uptake was stopped.
  • FIG. 2 shows that the uptake of uric acid was inhibited by rhein at 3.3 and 10 uM for 49.4% ⁇ 22.2%, and at 30 uM for 79.3% ⁇ 1.5%.
  • IC 50 of rhein in URAT 1 inhibition is 10 uM, which is about 2.8 ug/ml. Maintenance of plasma rhein concentration exceed 2.8 ug/ml may perform uric acid lowering effect.
  • a Phase 1, randomized, open-Label, single dose, 4-Treatment, 4-sequence, 4-period, crossover, pharmacokinetic study of a diacerein immediate-release formulation (Artrodar ® 50 mg Capsule) and three different doses of the diacerein controlled-release formulations of the present invention was conducted in healthy male and female volunteers under fed conditions.
  • Treatment B 1 x 75 mg Tablet
  • Treatment C 1 x 100 mg Tablet
  • Treatment D 2 x 100 mg Tablet (200 mg).
  • the comparison between the different formulations and doses is based on a comparison within subjects rather than between subjects.
  • the washout period of 7 days was estimated to be adequate in avoiding carry-over effects of the preceding treatments.
  • AUC 0 _ t AUC 0 _ ⁇ , C max , and T max for rhein in plasma of per-protocol (PP) population were determined and calculated by non-compartment methods. Analysis of Variance (ANOVA) was used for AUC 0 _ t , AUC 0 _ ⁇ . C max , and T max . T max was analyzed using an additional non-parametric test (Wilcoxon test).
  • Safety assessment was performed for all subjects who had been administered at least one dose of the study drug.
  • the investigator obtained and recorded all observed adverse events (AEs) on the CRF or those voluntarily reported, including its intensity and relationship assessment with the investigational products.
  • AEs adverse events
  • the investigator pursued and obtained information adequate to determine both the outcome of the AE and whether it met any seriousness criterion. All AEs had to be followed up until resolution or stabilization at a level acceptable to the investigator.
  • the controlled-release formulations of the present invention exhibited C max of rhein above 5.0 ⁇ g/ml, AUCo-t or AUCo- ⁇ of rhein above 35.0 ⁇ g ⁇ hr/ml, and T max of about 3 to 4.5 hours.
  • the formulations of the invention provided a blood concentration of rhein above 2.8 ug/ml (the treatment effective concentration in Example 2) for at least 4 hours (Treatment B: 4.2 hours; Treatment C: 7 hours; Treatment D: 12.7 hours) and had greater bioavailability than the commercial immediate-release formulation, with about 10% greater dose-normalized AUC and C max values. It was found that AUC and C max values increased generally proportional with increasing doses of diacerein.
  • the controlled-release formulations at 75 mg and 100 mg had similar tolerability to the immediate-release formulation at 50 mg, while the 200 mg dose was associated with a higher gastrointestinal AE incidence. Therefore, compared to Artrodar formulation, the formulations of the invention demonstrated improved safety in higher dose strengths at 75 mg and 100 mg, and provided reduced adverse side effects accordingly. This allows patients to be treated with a higher dose at 75 or 100 mg once per day without increasing the side effects.
  • Serum uric acid reduction valuation in the study of diacerein immediate-release formulation (Artrodar ® 50 mg Capsule) and three different doses of the diacerein controlled-release formulations of the present invention in healthy volunteers under fed conditions was conducted.
  • Example 3 In the pharmacokinetic study of Example 3, the effects of Artrodar ® 50 mg and three different doses of the tablets of the present invention (75, 100 and 200 mg) on serum uric acid of healthy volunteers under fed conditions were also post-analyzed for intend-to-treat (ITT) population. A total of 15 subjects were analyzed. The serum uric acid concentrations were compared by before and after treatments with paired t-test analysis.

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Abstract

L'invention concerne une préparation à libération contrôlée à base de diacéréine ou de ses analogues. L'invention concerne également un procédé de réduction des taux d'acide urique sanguins grâce à l'utilisation de cette préparation. Selon un mode de réalisation, l'invention concerne une formulation à libération contrôlée ayant peu d'effets secondaires indésirables et/ou une biodisponibilité plus élevée, comprenant une couche à libération immédiate et une couche à libération prolongée.
PCT/US2015/026678 2015-04-20 2015-04-20 Préparations à base de diacéréine et procédés de réduction des taux d'acide urique sanguins grâce à l'utilisation de cette dernière WO2016171656A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
EP15890063.9A EP3285754A4 (fr) 2015-04-20 2015-04-20 Préparations à base de diacéréine et procédés de réduction des taux d'acide urique sanguins grâce à l'utilisation de cette dernière
KR1020177032849A KR20180013880A (ko) 2015-04-20 2015-04-20 디아세레인을 함유하는 제제 및 이를 이용하여 요산의 혈중 농도를 감소시키는 방법
BR112017022509A BR112017022509A2 (pt) 2015-04-20 2015-04-20 formulações contendo diacereína e métodos de redução dos níveis sanguíneos de ácido úrico usando as mesmas
RU2017140079A RU2690372C2 (ru) 2015-04-20 2015-04-20 Лекарственные средства, содержащие диацереин, и способы снижения уровней мочевой кислоты в крови с его использованием
JP2017555702A JP2018513203A (ja) 2015-04-20 2015-04-20 ジアセレインを含有する製剤及びそれを用いて尿酸の血中濃度を低下させる方法
CA2983394A CA2983394A1 (fr) 2015-04-20 2015-04-20 Preparations a base de diacereine et procedes de reduction des taux d'acide urique sanguins grace a l'utilisation de cette derniere
MX2017013489A MX2017013489A (es) 2015-04-20 2015-04-20 Formulaciones que contienen diacereina y metodos para la reduccion de los niveles en sangre de acido urico usando los mismos.
CN201580081063.7A CN107708681A (zh) 2015-04-20 2015-04-20 含有双醋瑞因的制剂及使用其降低尿酸血液水平的方法
PCT/US2015/026678 WO2016171656A1 (fr) 2015-04-20 2015-04-20 Préparations à base de diacéréine et procédés de réduction des taux d'acide urique sanguins grâce à l'utilisation de cette dernière
AU2015392441A AU2015392441A1 (en) 2015-04-20 2015-04-20 Formulations containing diacerein and methods of lowering blood levels of uric acid using the same
IL255073A IL255073A0 (en) 2015-04-20 2017-10-16 Formulations containing diacerein and methods of using them to lower the amount of uric acid in the blood
CONC2017/0011722A CO2017011722A2 (es) 2015-04-20 2017-11-17 Formulaciones que contienen diacereína y métodos que las utilizan para disminuir el nivel del ácido úrico en sangre

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JP (1) JP2018513203A (fr)
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AU (1) AU2015392441A1 (fr)
BR (1) BR112017022509A2 (fr)
CA (1) CA2983394A1 (fr)
CO (1) CO2017011722A2 (fr)
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US20110311594A1 (en) * 2010-06-22 2011-12-22 Shou-Chiung Chen Controlled release compositions with reduced food effect
US20120232044A1 (en) * 2011-03-11 2012-09-13 Twi Biotechnology, Inc. Methods and compositions for treating hyperuricemia and metabolic disorders associated with hyperuricemia

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TWI473610B (zh) * 2008-10-28 2015-02-21 Twi Biotechnology Inc 包含雙醋瑞因（ｄｉａｃｅｒｅｉｎ）之醫藥組合物
KR101190708B1 (ko) * 2010-03-12 2012-10-12 주식회사 대웅제약 모사프리드 또는 이의 염을 포함하는 서방형 약학 조성물
BR112012032033A2 (pt) * 2010-06-16 2017-10-31 Takeda Pharmaceuticals Usa Inc novas formas de dosagem de libertação modificada de inibidor de xantina oxidorredutase ou inibidores de xantina oxidase

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US20110311594A1 (en) * 2010-06-22 2011-12-22 Shou-Chiung Chen Controlled release compositions with reduced food effect
US20120232044A1 (en) * 2011-03-11 2012-09-13 Twi Biotechnology, Inc. Methods and compositions for treating hyperuricemia and metabolic disorders associated with hyperuricemia

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IL255073A0 (en) 2017-12-31
JP2018513203A (ja) 2018-05-24
EP3285754A4 (fr) 2018-12-19
EP3285754A1 (fr) 2018-02-28
CN107708681A (zh) 2018-02-16
CA2983394A1 (fr) 2016-10-27
KR20180013880A (ko) 2018-02-07
AU2015392441A1 (en) 2017-11-09
BR112017022509A2 (pt) 2018-07-17
RU2017140079A3 (fr) 2019-05-20
RU2017140079A (ru) 2019-05-20
RU2690372C2 (ru) 2019-06-03
CO2017011722A2 (es) 2018-04-19
MX2017013489A (es) 2018-05-22

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