STABLE HOT-MELT EXTRUDATE CONTAINING VALSARTAN AND SACUBITRIL

Abstract

The present invention relates to a solid unit dosage form for oral administration (tablet or granules) containing a solid dispersion of valsartan and sacubitril in a polymeric matrix. The solid dispersion is prepared by hot-melt extrusion and may contain the active ingredients preferably in a non-crystalline state. LCZ696, (pseudo)polymorphic forms thereof as well as the individual drugs, e.g. valsartan disodium and sacubitril monosodium, may be subjected to the hot-melt extrusion process.

Claims

1. A process for preparing a tablet, comprising 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.

2. The process according to claim 1, wherein the valsartan and sacubitril are in a non-crystalline state.

3. The process according to claim 1, wherein the tablet comprises the valsartan and sacubitril in a ratio (mol/mol) of 1:1.

4. The process according to claim 1, wherein the valsartan and sacubitril are valsartan disodium and sacubitril monosodium.

5. The process according to claim 4, wherein the valsartan and sacubitril are selected from valsartan disodium, sacubitril monosodium and a complex of valsartan disodium and sacubitril monosodium.

6. The process according to claim 5, wherein the complex of valsartan disodium and sacubitril monosodium is crystalline or amorphous.

7. The process according to claim 6, wherein the crystalline complex of valsartan disodium and sacubitril monosodium is LCZ696 or a polymorphic or a pseudopolymorphic form thereof.

8. The process according to claim 1, wherein the polymer is selected from polyvinylpyrrolidone, poly(vinylpyrrolidone/vinylacetate), polyvinylcaprolactam/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/trimethylammonioethyl methacrylate chloride).

9. The process according to claim 8, wherein the polymer is polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graft copolymer, hydroxypropyl methylcellulose or poly(vinylpyrrolidone/vinylacetate) optionally in admixture with polyethylene glycol, preferably poly(vinylpyrrolidone/vinylacetate) or hydroxypropyl methylcellulose.

10. The solid unit dosage form according to claim 1, wherein the pharmaceutical excipient is selected from diluents, disintegrants, lubricants, glidants and mesoporous inorganic hygroscopic-stability increasing substances.

11. The process according to claim 1, further comprising film-coating the tablet.

Description

EXAMPLES

[0033] Hot-melt extrusion was performed with a Pharma 11 Twin-screw hot-melt extruder from Thermo Fisher Scientific Inc.

Examples 1 to 8

[0034]

TABLE-US-00001 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:

[0035] 1. Stage A materials were sifted through #35 mesh, added into double cone blender and blended for 5 minutes and subsequently processed in HME. [0036] 2. The extrudes were milled through 1575μ, 1143μ and finally 610μ-screens. [0037] 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. [0038] 4. Magnesium stearate and talc were sifted through 35 #mesh and blended with step 3 material in double cone blender for 5 minutes. [0039] 5. Step 4 lubricated blend was compressed into tablets on rotary tablet compression machine using suitable tooling and parameters. [0040] 6. Core tablets were coated in coating pan using Opadry® 00F540020 Pink suspension using Water as solvent.

[0041] 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.