MX2008007428A - Hcv prodrug formulation - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising a solid suspension prepared by hot melt extrusion of isobutyric acid (2R,3S,4R,5R)-5-(4-amino- 2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-bis-iso-butyryloxy-tetrahydro-furan-2-ylmethyl ester;hydrochloride salt (I) and a polyethylene glycol (PEG)/polypropylene glycol (PPG) block copolymer.

Description

FORMULATION OF PROFARMACOS FOR HEPATITIS C VIRUS DESCRIPTION OF THE INVENTION The present invention relates to a new formulation having 'azidocytidin-2', 3 ', 5' -tri-iso-butyrate (I) hydrochloride as an ingredient. active, and with a procedure to prepare the formulation. The composition has utility in the treatment of hepatitis C virus (HCV). The nucleoside derivatives often constitute potent antiviral agents (eg, HIV, HCV, Herpes simplex or CMV) or chemotherapeutic antineoplastic agents. Unfortunately, its utility is often limited by two factors. First, unfavorable pharmacokinetic properties that usually limit the absorption of the nucleoside in the intestine and the intracellular concentration of the nucleoside derivatives; and, second, suboptimal physical properties that restrict the formulation options that could be employed to enhance the release of the active ingredient. The prodrugs (P. Ettmayer et al., J. Med Chem. 2004 47 (10): 2393-2404; K. Beaumont et al., Curr. Drug Metab. 2003 4: 461-485; H. Bundgaard, Desn gn of Prodrugs: Bioreversible derives tives for various functi onal groups and chemi ca l in ti ties in Des ig n of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amersterdam 1985; G. M. Pauletti Ref. 193711 and others Adv. Drug Del ív. Rev. 1997 27: 235-256; R. J. Jones and N. 'Bischofberger, An tivira l Res. 1995 27; 1-15 and C. R. Wagner et al., Med. Res. Rev. 2000 20: 417-45) provide a technique for improving drug absorption. Typical examples of prodrugs include compounds containing biologically labile protecting groups attached to a functional moiety of the active compound. For the design of pronucleotides, alkylation, acylation or other lipophilic modifications of the hydroxy group (or groups) of the sugar fraction have been used. These pronucleotides can be hydrolyzed or dealkylated to generate the active compound. Unfortunately, a large amount of prodrugs that otherwise would be useful show a limited water solubility, which represents a major challenge for the formulation. Some traditional solutions at a low water solubility are micronization at a smaller particle size and, where possible, the conversion of a neutral compound into a more water-soluble salt. Solid dispersions represent a strategy for the formulation of poorly water-soluble compounds. The utility of solid dispersion systems in pharmaceutical formulation applications has been reviewed (W. L. Chiou and S. Riegelman, J. Pharm. Sci. 1971 60 (9): 1281-1302; C. Leuner and J. Dressman, Eur. J. Pha rm. Biopharm. 2000 50: 47-60; A. T. M. Sera uddm, J. Pharm. Sci. 1999 88 (10): 1058-1066, A. Forster and others Pharm. Technol. Eur. 2002 14 (10): 27; J. Breitenbach Eur. J. Pharm. and Biopharm. 2002: 54: 107-117; J. Breitenbach and M. Magerlem Drugs and the Pharma ceuti cal Sci ences 2003 133: 245-260 and K. A. Coppens et al., Pharm. Technol. 2006 30 (1): 62-70). Solid dispersion systems include eutectic mixtures, solid solutions and suspensions, crystalline solutions and suspensions or amorphous precipitates in crystalline carriers. Solid dispersions are an effective and practical technique for the formulation of water-soluble active ingredients. Disintegration and dispersion of the solution or solid suspensions produce fine colloidal particles of the active ingredient (IA) that facilitate its absorption in the gastrointestinal (GI) tract. The solid dispersions can be prepared by hot melt extrusion of a molten mixture of the IA and the carrier, or by rapid evaporation of a solvent from a solution of the IA and a carrier. Various solid carriers have been incorporated into solid dispersions including: polyethylene glycol (PEG), polyoxyethylene (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropylmethylcellulose (HMPC), hydroxypropylcellulose (HPC), carboxymethylethylcellulose (CMEC), phthalate hydroxypropylmethylcellulose, polyacrylates, polymethylacrylates, urea and sugars (for example, mannitol) (Leuner, supra). Although there are clearly many options, the identification of a carrier molecule that has the optimal properties for a particular active ingredient continues to be a considerable task. Among the solid dispersion formulations that have been studied in more depth and for a longer time are griseofulvin and PEG (L. Chiou and S. Riegelman, supra). PEGs are available in a wide variety of molecular weights, being the PEG whose molecular weights are approximately between 2000 and 6000 which present optimal physical properties for the preparation of solid dispersions with griseofulvin. Griseofulvin has a limited water solubility and its absorption by oral route is markedly low. The solid dispersions of griseofulvin and PEG are marketed as Gris-PEG®. PEGs are not good surfactants and the incorporation of emulsifiers, for example, polysorbate 80, polidocanol (Brij® 35) or sodium dodecyl sulfate, in the solid dispersion facilitate the dissolution process. An increase in the rate of release in formulations in the form of solid dispersion in PEG4000 has been observed in other drugs including: oxazepam (JM Gines et al., In t J. Pharm, 1996 143: 247-253), piroxicam (M Fernandez and others, Int. J. Pharm. 1993 98: 29-35), zoldipem (G. Trapani et al., Int. J. Pharm. 1999 184: 121-130), ketoprofen (MV Margarit and IC Rodríguez, Int. J. Pharm. 1994 108: 101-107 ), oxepam (R. Jachowicz et al., Int. J. Pharm., 1993 99: 321-325), nifedipine (H. Suzuki et al., Chem. Pharm. Bull. 1997 45: 1688-1693), phenytoin (R. Jachowicz, Int. J. Pharm., 1987, 35: 7-12), fenofibrate (MT Sheu et al., Int. J. Pharm., 1994, 103: 137-146), prednisolone (R. Jachowicz, Int. J. Pharm. 35: 1-5) and glyburide (GV Betageri et al., Int. J. Pharm, 1995 126: 155-160). In WO 97/49384 published on December 31, 1997, J. McGinity and F. Zhang describe pharmaceutical formulations containing an extrudable mixture by thermofusion of a therapeutic compound and a poly (oxyethylene) (PEO) of high molecular weight, and optionally containing polyethylene glycol as a plasticizer. The PEO used in the invention had a molecular weight range between 1,000,000 and 10,000,000. This application was subsequently recognized as U.S. Patent No. 6,488,963. In U.S. Patent Publication No. 2004/0253314 published on December 16, 2004, H.-U. Petereit et al. Describe thermofusion extrusion formulations containing an active pharmaceutical ingredient and a (meth) acrylate copolymer composed of 40 to 75% its weight by alkyl esters of C? - radically copolymerized from acrylic acid or by methacrylic acid. In U.S. Patent Publication No. 2005/0048112 published March 3, 2005, J. Breitenbach et al. Describe solid dosage dosage forms containing a solid dispersion of at least one HIV protease inhibitor, at least one water-soluble pharmaceutically acceptable polymer and at least one pharmaceutically active surfactant. acceptable, in which the water-soluble polymer has a Tg (vitreous transition temperature) of at least about 50 ° C. In U.S. Patent Publication No. 2005/0044529 published April 21, 2005, J. Rosenberg et al. Describe solid dosage forms of administration containing a solid dispersion of at least one HIV protease inhibitor, at least one water-soluble pharmaceutically acceptable polymer and at least one pharmaceutically active surfactant. acceptable. The present invention relates to a pharmaceutical composition containing a solid suspension prepared by hot-melt extrusion of (2R, 3S, 4R, 5R) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl isobutyrate) -2-azido-3, -bis-iso-butyryloxy-tetrahydro-furan-2-ylmethyl; hydrochloride (I; also referred to herein as 4'-azidocytidine-2 ', 3', 5'-tri-isobutyrate hydrochloride) and a copolymer of polyethylene glycol (PEG) / polypropylene glycol (PPG) blocks The present invention provides a pharmaceutical composition for the oral administration of 4'-azidocytidine-2 ', 3', 5'-tri-isobutyrate hydrochloride containing, in terms of the total weight of the composition, between about 250 mg and about 500 mg of 4 '-azidocytidine-2', 3 ', 5'-tri-isobutyrate hydrochloride (I). The compound is described and claimed in U.S. Patent No. 6,846,810 published January 2, 2005. TC Connolly et al. Describe an original nucleoside preparation process in U.S. Publication 20050038240, published February 17, 2005. Triacylated nucleoside I has been found to decrease viral load in patients infected with the hepatitis C virus (HCV). The hepatitis C virus is the leading cause of chronic liver diseases worldwide (N. Boyer et al., J. Hepa tol., 2000, 32: 98-112). Patients infected with HCV are at risk of developing liver cirrhosis and subsequent hepatocellular carcinoma. For this reason, HCV is the main indication for a liver transplant. Although I is available in crystalline form, it presents physicochemical properties dependent on pH. In addition, the compound easily forms a gel when it is exposed to water and is difficult to process with aqueous solutions. Although some cases have been described in which it has been possible to formulate limited water solubility compounds with solid dispersion formulations, each AI has unique properties and the fact of optimizing a formulation for a particular AI still represents an empirical challenge that supposes A big effort. For optimal release of the active ingredient it is necessary that there is an effective dispersion. The thermofusion formulation requires that both the active ingredient and the carrier exhibit sufficient thermal stability. It was essential to establish sufficient thermal stability for the AI containing an organic azide. In addition, drug treatment of viral diseases often requires the use of high doses to rapidly lower the viral load and avoid disorders that can lead to drug-resistant mutations. The required amount of active ingredient in the form of administration to produce high concentrations of this is considerable, which further increases the problems of solubility and limits the ability to include additional excipients that could otherwise be used. One reason for the success of amorphous solutions and suspensions is the presence therein of a hydrophilic carrier, so that the drug promotes the wetting of the active ingredient and potentially increases the solubility of the IA in the diffusion layer surrounding it. the particle (Forster, supra). It has been observed that the incorporation of emulsifiers sometimes improves the wetting characteristics and the solubility of the compounds in solid solutions / suspensions. Surfactants such as sodium lauryl sulfate and Tween 80 enhance the release rates of naproxen in PEG4000, 6000 and 20000 (C. Leuner and J. Dressman, supra). It has now been surprisingly discovered that polyethylene glycol (PEG) / polypropylene glycol (PPG) block copolymers provide a suitable matrix for solid suspensions of I and that it improves bioavailability as compared to other matrices. The compositions provided herein are amorphous suspensions wherein the blocking copolymer is an amorphous phase in which the crystalline compound I is suspended. The composition is prepared from a block copolymer with a melting point lower than that of I, and maintaining the heating zones of the extruder a temperatures between the melting point of I and that of the copolymer. The term "block copolymer" as used herein refers to a copolymer formed by two or more blocks (or segments) of different homopolymers. The term "homopolymer" refers to a polymer formed by a single monomer. There are many possible variations of block copolymers, which include simple two-block polymers with type A-B architecture and three-block polymers with type A-B-A or A-B-C architectures. The poloxamers (or LUTROL®) are type A-B-A block copolymers in which segment A is a hydrophilic polyethylene glycol homopolymer and segment B is a hydrophobic polypropylene glycol homopolymer. The poloxamers are marketed by BASF Corporation. Depending on the relative size of the blocks, the copolymer may be in solid, liquid or paste form. LUTROL® is a registered trademark of poloxamers. The terms poloxamer and LUTROL are used interchangeably in this document. Poloxamer 188 has an average molecular weight of about 8600, a melting point of 52-54 ° C and a HLB (hydrophilic-lipophilic balance) of 18-29 and the average particle size ranges from 1 miera to 500 microns. The polyoxyethylene units represent about 81% of the molecular weight. Poloxamer 188 is very easily soluble in water. In the formulation of the prodrug for HCV the Block copolymer limits exposure to moisture which causes undesired gelation of the AI. Other solid carriers that could be used to produce solid dispersions of I include Vitamin E-TPGS (Eastman Kodak), Gelucire 44/14, Gelucire 50/13 (Gattefosse, NJ), Solutol HS15, poloxamer 407, Lutrol F77, Cremophor RH40 (BASF , NJ), sucrose dipalmitate and sucrose distearate (Croda, NJ). In one embodiment of the present invention there is provided a pharmaceutical composition containing a solid suspension prepared by hot-melt extrusion of iso-butyrate (2R, 3S, 4R, 5R) -5- (4-amino-2-oxo-2-pyrimidine). 1-yl) -2-azido-3, 4-bis-iso-butyryloxy-tetrahydro-furan-2-ylmethyl, hydrochloride (I) and a block copolymer of PEG / PPG. In another embodiment of the present invention the solid suspension is combined with at least one carrier, diluent or excipient. In another embodiment of the present invention there is provided a pharmaceutical composition which is a solid suspension of (I) and a poloxamer. In another embodiment of the present invention, the pharmaceutical composition is a solid suspension of (I) and a poloxamer, combined with at least one carrier, diluent or excipient. Still another embodiment of the present invention provides a solid suspension of (I) and a poloxamer, contained in a compressed or in a capsule which may also contain additional carriers, diluents or excipients. In another embodiment of the present invention there is provided a pharmaceutical composition containing a solid suspension of (I) and poloxamer 188. Yet in another embodiment of the present invention there is provided a pharmaceutical composition containing a solid suspension of (I) and poloxamer 188 wherein the solid suspension contains 20 to 40% by weight of poloxamer 188. In another embodiment of the present invention there is provided a tablet containing a solid suspension of (I) and poloxamer 188, which contains microcrystalline cellulose, mannitol , crosprovidone, colloidal silicon dioxide, corn starch (or talcum) and magnesium stearate. In addition, the tablet may optionally contain sodium bicarbonate, arginine or maltodextrin, and be coated by coating material. In still another embodiment of the present invention there is provided a tablet containing a solid suspension of (I) and poloxamer 188, in which the solid suspension contains up to about 540 mg of I and from about 175 to about 260 mg of poloxamer 188, from about 125 to about 225 mg of microcrystalline cellulose (Avicel® PH 101), from about 70 to about 125 mg of mannitol (Parteck ™ 200), from about 90 to about 150 mg of crospovidone (Polyplasdone® XL), of about 10 to about 40 mg of colloidal silicon dioxide (Aerosil® 380), from about 10 to about 40 mg of corn starch (or talc), from about 10 to about 25 mg of magnesium stearate. The tablet of this embodiment can be optionally coated with yellow Opadry 03K 12429. In another embodiment of the present invention, a tablet is described which contains a solid suspension of (I) and poloxamer 188, in which the solid suspension contains up to about 537 mg of I and about 230 mg of poloxamer 188, about 175 mg of microcrystalline cellulose, about 72 mg of mannitol, about 120 mg of crospovidone, about 24 mg of colloidal silicon dioxide, about 24 mg of corn starch (or talc ) and about 18 mg of magnesium stearate, and the tablet is optionally coated with yellow Opadry 03K 12429. In another embodiment of the present invention there is described a tablet containing a solid suspension of (I) and poloxamer 188, in the that the solid suspension contains up to about 537 mg of I and about 179 mg of poloxamer 188, about 175 mg of microcrystalline cellulose, about 123 mg of mannitol, about 120 mg of crospovidone, about 24 mg of silicon dioxide loidal, about 24 mg of corn starch and about 18 mg of magnesium stearate, and the tablet is optionally coated with Opadry yellow 03K 12429. In another embodiment a pharmaceutical composition containing a solid suspension of I is described, poloxamer and a plasticizer. In this embodiment, the plasticizer increases the flexibility, malleability or extensibility of the extruded material. In addition, a plasticizer can reduce the melt viscosity and decrease the modulus of elasticity of the product. The plasticizers generally lower the glass transition temperature or the softening point of the block copolymer in order to allow a lower processing temperature, torque and extruder pressure during the extrusion process. Plasticizers also tend to lower the viscosity of the molten extrudate material. Some examples of plasticizers that can be used according to the invention are the following: triacetin, propylene glycol, polyethylene glycol with an approximate molecular weight of between 200 and 1000. { for example, PEG 4600), dibutyl phthalate, dibutyl sebacate, triethyl citrate, vegetable and mineral oils, fatty acids, C6-18 fatty acid glycerides, for example, Tween 80, and the like. In another embodiment of the present invention there is described a process for the preparation of a solid suspension of I and a block copolymer of PEG / PPG comprising the following steps: (i) mixing the solids in a mixer; . { ii) introducing the resulting mixture of solids into a heating zone of the extruder by thermofusion in which the temperature of the heating zone is in a range above the melting point of said block copolymer and below the melting point of I; . { i i) extrude the resulting molten material; and (iv) grinding the solid suspension to a particle size of between about 20 and about 2000 microns. In another embodiment of the present invention the particle size obtained by grinding is from about 100 to about 600 microns. In another embodiment of the present invention there is described a pharmaceutical composition formed by a solid suspension of I and poloxamer 188, in which the solid suspension contains between 55 and 70% approximately I (w / w), from 5 to 12% mannitol, 13 to 16% microcrystalline cellulose, 8 to 12% crospovidone, 1 to 3% colloidal silicon dioxide, 1 to 3% corn starch (or talcum) and 1 to 2% magnesium stearate. In one embodiment of the present invention, the solid suspension, together with the carriers, diluents or excipients, are incorporated into a tablet. The excipients are incorporated together with the solid suspension to confer the desired properties. Among the useful excipients that are usually included in the tablet formulations are the following: binders, surfactants, diluents, excipients for compression, disintegrants, anti-adherents, stabilizers, antioxidants, dyes, humectants and lubricants. The carriers, diluents and excipients which have proved their usefulness in the field of pharmaceutical technology are well known and are described in Remingto: The Science and Praxis of Pharmacy 1995, edited by EW Martin, Mack Publishing Company, edition 19, Easton, Pennsylvania. It is possible to use a large number of ingredients for various purposes even within the same formulation, and the excipients and diluents included herein can be substituted or altered without departing from the spirit of the invention. The tablets containing the solid suspension may be optionally coated. The membranous coating may also contain other coating excipients such as opacifiers, pigments, dyes and the like. It is considered that the choice of these materials and the amount to be used thereof are within the technique known in the field. The term "excipients" as used herein refers to inert materials that confer satisfactory processing and compression characteristics on the formulation, or confer the desired physical characteristics on the finished tablet. Diluents are inert ingredients that are added to adjust the volume in order to produce a practical size for compression. Typical diluents include: dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, starch, sodium chloride and powdered sugar. Sufficient amounts of diluents such as mannitol, lactose, sorbitol, sucrose or inositol facilitate the disintegration of the tablet and are often used in chewable tablets. Microcrystalline cellulose (AVICEL®) has been used as an excipient in direct compression formulas. The binders are added to the powders so that they confer a cohesive characteristic to the powder which allows the tablet to maintain its integrity. Among the materials normally used as binders are the following: starch, gelatin and sugars such as sucrose, glucose, dextrose, molasses or lactose. In some formulations, natural and synthetic gums such as acacia gum, sodium alginate, panwar gum, ghatti gum, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and ethylcellulose have also been used as binders. Lubricants are used to prevent adhesion of the tablet material to the surface of the dies and punches. Commonly used lubricants include: talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and PEG. Water-soluble lubricants include: sodium benzoate, benzoate mies sodium and sodium acetate, sodium chloride, leucine and Carbowax 4000. The glidants are incorporated to improve the flow characteristics of the tablet powder. Colloidal silicon dioxide (AEROSIL®) is a common glide. Talc can serve as a combined lubricant and glidant. A disintegrant is a substance, or a mie of substances, which is added to facilitate rupture or disintegration of the tablet after administration. Corn starch or dehydrated potato starch powder are very common disintegrants. They have a high affinity for water and swell when they are humidified in such a way that they lead to rupture of the tablet. A group of materials known as superdisintegrants includes croscarmellose, a cross-linked cellulose, crosprovidone, a cross-linked polymer and sodium starch glycolate, a cross-linked starch. The crosprovidone (POLYPLASDONE®) is a homopolymer of synthetic N-vinylpyrrolidone crosslinked insoluble but swollen fast. The examples that follow illustrate the preparation and biological evaluation of compounds that are within the scope of the invention. These examples and preparations are provided to provide those skilled in the art with the clear understanding and practice of the present invention. They should not be considered as limiting the scope of the invention, but as merely illustrative and representative thereof. The pharmaceutical chemist skilled in the art will know the excipients, diluents and carriers that can be used interchangeably, variations that do not depart from the essence of the invention. Example 1 The following composition represents a formulation made according to% by weight.

One skilled in the art will recognize that the amount of I can be easily modified to produce tablets or capsules of different potency by replacing part of the AI with an additional diluent and that altering the amount of I, or the solid dispersion. of I, does not depart from the essence of the invention.

Active ingredient I and poloxamer 188, and optionally a plasticizer, were mixed in a mixer. The mixed solid was placed in a Leistritz twin-screw extruder. The heating zones were adjusted to 45, 65, 65, 65, 65, 70, 75 and 80 ° C. The variation of the temperature of the zones was maintained at ± 5 ° C. These conditions are sufficient to melt poloxamer and excipients without melting compound I. The double screw was used at 100 ± 30 revolutions per minute and the flow rate of the powder was between 5 and 20 g / min., preferably between 10 and 15 g / min. Under these conditions, the polymer melts and forms a homogeneous coating around the active ingredient. The extruded mixture was collected at room temperature (15 to 30 ° C) in double-coated polyethylene containers. The extruded material was passed through a Fitz mill and the milled material was mixed with AVICEL PH101, mannitol, POLYPLASDONE XL and corn starch (optionally with talc instead of corn starch). Finally, magnesium stearate was added to the mixed material. The milled particle size was between 100 and 2000 microns. The resulting mixture was introduced into a tabletting machine and compressed into cores. A coating suspension can be prepared by combining Opadry and purified water, mixing for 45 min until the Opadry is completely dispersed. The The cores are placed in a perforated coating drum and heated with air injection at 45 ± 5 ° C with intermittent agitation until the exhaust air reaches 40 ± 5 ° C. Thereafter the inlet temperature is increased to 60 ± 5 ° C and the cores are coated with a continuous stirring coating suspension using a calibrated air spray system to apply 25 mg per particle of the coating film in one dry base. The coated tablets are dried by jogging until the water content is less than 2%, after which the tablets are cooled to RT and stored in a double-walled polyethylene coating container. Example 2 The following compositions were prepared: The features described in the preceding description, or in the following claims, expressed in their specific forms or in terms of a means of mode of the described function, or of a method or procedure for obtaining the described result, can be used as necessary, separately or in any combination of said characteristics, for the embodiment of the invention in its various forms. The preceding invention has been described in some detail in the form of illustration and example for the purpose of providing clarity and ease of understanding. The possibility of making changes and modifications within the scope of the appended claims will be apparent to one skilled in the art. Therefore, it should be understood that the foregoing description is meant to be illustrative and not restrictive. Accordingly, the scope of the invention should not be determined by reference to the foregoing description but in reference to the following appended claims, together with the full range of equivalents that these claims admit.

All patents and patent applications and publications cited in this application are incorporated herein in their entirety by way of reference for any purpose and to the same extent as if each patent or individual patent application or publication were individually named. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (14)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical composition characterized in that it contains a solid suspension prepared by hot-melt extrusion of (2R, 3S, 4R, 5R) -butyl isobutyrate. (4-amin-2-oxo-2 / i-p? Pm? D? Nl-? L) -2-azido-3, 4-jb? S-? So-butyryloxy-tetrahydro-furan- 2-? hydrochloride (I), and a polyethylene glycol (PEG) / polypropylene glycol (PPG) block copolymer.
2. 2. A composition according to claim 1, characterized in that it also comprises at least one diluent, carrier and / or excipient.
3. 3. A pharmaceutical composition according to claim 1, characterized in that the block copolymer of PEG / PPG is a poloxamer.
4. 4. A pharmaceutical composition according to claim 3 characterized in that it also contains at least one diluent, carrier and / or excipient.
5. 5. A pharmaceutical composition according to claim 3, characterized in that it is contained in a capsule or a tablet and the tablet or capsule optionally contain one or more carriers, diluents and / or excipients.
6. 6. - A pharmaceutical composition according to claim 5, characterized in that the solid suspension contains I and poloxamer 188.
7. 7. A pharmaceutical composition according to claim 6, characterized in that the solid suspension contains 20-40% (weight / weight). ) poloxamer 18
8. 8. 8. A pharmaceutical composition according to claim 7, characterized in that the solid suspension is contained in a tablet which in turn can also optionally contain one or more excipients selected from the group consisting of: microcpstalin cellulose , mannitol, crosprovidone, colloidal silicon dioxide, corn starch (or talcum), magnesium stearate, sodium bicarbonate, arginine, maltodextrin and a coating material.
9. 9. A pharmaceutical composition according to claim 8 characterized in that the tablet contains: and wherein the tablet is optionally coated with yellow Opadry 03K 12429.
10. 10. A pharmaceutical composition according to claim 9 characterized in that it contains: and wherein the tablet is optionally coated with yellow Opadry 03K 12429.
11. 11. A pharmaceutical composition according to claim 9 characterized in that it contains: and wherein the tablet is optionally coated with yellow Opadry 03K 12429.
12. 12. A pharmaceutical composition characterized in that it contains a solid suspension prepared by hot melt extrusion of I, a poloxamer 188 and a plasticizer.
13. 13. A process for preparing a solid suspension of I and a block copolymer of PEG / PPG characterized in that it comprises the following steps: (i) mixing the solids in a mixer; (ii) introducing the resulting solids mixture into a heating zone of the hot melt extruder where the temperature of the heating zone is in a range above the melting point of the block copolymer and lower than the melting point of I; (iii) extruding the resulting molten material; and, (iv) grinding the solid suspension to a particle size of between about 20 and about 2000 microns.
14. 14. A method according to claim 13, characterized in that the solid suspension is milled to a size between about 100 and about 600 microns.