The present invention relates to a gastro-resistant pharmaceutical composition comprising posaconazole.

Posaconazole is a triazole antifungal drug marketed under the tradename Noxafil* as a solution for injection, oral suspension and gastro-resistant tablet for the treatment and prophylaxis of invasive fungal infections. Noxafil* is in particular indicated for the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with a graft- versus-ho st-disease and patients with hematologic malignancies with prolonged neutropenia from chemotherapy. The oral suspension is indicated for the treatment of oropharyngeal candidiasis.

Posaconazole is a white powder with a low aqueous solubility, whereby posaconazole' s bioavailability in the oral suspension is significantly enhanced when coadministered with food. For this reason, the oral suspension should be administered during or immediately following a full meal to enhance the oral absorption of the drug. The gastro-resistant tablet has an improved bioavailability and can be administered without regard to food. It is commonly known that the dissolution behavior of a drug depends on its solid state. Different crystalline forms of a drug usually exhibit different dissolution profiles, whereby amorphous forms are generally much more soluble man their crystalline counterparts. In addition, the chemical and physical stability of a drug are depen- dent on the solid state. Quite often, metastable crystalline or amorphous forms of a drug have to be stabilized in the pharmaceutical composition in order to prevent chemical degradation and interconversion of the crystalline forms/recrystallization of the amorphous form and, thus, fluctuations in the bioavailability. WO 99/18097 discloses the crystalline forms I, II and III of posaconazole. Form I is the most stable form that does not convert into any other crystalline form under normal storage conditions or under specific stress conditions. The crystalline forms Π and III convert into the form I at temperatures between 100 and 125°C. WO 2009/147075 discloses the crystalline form Y of posaconazole. The form Y is as stable as form I but has a better water solubility, which results in an improved bioavailability.

WO 2010/000668 reports that the crystalline form IV of posaconazole has a better stability in an aqueous suspension and a better water solubility as form I due to a smaller particle size and, thus, larger specific surface area. The crystalline form IV can be directly used for a pharmaceutical composition, i.e. without the need of reducing the particle size by micronization. WO 2011/158248 discloses the crystalline form V of posaconazole, while WO 2011/003992 discloses the crystalline form II-S from which the other crystalline forms, in particular the crystalline form IV may be obtained.

As an alternative approach for overcoming the solubility problems encountered with posaconazole, WO 98/00113 suggests a pharmaceutical composition comprising a solid solution of the drug within a polymer. The solid solution is prepared by dissolving the drug and a soluble polymer in a suitable organic solvent, followed by removing the solvent, or by dissolving the drug in a suitable organic solvent and adding an insoluble polymer, followed by absorbing the solution into the insoluble polymeric matrix. Preferably, the polymer is povidone or crospovidone.

WO 2009/129301 discloses a solid solution of posaconazole within hydroxypropyl methylcellulose acetate succinate (HPMCAS) by spray-drying a solution containing the drug and the polymer. It is further suggested that the solid solutions may be prepared by using hot-melt extrusion.

WO 2009/129300 discloses the preparation of a solid solution containing posaconazole within a hydroxypropyl methylcellulose derivative, preferably HPMCAS. It has been found that posaconazole forms a solution with the polymer behaving as a eutec- tic having a melting point below the melting point of the drug (about 169°C). Hence, the use of hydroxypropyl methylcellulose derivatives for the preparation of the solid solution minimizes thermal decomposition and oxidation of posaconazole during the preparation compared to processes which utilize higher melting polymers. WO 2009/129300 further suggests that the solid solution may additionally contain a plasticizer and an antioxidant.

In view of the above described state of the art, the objective underlying the present invention was the provision of a pharmaceutical composition, in which posaconazole is physically and chemically stable. This objective is attained by the subject matter as defined in the claims.

The pharmaceutical composition of the present invention is a gastro-resistant pharmaceutical composition. Gastro-resistant formulations are designed to release the drug in the intestines. According to the European Pharmacopoeia 8.0, gastro-resistant dosage forms are delayed-release dosage forms that are intended to resist the gastric fluid and to release their drug(s) in the intestinal fluid. The gastro -resistance minimizes the food effect of the pharmaceutical composition of the present invention and, thus, improves the bioavailability of the drug. The gastro-resistant pharmaceutical composition of the present invention comprises posaconazole molecularly dispersed in a mixture containing an enteric polymer and a non-enteric polymer, wherein the mixture is prepared by hot-melt extrusion.

The enteric polymer is preferably selected from hypromellose derivatives, cellulose derivatives, polyvinylacetate derivatives and polymethacrylic acid derivatives. Examples of hypromellose derivatives include hydroxypropyl methylcellulose phtha- late (HPMCP, e.g. available as HP-50 or HP-55 from Shin-Etsu Chemical Co., Ltd. Japan), hydroxypropyl methylcellulose succinate and hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g. available as AQOAT ^® from Shin-Etsu Chemical Co., Ltd. Japan). An example of a polyvinylacetate derivative is polyvinylacetate phthalate (PVAP), while examples of cellulose derivatives include cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose acetate phthalate and hydroxypropylcellulose acetate phthalate. Examples of polymethacrylic acid derivatives include poly(methacrylic acid/methyl methacrylate) 1:1 (e.g. available as Eudragit ^® L 100 from Evonik, Germany), poly(methacrylic acid/methyl methacrylate) 1:2 (e.g. available as Eudragit ^® S 100 from Evonik, Germany) and poly(methacrylic acid ethyl acrylate) (e.g. available as KoUicoat ^® MAE from BASF SE, Germany). According to a preferred embodiment of the present invention, the enteric polymer is a polymethacrylic acid derivative selected from poly(methacrylic acid/methyl methacrylate) and poly(methacrylic acid/ethyl acrylate).

The pharmaceutical composition of the present invention contains a non-enteric polymer that is preferably selected from polyvinylpyrrolidone (povidone), poly(vinylpyrrolidone/vinylacetate) (copovidone), polyvinyl caprolactam/ polyvinyl- acetate polyethylene glycol graft copolymer, polyethylene glycol/polyvinyl alcohol graft copolymer, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, polyacrylates, polymethacrylates, vinylacetate polymers such as copolymers of vinyl acetate and crotonic acid, polyvinyl alcohol, partially saponified polyvinylalcohol, macrogolglycerol hydroxystearate, polyethylene glycol, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose and maltodextrins.

According to a preferred embodiment of the present invention, the pharmaceutical composition contains an antioxidant. Preferably, the antioxidant is contained in the mixture comprising posaconazole, the enteric polymer and the non-enteric polymer. Examples of antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium or potassium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, cysteine, acetyl cysteine, methionine, glutathione, sodium formaldehyde sulfoxylate, ascorbic acid and its derivatives like sodium ascorbate, ascorbyl palmitate, tocopherol and its derivatives, tocopheryl succinate, tocopheryl polyethylene glycol succinate (TPGS), and propyl gallate. Preferably, the antioxidant is propyl gallate. Typically, the antioxidant is present in the composition in an amount of 0.001-2 wt.-%, preferably 0.01-1 wt -%. Optionally the pharmaceutical composition of the present invention contains in addition an antioxidant synergist, e.g. citric acid, tartaric acid, or ethylenediaminetetra acetic acid (EDTA).

The mixture contained in the composition of the present invention may additionally contain a monomelic plasticizer, e.g. triethyl citrate, triacetin, dibutyl sebacate, diethyl phthalate, glycerylmonostearate, glycerine and propylene glycol.

Posaconazole has a melting point of 170-172°C, but it degrades at temperatures above 160°C. Hence, the hot-melt extrusion used for the preparation of the gastro- resistant pharmaceutical composition of the present invention has to be conducted at temperatures below 160°C. Preferably, the hot-melt extrusion is conducted at a tem- perature of 40-160°C, more preferred at a temperature of 120-150°C. The hot-melt extrusion has to be carried out at a temperature that allows the dissolution of the posaconazole used as staring material within the mixture of the enteric polymer and the non-enteric polymer. In principle, any crystalline form of posaconazole as well as the amorphous form may be used for the preparation of the gastro-resistant pharmaceutical composition of the present invention.

The temperature of the hot-melt extrusion can be decreased when using a mixture of an enteric polymer and a non-enteric polymer, so that it is possible to process polymers with relatively high glass transitions temperatures. In addition, the non-enteric polymer, in particular polyvinylpyrrolidone, poly(\½ylpyrroUdone vinylacetate) and polyvmylcaprolactam/polyvmylacetate/polyethylene glycol graft copolymer, may serve as a solubility enhancer for posaconazole and may avoid recrystallization of the drug during dissolution in the intestines. Moreover, since the hot-melt extrusion works at relatively low temperatures, it is possible to use relatively volatile antioxidants as BHA and BHT as well as antioxidants, which degrade at processing temperatures above 140°C, e.g. sodium metabisulflte.

Typically, the extrudate contains the enteric polymer and the non-enteric polymer in a weight ratio of 6:1 to 1 :1, preferably of 4:1 to 2:1 and more preferred of 3:1 to 2.5:1. Furthermore, the weight ratio of posaconazole to total polymer content of the extrudate is from 1:1 to 1:5, preferably from 1:2 to 1:4, and more preferred 1:2 to 1:2.5. According to a preferred embodiment of the present invention the enteric polymer is poly(methacrylic acid/ethyl acrylate) and the non-enteric polymer is selected from poly(vinylpyrrolidone vinylacetate), polyethylene glycol, hydroxypropyl cellulose and polyvinylpyrrolidone.

It has been found that the presence of a sugar alcohol in the mixture that is subjected to hot-melt extrusion may increase the chemical stability of posaconazole and also the processability, in particular, if an acidic polymer as poly(methacrylic acid/ethyl acrylate) is present. Preferred sugar alcohols are xylitol, sorbitol, mannitol, maltitol, isomalt, lactitol and erythritol.

The pharmaceutical composition of the present invention is preferably a granulate material, whereby the granules may be coated with an enteric polymer. It is preferred that the enteric coating of the granules and the enteric polymer constituent of the granules comprise the same enteric polymer. According to a preferred embodiment, the granules consist of posaconazole, an enteric polymer, a non-enteric polymer and, optionally, an antioxidant, a sugar alcohol and/or a plasticizer.

The granules may be filled into a capsule or compressed into a tablet The tablet, which is prepared by compressing the optionally enteric-coated granules of the present invention, may be coated with an enteric polymer or an immediate-release coating, too.

The capsule or tablet of the present invention may contain additional pharmaceutical excipients as extragranular component, e.g. diluents, binders, disintegrants, glidants and lubricants. Examples of diluents include microcrystalline cellulose, calcium hydrogen phosphate, lactose (anhydrous or monohydrate), and calcium carbonate. As binders may be used methyl cellulose, hydro xypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), pregelatinized starch, povidone and copovidone. Examples of disintegrants include croscarmellose sodium, sodium starch glycolate, polyvinylpolypyrrolidone (crospovidone) and low-substituted hydroxypropyl cellulose (L-HPC). As glidants silicone dioxide, talk and the like may be used, while mag- nesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and glycerol dibehenate are examples of suitable lubricants.

The following examples are intended to further illustrate the present invention. Examples

Hot melt extrusion was performed with a Pharma 11 Twin-screw hot melt extruder from Thermo Fisher Scientific Inc. The used film coating system Opadry II* 85F520152 yellow comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc and yellow iron oxide.

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Low- substituted hydroxypropylcellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and sodium stearyl fumarate were sifted and blended with the extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Process:

Posaconazole and the excipients of stage A were sifted and blended, and then subjected to hot melt extrusion. The extrudate was milled and coated with the material of stage B by top-spray granulation. Low-substituted hydroxypropyl cellulose, microcry stall ine cellulose, silicon dioxide, croscarmellose sodium, and sodium stearylfumarate of stage C were sifted and blended with the enteric-coated extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Low- substituted hydroxypropylcellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and magnesium stearate of stage B were sifted and blended with the extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Low- substituted hydroxypropylcellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxy- propyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxy- propyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage B were silted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Process:

The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to com- pression to obtain a tablet, which was finally film-coated.

Process:

The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to com- pression to obtain a tablet, which was finally film-coated.

Process:

The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to com- pression to obtain a tablet, which was finally film-coated.

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium and optionally propyl gallate of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated. Process:

The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Process:

Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Macrocrystalline cellulose, silicon dioxide, croscannellose sodium, and sodium stearyl fumarate were sifted and blended with the extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Example 13 - Stability tests

Stability testing was conducted according to guideline Q 1 A (R2) of International Conference on Harmonization (ICH). The film-coated tablets were stored either for 48 hours at 80 °C and 40 % relative humidity (80°C/40%RH) or for 3 and 6 months at accelerated conditions (40 °C and 75 % relative humidity, 40°C/75%RH). The film-coated tablets stored for 48 hours at 80°C and 40 % RH were not packed, whereas the film-coated tablets tested under accelerated conditions (40°C/75 % RH for 3 and 6 months) were packed in alu-alu blisters.

Example 14a-g Stability testing was conducted according to guideline Q 1 A (R2) of International Conference on Harmonization (ICH). The granulate was stored either for 48 hours at 80 °C and 40 % relative humidity (80°C/40%RH) or for 3 months at accelerated conditions (40 °C and 75 % relative humidity, 40°C/75%RH).

Process: Posaconazole and the excipients were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled.. The granules were subjected to the stability testing.