TW201637650A - Formulations containing diacerein and methods of lowering blood levels of uric acid using the same - Google Patents

Abstract

A controlled-release formulation containing diacerein or its analogs is provided. Also provided is a method of lowering blood levels of uric acid using this formulation.

Description

Formula containing diacerein and method for reducing the concentration of uric acid in blood

This invention relates to a diacerein formulation, and more particularly to a method of using such a formulation to reduce the concentration of uric acid in blood.

Chemically, rhein is 9,10-dihydro-4,5-dihydroxy-9,10-dioxy-2-indolecarboxylic acid having the structure of formula (I) (9,10- Dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracene carboxylic acid); one of its precursors is diacerein, which is a 4,5-bis (ethoxime) having the structure of formula (II) 9,10-Dihydro-4,5-dihydroxy-9,10-dioxy-2-indolecarboxylic acid (4,5-bis(acetyloxy) 9,10-dihydro-4,5-dihydroxy- 9,10-dioxo-2-anthracene carboxylic acid). Diacerein is completely converted to rhein before entering the systemic circulation, and exerts its physiological function in the form of rhein in the body.

Chemical formula (II)

Diacerein is an anti-inflammatory agent widely used in the treatment of osteoarthritis, which inhibits the signaling of interleukin-1 (IL-1). Currently available on the market is a 50 mg dose of diacerein capsules sold under different product names in different countries, including Art 50 ^® and Artrodar ^® . As disclosed in U.S. Patent No. 8,536,152, diacerein can also be used as an adjunctive therapy for type 2 diabetes. Although diacerein can be administered via the oral route, it is not fully absorbed by the digestive tract, and its oral bioavailability is estimated to be about 40% to 60%. Incomplete diacerein absorption can cause unwanted side effects such as diarrhea or soft stools. In vitro and in vivo tests have shown that unabsorbed diacerein is metabolized to rhein in the colon, which further causes diarrhea. Therefore, there is still a need in the art for diacerein formulations having reduced side effects and/or improved bioavailability compared to existing commercial formulations.

As disclosed in U.S. Patent No. 8,865,689, diacerein has been found to be effective in reducing blood uric acid concentrations and can be used to treat hyperuricemia or metabolic diseases associated with hyperuricemia. However, diacerein preparations specifically designed to lower blood uric acid concentrations have not yet been developed.

In view of the above needs, the present invention provides a diacerein formulation having improved properties, and its use in the treatment of diseases including, but not limited to, hyperuricemia, metabolic diseases associated with hyperuricemia, osteoarthritis Inflammation, as well as type 2 diabetes.

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

In another embodiment, the present invention provides a method for reducing uric acid in an individual. A method comprising administering to a subject in need thereof the above controlled release formulation.

In still another embodiment, the invention provides a method of reducing uric acid blood concentration in an individual comprising administering to a subject in need thereof a formulation comprising a therapeutically effective amount of a compound selected from the group consisting of: Vinegarine, rhein, monoethylidene rhein, and prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein when the formulation is administered to the individual, it provides at least one of the following pharmacokinetic parameters : (i) The highest blood concentration of rhein (C _max ) is higher than 5.0 μg/ml; (ii) the area under the concentration-time curve of rhein (AUC _0-t or AUC _0-∞ ) More than 35.0 micrograms. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours.

In still another embodiment, the invention provides a method of reducing uric acid blood levels in an individual comprising administering to a subject in need thereof a formulation comprising at least about 75 mg of a compound selected from the group consisting of: Diacerein, rhein, monoethylidene rhein, and its precursors and pharmaceutically acceptable salts.

The detailed technical contents and preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, in which FIG.

Figure 1 is a graph showing the dissolution profile of controlled release formulations A and F of the present invention, according to the United States Pharmacopoeia (USP) Apparatus II (paddle), 900 ml of a pH 6.8 phosphate buffered saline (PBS) solution at 37 °C. In the figure, measured at 50 rpm, Figure 2 shows the statistical bar graph of different doses of rhein to inhibit uric acid absorption; Figure 3 shows the individual receiving different diacerein A graph of the mean blood concentration of rhein versus time after treatment of the formulation; and Figure 4 shows a statistical bar graph of blood uric acid concentration before and after treatment with different diacerein formulations.

The term "immediate release" in this document refers to the release of a drug, such as diacerein, in a general or unmodified manner.

The term "controlled release" or "sustained release" as used herein refers to the gradual release of a drug at a predetermined rate over a period of time rather than an immediate release.

As used herein, the term "effective amount" refers to an amount that reduces or reduces one or more symptoms of a particular disease.

The term " _Cmax " in this context refers to the highest blood concentration observed, calculated as the average of the highest blood concentrations in each case.

The term "mean blood concentration" in this document refers to the arithmetic mean of the concentration in blood.

The term " _Tmax " herein refers to the time when the peak (maximum value) of the blood drug concentration is observed in each subject participating in the bioavailability test.

The term "AUC _0-∞ " or "AUC _0-inf " in this context refers to the average area under the curve of plasma/serum/blood concentration versus time (extrapolated to infinity). This was calculated as the arithmetic mean of the area under the curve of the blood concentration versus time (extrapolated from time 0 to infinity) in each subject participating in the bioavailability test.

In this context, the word "AUC _0-t " refers to the area under the curve of plasma/serum/blood concentration versus time (from time 0 to time t), where "t" is the last sample of the concentration at which each formulation can be measured. Time point.

The term "diacerein or its analogue" as used herein refers to diacerein, rhein, monoethylidene rhein, and its prodrugs and pharmaceutically acceptable salts.

In addition, the terms "a", "an" and "the" are used in the singular and plural terms.

In addition, the proportions of the ingredients are by weight percent unless otherwise stated herein.

As described above, in order 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 comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, monoethylidene rhein, and its prodrugs and pharmaceutically acceptable Accepting a salt (hereinafter referred to as "diacerein or its analog"); a filler; a binder; a disintegrating agent; and a lubricant; and the sustained release layer comprises a therapeutically effective amount of diacerein or the like a controlled release polymer; a filler; and a lubricant; and wherein the weight ratio of diacerein or an analogue thereof to the sustained release layer in the immediate release layer is from about 2:1 to about 1: 9.

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

Preferably, in the formulation of the present invention, the immediate release layer comprises from about 5% to about 60%, preferably from about 5% to about 50%, of diacerein or an analog thereof, from about 30% to about 95%, Preferably from about 40% to about 85% filler, from about 0.1% to about 20%, preferably from about 1% to about 10%, from about 0.1% to about 20%, preferably from about 1% to about 10%. % of the disintegrating agent, and from about 0.01% to about 5%, preferably from about 0.1% to about 2.5%, of the total weight of the immediate release layer; and the sustained release layer comprises from about 5% to about 60% Preferably, from about 5% to about 50% of diacerein or an analog thereof, from about 1% to about 60%, preferably from about 10% to about 50%, of controlled release polymer, from about 1% to about 70% Preferably, from about 10% to about 55% filler, from about 0.01% to about 5%, preferably from about 0.1% to about 2.5%, by total weight of the sustained release layer.

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, hydroxypropylmethylcellulose (HPMC), and hydroxypropylcellulose. Preferably, the binder is povidone.

Suitable disintegrating agents include, but are not limited to, sodium carboxymethyl cellulose, L-hydroxypropyl fibers , crospovidone, corn starch, sodium starch glycolate, starch, croscarmellose sodium salt, and alginic acid or its sodium salt. Preferably, the disintegrating agent is a croscarmellose sodium salt.

Suitable lubricants include, but are not limited to, light anhydrous citric acid, talc, stearic acid and its zinc, magnesium or calcium salts, and polyethylene glycol. Preferably, the lubricant is magnesium stearate.

Controlled release polymers useful in the present invention can be, for example, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthan gum, Guar gum, locust bean gum, polyvinyl ethyl ester, polyvinyl alcohol carboxyvinyl polymer, polyvinyl alcohol, dextran, scleroglucans, mannan, alginic acid and its derivatives , polyanhydride, polyamino acid, carboxymethyl cellulose, croscarmellose sodium salt, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethylguanamine, potassium methacrylate / divinylbenzene Copolymers, starches and derivatives thereof, β-cyclodextrin, linear or branched dextrin derivatives, ethyl cellulose, methyl cellulose, methacrylic acid copolymers, and cellulose derivatives. Preferably, the controlled release polymer is hydroxypropyl methylcellulose.

Since the preparation of the present invention has an adverse side effect of reduction or reduction, it can deliver a higher dose of diacerein and thus does not increase side effects such as diarrhea. Specifically, the preparation of the present invention can be administered to patients with higher doses of diacerein (such as Artrodar ^® once daily or twice 50 mg daily for a total of 50 or 100 mg). The dose, and may contain at least about 75 mg, preferably from about 75 to 200 mg, more preferably from about 75 to 100 mg of diacerein or a derivative thereof, thereby enhancing the therapeutic effect in a single dose.

On the other hand, the inventors of the present application found that a formulation containing at least about 75 mg of diacerein was more effective in reducing uric acid blood than Artrodar ^® (an immediate release preparation containing 50 mg of diacerein). Medium concentration. Accordingly, the formulations of the present invention comprise preferably at least about 75 mg, more preferably from about 75 to 200 mg, most preferably from about 75 to 100 mg of diacerein or an analog thereof.

In a dissolving test, the controlled release formulation of the present invention is measured at a speed of 50 rpm in 900 ml of a pH 6.8 phosphate solution at 37 ° C according to the United States Pharmacopoeia (USP) Apparatus II (paddle). Preferably, the following in vitro dissolution rate is achieved: after 1 hour, about 30% to about 45%, preferably about 35% to about 40%, of diacerein is released; after 4 hours, about 50% to about 60 is released. % of diacerein; after 8 hours, releasing about 60% to about 75%, preferably about 65% to about 75% of diacerein; and after 16 hours, releasing not less than about 80% Diacerein, in weight percent.

In one embodiment, the controlled release formulation of the present invention provides at least one of the following pharmacokinetic parameters when administered to an individual: (i) the highest blood concentration of rhein ( _Cmax ) is greater than 5.0 micrograms. / ML; (ii) The area under the concentration-time curve of the rhein blood (AUC _0-t or AUC _0-∞ ) is higher than 35.0 μg. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours. Formulations exhibiting the above pharmacokinetic parameters have reduced adverse side effects, reduced food effects, improved bioavailability, and/or better reduced blood uric acid concentration compared to conventional immediate release formulations.

Preferably, the formulation is a controlled release formulation that is administered once daily (i.e., once daily).

Since the preparation of the present invention has the above advantages, it is advantageous in the treatment of all diseases in which diacerein is effective. These diseases include, but are not limited to, hyperuricemia, metabolic diseases associated with hyperuricemia, osteoarthritis, and type 2 diabetes. Metabolic diseases associated with hyperuricemia include, but are not limited to, acute gout, chronic gout, gouty arthritis, gout attack, uric acid nephrolithiasis, gouty nephropathy, cardiovascular disease (eg hypertension and arteriosclerosis) , obesity, chronic kidney disease, and insulin resistance.

The preparation can be used to reduce gouty arthritis induced by hyperuricemia in an individual And the inflammatory effects of gout attacks; and/or dissolving kidney stones; and/or reducing the recurrence rate of acute inflammatory arthritis induced by hyperuricemia; and/or slowing 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 urate-lowering agents, to enhance the therapeutic effect of diacerein. Examples of anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. Examples of urate-reducing agents include, but are not limited to, xanthine oxidase inhibitors, uricosuric agents, urate oxidases, urinary alkalinizers, and fenofibrate.

The invention also provides a method of reducing the concentration of uric acid in an individual comprising administering to a subject in need thereof a formulation comprising diacerein or an analog thereof.

Formulations for use in this method may have the same structure, composition, and other properties as the formulations of the present invention described above. Alternatively, formulations suitable for use in the methods can have different structures and compositions as long as at least one of the following pharmacokinetic parameters can be provided when administered to an individual: (i) the highest blood concentration of rhein ( C _max ) is higher than 5.0 μg/ml; (ii) the area under the concentration-time curve of rhein (AUC _0-t or AUC _0-∞ ) is higher than 35.0 μg. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours.

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

The invention is further illustrated by the following specific embodiments. The embodiments are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[Preparation Example] Preparation of controlled release preparation containing diacerein

Ten controlled release lozenges containing 75 or 100 mg of diacerein were prepared according to Table 1 (a) and Table 1 (b). The prepared tablets were used in the following in vivo tests.

[Example 1] Dissolution test of diacerein controlled release preparation

In this example, the dissolution was carried out in accordance with the United States Pharmacopoeia (USP) Apparatus II (paddle). A pH 6.8 phosphate (PBS) solution was used as the dissolution medium. Samples were taken at appropriate intervals and the content of diacerein was analyzed by high performance liquid chromatography (HPLC).

Table 2 summarizes the dissolution data of the tablets A and F of the present invention, and Figure 1 shows the dissolution curve.

[Example 2] Human URAT1-dependent uric acid absorption test

Uric acid is primarily eliminated by urinary excretion and up to 90% of the filtered urate is resorbed. It is generally believed that a decrease in the excretion rate of urate increases the amount of uric acid in the blood, which in turn leads to hyperuricemia. URAT1 (urate transporter 1, SLC22A12 gene) is the major transporter responsible for tubule reabsorption of urate and is considered to be the primary mechanism for regulating blood urate levels. URAT1 has been thought to be genetically related to the amount of urate, and inhibition of URAT1 reduces blood uric acid.

In this assay, an in vitro assay was developed to investigate the absorption of uric acid [ ^8-14 C] regulated by hURAT1 in transiently transfected HEK293T cells (human embryonic kidney 293 cells containing the URAT1 transporter).

After transfecting the transfected HEK293T cells for 24 to 72 hours, they were again seeded in microdiscs. After the cells were covered with the microplate for at least 12 hours, the culture was removed and the cells were washed and cultured in 100 microliters of chlorine-free HBSS buffer for 5 to 10 minutes. Remove the buffer and add 50 μmol of uric acid [ ^8-14 C] (0.13 μm) to the cells with or without rhein (4 doses: 30, 10, 3.3 and 1.1 micromolar) 50 μl (per well) of chlorine-free HBSS buffer was incubated at 37 ° C for 5 minutes. At the end of the culture, the absorption of uric acid [ ^8-14 C] was stopped. The cells were washed 3 times, 50 microliters of 100 millimolar sodium hydroxide per well was added to dissolve the cells, and stirred at 600 rpm for at least 20 minutes. The lysate was collected, and 200 μl of Ultima Gold ^® XR scintillation fluid per well was added, and the mixture was stirred at 600 rpm for 10 minutes. Finally, count the microdisks. The results are shown in Figure 2.

As shown in Figure 2, rhein inhibited uric acid uptake by 49.4% ± 22.2% at 3.3 and 10 micromolar concentrations, and reached 79.3% ± 1.5% at 30 micromolar concentrations. In URAT1 inhibition, rhesnic acid has an IC ₅₀ value of 10 micromolar, which is equivalent to about 2.8 micrograms per milliliter. Maintaining blood rhein concentration in excess of 2.8 μg/ml may have the effect of lowering uric acid.

This test demonstrates that diacerein or an analog thereof can reduce blood uric acid by inhibiting URAT1 and is therefore useful for the treatment of hyperuricemia and metabolic diseases associated with hyperuricemia.

[Example 3] Pharmacokinetic test

The diacerein immediate release formulation (Artrodar ^® 50 mg capsules) and 3 different doses of the diacerein controlled release formulation of the present invention, for the first phase of healthy male and female volunteers under fed conditions / Random/open/single dose/4 treatments/4 sequential/4 time/crossover design pharmacokinetic tests.

METHODS: For healthy male and female volunteers, four-way (4-way) crossover was performed with Artrodar ^® 50 mg capsules and three different doses (75, 100, and 200 mg) of controlled release preparations by oral administration. Comparative pharmacokinetic tests. Different treatment procedures were separated by a 7 day washout period.

Test subjects: meet all test entry criteria and do not meet any exclusion criteria Healthy volunteers.

Procedure: The effects of diacerein administered at different doses and formulations were compared in a random manner and 7 days of wash time were scheduled during different treatment sessions. One of the treatment sequences as shown in Table 3 was randomly assigned to the subject. The trial begins with a screening visit, and only eligible subjects participate in the trial.

Comparisons between different formulations and doses are based on the comparison of the subject itself, rather than the comparison between the subject and the subject. The 7-day wash time was evaluated to be sufficient to avoid the effects of the sustained action of the previous treatment regimen.

A statistical method for determining and calculating the effectiveness/pharmacokinetic assessment according to the non-compartment method, including AUC ₀ of rhein in the blood of the per-protocol population (PP population) _t , AUC _0-∞ , C _max and T _max . AUC _0-t , AUC _0-∞ , C _max and T _{max were} calculated using a variance analysis (ANOVA). _{Tmax was also} analyzed using the non-parametric test method (Wilcoxon test).

Safety assessment was performed on all subjects who had taken at least one dose of the test drug. Researchers obtain and record all observed adverse events (AEs), including their strength and study drug, through a case record or a voluntary report by the subject. Relationship. For all adverse events, the researcher has sufficient information to determine the outcome of an adverse event and whether it meets any severity criteria. Keep track of all adverse events until they are resolved or reach a level of stability acceptable to the researcher.

The results of the pharmacokinetic test are shown in Tables 4, 5 and 3. A total of 23 subjects were screened, and 16 subjects were randomly assigned to each trial. A total of 13 subjects completed the entire trial (4 time periods) to assess pharmacokinetic data for the group of paintings. The table below only lists data obtained from subjects who completed the trial.

The safety results are shown in Table 6. There are no serious or major adverse events or deaths. During the trial, the most common adverse events were diarrhea, followed by nausea, vomiting, rash, increased sarcosine phosphokinase in the blood, contact dermatitis, hypotension, and lethargy. The diarrhea condition is almost the same between 50 mg capsules and 75 and 100 mg tablets. The intensity of all adverse events was minor and eventually resolved. The conclusion is that 50 mg of Artrodar ^® capsules and 75, 100 and 200 mg doses are safe to take.

The above results show that the controlled release preparation of the present invention exhibits a _Cmax value of rhein higher than 5.0 μg/ml, which is higher than 35.0 μg. Hour/ml of rhein AUC _0-t or AUC _0-∞ , and a T _max value of about 3 to 4.5 hours. In addition, the formulation of the present invention provides a blood concentration of rhein (above the therapeutically effective concentration in Example 2) of at least 2.8 μg/ml for at least 4 hours (treatment mode B: 4.2 hours; treatment mode C: 7 hours; treatment mode) D: 12.7 hours), and has a higher bioavailability than the immediate release formulation on the market, with dose normalized AUC and _Cmax values above about 10%. It was found that the AUC and _Cmax values increased approximately proportionally with the increased dose of diacerein.

The 75 mg and 100 mg controlled release formulations were similarly tolerated with the 50 mg immediate release formulation, but the 200 mg dose showed a higher incidence of gastrointestinal adverse events. Therefore, compared Artrodar ^® formulation, formulations of the invention exhibit improved safety at the higher dose of 75 mg and 100 mg, and thus provides reduced adverse side effects. This allows patients to be treated at a higher dose of 75 mg or 100 mg once a day without increasing side effects.

Under fed conditions, in the group administered the tablets of the present invention, the average of the highest blood concentration of rhein time is about 3.62 to 4.16 hours, compared to the group taking the capsules of Artrodar ^® for 5 hours. It has been reported that under fasting conditions, a _Tmax value of a single dose of 50 mg of diacerein administered orally in a healthy subject is 2.4 hours, but increases to 5.2 hours under fed conditions (Petitjean et al) ., Clinical Pharmacokinetics, November 1998, Volume 35, Issue 5, pp 347-359). Compared to Artrodar ^® capsule, under fed conditions, the formulations of the present invention is absorbed faster speed, and therefore have a lower food effect.

[Example 4] Blood uric acid test

Under fed conditions, diacerein immediate release formulation (Artrodar ^® 50 mg capsules) with 3 kinds of different doses of diacerein of the present invention by controlling the blood uric acid decreased release formulation in evaluation test in healthy volunteers.

Pharmacokinetics Test Example 3, the effect of 50 mg of Artrodar ^® with 3 different doses of the present invention, tablets (75, 100, and 200 mg) to healthy volunteers in blood uric acid levels also under fed conditions Follow-up intent-to-treat (ITT) analysis. A total of 15 subjects were analyzed. The blood uric acid concentration before and after treatment was compared by paired t-test analysis.

The results are shown in Figure 4. After treatment with A (50 mg Artrodar ^® ), there was no significant difference in blood uric acid concentration compared with pre-treatment. However, after treatment mode B, the concentration of uric acid in the blood decreased compared with that before treatment. Treatment C and treatment D also showed the same results. This difference in lowering uric acid in the blood may be due to the fact that rhein is maintained at a sustained blood concentration greater than 2.8 μg/ml for different durations. As shown in Fig. 3, the treatment mode A only transiently reaches a concentration of more than 2.8 μg/ml of rhein blood, which is insufficient to exert the effect of lowering uric acid.

This test shows that the controlled release formulation of the present invention is large at different doses above 75 mg. The width reduces uric acid in the blood.

The above embodiments are merely illustrative of the principles and effects of the invention and are not intended to limit the invention. Modifications and variations of the above-described embodiments can be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of protection of the present invention should be as set forth in the scope of the patent application described hereinafter.

Claims (20)

A use of a controlled release formulation comprising an immediate release layer and a sustained release layer for the manufacture of a medicament for reducing uric acid levels in an individual. The use of claim 1, wherein the immediate release layer comprises a therapeutically effective amount of a compound selected from the group consisting of diacerein, rhein, monoethylidene rhein, a prodrug thereof, and a pharmaceutically acceptable Receiving a salt; a filler; a binder; a disintegrating agent; and a lubricant; and the sustained release layer comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, and monoethylidene Yellow acid, and its prodrugs and pharmaceutically acceptable salts; a controlled release polymer; a filler; and a lubricant; and wherein the compound is present in the immediate release layer in proportion to its weight in the sustained release layer It is from about 2:1 to about 1:9. The use of claim 1, wherein the immediate release layer comprises from about 5% to about 60% of a compound selected from the group consisting of: diacerein, rhein, monoethylidene rhein, and precursors thereof And pharmaceutically acceptable salts, from about 30% to about 95% filler, from about 0.1% to about 20% binder, from about 0.1% to about 20% disintegrating agent, and from about 0.01% to about 5% a lubricant, based on the total weight of the immediate release layer; and the sustained release layer comprises from about 5% to about 60% of a compound selected from the group consisting of: diacerein, rhein, monoethyl rhodamine An acid, a precursor thereof, and a pharmaceutically acceptable salt, from about 1% to about 60% of a controlled release polymer, from about 1% to about 70% of a filler, from about 0.01% to about 5% of a lubricant, The total weight of the sustained release layer. The use of claim 1, wherein the controlled release polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, sodium alginate, carbomer, carboxymethylcellulose Sodium salt, xanthan gum, guar gum, locust bean gum, polyvinyl ethyl ester, polyvinyl alcohol carboxyvinyl polymer, polyethyl b Enol, dextran, scleroglucans, mannan, alginic acid and derivatives thereof, polyanhydride, polyamino acid, carboxymethyl cellulose, croscarmellose sodium salt, Polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethylguanamine, potassium methacrylate/divinylbenzene copolymer, starch and its derivatives, β-cyclodextrin, linear or branched dextrin derivative , ethyl cellulose, methyl cellulose, methacrylic acid copolymers, cellulose derivatives, and combinations thereof. The use of claim 1 wherein the formulation comprises at least about 75 mg of diacerein. The use of claim 1, wherein when the formulation is administered to the individual, it provides at least one of the following pharmacokinetic parameters: (i) the highest blood concentration value ( _Cmax ) of rhein is higher than 5.0 μg/ml; (ii) The area under the concentration-time curve of the rhein (AUC _0-t or AUC _0-∞ ) is higher than 35.0 μg. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours. The use of claim 1, wherein the formulation is a controlled release formulation administered once daily. The use of claim 1, wherein the patient suffers from a disease selected from the group consisting of hyperuricemia, metabolic diseases associated with hyperuricemia, osteoarthritis, and type 2 diabetes. A use of a formulation for the manufacture of a medicament for reducing the concentration of uric acid in an individual, the formulation comprising a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, monoethyl rhodamine An acid, a prodrug thereof, and a pharmaceutically acceptable salt; wherein when the formulation is administered to the subject, it provides at least one of the following pharmacokinetic parameters: (i) the highest blood concentration of rhein The value (C _max ) is higher than 5.0 μg/ml; (ii) the area under the concentration-time curve of rhein (AUC _0-t or AUC _0-∞ ) is higher than 35.0 μg. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours. The use of claim 9, wherein the formulation is a controlled release formulation and comprises an immediate release layer and a sustained release layer. The use of claim 9, wherein the immediate release layer comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, monoethylidene rhein, a prodrug thereof, and a pharmaceutically acceptable Receiving a salt; a filler; a binder; a disintegrating agent; and a lubricant; and the sustained release layer comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, and monoethylidene Yellow acid, and its prodrugs and pharmaceutically acceptable salts; a controlled release polymer; a filler; and a lubricant; and wherein the compound is present in the immediate release layer in proportion to its weight in the sustained release layer It is from about 2:1 to about 1:9. Use of a preparation for the manufacture of an agent for reducing the concentration of uric acid in an individual, the preparation comprising at least about 75 mg of a compound selected from the group consisting of: diacerein, rhein, monoethyl hydrazide Flavinic acid, its precursors and pharmaceutically acceptable salts. The use of claim 12, wherein when the formulation is administered to the individual, it provides at least one of the following pharmacokinetic parameters: (i) the highest blood concentration value ( _Cmax ) of rhein is higher than 5.0 μg/ml; (ii) The area under the concentration-time curve of the rhein (AUC _0-t or AUC _0-∞ ) is higher than 35.0 μg. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours. The use of claim 12, wherein the formulation is a controlled release formulation and comprises an immediate release layer and a sustained release layer. The use of claim 12, wherein the immediate release layer comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, monoethylidene rhein, precursors thereof, and medicinal Acceptable salts; fillers; binders; disintegrating agents; and lubricants; and the sustained release layer comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, monoethylidene Rhein, a precursor thereof, and a pharmaceutically acceptable salt; a controlled release polymer; a filler; and a lubricant; and wherein the compound is weighted in the sustained release layer in the immediate release layer The ratio is from about 2:1 to about 1:9. A controlled release formulation having reduced adverse side effects comprising an immediate release layer and a sustained release layer, wherein the immediate release layer comprises a therapeutically effective amount of a compound selected from the group consisting of: diacerein, rhein, Monoethyl decyl rhein, a prodrug thereof and a pharmaceutically acceptable salt; a filler; a binder; a disintegrating agent; and a lubricant; and the sustained release layer comprises a therapeutically effective amount selected from the group consisting of a compound: diacerein, rhein, monoethylidene rhein, and a prodrug thereof and a pharmaceutically acceptable salt; a controlled release polymer; a filler; and a lubricant; and wherein the compound is The ratio of the weight in the immediate release layer to the sustained release layer is from about 2:1 to about 1:9. The preparation of claim 16, wherein the immediate release layer comprises from about 5% to about 60% of a compound selected from the group consisting of: diacerein, rhein, monoethylidene rhein, and precursors thereof And pharmaceutically acceptable salts, from about 30% to about 95% filler, from about 0.1% to about 20% binder, from about 0.1% to about 20% disintegrating agent, and from about 0.01% to about 5% a lubricant, based on the total weight of the immediate release layer; and the sustained release layer comprises from about 5% to about 60% of a compound selected from the group consisting of: diacerein, rhein, monoethyl rhodamine An acid, a precursor thereof, and a pharmaceutically acceptable salt, from about 1% to about 60% of a controlled release polymer, from about 1% to about 70% of a filler, from about 0.01% to about 5% of a lubricant, The total weight of the sustained release layer. The preparation of claim 16, wherein the controlled release polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, sodium alginate, carbomer, carboxymethylcellulose Sodium salt, xanthan gum, guar gum, locust bean gum, polyvinyl ethyl ester, polyvinyl alcohol carboxyvinyl polymer, polyvinyl alcohol, dextran, scleroglucans ), mannan, alginic acid and its derivatives, polyanhydride, polyamino acid, carboxymethyl cellulose, croscarmellose sodium salt, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethyl Indoleamine, potassium methacrylate/divinylbenzene copolymer, starch and its derivatives, β-cyclodextrin, linear or branched dextrin derivative, ethyl cellulose, methyl cellulose, methyl Acrylic copolymers, cellulose derivatives, and combinations thereof. The preparation of claim 16, wherein when the preparation is administered to the individual, it provides at least one of the following pharmacokinetic parameters: (i) the highest blood concentration value ( _Cmax ) of rhein is higher than 5.0 μg/ml; (ii) The area under the concentration-time curve of the rhein (AUC _0-t or AUC _0-∞ ) is higher than 35.0 μg. Hour/ml; (iii) the time (T _max ) at which the highest blood concentration of rhein is up to about 3 to 4.5 hours after oral administration to the individual under fed conditions; and (iv) blood of rhein The medium concentration value is higher than 2.8 μg/ml for at least 4 hours. The preparation of claim 16, which is a controlled release formulation administered once daily.