RU2690372C2 - Medicines containing diacerein, and methods for reducing uric acid levels in blood with using thereof - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: group of inventions refers to reduction of uric acid level in blood. That is ensured by administering a controlled release drug containing an immediate-release layer containing 5 % to 60 % by weight of a compound selected from a group consisting of diacerein, rhein, monoacetylreine and a pharmaceutically acceptable salt thereof; from 30 % to 95 % by weight of filler; from 0.1 % to 20 % of binding agent; from 0.1 % to 20 % by weight of disintegrating agent; and from 0.01 % to 5 % by weight of lubricating agent; and a sustained release layer containing from 5 % to 60 % by weight of a compound selected from a group consisting of diacerein, rhein, monoacetylreine and a pharmaceutically acceptable salt thereof; from 1 % to 60 % by weight of the controlled-release polymer; from 1 % to 70 % by weight of filler and from 0.01 % to 5 % of lubricating agent in terms of total weight of sustained release layer; wherein the weight ratio of said compound in the immediate release layer to that in the sustained release layer is 2:1 to 1:9. Also disclosed is a controlled-release medicament.EFFECT: invention provides reducing blood uric acid level in a patient and wherein the drug provides plasma rhein concentration higher than 2,8 mcg/ml for 4 hours.11 cl, 4 dwg, 6 tbl, 4 ex

Description

The technical field to which the invention relates.

This invention relates to drugs with diacerein, in particular, to a method of reducing the level of uric acid in the blood with the help of this drug.

Description of the prior art

Chemically, rhein is 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-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 transformed into reine before it reaches the systemic blood flow, and performs a physiological function in the body in the form of reine.

Diacerein is an anti-inflammatory agent widely used in the treatment of osteoarthritis, which, as has been demonstrated, inhibits interleukin-1 (IL-1) signaling. Currently, diacerein capsules are available in dosages of 50 mg and are sold in different countries under various brand names, including Art 50®, Artrodar®, etc. As disclosed in US Pat. No. 8,536,152, diacerein can also be used as an additional treatment for type II diabetes. Although diacerein can be administered orally, _t cannot be completely absorbed by the digestive tract, and the oral bioavailability of diacerein is estimated to be approximately 40-60%. Incomplete absorption of diacerein can lead to undesirable side effects, such as diarrhea or unformed stools. In vitro and in vivo studies have shown that unabsorbed diacerein is metabolized to Rein in the colon, which then causes a laxative effect. Thus, in this area there is still a need for a drug with diacerein, with reduced adverse side effects and / or higher bioavailability compared with current commercial drugs.

 As disclosed in US Pat. No. 8,865,689, diacerein has been found to be effective in lowering the level of uric acid in the blood and can be used to treat hyperuricemia or a metabolic disorder associated with hyperuricemia. However, no drugs with diacerein specific for reducing uric acid levels in the blood have yet been developed.

In view of the above requirements, the present invention provides a drug with diacerein with improved properties, as well as its use in the treatment of diseases, including, but not limited to, hyperuricemia, metabolic disorders associated with hyperuricemia, osteoarthritis and type II diabetes mellitus.

SUMMARY OF INVENTION

In one embodiment, the present invention provides a controlled release drug 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 reducing the level of uric acid in the blood, comprising administering the aforementioned drug with controlled release to a subject in need thereof.

In another embodiment, the present invention provides a method for reducing a blood uric acid level in a subject, comprising administering to a subject in need a drug comprising a therapeutically effective amount of a compound selected from the group consisting of diacerein, reina, mono acetylrein, a prodrug and a pharmaceutically acceptable a salt, wherein when administered to a specified subject, it provides at least one of the following pharmacokinetic parameters: (i) maximum concentration C _max of rhein in plasma above 5.0 mcg / ml; (ii) the area under the “time-concentration” curve of AUC _0-t or AUC _0-∞ Rein is higher than 35.0 µg h / ml; (iii) T _max from about 3 to 4.5 hours after oral administration to a subject under non-fasted conditions; and (iv) plasma concentration of Rein above 2.8 µg / ml for at least 4 hours.

In another implementation, the present invention provides a method of reducing the level of uric acid in the blood of a subject, comprising administering to a subject in need, a medicament containing at least about 75 mg of a compound selected from the group consisting of diacerein, reina, mono acetylrein , its prodrugs and pharmaceutically acceptable salts.

Detailed technologies and preferred embodiments implemented for the subjects of the present invention are described in the following paragraphs, the accompanying graphic materials for those skilled in the art to better understand the features of the claimed invention.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

FIG. 1 shows the solubility profiles of the controlled-release drugs A and F according to this invention, measured using the United States Pharmacopeia Apparatus II (Paddle) apparatus at 50 rpm in 900 ml of PBS with a pH of 6.8 at 37 ° C;

in FIG. 2 is a statistical histogram showing inhibition of uric acid absorption at various doses of rhein;

in FIG. 3 shows averaged plasma concentration-time profiles of Rein after patients have been given various drugs with diacerein; and

in FIG. 4 is a statistical histogram showing the serum uric acid concentration before and after the administration of various drugs with diacerein.

DETAILED DESCRIPTION OF THE INVENTION

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

The term “controlled release”, or “CR”, and “sustained release”, or “ER”, as used herein, refers to the gradual release of a drug at a given rate, other than the nature of immediate release, over a period of time.

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

As used herein, the term “C _max ” refers to the maximum plasma concentration observed, calculated as the average value for individual maximum plasma concentrations.

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

As used herein, the term “T _max ” refers to the time at which the peak (maximum) concentration of drug in the blood plasma is observed for each individual participating in the bioavailability study.

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

As used in this document, the term “AUC _0-t ” refers to the area under the plasma / serum / blood concentration – time curve from zero time point to time point t, where “t” is the last time point of a sample taken at a measurable concentration for individual drug.

The term "diacerein or its analogs" as used herein refers to diacerein, reina, mono acetylrein or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Unless otherwise indicated, the terms in the singular used in this description (especially in the claims below) should be understood to encompass both a singular and a plural form.

As indicated above, to reduce adverse side effects and / or improve the bioavailability of diacerein, this invention provides a controlled release drug 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, reina, mono acetylrhein, its prodrugs, and a pharmaceutically acceptable salt (hereinafter referred to as “diacerein or its analogues”); filler; binding agent; disintegrating agent; and lubricating agent; and the sustained release layer comprises a therapeutically effective amount of diacerein or its analogs, a controlled release polymer, a filler, and a lubricant; where the weight ratio of diacerein or its analogs in the immediate release layer to that in the sustained release layer is from about 2: 1 to about 1: 9.

In one embodiment, said drug also contains a cosmetic coating.

Preferably, in the medicaments of the present invention, the immediate release layer comprises from about 5% to about 60% by weight, preferably from about 5% to about 50% by weight of diacerein or its analogs; from about 30% to about 95% by weight, preferably from about 40% to about 85% by weight of filler; from about 0.1% to about 20% by weight, preferably from about 1% to about 10% by weight of a binding agent; from about 0.1% to about 20% by weight, preferably from about 1% to about 10% by weight of a disintegrant; and from about 0.01% to about 5% by weight, preferably from about 0.1% to about 2.5% by weight of the lubricant of _the agent, based on 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%, by weight of diacerein or its analogs; from about 1% to about 60% by weight, preferably from about 10% to about 50% by weight of a controlled release polymer; from about 1% to about 70% by weight, preferably from about 10% to about 55% by weight of filler; and from about 0.01% to about 5% by weight, preferably from about 0.1% to about 2.5% by weight of the lubricant, based on the total weight of the sustained release layer.

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

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

Suitable disintegrating agents include, but are not limited to, sodium carboxymethylcellulose, L-hydroxypropylcellulose, crospovidone, corn starch, sodium starch glycolate, sodium croscarmellose, 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 salt, and polyethylene glycol. Preferably, the lubricant is magnesium stearate.

Polymers with controlled release which can be used in the present invention may be, for example, hydroxypropylmethyl cellulose (hydroxypropyl methylcellulose, HPMC), hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, polyvinyl acetate, polyvinyl alcohol, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and its derivatives, polyanhydrides, polyamino acids, carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, karboksimetilamid, a copolymer of potassium methacrylate / divinylbenzene copolymer, starches and their derivatives, β-cyclodextrin, dextrin derivatives with linear or branched chains, ethylcellulose, methylcellulose, methacrylic acid copolymers and cellulose derivatives. Preferably, the controlled release polymer is hydroxypropyl methylcellulose (HPMC).

Because the drugs of the present invention reduce adverse side effects, they can deliver a higher dose of diacerein without increasing side effects such as diarrhea.

In particular, they can be administered to patients at a higher dose compared to commercial preparations of diacerein (for example, Artrodar®, 50 mg QD or BID, 50 or 100 mg per day in general), and they 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 its analogues, thereby increasing the effectiveness of treatment in a single dose.

In another aspect of the invention, the authors of this application have found that a drug containing at least about 75 mg of diacerein is more effective in reducing blood uric acid levels than Artrodar® (immediate release drug containing 50 mg of diacerein). Thus, the drug of the present invention preferably contains at least about 75 mg, more preferably about 75 to 200 mg, most preferably about 75 to 100 mg of diacerein or its analogs.

In the test for solubility, the controlled-release drug preferably has an in vitro dissolution rate, as measured in accordance with USP, Pharmacopeia (USP) using a paddle at 50 rpm in 900 ml PBS with pH 6.8 at 37 ° C, from about 30% to about 45%, preferably from about 35% to about 40% by weight of diacerein released after 1 hour; from about 50% to about 60% by weight of diacerein released after 4 hours; from about 60% to about 75%, preferably from about 65% to about 75% by weight of diacerein released after 8 hours; and at least 80% by weight of diacerein released after 16 hours.

In one embodiment, the controlled release drug of the present invention, when administered to a subject, can provide at least one of the following pharmacokinetic parameters: (i) the maximum plasma concentration of C _max Rein in the plasma is greater than 5.0 μg / ml; (ii) the area under the “time – concentration” curve of AUC ₀ - _t or AUC _0-∞ Rein is higher than 35.0 µg h / ml; (iii) T _max from about 3 to 4.5 hours after oral administration to a subject under non-fasted conditions; and (iv) plasma concentration of Rein above 2.8 µg / ml for at least 4 hours. A drug that demonstrates the above pharmacokinetic parameters demonstrates reduced „adverse side effects, reduced nutritional effect, higher bioavailability and / or an improved effect of lowering the level of uric acid in the blood compared to the usual immediate-release drug.

Preferably, the drug is a disposable controlled-release drug (i.e., taken once a day).

Since the drug according to the invention has the above-mentioned advantages, it can be used in the treatment of all diseases for which diacerein is therapeutically effective. These diseases include, but are not limited to, hyperuricemia, a metabolic disorder associated with hyperuricemia, osteoarthritis and type II diabetes. A metabolic disorder associated with hyperuricemia includes, but is not limited to, acute gout, chronic gout, gouty arthritis, outbreaks of gout, uric acid nephropathy, gouty nephropathy, cardiovascular diseases (eg, hypertension and atherosclerosis), obesity, chronic kidney disease, insulin resistance.

The drug can be used to reduce the inflammatory effects of gouty arthritis and gout outbreaks induced by hyperuricemia; and / or to dissolve kidney stones; and / or to reduce the frequency of recurrences of acute inflammatory arthritis induced by hyperuricemia; and / or to slow the progression of uric nephropathy in a subject.

In one embodiment, said drug may also contain one or more additional therapeutic agents, such as an anti-inflammatory agent or an agent reducing the level of urates, to enhance the therapeutic effect of diacerein. Examples of anti-inflammatory agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (non-steroidal anti-inflammatory drugs, NSAIDs), corticosteroids and colchicines. Examples of urate-reducing agents include, but are not limited to, xanthine oxidase inhibitors, uricosuric agents, urate oxidase, urine alkalizers, and fenofibrate.

The present invention also relates to a method for reducing the level of uric acid in the blood of a subject, comprising administering to a subject in need thereof a medicament containing diacerein or its analogs.

Drugs that can be used in this method may have the structure, composition, and other properties mentioned above for the drug of the present invention. Alternatively, medicaments suitable for this method may have a different structure and drug as long as they are administered to a subject they can provide at least one of the following pharmacokinetic parameters: (i) the maximum plasma concentration of C _max Rein is higher 5.0 µg / ml; (ii) the area under the “time – concentration” curve of AUC _0-t or AUC _0-∞ , reina above 35.0 µg h / ml; (iii) T _max from about 3 to 4.5 hours after oral administration to a subject under non-fasted conditions; and (iv) plasma concentration of Rein above 2.8 µg / ml for at least 4 hours.

In another embodiment, the medicament used in this 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.

Further, the present invention will be illustrated in more detail with reference to the following examples and experiments. However, these examples are given only for the purpose of illustration and do not limit the scope of this invention.

[Production Example] Preparation of a controlled release drug containing diacerein

In accordance with Tables 1 (a) and 1 (b), ten controlled release tablet formulations containing 75 or 100 mg of diacerein were prepared. The resulting tablets were used in the following in vivo study.

[EXAMPLE 1] Quantitative Dissolution Data for Diacerein Controlled-Release Drug

In this example, dissolution was performed using a USP Apparatus II apparatus (Paddle). As a medium for dissolution used buffer solution of PBS with a pH of 6.8. Samples were taken at suitable time intervals and analyzed for the content of diacerein using high pressure liquid chromatography (HPLC).

Table 2 shows the raw data on the solubility of tablets A and F according to this invention, and figure 1 shows the solubility profiles.

[Example 2] Analysis of the absorption of uric acid based on URAT1

Uric acid is mainly excreted through urine excretion, and up to 90% of filtered urate is reabsorbed. It is believed that reducing the rate of urate excretion increases the level of uric acid in serum, which leads to hyperuricemia. URAT1 (urate 1 transporter, gene SLC22A12) is the main transporter responsible for the tubular reabsorption of urates, and is considered the main mechanism for regulating urate levels in the blood. URAT1 is genetically associated with urate levels, and inhibition of URAT1 can reduce serum uric acid.

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

After incubation of transfected HEK293T cells for 24-72 hours, they were re-seeded into a microplate. At least 12 hours after seeding the cells, the culture medium was removed and the cells were washed and then incubated in 100 μl of C1-free HBSS buffer for 5-10 minutes. The buffer was removed and 50 μl per well of C1-free HBSS buffer containing 50 μmol of uric acid [ ^8-14 C] (0.13 μCi / well) with or without rhein (in four doses: 30, 10, 3.3 and 1.1 μM), to cells incubated for 5 minutes at 37 ° C. At the end of the incubation, the absorption of uric acid [ ^8-14 C] was stopped. The cells were washed three times and 50 μl per well of 100 mM NaOH was added to the cells for lysis, and then they were shaken at 600 rpm for at least 20 minutes. The cell lysate was collected and added 200 μl per well of UltimaGold TM XR scintillation, and the mixture was shaken at 600 rpm for 10 minutes. Finally, the microplate was analyzed. The results are shown in FIG. 2. 2.

In FIG. 2 shows that uric acid uptake was inhibited by rhein at 3.3 and 10 μM with a value of 49.4 ± 22.2% and at 30 μM with a value of 79.3 ± 1.5%. Rein IC ₅₀ in the inhibition of URAT1 is 10 μM, which is approximately 2.8 μg / ml. Maintaining plasma concentrations of rhein in excess of 2.8 µg / ml may have a lowering effect on uric acid levels.

This study shows that diacerein or its analogs can reduce serum uric acid levels by inhibiting URAT1 and, thus, can be used to treat hyperuricemia and metabolic disorders associated with hyperuricemia.

[EXAMPLE 3] Pharmacokinetic study

Phase 1 randomized, open (no placebo control), single-dose, with 4 administration options, 4 administration sequences, 4 duration periods, a cross-pharmacokinetic study of a drug with diacerein with immediate release (Artrodar® 50 mg capsules) and three different doses of the drug with controlled release of diacerein according to the present invention was carried out on healthy male and female volunteers in non-fasted conditions.

Methodology: Artrodar® 50 mg, a 4-sided comparative pharmacokinetic study of three different doses of controlled-release drug (75, 100, and 200 mg) was carried out with peroral injection of healthy male and female volunteers. There was a 7-day washout period separating the administration periods.

Subjects: Healthy volunteers met all the inclusion criteria and none of the exclusion criteria from the study.

Procedure: Diacerein, administered in different drugs and doses, was compared in a randomized manner with a washout period of 7 days between periods. Volunteers were randomly assigned to one of the treatment sequences, as shown in the following table 3. The study began with a screening visit. Only eligible volunteers participated in the study.

- Procedure A: 1 capsule Artrodar® 50 mg

- Procedure B: 1 tablet 75 mg

- Procedure C: 1 tablet 100 mg

- Procedure D: 2 tablets of 100 mg (200 mg)

Comparison of different drugs and doses is based on comparison of one volunteer, and not between volunteers. The estimated washout period of 7 days was sufficient to prevent the transient effects of previous procedures.

The statistical method (s) for evaluating the efficacy / pharmacokinetics: AUC _0-t , AUC _0-∞ , C _max and T _max for Rein in the plasma of a population using the protocol (per-protocol, PP) were determined and calculated using non-compartmental approaches. For AUC _0-t , AUC _0-∞ , C _max and T _max , analysis of variance (ANOVA) was used. Tmax was analyzed using an additional non-parametric test (Wilcoxon test).

A safety assessment was performed for all volunteers who were given at least one dose of the study drug. The researcher received and registered all observed adverse events (AE) on an individual registration card (case report form, CRF) or from those who voluntarily reported them, including an assessment of the intensity and connection with the products under investigation. For all AEs, the researcher sought and obtained information sufficient to determine both the outcome of the AE and whether it meets any severity criteria. All AEs should have been observed until resolution or stabilization at a level acceptable to the researcher.

The pharmacokinetic results are shown in Tables 4 and 5 and in FIG. Subjects (n = 23) were screened, and 16 volunteers were randomly assigned to the study. 13 volunteers completed a full study (4 periods) to assess pharmacokinetics in the population according to the protocol. The following tables show data only for these volunteers.

The results of the safety assessment are presented in Table 6. No significant adverse events, death or serious adverse events were reported. During the study, the most frequently reported side effects were diarrhea, accompanied by nausea, vomiting, rash, elevated creatine levels, blood phosphokinase, contact dermatitis, hypotension, and drowsiness. Cases of diarrhea were almost the same for a 50 mg capsule and 75 mg and 100 mg tablets. It was reported that all adverse events were weak in intensity and resolved at the end. In conclusion, Artrodar 50 mg capsules and 75, 100, and 200 mg tablets are safe to use.

The results above showed that controlled-release drugs according to this invention exhibit C _{max of} Rein above 5.0 μg / ml, AUC _0-t or AUC _{0-∞ of} Rein above 35.0 µg h / ml and T _max from about 3 up to 4.5 hours. In addition, the drugs according to the invention provided a concentration of Rein in the blood above 2.8 μg / ml (effective concentration of administration in Example 2) for at least 4 hours (administration B: 4.2 hours; administration C: 7 hours; administration D: 12.7 hours) and had greater bioavailability than the commercial _t drug with immediate release, with about 10% higher dose-normalized AUC and C _max values. It was found that the AUC and C _max values are generally proportional to the increase in doses of diacerein.

Drug controlled release at a dose of 75 mg and 100 mg had tolerability similar to the drug with an immediate release at a dose of 50 mg, while the dose of 200 mg was associated with a higher incidence of gastrointestinal AE cases. Thus, compared with the Artrodar® drug, the drugs according to this invention showed increased safety at higher doses at a dose of 75 mg and 100 mg and, accordingly, reduced adverse side effects. This allows patients to administer a higher dose of 75 or 100 mg once a day without increasing side effects.

The average peak peaks of rein concentrations in the blood were approximately 3.62-4.16 hours after administration in the group according to the invention, taking the tablets, and 5.00 hours after administration in the group receiving Artrodar® capsules under non-fasted conditions. An empty stomach T _{max of} diacerein was shown to be 2.4 hours after a single oral administration of 50 mg to healthy volunteers and increased to 5.2 hours with food intake (Petitjean et al., Clinical Pharmacokinetics, November 1998, Volume 35, Issue 5, pp 347-359). The drugs according to the invention were absorbed more quickly under non-fasted conditions and showed less nutritional effect compared to the Artrodar® capsule.

EXAMPLE 4 Study of serum levels of uric acid

In the study of the drug with the immediate release of diacerein (Artrodar® 50 mg capsule) and three different doses of the drug with controlled release of diacerein according to this invention, the reduction of serum uric acid in healthy volunteers under non-fasted conditions was evaluated.

In the pharmacokinetic study according to example 3, the effect of Artrodar® 50 mg and three different doses of tablets according to the invention (75, 100 and 200 mg) on the level of uric acid in the serum of healthy volunteers under non-fasting conditions was also analyzed for the intended treatment population (intend -to-treat, ITT). 15 subjects were analyzed. Serum uric acid concentrations were compared before and after treatment with the paired t-test.

The results are shown in FIG. 4. Serum uric acid concentrations after Procedure A (Artrodarr 50 mg) did not significantly differ from those after administration. However, serum uric acid concentration was reduced after B administration compared to the value before the administration. The same results were demonstrated in procedure C and Procedure D. This difference in the decrease in serum uric acid levels may be due to the duration with which rhein remained in the blood in an effective concentration above 2.8 µg / ml. As shown in FIG. 3, procedure A made it possible to achieve a rein concentration in the blood above 2.8 µg / ml for a rather short period of time, which was insufficient for the effect of reducing the level of urates.

This study showed that the serum level of uric acid was significantly reduced with the administration of the controlled-release drug in accordance with this invention in various doses above 75 mg.

The above description of the invention relates to detailed technical content and its inventive features. Specialists in this field will be able to make many modifications and substitutions based on the description and proposals of the described invention, without departing from its characteristics.

Claims (11)

1. A method of reducing uric acid levels in a patient’s blood, comprising administering to a patient in need a controlled-release drug comprising an immediate release layer and a sustained-release layer, where the immediate release layer contains a therapeutically effective amount of the compound selected from the group consisting of diacerein, Rein, mono acetylrein and its pharmaceutically acceptable salt; filler; binding agent; disintegrating agent; and lubricating agent; and the sustained release layer contains a therapeutically effective amount of a compound selected from the group consisting of diacerein, rein, mono acetylrhein and a pharmaceutically acceptable salt thereof; controlled release polymer; filler; and lubricating agent; where the immediate release layer contains from 5% to 60% by weight of a compound selected from the group consisting of diacerein, reina, mono acetylrein and its pharmaceutically acceptable salt; from 30% to 95% by weight of filler; from 0.1% to 20% of a binding agent; from 0.1% to 20% by weight of a disintegrant; and from 0.01% to 5% by weight of a lubricant; and the sustained release layer contains from 5% to 60% by weight of a compound selected from the group consisting of diacerein, reina, mono acetylrein and its pharmaceutically acceptable salt; 1% to 60% by weight of a controlled release polymer; from 1% to 70% by weight of filler; and from 0.01% to 5% of a lubricant based on the total weight of the sustained release layer; and where the weight ratio of said compound in the immediate release layer to that in the sustained release layer is from 2: 1 to 1: 9; where, when administering a drug to a specified patient, the drug provides plasma concentration of Rein above 2.8 μg / ml for 4 hours, and where the total amount of said controlled-release drug compound is from 75 mg to 100 mg, and where said patient is has a disease or condition selected from the group consisting of hyperuricemia, metabolic disorder associated with hyperuricemia, osteoarthritis, and type 2 diabetes mellitus. 2. The method according to claim 1, wherein the controlled release polymer is selected from the group comprising hydroxypropylmethyl cellulose (acetate), hydroxypropyl cellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthan gum, guar gum, carob bean gum, polyvinyl acetate, polyvinyl acetate, polyvinyl acetate. polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and its derivatives, polyanhydrides, polyamino acids, carboxymethylcellulose, sodium carboxymethylcellulose cross-linked w, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, karboksimetilamid, a copolymer of potassium methacrylate / divinylbenzene copolymer, starches and their derivatives, β-cyclodextrin, dextrin derivatives with linear or branched chains, ethylcellulose, methylcellulose, methacrylic acid copolymers, cellulose derivatives, and any combination thereof. 3. A method according to claim 1, wherein the drug contains 75 mg of diacerein. 4. The method of claim 1, wherein upon administration of the drug to the specified patient, the drug provides one of the following pharmacokinetic parameters: (i) the maximum plasma concentration of C _{max in} Rein is above 5.0 μg / ml; (ii) the area under the “time – concentration” curve of AUC _0-t or AUC _0-∞ Rein above 35.0 µg h / ml; (iii) T _max from 3 to 4.5 hours after oral administration to a subject under non-fasted conditions. 5. The method according to p. 1, where the drug is a drug with controlled release with a single dose per day. 6. A method of reducing the level of uric acid in the blood of a patient, comprising administering to a patient who needs it a drug containing a therapeutically effective amount of a compound selected from the group consisting of diacerein, reina, mono acetylrein and a pharmaceutically acceptable salt, where upon administration of the drug means to the specified patient, the drug provides one of the following pharmacokinetic parameters: (i) the maximum plasma concentration of C _{max of} Rein is above 5.0 μg / ml; (ii) the area under the “time – concentration” curve of AUC _0-t or AUC _0- ∞ Rein above 35.0 µg h / ml; (iii) T _max from 3 to 4.5 hours after oral administration to a subject under non-fasted conditions; and (iv) plasma concentration of Rein is higher than 2.8 µg / ml for 4 hours. - where the drug is a controlled release drug and contains an immediate release layer and a sustained release layer, where the immediate release layer contains from 5 % to 60% by weight of a compound selected from the group consisting of diacerein, Reina, mono acetylrein and its pharmaceutically acceptable salt; from 30% to 95% by weight of filler; from 0.1% to 20% of a binding agent; from 0.1% to 20% by weight of a disintegrant; and from 0.01% to 5% by weight of a lubricant; and the sustained release layer contains from 5% to 60% by weight of a compound selected from the group consisting of diacerein, reina, mono acetylrein and its pharmaceutically acceptable salt; 1% to 60% by weight of a controlled release polymer; from 1% to 70% by weight of filler; and from 0.01% to 5% of a lubricant, based on the total weight of the sustained release layer; and where the weight ratio of said compound in the immediate release layer to that in the sustained release layer is from 2: 1 to 1: 9; where, when administering a drug to a specified patient, the drug provides plasma concentration of Rein above 2.8 μg / ml for 4 hours, and where the total amount of said controlled-release drug compound is from 75 mg to 100 mg. 7. The method according to p. 6, where the drug contains 75 mg of a compound selected from the group consisting of diacerein, Reina, monoacetylrhein and a pharmaceutically acceptable salt. 8. Drug controlled release with reduced adverse side effects, containing a layer with an immediate release and a layer with a slow release, where the weight ratio of the compound in the layer with immediate release to that in a layer with a slow release from 2: 1 to 1: 9 where the immediate release layer contains from 5% to 60% by weight of a compound selected from the group consisting of diacerein, rein, mono acetylrein and its pharmaceutically acceptable salt; from 30% to 95% by weight of filler; from 0.1% to 20% of a binding agent; from 0.1% to 20% by weight of a disintegrant; and from 0.01% to 5% by weight of a lubricant; and the sustained release layer contains from 5% to 60% by weight of a compound selected from the group consisting of diacerein, reina, mono acetylrein and its pharmaceutically acceptable salt; 1% to 60% by weight of a controlled release polymer; from 1% to 70% by weight of filler; and from 0.01% to 5% of a lubricant based on the total weight of the sustained release layer; and where the weight ratio of said compound in the immediate release layer to that in the sustained release layer is from 2: 1 to 1: 9; where, when administering a drug to a specified patient, the drug provides plasma concentration of Rein above 2.8 μg / ml for 4 hours, and where the total amount of said controlled-release drug compound is from 75 mg to 100 mg. 9. The drug according to claim 8, wherein the controlled release polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar gum, gum tree gum, flooring, apply, and then apply blue polymeric cellulose, guar gum, carob bean gum, xanthan gum, guar gum, gum tree gum, ginger, gum bean gum, guar gum, carob bean gum, ginger, ginger, guar gum, gum bean gum, white pink, and you will need to put the gum, xanthan gum, guar gum, gum bean gum, and you will need to put the glue, the ginger, the guar gum, the gum tree gum, the layer, the layer, and the layer, the layer, the layer, the layer, the layer, the layer, the layer, the layer, the layer, the layer, the layer, the layer, the layer; alcohol, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and its derivatives, polyanhydrides, polyamino acids, carboxymethylcellulose, cross-linked sodium carb oxymethylcellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, carboxymethylamide, potassium methacrylate / divinylbenzene, starches and their derivatives, atelodextrin 10. The medicament according to claim 8, wherein upon administration of the medicament to said patient, the medicament provides one of the following pharmacokinetic parameters: (i) the maximum plasma concentration of C _max Rein in the plasma is greater than 5.0 μg / ml; (ii) the area under the “time – concentration” curve of AUC _0-t or AUC _0-∞ Rein above 35.0 µg h / ml; (iii) T _max from 3 to 4.5 hours after oral administration to a subject under non-fasted conditions. 11. The medicament of claim 8, which is a once-daily controlled release drug.

Images