JP2018513203A - Formulation containing diacerein and method for reducing blood concentration of uric acid using the same - Google Patents

Abstract

Controlled release formulations containing diacerein or analogs thereof are provided. Also provided is a method of reducing the blood concentration of uric acid using this formulation. In one embodiment, the present invention provides a controlled release formulation with reduced adverse side effects and / or higher bioavailability, comprising an immediate release layer and a sustained release layer.

Description

  The present invention relates to a diacerein preparation, and in particular to a method for reducing the blood concentration of uric acid using this preparation.

Chemically, lane is 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracenecarboxylic acid having the structure of formula (I), and one of its prodrugs diacerein is 4,5-bis (acetyloxy) 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracenecarboxylic acid having the structure of formula (II). Diacerein is completely converted to rain before reaching the systemic circulation and exerts its physiological functions in the form of rain in the body.
Formula (I)

式（ＩＩ）

Formula (II)

Diacerein is an anti-inflammatory agent that is widely used in the treatment of osteoarthritis that has been demonstrated to inhibit interleukin-1 (IL-1) signaling. Currently, diacerein capsules are available in 50 mg strength and are sold in various countries under various trade names including Art 50 ^(R) , Artrodar ^(R) , etc. As disclosed in US Pat. No. 8,536,152, diacerein can also be used as an adjuvant therapy for type II diabetes. Diacerein can be administered by the oral route, but cannot be completely absorbed by the gastrointestinal tract, and the oral bioavailability of diacerein is estimated to be approximately 40% to 60%. Incomplete absorption of diacerein may cause undesirable side effects such as diarrhea or loose stool. In vitro and in vivo studies have shown that unabsorbed diacerein is metabolized to lane in the colon, which subsequently induces laxative effects. Thus, there remains a need in the art for diacerein formulations that have reduced adverse side effects and / or higher bioavailability compared to current commercial formulations.

  As disclosed in US Pat. No. 8,865,689, diacerein has been found to be effective in reducing blood uric acid levels and is associated with hyperuricemia or hyperuricemia Can be used to treat metabolic disorders. However, no diacerein formulation specific to lowering blood uric acid levels has been developed so far.

US Pat. No. 8,536,152 US Pat. No. 8,865,689

  In view of the above needs, the present invention provides a diacerein formulation having improved properties, and, without limitation, hyperuricemia, metabolic abnormalities associated with hyperuricemia, osteoarthritis and type 2 diabetes Use of the formulation in treating diseases such as

  In one embodiment, the present invention provides a controlled release formulation with reduced adverse side effects and / or higher bioavailability, comprising an immediate release layer and a sustained release layer.

  In another embodiment, the present invention provides a method for lowering blood levels of uric acid in a subject, comprising administering the controlled release formulation to a subject in need thereof.

In another embodiment, the present invention provides a method of reducing blood levels of uric acid in a subject, comprising a therapeutically effective amount of diacerein, lane, monoacetyl lane, prodrug and pharmaceutically acceptable thereof. Provided is a method comprising administering to a subject in need thereof a formulation comprising a compound selected from the group consisting of a salt, the formulation having the following pharmacokinetic parameters when administered to said subject: (I) Maximum plasma concentration C _{max of} rain exceeding 5.0 μg / ml; (ii) Area AUC _0-t or AUC _0-∞ under concentration time curve of rain exceeding 35.0 μg · hr / ml; (iii) A) T _{max of} about 3 to 4.5 hours after oral administration to a fed subject; and (iv) a plasma concentration of at least 2.8 μg / ml for at least 4 hours Provide one.

  In another embodiment, the present invention is a method for reducing blood levels of uric acid in a subject, selected from the group consisting of diacerein, lane, monoacetyl lane, prodrug and pharmaceutically acceptable salts thereof. There is provided a method comprising administering a formulation containing at least about 75 mg of a compound to a subject in need thereof.

  In order that those skilled in the art will be able to fully appreciate the features of the present invention, the detailed techniques and preferred embodiments implemented for the present invention are described in the following paragraphs and the accompanying drawings.

FIG. 1 shows the dissolution profiles of controlled release formulations A and F of the present invention as measured by the United States Pharmacopeia (USP) apparatus II (paddle) at 37 ° C. in 50 rpm, 900 ml of PBS pH 6.8. FIG. 2 is a statistical bar graph showing the inhibition of uric acid intake by various doses of rain. FIG. 3 shows the mean plasma concentration time profile of Rain after the subject has been treated with various diacerein formulations. FIG. 4 is a statistical bar graph showing serum uric acid levels before and after treatment with various diacerein formulations.

  The term “immediate release” or “IR” as used herein means that a drug (eg, diacerein) is released in a conventional or unmodified manner.

  The terms “controlled release” or “CR” and “sustained release” or “ER” as used herein refer to the gradual release of a drug at a predetermined rate other than immediate release over a period of time.

  The term “therapeutically effective amount” as used herein refers to an amount that reduces or reduces one or more symptoms of a disease.

The term “C _max ” as used herein refers to the maximum observed plasma concentration calculated as the average of the individual maximum plasma concentrations.

  The term “mean plasma concentration” as used herein refers to the arithmetic mean of plasma concentrations.

The term “T _max ” as used herein refers to the time when a peak (maximum) is observed in plasma drug concentration for each individual who participated in a bioavailability study.

The term “AUC _0-∞ ” or “AUC _inf ” as used herein refers to the average area under an infinitely extrapolated plasma / serum / blood concentration time curve. This is calculated as the arithmetic mean of the area under the plasma concentration time curve extrapolated from time zero to infinity, calculated for each individual participating in the bioavailability study.

The term “AUC _0-t ” as used herein refers to the area under the plasma / serum / blood concentration time curve from time zero to time t, where “t” is for an individual formulation. It is the time when the last sample was collected at a measurable concentration.

  The term “diacelein or an analog thereof” as used herein refers to diacerein, lane, monoacetyl lane, or a pharmaceutically acceptable salt or prodrug thereof.

  Unless otherwise stated herein, the terms “a (an)”, “the”, etc. used herein (especially in the claims that follow) refer to both the singular and plural forms. It should be understood as including.

  As mentioned above, to improve the adverse side effects and / or bioavailability of diacerein, the present invention provides a controlled release formulation comprising an immediate release layer and a sustained release layer.

  In one embodiment, the immediate release layer is a compound selected from the group consisting of therapeutically effective amounts of diacerein, rhein, monoacetyllein, prodrugs and pharmaceutically acceptable salts thereof (hereinafter “ A sustained release layer comprising a therapeutically effective amount of diacerein or an analog thereof, a controlled release polymer, a filler, and a lubricant. Wherein the weight ratio of diacerein or analog thereof in the immediate release layer to diacerein or analog thereof in the sustained release layer is from about 2: 1 to about 1: 9.

  In one embodiment, the formulation further comprises a cosmetic coating.

  Preferably, in the formulations of the present invention, the immediate release layer is about 5% to about 60% by weight, preferably about 5% to about 50% by weight of diacerein or its, based on the total weight of the immediate release layer Analogue, about 30% to about 95% by weight, preferably about 40% to about 85% by weight filler, about 0.1% to about 20%, preferably about 1% to about 10% % Binder, about 0.1% to about 20% by weight, preferably about 1% to about 10% by weight disintegrant, and about 0.01% to about 5% by weight, preferably about 0.1%. 1% to about 2.5% by weight of the lubricant, and the sustained release layer is about 5% to about 60% by weight, preferably about 5% to about 50%, based on the total weight of the sustained release layer. % By weight of diacerein or an analog thereof, about 1% to about 60% by weight, preferably about 10% to 50 wt% controlled release polymer, about 1 wt% to about 70 wt%, preferably about 10 wt% to about 55 wt% filler, and about 0.01 wt% to about 5 wt%, preferably about 0 .1% to about 2.5% by weight of lubricant.

  Examples of fillers include but are not limited to lactose monohydrate, anhydrous lactose, and starch. Preferably, the filler is lactose monohydrate.

  Examples of binders include but are not limited to povidone, starch, gelatin, tragacanth, methylcellulose, hypromellose, and hydroxypropylcellulose. Preferably, the binder is povidone.

  Suitable disintegrants include, but are not limited to, sodium carboxymethylcellulose, L-hydroxypropylcellulose, clopovidone, corn starch, sodium starch glycolate, starch, croscarmellose sodium, and alginic acid or its sodium salt. . Preferably, 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 salts, and polyethylene glycol. Preferably, the lubricant is magnesium stearate.

  Controlled release polymers that can be used in the present invention include, for example, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol carboxy Vinyl polymer, polyvinyl alcohol, glucan, scleroglucan, mannan, xanthan, alginic acid and its derivatives, polyanhydride, polyamino acid, carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethylamide, potassium methacrylate / Divinylbenzene copolymer, starch and its derivatives, β-cycl Dextrin, dextrin derivatives having a linear or branched chain, ethylcellulose, methylcellulose, may be methacrylic acid copolymer, and cellulose derivatives. Preferably, the controlled release polymer is hydroxypropyl methylcellulose (HPMC).

Since the formulations of the present invention have reduced adverse side effects, higher doses of diacerein can be delivered without increasing side effects such as diarrhea. In particular, commercially available diacerein drug ^(e.g., Artrodar ^{(R), 50mgQ.D.} Or B.I.D, day 50 or 100mg in total) can be administered to a patient at a higher dose as compared to at least About 75 mg, preferably about 75-200 mg, more preferably about 75-100 mg of diacerein or an analog thereof may be included, thereby enhancing the therapeutic effect at a single dose.

In another aspect, the inventors of the present application have found that a formulation containing at least about 75 mg of diacerein reduces the blood concentration of uric acid to an Arttrodar® ⁽ immediate containing 50 mg of diacerein. The release formulation was found to be more effective. Therefore, the formulations of the present invention preferably comprise at least about 75 mg, more preferably about 75-200 mg, most preferably about 75-100 mg of diacerein or an analog thereof.

  In the dissolution test, the controlled release formulation is about 30% to about 45 after 1 hour by weight as measured by the United States Pharmacopeia (USP) apparatus II (paddle) at 900 rpm pH 6.8 PBS at 50 rpm. %, Preferably from about 35% to about 40% of diacerein; after about 4 hours, about 50% to about 60% of diacerein is released; after 8 hours, from about 60% to about 75%, preferably from about 65% It preferably has an in vitro dissolution rate that releases about 75% diacerein; and after about 16% releases more than about 80% diacerein.

In one embodiment, the controlled release formulation of the present invention may provide at least one of the following pharmacokinetic parameters when administered to a subject: (i) in a maximal plasma of rain above 5.0 μg / ml Concentration C _max ; (ii) Area under the concentration time curve for rain exceeding 35.0 μg · hr / ml AUC _0-t or AUC _0-∞ ; (iii) About 3 to 4 after oral administration to a subject in the fed state A T _{max of} 5 hours; and (iv) a plasma concentration of rhein exceeding 2.8 μg / ml for at least 4 hours. Formulations that exhibit the above pharmacokinetic parameters are better when reducing reduced adverse side effects, reduced food efficacy, higher bioavailability, and / or blood uric acid levels compared to conventional immediate release formulations The effect.

  The formulation is preferably a controlled release formulation once a day (ie, taken once a day).

  Because the formulations of the present invention have the advantages described above, it is beneficial to be used to treat all diseases in which diacerein is therapeutically effective. These diseases include, but are not limited to, hyperuricemia, metabolic abnormalities associated with hyperuricemia, osteoarthritis and type 2 diabetes. Metabolic abnormalities associated with hyperuricemia include but are not limited to acute gout, chronic gout, gouty arthritis, gout flare, uric acid nephrolithiasis, gout nephropathy, cardiovascular disease (eg, hypertension And atherosclerosis), obesity, chronic kidney disease, and insulin resistance.

  The formulation reduces the inflammatory effects of gouty arthritis and gout flare induced by hyperuricemia in the subject; and / or dissolves kidney stones; and / or acute inflammation induced by hyperuricemia Can be used to reduce the recurrence rate of osteoarthritis; and / or slow the progression of urate nephropathy.

  In one embodiment, the formulation may further comprise one or more additional therapeutic agents, such as anti-inflammatory agents or uric acid lowering agents, to enhance the therapeutic effect of diacerein. Examples of anti-inflammatory drugs include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. Examples of uric acid lowering drugs include, but are not limited to, xanthine oxidase inhibitors, uric acid excretion drugs, uric acid oxidases, urinary alkalinizers, and fenofibrate.

  The present invention also provides a method of reducing blood levels of uric acid in a subject, comprising administering a formulation containing diacerein or an analog thereof to a subject in need thereof.

The formulations that can be used in this method can have structures, compositions and other properties similar to those defined above for the formulations of the present invention. Alternatively, formulations suitable for this method include the following pharmacokinetic parameters when administered to a subject: (i) maximum plasma concentration C _{max of} rain above 5.0 μg / ml; (ii) 35.0 μg · hr / Area AUC _0-t or AUC _0-∞ under the concentration time curve of rain in excess of ml; (iii) T _{max of} about 3 to 4.5 hours after oral administration to a fed subject; and (iv) at least 4 It may have a different structure and composition as long as it can provide at least one of the plasma concentrations of lane above 2.8 μg / ml over time.

  In another embodiment, the formulation used in the method contains at least about 75 mg, preferably about 75-200 mg, more preferably about 75-100 mg of diacerein or an analog thereof.

  The invention will now be further described in connection with the following examples. However, these examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[Preparation Example] Preparation of controlled-release formulation containing diacerein Ten controlled-release tablet formulations containing 75 or 100 mg of diacerein were prepared according to Tables 1 (a) and 1 (b). The prepared tablets were used for the following in vivo studies.

Example 1 Dissolution Assay of Diacerein Controlled Release Formulation In this example, dissolution was performed according to USP apparatus II (paddle). A solution of PBS pH 6.8 was used as the dissolution medium. Samples were taken at appropriate time intervals and analyzed for diacerein content using high pressure liquid chromatography (HPLC).

  Table 2 summarizes the raw data of dissolution of tablets A to F of the present invention, and FIG. 1 shows the dissolution profile.

[Example 2] Human URAT1-dependent uric acid uptake assay Uric acid is excreted mainly by urinary excretion, and up to 90% of the filtered uric acid is reabsorbed. A decrease in the rate of uric acid excretion is thought to increase serum uric acid and cause hyperuricemia. URAT1 (uric acid transporter 1, SLC22A12 gene) is a main transporter responsible for uric acid tubular reabsorption and is considered to be a major mechanism for regulating blood uric acid levels. URAT1 is genetically associated with uric acid levels, and inhibition of URAT1 can reduce serum uric acid.

This study established the in vitro method to study hURAT1- mediated uric acid ^[8-14 C] uptake in HEK293T cells transiently transfected human embryonic kidney 293 cells containing URAT1 transporter .

Transfected HEK293T cells were incubated for 24-72 hours and then replated on microplates. At least 12 hours after seeding, the culture medium was removed and the cells were washed and then incubated in 100 μl of Cl-free HBSS buffer for 5-10 minutes. Remove the buffer and add 50 μl Cl-free HBSS buffer containing 50 μM uric acid [ ^8-14 C] (0.13 μCi / well) with or without rain (30, 10, 3.3 and 1). (4 doses of 1 μM) and cells were incubated at 37 ° C. for 5 minutes. At the end of incubation, uric acid [ ^8-14 C] intake was stopped. The cells were washed three times and 50 μl of 100 mM NaOH was added per well to lyse the cells and then agitated for at least 20 minutes at 600 rpm. Cell lysates were collected, UltimaGold ™ XR scintillation was added at 200 μl per well and the mixture was agitated at 600 rpm for 10 minutes. Finally, the microplate was counted. The results are shown in FIG.

FIG. 2 shows that uric acid intake was inhibited by rain at 49.4% ± 22.2% at 3.3 and 10 uM and 79.3% ± 1.5% at 30 uM. Lane's IC _{50 for} URAT1 inhibition is 10 uM, which is about 2.8 μg / ml. Maintenance of plasma rain concentration above 2.8 μg / ml can exert a uric acid lowering effect.

  This study can be used by diacerein or its analogs to lower serum uric acid by inhibiting URAT1, and thus to treat metabolic abnormalities associated with hyperuricemia and hyperuricemia. It shows that you can do it.

[Example 3] Phase 1 of diacerein controlled release formulations of pharmacokinetic studies diacerein immediate release formulation ^(Artrodar (R) 50mg capsules) and three different doses of the present invention, a randomized, open-label, single dose, 4 Treatment, 4-sequence, 4-period, crossover, pharmacokinetic studies were conducted on healthy male and female volunteers in the fed state.

The method was carried out healthy male and female ^Artrodar by oral administration to volunteers (R) 50 mg and three different doses of controlled-release formulations of (75, 100 and 200 mg) 4-way crossover comparative pharmacokinetic study. A 7 day washout period separated the treatment period.

  Subjects: Healthy volunteers who met all test criteria and did not meet any of the study exclusion criteria.

  Procedure: Diacerein was administered in various formulations and doses were compared at random with a 7 day washout period between treatment periods. Subjects were randomly assigned to one of the treatment sequences in Table 3 below. The study began at the screening visit. Only eligible subjects participated in the study.

  Comparison of different formulations and doses is based on comparisons within subjects, not between subjects. A 7 day washout period was estimated to be adequate to avoid the carryover effect of the previous treatment.

Statistical methods for efficacy / pharmacokinetic assessment: AUC _0-t , AUC _0-∞ , C _max , and T _max of plasma rain of per protocol (PP) population were determined and calculated by non-compartmental method. Analysis of variance (ANOVA) was used for AUC _0-t , AUC _0-∞ , C _max , and T _max . T _max was analyzed using an additional nonparametric test (Wilcoxon test).

  Safety assessments were performed on all subjects who received at least one dose of study drug. Researchers obtained and observed all observed adverse events (AEs) or spontaneously reported events, including their strength and causal assessments with study drug. For all AEs, researchers sought and obtained the appropriate information to determine the outcome of AEs and whether they met some severity criteria. All AEs had to be pursued until a level of resolution or stability acceptable to the researchers was obtained.

  The pharmacokinetic results are shown in Tables 4 and 5 and FIG. Subjects (n = 23) were screened and 16 subjects were randomized into the study. Thirteen subjects completed the entire study (4 periods) to assess the pharmacokinetics of the PP population. Only the data obtained from these subjects is reported in the table below.

The safety results are shown in Table 6. No significant adverse events, deaths, or serious adverse events were reported. The most commonly reported adverse events during the study were diarrhea, followed by nausea, vomiting, rash, elevated blood creatine phosphokinase, contact dermatitis, hypotension and somnolence. Diarrhea events are almost the same for 50 mg capsules and 75 mg and 100 mg tablets. All adverse events were reported as mild in intensity and resolved at the end. In conclusion, the tablets of Artrodar ^(R) capsules as well as 75, 100 and 200mg of 50mg is safe to use.

The above results indicate that the controlled release formulation of the present invention has a C _max of lanes above 5.0 μg / ml, AUC _0-t or AUC _{0-∞ of} lanes above 35.0 μghr / ml, and about 3-4 It showed a T _max of 5 hours. In addition, the formulation of the present invention has a lane blood concentration greater than 2.8 μg / ml (a therapeutically 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 a higher bioavailability than a commercial immediate release formulation with dose-normalized AUC and C _max values greater than about 10%. AUC and _Cmax values were found to increase approximately proportionally with increasing doses of diacerein.

The 75 mg and 100 mg controlled release formulations were tolerated similarly to the 50 mg immediate release formulation, but the 200 mg dose was associated with a higher incidence of gastrointestinal AE. Therefore, as compared with Artrodar ^(R) formulation, the formulation of the present invention exhibit safety improved at higher dose intensity of 75mg and 100mg, thus adverse side effects was reduced. This makes it possible to treat patients with higher doses of 75 or 100 mg once a day without increasing the side effects.

Mean blood rain is approximately 3.62 to 4.16 hours after administration in tablet group of the present invention, the Artrodar ^(R) capsules group under fed conditions has reached the peak concentration in 5.00 hours. Diacelein's fasting T _max is 2.4 hours after a single oral dose of 50 mg in healthy volunteers and has been demonstrated to increase to 5.2 hours with food (Petitjean et al.,). Clinical Pharmacokinetics, November 1998, Volume 35, Issue 5, pp 347-359). Formulations of the present invention, as compared to Artrodar ^(R) capsules, are absorbed more quickly under fed conditions, it showed less food effect.

[Example 4] The reduction serum uric acid evaluated in studies of diacerein controlled release formulation of serum uric acid study diacerein immediate release formulation in healthy volunteers fed state (Artrodar (R) ^50mg capsules) and three different doses of the present invention went.

In pharmacokinetic studies of Example 3, effects, treatment contemplates analysis of serum uric acid in healthy volunteers fed state of ^Artrodar (R) tablets of the present invention of 50mg and three different doses (75, 100 and 200 mg) ( ITT) Post hoc analysis. A total of 15 subjects were analyzed. Serum uric acid levels were compared before and after treatment by paired t-test analysis.

The results are shown in FIG. Serum uric acid concentration after treatment A ^(Artrodar (R) 50mg) were not significantly different from pre-treatment. However, the serum uric acid concentration was lower after treatment B than before treatment. The same results were shown for treatment C and treatment D. This difference in lowering serum uric acid may be due to the duration that lane was maintained at an effective blood concentration above 2.8 μg / ml. As shown in FIG. 3, treatment A reached a lay blood concentration exceeding 2.8 μg / ml for a very short period of time, which was insufficient to exert the effect of reducing uric acid. It was.

  This study revealed that serum uric acid was significantly reduced by various doses of the controlled release formulation of the present invention above 75 mg.

  The above disclosure relates to detailed technical contents and inventive features thereof. Those skilled in the art will be able to make various modifications and changes based on the above disclosure and suggestions of the present invention without departing from the characteristics thereof.

Claims (20)

  A method of reducing blood concentration of uric acid in a subject comprising administering a controlled release formulation comprising an immediate release layer and a sustained release layer to a subject in need thereof.   The immediate release layer comprises a compound selected from the group consisting of therapeutically effective amounts of diacerein, lane, monoacetyl lane, prodrugs and pharmaceutically acceptable salts thereof; a filler; a binder; a disintegrant; and a lubricant. The sustained release layer comprises a therapeutically effective amount of diacerein, lane, monoacetyl lane, prodrug and a pharmaceutically acceptable salt thereof; a controlled release polymer; a filler; and a lubricant; The method of claim 1, wherein the weight ratio of the compound in the immediate release layer to the compound in the sustained release layer is from about 2: 1 to about 1: 9.   The immediate release layer is selected from the group consisting of about 5 wt% to about 60 wt% diacerein, lane, monoacetyl lane, prodrug and pharmaceutically acceptable salts thereof, based on the total weight of the immediate release layer. About 30% to about 95% by weight filler; about 0.1% to about 20% by weight binder; about 0.1% to about 20% by weight disintegrant; The sustained release layer comprises from about 5% to about 60% by weight of diacerein, lane, monoacetyl lane, prodrug, and the like, based on the total weight of the sustained release layer. A compound selected from the group consisting of pharmaceutically acceptable salts thereof; about 1% to about 60% by weight controlled release polymer; about 1% to about 70% by weight filler; and about 0.01% by weight -Containing about 5% by weight lubricant The method according to 1.   Controlled release polymers are hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol carboxyvinyl polymer, polyvinyl alcohol, glucan, sclero. Glucan, mannan, xanthan, alginic acid and derivatives thereof, polyanhydrides, polyamino acids, carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethylamide, potassium methacrylate / divinylbenzene copolymer, starch and derivatives thereof, β-cyclodextrin, linear or branched Dextrin derivatives, ethyl cellulose, methyl cellulose, methacrylic acid copolymers, cellulose derivatives, and selected from the group consisting of any combination method of claim 1.   The method of claim 1, wherein the formulation comprises at least about 75 mg diacerein. When the formulation is administered to the subject, the following pharmacokinetic parameters: (i) Maximum plasma concentration C _{max of} rain above 5.0 μg / ml; (ii) Rain above 35.0 μg · hr / ml The area under the concentration time curve AUC _0-t or AUC _0-∞ , (iii) T _{max of} about 3 to 4.5 hours after oral administration to a fed subject; and (iv) 2 for at least 4 hours. 2. The method of claim 1, wherein the method provides at least one plasma concentration of rhein greater than 8 μg / ml.   2. The method of claim 1, wherein the formulation is a once daily controlled release formulation.   2. The method of claim 1, wherein the subject has a disease or disorder selected from the group consisting of hyperuricemia, metabolic abnormalities associated with hyperuricemia, osteoarthritis, and type 2 diabetes. A method for reducing the blood concentration of uric acid in a subject comprising a therapeutically effective amount of a compound selected from the group consisting of diacerein, lane, monoacetyl lane, prodrug and pharmaceutically acceptable salts thereof. Administration to a subject in need thereof, when the formulation is administered to said subject, the following pharmacokinetic parameters: (i) maximum plasma concentration C _{max of} lanes above 5.0 μg / ml; ii) Area under the concentration time curve of lanes above 35.0 μg · hr / ml AUC _0-t or AUC _0-∞ ; (iii) about 3 to 4.5 hours T after oral administration to a fed subject _max ; and (iv) at least one of the plasma concentrations of rhein exceeding 2.8 μg / ml for at least 4 hours.   The method of claim 9, wherein the formulation is a controlled release formulation, comprising an immediate release layer and a sustained release layer.   The immediate release layer comprises a compound selected from the group consisting of therapeutically effective amounts of diacerein, lane, monoacetyl lane, prodrugs and pharmaceutically acceptable salts thereof; a filler; a binder; a disintegrant; and a lubricant. A compound in which the sustained release layer is selected from the group consisting of therapeutically effective amounts of diacerein, lane, monoacetyl lane, prodrugs and pharmaceutically acceptable salts thereof; a controlled release polymer; a filler; and a lubricant; The method of claim 9, wherein the weight ratio of the compound in the release layer to the compound in the sustained release layer is from about 2: 1 to about 1: 9.   A method for reducing the blood concentration of uric acid in a subject comprising at least about 75 mg of a compound selected from the group consisting of diacerein, lane, monoacetyl lane, prodrug, and pharmaceutically acceptable salts thereof. Administering to a subject in need thereof. When the formulation is administered to the subject, the following pharmacokinetic parameters: (i) Maximum plasma concentration C _{max of} rain above 5.0 μg / ml; (ii) Rain above 35.0 μg · hr / ml Area under the concentration time curve AUC _0-t or AUC _0-∞ ; (iii) T _{max of} about 3 to 4.5 hours after oral administration to a fed subject; and (iv) 2 for at least 4 hours. 13. The method of claim 12, wherein said method provides at least one of the plasma concentrations of rhein above .8 [mu] g / ml.   13. The method of claim 12, wherein the formulation is a controlled release formulation and comprises an immediate release layer and a sustained release layer.   The immediate release layer comprises a compound selected from the group consisting of therapeutically effective amounts of diacerein, lane, monoacetyl lane, prodrugs and pharmaceutically acceptable salts thereof; a filler; a binder; a disintegrant; and a lubricant. A sustained-release layer comprising a compound selected from the group consisting of a therapeutically effective amount of diacerein, lane, monoacetyl lane, prodrug and pharmaceutically acceptable salts thereof, a controlled release polymer; a filler; and a lubricant; 13. The method of claim 12, wherein the weight ratio of the compound in the immediate release layer to the compound in the sustained release layer is from about 2: 1 to about 1: 9.   A controlled release formulation with reduced adverse side effects comprising an immediate release layer and a sustained release layer, wherein the immediate release layer is acceptable as a therapeutically effective amount of diacerein, lane, monoacetyl lane, prodrug and pharmaceutically A compound selected from the group consisting of its salts; a filler; a binder; a disintegrant; and a lubricant; a sustained release layer is acceptable as a therapeutically effective amount of diacerein, lane, monoacetyl lane, prodrug and pharmaceutically A compound selected from the group consisting of: a salt thereof; a controlled release polymer; a filler; and a lubricant; wherein the weight ratio of the compound in the immediate release layer to the compound in the sustained release layer is about 2: 1 to The formulation, which is about 1: 9.   The immediate release layer is selected from the group consisting of about 5 wt% to about 60 wt% diacerein, lane, monoacetyl lane, prodrug and pharmaceutically acceptable salts thereof, based on the total weight of the immediate release layer. About 30% to about 95% by weight filler; about 0.1% to about 20% by weight binder; about 0.1% to about 20% by weight disintegrant; The sustained release layer comprises from about 5% to about 60% by weight of diacerein, lane, monoacetyl lane, prodrug, and the like, based on the total weight of the sustained release layer. A compound selected from the group consisting of pharmaceutically acceptable salts thereof; about 1% to about 60% by weight controlled release polymer; about 1% to about 70% by weight filler; and about 0.01% by weight -Containing about 5% by weight lubricant The formulation according to 16.   Controlled release polymers are hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol carboxyvinyl polymer, polyvinyl alcohol, glucan, sclero. Glucan, mannan, xanthan, alginic acid and derivatives thereof, polyanhydrides, polyamino acids, carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethylamide, potassium methacrylate / divinylbenzene copolymer, starch and derivatives thereof, β-cyclodextrin, linear or branched Dextrin derivatives, ethyl cellulose, methyl cellulose, methacrylic acid copolymers, cellulose derivatives, and selected from the group consisting of any combination formulation of claim 16. When the formulation is administered to a subject, the following pharmacokinetic parameters: (i) Maximum plasma concentration C _{max of} lanes above 5.0 μg / ml; (ii) Concentration of lanes above 35.0 μg · hr / ml 1. Area under the time curve AUC _0-t or AUC _0-∞ ; (iii) T _{max of} about 3 to 4.5 hours after oral administration to a fed subject; and (iv) for at least 4 hours. 17. The formulation of claim 16, wherein the formulation provides at least one plasma concentration of rhein greater than 8 μg / ml.   The formulation according to claim 16, which is a once-daily controlled release formulation.

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