Patent Publication Number: US-2022226247-A1

Title: Stable hot-melt extrudate containing valsartan and sacubitril

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a Divisional of copending U.S. application Ser. No. 16/498,909, filed on Sep. 27, 2019, which was filed as the National Phase of PCT International Application No. PCT/EP2018/058207, filed on Mar. 29, 2018, which claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 62/513,605, filed on Jun. 1, 2017 and under 35 U.S.C. 119(a) to Patent Application No. 201711011677, filed in India on Mar. 31, 2017, all of which are hereby expressly incorporated by reference into the present application. 
    
    
     The present invention relates to a solid dispersion containing valsartan and sacubitril as well as to a pharmaceutical composition containing such a solid dispersion. 
     The combination valsartan and sacubitril is marketed under the tradename Entresto® in the form of film-coated tablets for the prevention of heart failure in patients with chronic heart failure. Entresto® contains the drug combination in the form of a cocrystal consisting of valsartan disodium, sacubitril monosodium and 2.5 molecules water. The cocrystal has been designated as LCZ696; its preparation and physical/chemical properties are described in WO 2007/056546 and in  Tetrahedron Letters  2012, 53, 275-276. In the Tetrahedron Letters, it is further reported that a desolvated crystalline form exists because the crystalline structure of LCZ696 is maintained up to the melting temperature (around 138° C.), in spite of the fact that two water molecules are lost during the heating. 
     Various polymorphic forms, pseudopolymorphic forms of LCZ696, i.e. crystalline forms in which the cocrystal contains either more molecules or less molecules of water than 2.5 molecules, and amorphous forms of LCZ696 are known, which are described in WO 2016/037552, WO 2016/049663, WO 2016/051393, WO 2016/125123, WO 2016/151525, WO 2016/201238, WO 2017/009784 and WO 2017/012917. 
     The Entresto® film-coated tablet is an immediate-release tablet that contains, besides LCZ696, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, magnesium stearate, talc and colloidal silicon dioxide as pharmaceutical excipients. Three strengths of the tablet are marketed, which contain, on the basis of the free acid weight of the drugs, 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg of sacubitril/valsartan. WO 2009/061713 discloses an immediate-release tablet containing LCZ696 prepared by direct compression or dry-granulation. In the preparation of the tablet, moisture, excessive heat and high shear forces should be avoided in order to prevent amorphization as well as dissociation of the drug components of LCZ696. 
     WO 2017/000864 describes a direct compression method for preparing a tablet containing LCZ696, in which a mixture of the drug, a hydrophilic diluent, a binder and a disintegrant is subjected to compression. 
     WO 2017/012600 discloses a tablet containing a physical mixture of sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof that can be prepared by direct compression, dry-granulation or wet-granulation. The tablets are very sensitive to moisture, so that packaging under nitrogen atmosphere is recommended in order to prevent the degradation of the drugs. 
     WO 2017/037596 discloses an amorphous solid dispersion of LCZ696 prepared by rotational distillation, spray-drying or freeze-drying a solution containing LCZ696 and a pharmaceutical excipient such as a polymer or magnesium aluminometasilicate (e.g. Neusilin®). 
     The objective underlying the present invention was the provision of a solid unit dosage form for oral administration that contains valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof, optionally in form of a complex of the two active ingredients, in a physically and chemically stable form. It was a further objective of the present invention to provide a physico-mechanical stable solid unit dosage form containing these active ingredients. These objectives are attained by the subject matter as defined in the claims. 
     The solid unit dosage form of the present invention is an immediate-release solid unit dosage form for oral administration, preferably an optionally film-coated tablet or granules filled in a pouch. The solid unit dosage form contains a solid dispersion comprising valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof as active ingredients. The active ingredients are dispersed in a matrix containing a polymer, wherein the solid dispersion is prepared by hot-melt extrusion. The expression “solid dispersion” as used herein relates to a drug molecularly dissolved in the solid excipient(s) matrix (solid solution) or a drug dispersed as crystalline or amorphous particles in the solid excipient(s) matrix. 
     The active ingredients are preferably in a non-crystalline state (i.e. molecularly dissolved or in the form of amorphous particles). The absence of crystalline drug in the solid dispersion can be determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM), respectively. The solid dispersion preferably comprises the active ingredients in a ratio (mol/mol) of 1:1. 
     According to a preferred embodiment of the present invention, the solid dispersion contains valsartan disodium and sacubitril monosodium, preferably in a ratio (mol/mol) of 1:1. The solid dispersion is prepared by subjecting a mixture containing the polymer and the active ingredients to hot-melt extrusion, wherein the active ingredients are selected from valsartan disodium, sacubitril monosodium and a complex of valsartan disodium and sacubitril monosodium. U.S. Pat. No. 5,217,996 discloses a process for the preparation of sacubitril and its pharmaceutically acceptable salts, in particular, the monosodium salt of sacubitril, and various salts of valsartan, e.g. its disodium salt, are disclosed in WO 02/06253. 
     For the preparation of the solid dispersion of the present invention, the complex of valsartan disodium and sacubitril monosodium, either in crystalline or amorphous form, can be used in the hot-melt extrusion process. Alternatively, the individual drugs, i.e. valsartan and sacubitril, or pharmaceutically acceptable salts thereof, either in crystalline or amorphous form, may be subjected to the hot-melt extrusion process. Examples of a crystalline complex of valsartan disodium and sacubitril monosodium include LCZ696 or a polymorphic or a pseudopolymorphic form thereof. The expression “pseudopolymorphic form” relates to crystalline hydrates of the complex of valsartan disodium and sacubitril monosodium other than the hemipentahydrate LCZ696, which contain either more water molecules or less water molecules than 2.5 molecules in the crystal lattice. 
     The solid dispersion of the present invention contains a polymer that is preferably selected from polyvinylpyrrolidone, poly(vinylpyrrolidone/vinylacetate), polyvinyl-caprolactam/polyvinylacetate/polyethylene glycol graft copolymer, polyethylene glycol/polyvinyl alcohol graft copolymer, poly(ethylene oxide), poly(ethylene oxide/propylene oxide), macrogolglycerol hydroxystearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, D-α-tocopheryl polyethylene glycol succinate, poly(butyl methacrylate/2-dimethylaminoethyl methacrylate/methyl methacrylate), poly(ethyl acrylate/methyl methacrylate) and poly(ethyl acrylate/methyl methacrylate/trimethylammonio ethyl methacrylate chloride). According to a preferred embodiment of the present invention, the polymer is selected from polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graft copolymer, hydroxypropyl methylcellulose and poly(vinylpyrrolidone/vinylacetate) optionally in admixture with polyethylene glycol. Mixtures of polymers may be contained in the solid dispersion of the present invention. 
     Sacubitril and their pharmaceutically acceptable salts, such as sacubitril monosodium, as well as the amorphous complex of valsartan disodium and sacubitril monosodium are solid but very hygroscopic substances. These substances become deliquescent and sticky when exposed to air humidity. The polymer constituting the matrix of the solid dispersion of the present invention serves the purpose to protect the active ingredients from moisture. Thus, the present invention also relates to the use of polymers for protecting the active ingredients from moisture-induced chemical and physical (polymorph conversion, recrystallization or amorphization) degradation. 
     It is well known that the handling and the formulation of hygroscopic and deliquescent, sticky active ingredients into solid pharmaceutical formulations is difficult and requires extensive precautions. When water absorption occurs during manufacturing, the consequences include processing problems such as stickiness, clumping, poor release from punches, poor flow characteristics and poor compressibility. Moreover, the physico-mechanical properties and appearance of solid dosage forms comprising a hygroscopic or deliquescent active ingredient are often insufficient, especially after storage. For example, an insufficient tablet hardness as well as unacceptable crumbling or even liquifying of the solid dosage forms may occur. Thus, the present invention also relates to the use of polymers for reducing or eliminating manufacturing and physico-mechanical stability problems of solid dosage forms, which are associated with the hygroscopicity and deliquescence of sacubitril or salts thereof, such as sacubitril monosodium, or a complex of valsartan disodium and sacubitril monosodium as active ingredients. 
     The solid dispersion may additionally contain a monomeric plasticizer, e.g. triethylcitrate, triacetin, dibutyl sebacate, diethyl phthalate, glycerylmonostearate, glycerine or propylene glycol, or a polymeric plasticizer such as polyethylene glycol or poly(ethylene oxide/propylene oxide). In order to increase the hygroscopic stability of the solid dispersion, a porous, preferably mesoporous inorganic stabilizer can be incorporated, such as mesoporous silica. A mesoporous material is a material containing pores with diameters between 2 and 50 nm. Suitable mesoporous silica products are commercially available under the tradename Syloid®. As an alternative to mesoporous silica, mesoporous magnesium aluminometasilicate may be used, e.g. the magnesium aluminometasilicates marketed under the tradename Neusilin®. A further alternative is mesoporous magnesium carbonate, which is available under the tradename Upsalite®. 
     Typically, the solid dispersion contains the active ingredients and the polymer in a weight ratio of 3.5:1 to 1:3.5, preferably from 2:1 to 1:1.5 (total weight of the active ingredients, calculated on the basis of the free acid weight of the drugs, to the total weight of the polymer(s)). 
     The solid dispersion of the present invention is contained in the solid unit dosage form for oral administration together with a pharmaceutical excipient. Preferably, the pharmaceutical excipient is selected from diluents, disintegrants, mesoporous inorganic hygroscopic-stability increasing substances, lubricants and glidants. The solid unit dosage form may be an optionally film-coated tablet. The film coating may be a moisture-barrier film coating in order to increase the hygroscopic stability of the tablet. Alternatively, the milled extrudate may be filled in sachets without additional pharmaceutical excipients. 
     Examples of diluents include microcrystalline cellulose, calcium hydrogen phosphate, lactose (anhydrous or monohydrate) and calcium carbonate. Examples of disintegrants include croscarmellose sodium, sodium starch glycolate, polyvinyl-polypyrrolidone (crospovidone) and low-substituted hydroxypropyl cellulose (L-HPC). As glidants silicon dioxide, talc and the like may be used, while magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and glycerol dibehenate are examples of suitable lubricants. Examples of mesoporous inorganic hygroscopic-stability increasing substances include silica products (e.g. Syloid®), magnesium aluminometasilicate products (e.g., Neusilin®) and magnesium carbonate products (Upsalite®). 
     The solid unit dosage forms of the present invention are contained in blister packages, bottles or sachets made for example from PVC, PVDC, PCTFE, COC, PET, PA, Alu, PE or PP and combinations or multilayer films thereof. These packages may comprise a moisture barrier layer and/or they may be packed together with desiccants. 
     The present invention further relates to a process for preparing an optionally film-coated tablet. The process comprises the steps:
         i) subjecting
           (a) a mixture containing valsartan or a pharmaceutically acceptable salt thereof, sacubitril or a pharmaceutically acceptable salt thereof, and a polymer to hot-melt extrusion, or   (b) a mixture containing a complex of valsartan disodium and sacubitril monosodium, and a polymer to hot-melt extrusion, or   (c) a first mixture containing valsartan or a pharmaceutically acceptable salt thereof and a polymer to hot-melt extrusion to obtain a first extrudate, a second mixture containing sacubitril or a pharmaceutically acceptable salt thereof and a polymer to hot-melt extrusion to obtain a second extrudate, optionally subjecting a mixture containing the first extrudate and the second extrudate to hot-melt extrusion,   
           ii) milling the extrudate obtained in step (i)(a), (b) or (c) to obtain granules,   iii) preparing a mixture containing the granules obtained in step (ii) and a pharmaceutical excipient,   iv) compressing the mixture obtained in step (iii) into the tablet.       

     Alternatively, the granules obtained in step (ii) may be filled in sachets. Alternatively, the granules obtained in step (ii) may be filled in capsules, wherein the granules obtained in step (ii) may be optionally mixed with a pharmaceutical excipient before filling in capsules. 
     Typically, the maximum temperature applied in the hot-melt extrusion is 120° C. to 160° C., preferably 130° C. to 150° C. and more preferably 135° C. to 145° C. The hot-melt extrusion has to be carried out at a temperature that allows the dissolution of the active ingredients in the polymer-containing matrix. Optionally, a degassing unit may be employed during hot-melt extrusion processing. 
     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. 
     Examples 1 to 8 
       
     
       
         
           
               
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex. 1 
                 Ex. 2 
                 Ex. 3 
                 Ex. 4 
                 Ex. 5 
                 Ex. 6 
                 Ex. 7 
                 Ex. 8 
               
               
                 Ingredients 
                 [mg] 
                 [mg] 
                 [mg] 
                 [mg] 
                 [mg] 
                 [mg] 
                 [mg] 
                 [mg] 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Stage-A (Dry mix 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 for extrusion) 
               
               
                 Sacubitril/Valsartan complex 
                 228.516* 
                 228.516* 
                 228.516* 
                 228.516* 
                 — 
                 — 
                 — 
                 — 
               
               
                 (crystalline) 
               
               
                 Sacubitril/Valsartan complex 
                 — 
                 — 
                 — 
                 — 
                 237.553* 
                 — 
                 237.553* 
                 237.553* 
               
               
                 (amorphous) 
               
               
                 Sacubitril monosodium 
                 — 
                 — 
                 — 
                 — 
                 — 
                 103.664* 
                 — 
                 — 
               
               
                 Valsartan disodium 
                 — 
                 — 
                 — 
                 — 
                 — 
                 120.649* 
                 — 
                 — 
               
               
                 HPMC 15 cps 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 142.532 
                 — 
               
               
                 Copovidone 
                 137.110 
                 114.258 
                 137.110 
                 137.110 
                 142.532 
                 134.588 
                 — 
                 142.532 
               
               
                 (Kollidon VA 64) 
               
               
                 Polyethylene glycol 
                 — 
                 — 
                 — 
                 13.711 
                 — 
                 — 
                 — 
                 — 
               
               
                 (PEG 3350) 
               
               
                 Colloidal silica (Syloid ® 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 5.000 
                 5.000 
               
               
                 AL-1FP) 
               
               
                 Stage-B (Pre-lubrication/ 
               
               
                 blending) 
               
               
                 Microcrystalline cellulose 
                 12.374 
                 25.226 
                 12.374 
                 8.663 
                 7.915 
                 9.099 
                 1.915 
                 1.915 
               
               
                 (Comprecel ® PH 102) 
               
               
                 Low substituted HPC 
                 10.000 
                 10.000 
                 10.000 
                 10.000 
                 10.000 
                 10.000 
                 10.000 
                 10.000 
               
               
                 (L-HPC LH11) 
               
               
                 Crospovidone Type A 
                 20.000 
                 20.000 
                 20.000 
                 20.000 
                 20.000 
                 20.000 
                 20.000 
                 20.000 
               
               
                 (Polyplasdone ® XL) 
               
               
                 Colloidal anhydrous silica 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 — 
                 — 
               
               
                 (Aerosil ® 200) 
               
               
                 Colloidal silica (Syloid ® 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 9.000 
                 9.000 
               
               
                 244FP) 
               
               
                 Stage-B (Lubrication) 
               
               
                 Talc 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
               
               
                 Magnesium stearate 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
                 4.000 
               
               
                 Core Tablet Weight 
                 420.000 
                 410.000 
                 420.000 
                 430.000 
                 430.000 
                 410.000 
                 434.000 
                 434.000 
               
               
                 Stage-C (Film-Coating) 
               
               
                 Opadry ® 00F540020 Pink 
                 16.000 
                 16.000 
                 16.000 
                 16.000 
                 16.000 
                 16.000 
                 16.000 
                 16.000 
               
               
                 Water, Purified 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                 Film-Coated Tablet Weight 
                 436.000 
                 426.000 
                 436.000 
                 446.000 
                 416.000 
                 426.000 
                 450.000 
                 450.000 
               
               
                 Zone [° C.] 
               
            
           
           
               
               
               
            
               
                 Z2 
                 40 
                 40 
               
               
                 Z3 
                 70 
                 70 
               
               
                 Z4 
                 100 
                 100 
               
               
                 Z5 
                 120 
                 120 
               
               
                 Z6 
                 150 
                 140 
               
               
                 Z7 
                 140 
                 130 
               
               
                 Z8 
                 130 
                 120 
               
               
                 Die [° C.] 
                 120 
                 120 
               
            
           
           
               
               
            
               
                 Feed rate 
                 Manual 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Screw [rpm] 
                 150 
                 150 
                 150 
                 150 
                 150 
                 150 
                 150 
                 150 
               
               
                 Die pressure [?] 
                 6 
                 7 
                 4 
                 3 
                 21 
                 16 
                 12 
                 16 
               
               
                 Melt temp. [° C.] 
                 125 
                 124 
                 124 
                 123 
                 122 
                 122 
                 121 
                 123 
               
               
                 Torque [%] 
                 36 
                 39 
                 35 
                 29 
                 43 
                 51 
                 52 
                 75 
               
               
                   
               
               
                 *Contain 97 mg sacubitril and 103 mg valsartan, respectively 
               
            
           
         
       
     
     Process: 
     
         
         1. Stage A materials were sifted through #35 mesh, added into double cone blender and blended for 5 minutes and subsequently processed in HME. 
         2. The extrudes were milled through 1575μ, 1143μ and finally 610μ-screens. 
         3. Crospovidone, L-HPC, microcrystalline cellulose and colloidal anhydrous silica were sifted through #35 mesh and blended with milled extrudes in double cone blender for 10 minutes. 
         4. Magnesium stearate and talc were sifted through 35 #mesh and blended with step 3 material in double cone blender for 5 minutes. 
         5. Step 4 lubricated blend was compressed into tablets on rotary tablet compression machine using suitable tooling and parameters. 
         6. Core tablets were coated in coating pan using Opadry® 00F540020 Pink suspension using Water as solvent. 
       
    
     The extrudes showed a good grindability. The milled extrudes contained the active ingredients in non-crystalline state. The physical and chemical stability was high. The milled extrudes showed good compressibility. No crystalline drugs could be detected in the tablets after storage for two months at 40° C./75% RH in a clear PVC-PVDC packaging, and the chemical stability of the drugs was high. The physico-mechanical stability of the tablets before and after storage for two months at 40° C./75% RH in a clear PVC-PVDC packaging was high.