FR2920991A1 - Composition, useful to treat inflammation, preferably osteoarthritis, comprises diacerhein, polyols comprising mannitol, sorbitol, maltitol, maltol, lactitol or xylitol, and optionally excipients comprising e.g. fillers and lubricants - Google Patents

Abstract

Pharmaceutical composition comprises diacerhein or its salt or ester, one or more polyols, and optionally one or more excipients. Independent claims are included for: (1) a process to improve the solubilization kinetics of the diacerhein in the solvents comprising combining diacerhein and one or more polyols; and (2) a process for preparing the diacerhein and polyol based composition, comprising spraying an organic solution containing diacerhein or one of its salts or esters, optionally in the presence of polyol, in a fluid stream under supercritical pressure to form and collect the particles. ACTIVITY : Antiinflammatory. Antiarthritic; Osteopathic. MECHANISM OF ACTION : None given.

Description

The present invention relates to a composition based on diacerein, and more particularly to a novel composition comprising diacerein or a salt thereof and one or more polyols, and if necessary one or more pharmaceutically acceptable excipients. Diacerhein, or 4,5-bis (acetyloxy) -9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracene carboxylic acid, is used therapeutically, in particular as a medicament for the treatment of osteoarthritis. Diacerein has a unique mode of action that sets it apart from nonsteroidal anti-inflammatory drugs (NSAIDs) and other conventional drugs. Its melting point is 217-218 ° C. Its molecular weight is 368.29 and its crude chemical formula is C19H1208. Diacerein may be represented by the following general formula: ## STR1 ## Diacerein is substantially insoluble in solvents compatible with pharmaceutical use, particularly water, alcohols, acetone, dichloromethane, and the like. chloroform. In addition, diacerein may be administered orally, but it is not fully absorbed by the gastrointestinal tract, and such incomplete absorption could lead to undesirable side effects, such as laxative effects. To overcome these difficulties, various derivatives have been proposed in the literature as well as pharmaceutical compositions and specific dosage forms. For example, EP-A-243,968 discloses a water-soluble diacetal potassium salt which can be used in the preparation of compositions for parenteral administration. It is known on the other hand that the solubilization and / or the wettability of a substance can be improved by treatment with a surfactant, which generally has the effect of promoting the bioavailability of the active ingredient. It is also known that the grinding of insoluble active principles in the presence of certain water-soluble polymers improves the solubility and bioavailability of the product (Yamamoto et al., J. Pharm Sci (1976) 65, pp. 1484-88). Various patents and patent applications describe compositions comprising diacerein. For example, EP 243,968 proposes parenteral preparations of diacerein salts. U.S. Patent 6,124,358 and EP 904,061 disclose a pharmaceutical composition comprising rhein or diacerhein, or a pharmaceutically acceptable salt or ester thereof. Although it is possible to improve the bioavailability of diacerhein by comicronization, as described in the aforementioned US Pat. Nos. 6,124,358 and 904,061, it appears desirable to develop new formulations or compositions that may further increase bioavailability and a search path may be to act on the kinetics The US Pat. No. 5,149,542 (EP 263,083), 4,861,599 (EP 264,989) and 5,275,824 (EP 446,753) provide controlled release compositions. US Patents 5,225,192 (EP 364,944) and 5,569,469 describe various poorly soluble drugs on polymeric supports. US Patent 5,952,383 and European Patent EP 862,423 provide pharmaceutical compositions containing diacerhein, rhein or a salt thereof, as well as various excipients.

Numerous references in the scientific literature and patent publications mention the use of polyols such as mannitol and sorbitol as fillers in formulations, or as sensitizers for improving the sensation experienced in the mouth in the case of use of disintegrating agents for tablets. For example, patents and patent applications WO 2007080601, EP 589,981, EP 906,089, EP 1,109,534, US 6,328,994, WO 2007001086, US 20070196494, US 20060240101, WO 2006057912, US 20060057199 can be referred to. Polyols such as mannitol are used in various orally disintegrating formulations, but not in conventional immediate release formulations because agents such as disintegrating tablets disintegrate in the mouth and not in the gastrointestinal tract as in the case of conventional immediate release tablets. The inventors of the present application have observed that polyols such as mannitol and sorbitol, when used with other water-insoluble drugs, such as fenofibrate, irbesartan, aripiprazole, entacapone, either in the form of a physical mixture or in the form of a complex, do not see their solubility significantly improved. No significant difference in solubility or percentage of release of these poorly soluble active principles has been found, whether used in formulations alone or in the presence of polyols. In researching the means of solubilizing substances which are difficult to dissolve in water and alcohols, the Applicant has unexpectedly found that under certain conditions the solubility and dissolution kinetics of diacerein could be significantly improved. in comparison with a commercially available formulation, such as that of ART 50, when the diacerein is in the presence of a polyol, whether as a mixture, complex or any other form of association. Thus, the known formulation ART 50 releases about 14% by weight of diacerein in 60 minutes, while a pharmaceutical composition according to the present invention releases about 80 to 100% of diacerein in 60 minutes. This significant increase in diacerein release is due to the dispersion of the diacerein in the polyol matrix, leading to an improvement in wettability, solubility and, consequently, in the percentage of diacerein released. This results in a better bioavailability, and consequently a decrease in undesirable side effects. The present invention relates to a novel composition based on diacerhein, or a pharmaceutically acceptable salt or ester thereof, and one or more polyols, as well as optionally one or more pharmaceutically acceptable excipients having a solubility improved over that of diacerein alone, as well as its use in human and veterinary therapy, particularly for the treatment of inflammation, and more particularly for the treatment of osteoarthritis. The present invention also relates to a novel composition comprising diacerein, or a pharmaceutically acceptable salt or ester thereof, and a polyol as well as optionally one or more pharmaceutically acceptable excipients, wherein the diacerein is mixed with the polyol. The present invention also relates to a novel composition comprising diacerein, or a pharmaceutically acceptable salt or ester thereof, and a polyol as well as optionally one or more pharmaceutically acceptable excipients, wherein the diacerein and the polyol form a complex. The present invention also relates to a novel composition comprising diacerein, or a pharmaceutically acceptable salt or ester thereof, and a polyol and optionally one or more pharmaceutically acceptable excipients, wherein the diacerein is adsorbed on the polyol. The present invention also relates to a novel composition based on diacerhein, or a pharmaceutically acceptable salt or ester, characterized by its crystallographic data. The present invention also relates to a novel composition based on diacerhein, or a pharmaceutically acceptable salt or ester thereof, characterized by its X-ray diffraction peaks at a 2 theta angle of 9.6 and 13.52 °. The X-ray diffraction spectrum of a pharmaceutical composition according to the present invention comprising diacerein is represented in FIG. 1, and that of a standard diacerhein (active principle alone) is represented in FIG. 2. X-ray spectroscopy analysis of The samples obtained show the presence of a new crystallographic entity-defined, as shown in Figure 1 representing the spectrum of samples according to the invention (Example 4) compared to that of a standard diacerhein (Figure 2). In another aspect, the present invention relates to a pharmaceutical composition comprising diacerein, or a pharmaceutically acceptable salt or ester thereof, and a polyol and optionally one or more pharmaceutically acceptable excipients, wherein the diacerein has a dissolution profile. such that more than 75% of the diacerein is released in 30 minutes, the release rate being measured using a Type 2 device (USP, dissolution, paddle shaker, 75 rpm) using 1,000 ml of buffer phosphate at pH 5.7 at 37 ° C 0.5 °. The invention also relates to a method for preparing such a composition based on diacerein and polyol by a technique using a supercritical fluid, consisting of spraying an organic solution containing diacerein or a salt or ester, the case optionally in the presence of polyol, in a stream of supercritical pressure fluid to form and collect particles. Finally, the subject of the invention is a process for improving the dissolution kinetics of diacerein in pharmaceutically acceptable solvents, in particular in an aqueous or alcoholic medium, comprising combining diacerein and one or more polyols, as well as the pharmaceutical composition with resulting diacerein base, for oral administration having excellent bioavailability. The novel diacerein composition according to the present invention consists of microparticles combining diacerhein and one or more polyols, in combination optionally with one or more suitable excipients and carriers, for pharmaceutical dosage form. The weight ratio of diacerein to polyol in the composition of the present invention is preferably 1:10 to 1: 1.

The new composition of the invention can be prepared by various methods, such as an anti-solvent technique, by solvent evaporation, by mixing, by spraying drying, grinding in colloidal media, mixing at high speed or by trituration.

Thus, the novel diacerein and polyol composition according to the present invention can be prepared by an anti-solvent method technique consisting in spraying an organic solution of the active ingredient, optionally combined with one or more excipients, in a fluid stream. , for example carbon dioxide, at supercritical pressure, and collect the particles formed. By this method, the anti-solvent effect of the fluid results in the formation of particles that are collected on a filter or on a granular bed of excipient, and the residual organic solvent is then removed.

According to a first variant of the process of the invention, the diacerein is dissolved in an organic solvent and then the solution is sprayed into a stream of supercritical pressure fluid to form microparticles collected on a granular bed of polyol, mixed with other excipients pharmaceutically acceptable and put in pharmaceutical form. According to a second variant, the diacerein and the polyol are dissolved in an organic solvent, and the solution is then sprayed into a stream of supercritical pressure fluid to form microparticles which are collected, for example on a filter, mixed with other pharmaceutically acceptable excipients and put into pharmaceutical form.

The diacerein and polyol composition obtained by this anti-solvent process by means of a supercritical fluid has a further improved solubility compared to that of a simple mixture of diacerhein and polyol. The supercritical pressure fluid used in the process may be selected from carbon dioxide, water, ethane and xenon, with carbon dioxide being preferentially used. The organic solvent used in the process of the invention is chosen from those capable of dissolving diacerein, and for example N-methylpyrrolidone, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, ketones such as acetone, alcohols and water, isolated or mixed. As indicated above, the pharmaceutical composition of the invention may also be prepared by trituration of the diacerein with a polyol, drying the triturate and mixing it with one or more other pharmaceutically acceptable excipients and then putting it into pharmaceutical form.

Alternatively, the pharmaceutical composition of the invention may also be prepared by trituration of diacerein with a polyol and one or more surfactants, drying the triturate and mixing it with one or more other pharmaceutically acceptable excipients and then putting it on in pharmaceutical form. The surfactant may be chosen from those commonly used in the art, and for example an amphoteric, nonionic, anionic or cationic surfactant.

Suitable surfactants are sodium lauryl sulphate, monooleolate, monolaurate, monopalmitate, monostearate or other polyoxyethylene sorbitan ester, sodium dioctylsulfosuccinate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol cholesterol, polyoxyethylene castor oil, glycerides of polyoxyethylenated fatty acids, poloxamer, cremophor RH 40, etc. The polyol used in the compositions of the invention may especially be mannitol, maltitol, maltol, sorbitol, lactitol, or xylitol.

The pharmaceutical compositions according to the present invention may be presented in the form of tablets, capsules, capsules, powders, granules, sachets, lozenges and pellets. The process for improving the dissolution kinetics of the diacerein according to the invention in pharmaceutically acceptable solvents, more particularly in water and alcohols, consists in spraying an organic solution of diacerhein, associated if necessary with one or more excipients. in a flow of fluid, for example carbon dioxide, under supercritical conditions, in the presence of polyol, either in the spraying solution or in the excipient bed for collecting the particles formed. The pharmaceutical composition based on diacerein and polyols according to the invention may comprise pharmaceutically acceptable excipients such as fillers, lubricants, disintegrating agents and plasticizers. Suitable fillers may be chosen for example from microcrystalline cellulose, mannitol, calcium phosphate, calcium sulphate, kaolin, dry starch, pulverized sugar, etc. The lubricant may be selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, a hydrogenated vegetable oil, or glyceryl behenate. A suitable fluidifying agent may be, for example, colloidal silica dioxide, talc or corn starch. The disintegrant may be more particularly starch, croscarmellose sodium, crospovidone, sodium starch glycolate, etc. The following examples illustrate the invention without limiting its scope.

EXAMPLE 1 Capsules of compositions according to the invention based on diacerhein having the composition indicated below, where the parts are expressed by weight are prepared in Table 1 below.

Table 1 handles part 25 diacerein sorbitol part 2. Microcrystalline Cellulose 5-60 Croscarmellose Sodium 1-25 Magnesium Stearate 1-15 Diacerein is mixed with sorbitol and triturated with a minimal amount of water to form a paste. This slurry is dried and sieved to form (% POP) 10-90 0.5-20 of the granules, and mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The mixture obtained is introduced into capsules with a gelatin wall.

In this way capsules containing 50 mg of diacerein are obtained, the dissolution rate of which is measured. The results are shown in Table 2 below comparing a known commercially available diacerein (ART 50) and the composition of Example (Inv.) Also containing 50 mg of diacerein.

Table 2 Duration (min.)% Dissol. (ART 50) Dissol. (Inv.) 5 3 29 10 4 53 5 68 7 76 30 9 82 45 11 89 60 14 90 Determination of the dissolution rate was measured using a USP type 2 apparatus (75 rpm) using 1000 ml of phosphate buffer at pH 5.7 at 37 ° C. and 0.5 ° C. as the medium.

EXAMPLE 2 Capsules having the composition indicated below where the parts are expressed by weight are prepared in Table 3 below.

Table 3 manages part: (% w / w) diacerein 10-60 sorbitol 0.5-20 sodium docusate 1-20 sodium lauryl sulfate 1-20 2nd part. glycine 1-20 lactose 5-40 crospovidone 5-40 Diacerein is mixed with sorbitol, sodium docusate and sodium lauryl sulfate and triturated with a minimal amount of water to form a pasty mass. This pasty mass is dried and sieved to form granules, 10 and mixed with glycine, lactose and crospovidone. The mixture obtained is introduced into capsules with a gelatin wall. In this way capsules containing 50 mg of diacerein are obtained, the dissolution rate of which is measured. The results are shown in Table 4 below.

Table 4 Duration (min.)% Dissol. (ART 50) Dissol. (Inv.) 5 3 16 4 35 5 50 7 60 30 9 72 45 11 78 60 14 82 Determination of the dissolution rate was measured using a type 2 apparatus to USP 20 standards (75 rpm). using as medium 1000 ml of phosphate buffer at pH 5.7 at 37 ° C 0.5 ° C.

EXAMPLE 3 Capsules having the composition indicated below where the parts are expressed by weight are prepared in Table 5 below.

Table 5 1st part. diacerein N-methyl pyrrolidone mannitol 2nd part. microcrystalline cellulose croscarmellose sodium magnesium stearate (% w / w) 10-90 q.s. Diacerein is solubilized in N-methylpyrrolidone (NMP) and the solution is sprayed with a flow rate of 3 ml / min. in a stream of 15 kg / h of CO2 at supercritical pressure (spraying conditions: 100 bar, 40 ° C) on a bed of mannitol in the spray reactor.

The particles thus formed are captured on a bed made of mannitol, and mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The mixture obtained is introduced into capsules with a gelatin wall.

In this way capsules containing 50 mg of diacerein are obtained, the dissolution rate of which is measured. The results are shown in Table 6 below.

Table 6 Time (min.)% Dissol. (ART 50) Dissol. (Inv.) 5 3 27 10 4 45 15 5 60 20 7 69 30 9 82 45 11 88 60 14 91 The determination of the dissolution rate was measured using a USP type 2 apparatus (75 trs). / min.) using 1000 ml phosphate buffer pH 5.7 at 37 ° C 0.5 ° C as medium.

EXAMPLE 4 Capsules having the composition indicated below after which the parts are expressed by weight are prepared in Table 7 below.

Table 7 manages part: diacerein 10 mannitol N-methyl pyrrolidone 2nd part. microcrystalline cellulose croscarmellose sodium Magnesium stearate 5-60 1-25 1-15 Diacerein and mannitol are dissolved in N-methylpyrrolidone (NMP) and the solution is sprayed with a flow rate of 3 ml / ml ... into a stream of 15 kg / h of supercritical pressure CO 2 (spray conditions: 100 bar, 40 ° C). The particles thus formed are collected on a filter and mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The mixture obtained is introduced into capsules with a gelatin wall. Thus, capsules of 50 mg of diacerein are obtained, the rate of dissolution of which is measured in comparison with the known composition (ART 50). The results are shown in Table 8 below.

Table 8 Duration (min.)% Dissol. (ART 50) Dissol. (Inv.) 3 92 4 100 5 100 7 100 30 9 100 45 11 100 60 14 100 Determination of the dissolution rate was measured using USP type 2 apparatus (75 rpm). ) using as medium 1000 ml of phosphate buffer at pH 5.7 at 37 ° C 0.5 ° C. The attached FIG. 3 shows the dissolution profiles of the samples of Examples 1, 2 and 4 according to the invention and of the ART 50 comparison composition. 10

Claims (17)

A pharmaceutical composition comprising diacerein or a salt or ester thereof, and one or more polyols, and optionally one or more pharmaceutically acceptable excipients. 2. Composition according to claim 1, characterized in that the diacerhein is mixed with the polyol. 3. Composition according to claim 1, characterized in that the diacerhein is in the form of complex with the polyol. 4. Composition according to claim 1, characterized in that the diacerein is adsorbed on the polyol. A pharmaceutical composition comprising diacerein or a salt or ester thereof, characterized in that the X-ray diffraction pattern of diacerein has peaks at a 2θ theta of 9.6 and 13.52 °. A pharmaceutical composition comprising diacerein, or a salt or ester thereof, and a polyol and optionally one or more pharmaceutically acceptable excipients, wherein the diacerein has a dissolution profile such that more than 75% of the diacerein is released in 30 minutes, the release rate being measured by means of a Type 2 apparatus (USP, dissolution, paddle stirrer, 75 rpm) using 1000 ml of phosphate buffer at pH 5.7, at 37 ° C. C 0.5 °. 7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that the polyol is selected from mannitol, maltitol, maltol, sorbitol, lactitol, or xylitol. 8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the weight ratio between diacerhein and the polyol is between 1:10 and 1: 1. 9. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is in the form of tablets, capsules, capsules, powders, granules, sachets, pellets and pellets. 10. Pharmaceutical composition according to any one of the preceding claims, characterized in that the excipient is selected from fillers, lubricants, disintegrating agents and fluidifiers. 11. Pharmaceutical composition according to claim 7, characterized in that the polyol is sorbitol or mannitol. 12. A method for improving the dissolution kinetics of diacerein in pharmaceutically acceptable solvents, comprising combining diacerein and one or more polyols. A process for preparing a diacerein and polyol composition comprising spraying an organic solution containing diacerein or a salt or ester thereof, optionally in the presence of polyol, into a pressurized fluid stream. supercritical to form and collect particles. 14. The method of claim 13, characterized in that the supercritical fluid is selected from carbon dioxide, water, ethane and xenon. 25 15. The method of claim 13, characterized in that the diacerhein is dissolved in an organic solvent, then the solution is sprayed into a stream of supercritical pressure fluid to form microparticles collected on a granular bed of polyol. 30 The method of claim 13, characterized in that the diacerein and the polyol are dissolved in an organic solvent, and the solution is then sprayed into a supercritical pressure fluid stream to form microparticles which are collected. 17. The method of claim 13, characterized in that the solvent is selected from N-methyl-pyrrolidone, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, ketones, alcohols and water, singly or in mixture.