EP4337175A1 - Formulation pharmaceutique de valsartan et de sacubitril - Google Patents

Formulation pharmaceutique de valsartan et de sacubitril

Info

Publication number
EP4337175A1
EP4337175A1 EP22728900.6A EP22728900A EP4337175A1 EP 4337175 A1 EP4337175 A1 EP 4337175A1 EP 22728900 A EP22728900 A EP 22728900A EP 4337175 A1 EP4337175 A1 EP 4337175A1
Authority
EP
European Patent Office
Prior art keywords
total weight
formulation
composition
formulation according
cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22728900.6A
Other languages
German (de)
English (en)
Inventor
Marko Benkovic
Dejan Klement
Klavdija Meznar
Katja PODGORSEK
Janika Slanc Vovk
Klemen KORASA
Matej Smrkolj
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA dd filed Critical KRKA dd
Publication of EP4337175A1 publication Critical patent/EP4337175A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the invention relates to a pharmaceutical formulation comprising a mixture of a first granular composition comprising valsartan disodium salt and a second composition, which is preferably non- granular, comprising or essentially consisting of sacubitril sodium salt.
  • the second composition may be non-granular or granular.
  • the invention further relates to a pharmaceutical dosage form comprising such pharmaceutical formulation and to a process for preparing such pharmaceutical formulation.
  • compositions and dosage forms comprising valsartan are known from the prior art, e.g. from WO 2008 076 780 A2, KR 2014 0092695 A, and JP 2015 209 386 A.
  • Various dosage forms comprising valsartan and sacubitril or their pharmaceutically acceptable salts in amorphous or crystalline form with one or more pharmaceutically acceptable excipients are known from the prior art.
  • it can be referred to e.g. WO 2017 042 700 Al, WO 2017 036 420 Al, WO 2017 020 841 Al, WO 2017 012 917 Al, WO 2017 009 784 Al, and WO 2017 000 864 Al.
  • dosage forms comprising valsartan and sacubitril as two separate active compounds in separate entities are also known from the prior art, e.g. from WO 2017 012 600 Al, WO 2019 008 485 Al, WO 2019 020 706 Al, and EP 3 766 484 Al.
  • the pharmaceutical formulations comprising valsartan and sacubitril of the prior art and the methods for their preparation are not satisfactory in every respect and there is a demand for improved pharmaceutical formulations.
  • the pharmaceutical formulations should have improved stability and flow properties thereby facilitating processability of tableting mixtures.
  • the pharmaceutical dosage forms should provide robust and fast dissolution profdes and should be preparable in an easy manner.
  • advantageous pharmaceutical formulations can be prepared comprising a first granular composition and a second composition, which is preferably non-granular.
  • the first granular composition comprises valsartan disodium salt, preferably in an amorphous form.
  • the second composition which is preferably non-granular, comprises sacubitril sodium salt, preferably in a crystalline form.
  • the second composition may be non-granular or granular. It has been surprisingly found that such granulated pharmaceutical formulations exhibit improved stability compared to phar maceutical formulations comprising both active ingredients in the same phase. It has been surprisingly found that both active ingredients remain in the desired form throughout their shelf life.
  • such granulated pharmaceutical formulations can be advantageously prepared by wet granulation.
  • first granular composition comprising the valsartan disodium salt by wet granulation
  • improved flow characteristics of the granulate can be achieved compared to dry granulation.
  • wet granulation e.g. fluid bed granulation
  • valsartan disodium salt dissolved in the granulation fluid leads to a faster flow time and a lower repose angle compared to dry granulation of valsartan disodium salt.
  • valsartan disodium salt can be advantageously granulated from aqueous granulation liquids, i.e. organic solvents can be avoided which would other wise require specific granulation equipment and security measures.
  • sacubitril sodium can be added during the prep aration of the pharmaceutical formulation (tableting mixture) as a second composition, which is prefer ably non-granular, because the flow properties of sacubitril sodium are adequate for enabling a good level of processability.
  • the second composition may be non-granular or granular, and when the second composition is a second granular composition, it may be dry granulated, hot-melt granulated or wet granulated.
  • a first aspect of the invention relates to a pharmaceutical formulation comprising a mixture of
  • a second composition preferably a non-granular composition, comprising or essentially consisting of sacubitril sodium salt.
  • the second composition may be non-granular or granular.
  • valsartan may be used in the form of valsartan disodium salt or alterna tively in the form of the free acid, wherein the valsartan disodium salt is formed in situ. It is contemplated that the valsartan disodium salt may be formed in situ by contacting the free acid with a suitable sodium compound such as e.g. sodium hydroxide.
  • essentially consisting of or "essentially the total amount preferably refers to a content of at least 95 wt.-%, more preferably at least 98 wt.-%, still more preferably at least 99.0 wt.-%, yet more preferably at least 99.90 wt.-%, and in particular 100 wt.-%.
  • the pharmaceutical formulation according to the invention is a solid mixture comprising
  • the first granular composition may be prepared by dry granulation, hot-melt granulation or wet granulation, preferably the first granular composition has been obtained by wet granulation (see Examples 1 to 14).
  • the pharmaceutical formulation according to the invention is a solid mixture comprising
  • the second composition which is granular as well, i.e. a second granular composition (second intra granular phase).
  • the pharmaceutical formulation according to the invention is a solid mixture comprising
  • the second composition which is granular as well, i.e. a second granular composition (second intra granular phase);
  • composition which is preferably non-granular (extragranular phase).
  • the second granular composition has been obtained by dry granula tion or hot-melt granulation, preferably by dry granulation, e.g. roller compaction (see Example 8).
  • the second granular composition has been obtained by wet granulation, e.g. fluidized bed granulation (see Examples 9 and 10).
  • the pharmaceutical formulation according to the invention essentially consists of the first granular composition and the second composition, which is preferably non-granular.
  • the pharmaceutical formulation according to the invention es sentially consists of the first granular composition, the second composition which is granular as well (i.e. second granular composition), and the third composition.
  • the third composition com prises neither valsartan disodium salt nor sacubitril sodium salt.
  • the pharmaceutical formulation according to the invention can preferably be regarded as an intermediate product, e.g. a tableting mixture, useful for the preparation of compressed or compacted pharmaceutical dosage forms, particularly for the preparation of tablets.
  • the pharmaceutical formulation according to the invention is a mixture.
  • the mixture comprises the first granular composition and the second composition, which is preferably non-granular.
  • the mix ture is typically a homogenous mixture, where the granules of the first granular mixture are intimately mixed with the constituents of the second composition, and optionally with a third composition.
  • the second composition is a second granular compositions
  • the granules of the first granular composition are mixed with the granules of the second granular composition, and optionally with a third composition.
  • the pharmaceutical formulation according to the invention i.e.
  • the mixture comprising the first granular composition and the second composition is compressed or compacted into tablets, the tablets thus obtained contain the first granular composition and the second composition in admixture with one another.
  • compression or compaction does not provide e.g. layer tablets where the first granular composition forms one layer and the second composition forms another separate layer.
  • the valsartan disodium salt is essentially molecularly dispersed within the first granular composition.
  • the valsartan disodium salt has a degree of crystallinity of at most 90%, preferably of at most 80%, more preferably at most 70%, still more preferably at most 60%, yet more preferably at most 50%, even more preferably at most 40%, most preferably at most 30% and in particular at most 20%.
  • the degree of crystallinity can be determined by methods that are known to the skilled person. In this regard reference can be made to e.g. M. Skotnicki et ah, Mol. Pharmaceutics 2016, 13, 1, 211— 222, Title: Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR.
  • the relative degree of crystallinity can also be determined e.g. based on X-ray powder diffraction patterns. Its value can be determined by a known method of broadening of the diffraction maxima (FWHM- values), preferably of the principal XRPD reflexion signal and preferably by measuring a calibration curve with samples of known crystallinity.
  • the valsartan disodium salt is present in amorphous form.
  • the valsartan disodium salt is essentially amorphous.
  • at least 80 wt.-% of the valsartan disodium salt that is comprised in the formulation is present in amorphous form; preferably at least 85 wt.-%, more preferably at least 90 wt.-%, and in particular essentially the total amount.
  • essentially the total amount of the valsartan disodium salt that is comprised in the formulation is present in the first granular composition.
  • the weight content of valsartan disodium salt rel ative to the total weight of the formulation is at least 7.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 13 wt.-%, still more preferably at least 16 wt.-%, yet more preferably at least 19 wt.- %, even more preferably at least 22 wt.-%, most preferably at least 25 wt.-%, and in particular at least 28 wt.-%.
  • the weight content of valsartan disodium salt rel ative to the total weight of the formulation is at most 60 wt.-%, preferably at most 55 wt.-%, more preferably at most 50 wt.-%, still more preferably at most 45 wt.-%, yet more preferably at most 40 wt- %, even more preferably at most 35 wt.-%, most preferably at most 30 wt.-%, and in particular at most 25 wt.-%.
  • the weight content of valsartan disodium salt rel ative to the total weight of the formulation is within the range of from 20 ⁇ 2.0 wt.-%, or 22 ⁇ 4.0 wt.-%, or 22 ⁇ 2.0 wt.-%, or 24 ⁇ 6.0 wt.-%, or 24 ⁇ 4.0 wt.-%, or 24 ⁇ 2.0 wt.-%, or 26 ⁇ 8.0 wt.-%, or 26 ⁇ 6.0 wt.- %, or 26 ⁇ 4.0 wt.-%, or 26 ⁇ 2.0 wt.-%, or 30 ⁇ 10 wt.-%, or 30 ⁇ 8.0 wt.-%, or 30 ⁇ 6.0 wt.-%, or 30 ⁇ 4.0 wt.-%, or 30 ⁇ 2.0 wt.-%.
  • valsartan disodium salt no other forms of valsartan are present.
  • At least a portion of the sacubitril sodium salt is present in crystalline form.
  • At least 80 wt.-% of the sacubitril sodium salt that is comprised in the formulation is present in crystalline form; preferably at least 85 wt.-%, more preferably at least 90 wt.-%, still more preferably at least 95 wt.-%, yet more preferably at least 98 wt.-%, even more preferably at least 99 wt- %, and in particular essentially the total amount.
  • the weight content of sacubitril sodium salt rela tive to the total weight of the formulation is at least 4.0 wt.-%, preferably at least 7.0 wt.-%, more preferably at least 10 wt.-%, still more preferably at least 13 wt.-%, yet more preferably at least 16 wt.- %, even more preferably at least 19 wt.-%, most preferably at least 22 wt.-%, and in particular at least 25 wt.-%.
  • the weight content of sacubitril sodium salt rela tive to the total weight of the formulation is at most 55 wt.-%, preferably at most 50 wt.-%, more pref erably at most 45 wt.-%, still more preferably at most 40 wt.-%, yet more preferably at most 35 wt.-%, even more preferably at most 30 wt.-%, most preferably at most 25 wt.-%, and in particular at most 22 wt.-%.
  • the weight content of sacubitril sodium salt rela tive to the total weight of the formulation is within the range of from 18 ⁇ 2.0 wt.-%, or 20 ⁇ 4.0 wt.-%, or 20 ⁇ 2.0 wt.-%, or 22 ⁇ 6.0 wt.-%, or 22 ⁇ 4.0 wt.-%, or 22 ⁇ 2.0 wt.-%, or 24 ⁇ 8.0 wt.-%, or 24 ⁇ 6.0 wt.-%, or 24 ⁇ 4.0 wt.-%, or 24 ⁇ 2.0 wt.-%, or 26 ⁇ 10 wt.-%, or 26 ⁇ 8.0 wt.-%, or 26 ⁇ 6.0 wt.-%, or 26 ⁇ 4.0 wt.- %, or 26 ⁇ 2.0 wt.-%.
  • sacubitril sodium salt no other forms of sacubitril are present
  • the weight ratio of the valsartan disodium salt to the sacubitril sodium salt is within the range of from 1.5: 1.0 to 1.0: 1.5, preferably 1.4: 1.0 to 1.0: 1.4, more preferably 1.3: 1.0 to 1.0: 1.3, still more preferably 1.2: 1.0 to 1.0: 1.2, and yet more preferably 1.1: 1.0 to 1.0: 1.1.
  • the weight content of the first granular composi tion relative to the total weight of the formulation is at least 40 wt.-%, preferably at least 45 wt.-%, more preferably at least 50 wt.-%, still more preferably at least 55 wt.-%, yet more preferably at least 60 wt.-%, even more preferably at least 65 wt.-%, most preferably at least 69 wt.-%, and in particular at least 73 wt.-%.
  • the weight content of the first granular composi tion relative to the total weight of the formulation is at most 96 wt.-%, preferably at most 92 wt.-%, more preferably at most 88 wt.-%, still more preferably at most 84 wt.-%, yet more preferably at most 80 wt.-%, even more preferably at most 76 wt.-%, most preferably at most 73 wt.-%, and in particular at most 68 wt.-%.
  • the weight content of the first granular composi tion relative to the total weight of the formulation is within the range of from 61 ⁇ 2.0 wt.-%, or 66 ⁇ 5.0 wt.-%, or 66 ⁇ 2.0 wt.-%, or 71 ⁇ 10 wt.-%, or 71 ⁇ 5.0 wt.-%, or 71 ⁇ 2.0 wt.-%, or 76 ⁇ 15 wt.-%, or 76 ⁇ 10 wt.-%, or 76 ⁇ 5.0 wt.-%, or 76 ⁇ 2.0 wt.-%.
  • the weight content of the second composition which is preferably non-granular, relative to the total weight of the formulation is at least 3.0 wt.-%, preferably at least 7.0 wt.-%, more preferably at least 11 wt.-%, still more preferably at least 15 wt.-%, yet more preferably at least 19 wt.-%, even more preferably at least 23 wt.-%, most preferably at least 27 wt.-%, and in particular at least 32 wt.-%.
  • the weight content of the second composition which is preferably non-granular, relative to the total weight of the formulation is at most 60 wt.-%, preferably at most 55 wt.-%, more preferably at most 50 wt.-%, still more preferably at most 45 wt.-%, yet more preferably at most 40 wt.-%, even more preferably at most 35 wt.-%, most preferably at most 31 wt.-%, and in particular at most 27 wt.-%.
  • the weight content of the second composition which is preferably non-granular, relative to the total weight of the formulation is within the range of from 23 ⁇ 2.0 wt.-%, or 25 ⁇ 4.0 wt.-%, or 25 ⁇ 2.0 wt.-%, or 27 ⁇ 6.0 wt.-%, or 27 ⁇ 4.0 wt.-%, or 27 ⁇ 2.0 wt.-%, or 29 ⁇ 8.0 wt.-%, or 29 ⁇ 6.0 wt.-%, or 29 ⁇ 4.0 wt.-%, or 29 ⁇ 2.0 wt.-%, or 31 ⁇ 10 wt.-%, or 31 ⁇ 8.0 wt.-%, or 31 ⁇ 6.0 wt.-%, or 31 ⁇ 4.0 wt.-%, or 31 ⁇ 2.0 wt.-%, or 33 ⁇ 12 wt.-%, or 33 ⁇ 10 wt.-%, or 33 ⁇ 8.0 wt.-%, or 33 ⁇ 6.0 wt.-%, or 33 ⁇ 4.0
  • the first granular composition is wet granulated, preferably from an aqueous starting material.
  • the second compo sition may be wet granulated, hot-melt granulated or dry granulated, preferably dry granulated.
  • the first granular composition has a flow time of at most 60 s, preferably at most 55 s, more preferably at most 50 s, still more preferably at most 45 s, yet more preferably at most 40 s, even more preferably at most 35 s, most preferably at most 30 s, and in particular at most 25 s; preferably determined in accordance with Ph. Eur. 2.9.16.
  • the first granular composition has a repose angle of at most 70°, preferably at most 65°, more preferably at most 60°, still more preferably at most 55°, yet more preferably at most 50°, even more preferably at most 45°, most preferably at most 40°, and in particular at most 37°; preferably determined in accordance with Ph. Eur. 2.9.36.
  • the first granular composition has a bulk volume of at least 1.0 ml/g. preferably at least 1.4 ml/g, more preferably at least 1.8 ml/g, still more preferably at least 2.2 ml/g, yet more prefer ably at least 2.6 ml/g, even more preferably at least 3.0 ml/g, most preferably at least 3.4 ml/g, and in particular at least 3.8 ml/g; preferably determined in accordance with Ph. Eur. 2.9.34.
  • the first granular composition has a tapped volume of at least 0.8 ml/g, preferably at least 1.1 ml/g, more preferably at least 1.4 ml/g, still more preferably at least 1.7 ml/g, yet more prefer ably at least 2.0 ml/g, even more preferably at least 2.3 ml/g, most preferably at least 2.6 ml/g, and in particular at least 2.9 ml/g; preferably determined in accordance with Ph. Eur. 2.9.34.
  • the first granular composition comprises one or more diluents, one or more binders, one or more disintegrants, one or more glidants, one or more lubri cants, and/or mixtures thereof.
  • the first granular composition comprises one or more diluents.
  • a diluent is considered equivalent to a filler.
  • both excipients perform the same functions, namely to increase the weight and improve the uniformity of the contents.
  • the one or more diluents are independently of one another selected from the group consisting of
  • lactose e.g. lactose mono hydrate, anhydrous lactose, spray dried and/or granulated lactose; sucrose, fructose, dextrates, sac charose, raffmose, trehalose, fructose, and dextrin;
  • - sugar alcohols preferably selected from xylitol, mannitol, maltitol, isomalt, and sorbitol;
  • cellulose or cellulose derivatives preferably powdered cellulose, microcrystalline cellulose, or silic- ified microcrystalline cellulose;
  • - starch or starch derivatives preferably low moisture starch, com starch, pregelatinized starch, or low moisture pregelatinized starch; - silicates; preferably magnesium aluminometasilicate such as Neusilin;
  • - salts of phosphoric acid preferably calcium salts of phosphoric acid; preferably selected from cal cium hydrogen phosphate anhydrous and calcium hydrogen phosphate hydrate;
  • - salts of carbonic acid preferably calcium carbonate, sodium carbonate, potassium carbonate, calcium hydrogencarbonate, sodium hydrogencarbonate, or potassium hydrogencarbonate;
  • microcrystalline cellulose preferably from microcrystalline cellulose, saccharides (preferably selected from lactose and saccha rose), sugar alcohols (preferably mannitol), and mixtures thereof; more preferably mannitol, microcrystalline cellulose (such as Avicel PH101) and mixtures thereof; still more preferably microcrystalline cellulose.
  • the total weight content of the one or more diluents relative to the total weight of the formulation is at least 4.0 wt.-%, preferably at least 8.0 wt.-%, more preferably at least 12 wt.-%, still more preferably at least 16 wt.-%, yet more preferably at least 20 wt.-%, even more preferably at least 24 wt.-%, most preferably at least 28 wt.-%, and in particular at least 32 wt.-%;
  • the total weight content of the one or more diluents relative to the total weight of the formulation is at most 50 wt.-%, preferably at most 45 wt.-%, more preferably at most 40 wt.-%, still more preferably at most 35 wt.-%, yet more preferably at most 32 wt.-%, even more preferably at most 28 wt.-%, most preferably at most 24 wt.-%, and in particular at most 20 wt.-%.
  • the total weight content of the one or more diluents relative to the total weight of the formulation is within the range of from 16 ⁇ 2.0 wt.-%, or 18 ⁇ 4.0 wt.-%, or 18 ⁇ 2.0 wt.-%, or 20 ⁇ 6.0 wt.-%, or 20 ⁇ 4.0 wt.-%, or 20 ⁇ 2.0 wt.-%, or 24 ⁇ 10 wt.-%, or 24 ⁇ 6.0 wt.-%, or 24 ⁇ 4.0 wt.-%, or 24 ⁇ 2.0 wt.-%, or 28 ⁇ 10 wt.-%, or 28 ⁇ 6.0 wt.-%, or 28 ⁇ 4.0 wt.-%, or 28 ⁇ 2.0 wt.-%, or 32 ⁇ 10 wt.-%, or 32 ⁇ 6.0 wt.-%, or 32 ⁇ 4.0 wt.-%, or 32 ⁇ 2.0 wt.-%.
  • the first granular composition comprises one or more binders.
  • the one or more binders are independently of one another selected from the group consisting of
  • cellulose ethers preferably selected from hydroxyethyl cellulose, hydroxypropyl cellulose, and hy- droxypropyl methyl cellulose;
  • hydroxypropyl cellulose and polyvinylpyrrolidone preferably wherein the hydroxypropyl cellulose is not a low substituted hydroxypropyl cellulose; more preferably polyvinylpyrrolidone.
  • Polyvinylpyrrolidone is the linear polymer of N-vinylpyrrolidone and is for example sold under the name Povidone K30, commercially available from the HARKE Group. PVP is typically used as binder in pharmaceutical tablets.
  • hydroxypropyl cellulose which is preferably not a low sub stituted hydroxypropyl cellulose, may contain from 53.4% to 80.5% of hydroxypropoxy groups, calcu lated on the dried base.
  • not low substituted hydroxypropyl cellulose is any hydroxypropyl cellulose other than low substituted hydroxypropyl cellulose.
  • Exemplary hydroxypropyl celluloses are sold under the tradename Klucel ® , commercially available from Ashland.
  • the total weight content of the one or more binders relative to the total weight of the formulation is at least 2.5 wt.-%, preferably at least 3.0 wt.-%, more preferably at least 3.5 wt.-%, still more preferably at least 4.0 wt.-%, yet more preferably at least 4.5 wt.-%, even more preferably at least 5.0 wt.-%, most preferably at least 5.5 wt.-%, and in particular at least 6.0 wt.- %.
  • the total weight content of the one or more binders relative to the total weight of the formulation is at most 14 wt.-%, preferably at most 12 wt.-%, more preferably at most 10 wt.-%, still more preferably at most 8.0 wt.-%, yet more preferably at most 6.5 wt.-%, even more preferably at most 5.5 wt.-%, most preferably at most 4.5 wt.-%, and in particular at most 3.5 wt- %.
  • the total weight content of the one or more binders relative to the total weight of the formulation is within the range of from 3.0 ⁇ 0.5 wt.-%, or 4.0 ⁇ 1.0 wt.-%, or 4.0 ⁇ 0.5 wt.-%, or 5.0 ⁇ 2.0 wt.-%, or 5.0 ⁇ 1.0 wt.-%, or 5.0 ⁇ 0.5 wt.-%, or 6.0 ⁇ 3.0 wt.-%, or 6.0 ⁇ 2.0 wt.-%, or 6.0 ⁇ 1.0 wt.-%, or 6.0 ⁇ 0.5 wt.-%.
  • the first granular composition comprises one or more disintegrants.
  • the one or more disintegrants are independently of one another se lected from the group consisting of
  • - cellulose or cellulose derivatives preferably microcrystalline cellulose, low substituted hydroxypro- pyl cellulose, methylcellulose, sodium salts of carboxymethyl cellulose, calcium salts of carboxyme- thyl cellulose, cross-linked carboxymethylcellulose and salts thereof (e.g. croscarmellose sodium and/or croscarmellose calcium);
  • starch and starch derivatives preferably native starch, pregelatinized starch, sodium starch glycol- late, or hydroxypropyl starch;
  • heteroglycanes preferably alginic acid, sodium alginate, calcium alginate, agar, or guar gum;
  • glucosamines preferably chitosan
  • low substituted hydroxypropyl cellulose is 0-(2-hydroxypropy- lated) cellulose containing from 5.0% to 16.0% of hydroxypropoxy groups, calculated on the dried basis.
  • Crospovidone polyvinylpolypyrrolidone, PVPP
  • PVPP polyvinylpolypyrrolidone
  • PVP poly vinylpyrrolidone
  • the first granular composition comprises low substituted hydroxypropyl cellulose in combination with crospovidone.
  • the total weight content of the one or more disintegrants in the first granular composition relative to the total weight of the formulation is at least 5.0 wt.-%, preferably at least 6.0 wt.-%, more preferably at least 7.0 wt.-%, still more preferably at least 8.0 wt.-%, yet more preferably at least 9.0 wt.-%, even more preferably at least 10 wt.-%, most preferably at least 11 wt.-%, and in particular at least 13 wt.-%.
  • the total weight content of the one or more disintegrants in the first granular composition relative to the total weight of the formulation is at most 45 wt.-%, preferably at most 40 wt.-%, more preferably at most 35 wt.-%, still more preferably at most 30 wt.-%, yet more preferably at most 25 wt.-%, even more preferably at most 20 wt.-%, most preferably at most 15 wt.-%, and in particular at most 12 wt.-%.
  • the total weight content of the one or more disintegrants in the first granular composition relative to the total weight of the formulation is within the range of from 11 ⁇ 2.0 wt.-%, or 12 ⁇ 3.0 wt.-%, or 12 ⁇ 2.0 wt.-%, or 13 ⁇ 4.0 wt.-%, or 13 ⁇ 3.0 wt.-%, or 13 ⁇ 2.0 wt.-%, or 14 ⁇ 5.0 wt.-%, or 14 ⁇ 4.0 wt.-%, or 14 ⁇ 3.0 wt.-%, or 14 ⁇ 2.0 wt.-%.
  • the first granular composition comprises low substituted hydroxy- propyl cellulose.
  • the total weight content of the low substituted hydroxypropyl cellu lose in the first granular composition relative to the total weight of the formulation is at least 6.0 wt.-%, preferably at least 6.5 wt.-%, more preferably at least 7.0 wt.-%, still more preferably at least 7.5 wt- %, yet more preferably at least 8.0 wt.-%, even more preferably at least 8.5 wt.-%, most preferably at least 9.0 wt.-%, and in particular at least 9.5 wt.-%.
  • the total weight content of the low substituted hydroxypropyl cellu lose in the first granular composition relative to the total weight of the formulation is at most 45 wt.-%, preferably at most 40 wt.-%, more preferably at most 35 wt.-%, still more preferably at most 30 wt.-%, yet more preferably at most 25 wt.-%, even more preferably at most 20 wt.-%, most preferably at most 15 wt.-%, and in particular at most 10 wt.-%.
  • the total weight content of the low substituted hydroxypropyl cellu lose in the first granular composition relative to the total weight of the formulation is within the range of from 8.3 ⁇ 0.5 wt.-%, or 8.8 ⁇ 1.0 wt.-%, or 8.8 ⁇ 0.5 wt.-%, or 9.3 ⁇ 1.5 wt.-%, or 9.3 ⁇ 1.0 wt.-%, or 9.3 ⁇ 0.5 wt.-%, or 9.8 ⁇ 2.0 wt.-%, or 9.8 ⁇ 1.5 wt.-%, or 9.8 ⁇ 1.0 wt.-%, or 9.8 ⁇ 0.5 wt.-%.
  • the first granular composition comprises no low substituted hydroxypropyl cellulose.
  • the first granular composition comprises crospovidone.
  • the total weight content of the crospovidone in the first granular composition relative to the total weight of the formulation is at least 0.5 wt.-%, preferably at least 1.0 wt.-%, more preferably at least 1.5 wt.-%, still more preferably at least 2.0 wt.-%, yet more preferably at least 2.5 wt.-%, even more preferably at least 3.0 wt.-%, most preferably at least 3.5 wt.-%, and in particular at least 4.0 wt.-%.
  • the total weight content of the crospovidone in the first granular composition relative to the total weight of the formulation is at most 20 wt.-%, preferably at most 15 wt.-%, more preferably at most 12 wt.-%, still more preferably at most 10 wt.-%, yet more preferably at most 8.0 wt.-%, even more preferably at most 6.0 wt.-%, most preferably at most 5.0 wt.-%, and in particular at most 4.0 wt.-%.
  • the total weight content of the crospovidone in the first granular composition relative to the total weight of the formulation is within the range of from 1 2 ⁇ 0.5 wt.-%, or 1.7 ⁇ 1.0 wt.-%, or 1.7 ⁇ 0.5 wt.-%, or 2.7 ⁇ 2.0 wt.-%, or 2.7 ⁇ 1.0 wt.-%, or 2.7 ⁇ 0.5 wt.-%, or 3.7 ⁇ 3.0 wt- %, or 3.7 ⁇ 2.0 wt.-%, or 3.7 ⁇ 1.0 wt.-%, or 3.7 ⁇ 0.5 wt.-%, or 4.7 ⁇ 4.0 wt.-%, or 4.7 ⁇ 3.0 wt.-%, or 4.7 ⁇ 2.0 wt.-%, or 4.7 ⁇ 1.0 wt.-%, or 4.7 ⁇ 0.5 wt.-%.
  • the first granular composition comprises no crospovidone.
  • the first granular composition comprises one or more glidants.
  • the one or more glidants are independently of one another selected from the group consisting of colloidal silica such as Aerosil 200, talc, magnesium trisilicate, and mix tures thereof; preferably colloidal silica, talc and mixtures thereof.
  • the first granular composition comprises talc in combination with colloidal silica.
  • the total weight content of the one or more glidants relative to the total weight of the formulation is at least 0.8 wt.-%, preferably at least 0.9 wt.-%, more preferably at least 1.0 wt.-%, still more preferably at least 1.1 wt.-%, yet more preferably at least 1.2 wt.-%, even more preferably at least 1.3 wt.-%, most preferably at least 1.4 wt.-%, and in particular at least 1.5 wt.- %.
  • the total weight content of the one or more glidants relative to the total weight of the formulation is at most 5.5 wt.-%, preferably at most 5.0 wt.-%, more preferably at most 4.5 wt.-%, still more preferably at most 4.0 wt.-%, yet more preferably at most 3.5 wt.-%, even more preferably at most 3.0 wt.-%, most preferably at most 2.5 wt.-%, and in particular at most 2.0 wt- %.
  • the total weight content of the one or more glidants relative to the total weight of the formulation is within the range of from 1.0 ⁇ 0.5 wt.-%, or 1.5 ⁇ 1.0 wt.-%, or 1.5 ⁇ 0.5 wt.-%, or 2.5 ⁇ 2.0 wt.-%, or 2.5 ⁇ 1.0 wt.-%, or 2.5 ⁇ 0.5 wt.-%.
  • the first granular composition comprises talc.
  • the total weight content of the talc relative to the total weight of the formulation is at least 0.3 wt.-%, preferably at least 0.4 wt.-%, more preferably at least 0.5 wt.-%, still more preferably at least 0.6 wt.-%, yet more preferably at least 0.7 wt.-%, even more preferably at least 0.8 wt.-%, most preferably at least 0.9 wt.-%, and in particular at least 1.0 wt.-%.
  • the total weight content of the talc relative to the total weight of the formulation is at most 2.4 wt.-%, preferably at most 2.2 wt.-%, more preferably at most 2.0 wt.-%, still more preferably at most 1.8 wt.-%, yet more preferably at most 1.6 wt.-%, even more preferably at most 1.4 wt.-%, most preferably at most 1.2 wt.-%, and in particular at most 1.1 wt.-%.
  • the total weight content of the talc relative to the total weight of the formulation is within the range of from 0.5 ⁇ 0.2 wt.-%, or 1.0 ⁇ 0.5 wt.-%, or 1.0 ⁇ 0.2 wt.-%, or 1.5 ⁇ 1.0 wt.-%, or 1.5 ⁇ 0.5 wt.-%, or 1.5 ⁇ 0.2 wt.-%.
  • the first granular composition comprises colloidal silica.
  • the total weight content of the colloidal silica relative to the total weight of the formulation is at least 0.15 wt.-%, preferably at least 0.2 wt.-%, more preferably at least 0.25 wt.-%, still more preferably at least 0.3 wt.-%, yet more preferably at least 0.35 wt.-%, even more preferably at least 0.4 wt.-%, most preferably at least 0.45 wt.-%, and in particular at least 0.5 wt.-%.
  • the total weight content of the colloidal silica relative to the total weight of the formulation is at most 2.0 wt.-%, preferably at most 1.8 wt.-%, more preferably at most 1.6 wt.-%, still more preferably at most 1.4 wt.-%, yet more preferably at most 1.2 wt.-%, even more preferably at most 1.0 wt.-%, most preferably at most 0.8 wt.-%, and in particular at most 0.6 wt.-%.
  • the total weight content of the colloidal silica relative to the total weight of the formulation is within the range of from 0.3 ⁇ 0.2 wt.-%, or 0.5 ⁇ 0.4 wt.-%, or 0.5 ⁇ 0.2 wt- %, or 0.7 ⁇ 0.6 wt.-%, or 0.7 ⁇ 0.4 wt.-%, or 0.7 ⁇ 0.2 wt.-%.
  • the first granular composition comprises or essentially consists of
  • binder preferably polyvinylpyrrolidone
  • disintegrants preferably low substituted hydroxpropyl-cellulose and/or crospovidone; more preferably two disintegrants; preferably low substituted hydroxpropyl-cellulose and cro spovidone; and
  • the first granular composition comprises or essentially consists of
  • binder preferably polyvinylpyrrolidone
  • disintegrants preferably low substituted hydroxypropyl-cellulose and/or crospovidone; more preferably one disintegrant; preferably crospovidone; and
  • the first granular composition comprises or essentially consists of
  • valsartan disodium salt preferably with a total weight content of from 22 to 30 wt.-%;
  • one diluent preferably with a total weight content of from 17 to 34 wt.-%;
  • one binder preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%;
  • one or two disintegrants preferably with a total weight content of from 0.01 to 15 wt.-%, more pref erably 4.0 to 15 wt.-%;
  • one or two glidants preferably with a total weight content of from 0.5 to 2.0 wt.-%; in each case relative to the total weight of the formulation.
  • the first granular composition comprises or essentially consists of - valsartan disodium salt, preferably with a total weight content of from 22 to 30 wt.-%;
  • microcrystalline cellulose or mannitol optionally, microcrystalline cellulose or mannitol; preferably with a total weight content of from 17 to 34 wt.-%;
  • polyvinylpyrrolidone or hydroxypropyl cellulose which is not low substituted hydroxypropyl cellu lose; preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%;
  • talc and/or colloidal silica optionally, talc and/or colloidal silica; preferably with a total weight content of from 0.5 to 2.0 wt.-
  • the first granular composition comprises or essentially consists of
  • valsartan disodium salt preferably with a total weight content of from 22 to 30 wt.-%;
  • microcrystalline cellulose or mannitol optionally, microcrystalline cellulose or mannitol; preferably with a total weight content of from 17 to 34 wt.-%;
  • polyvinylpyrrolidone preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%;
  • talc and/or colloidal silica optionally, talc and/or colloidal silica; preferably with a total weight content of from 0.5 to 2.0 wt.-
  • the first granular composition comprises or essentially consists of
  • valsartan disodium salt preferably with a total weight content of from 22 to 30 wt.-%;
  • microcrystalline cellulose preferably with a total weight content of from 17 to 34 wt.-%;
  • polyvinylpyrrolidone preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%;
  • talc and/or colloidal silica optionally, talc and/or colloidal silica; preferably with a total weight content of from 0.5 to 2.0 wt.-
  • the first granular composition comprises or essentially consists of
  • valsartan disodium salt preferably with a total weight content of from 22 to 30 wt.-%;
  • mannitol optionally, mannitol; preferably with a total weight content of from 17 to 34 wt.-%;
  • polyvinylpyrrolidone preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%;
  • talc and/or colloidal silica optionally, talc and/or colloidal silica; preferably with a total weight content of from 0.5 to 2.0 wt.-
  • the first granular composition comprises or essentially consists of
  • valsartan disodium salt preferably with a total weight content of from 22 to 30 wt.-%;
  • microcrystalline cellulose or mannitol optionally, microcrystalline cellulose or mannitol; preferably with a total weight content of from 17 to 34 wt.-%;
  • hydroxypropyl cellulose which is not low substituted hydroxypropyl cellulose; preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%;
  • talc and/or colloidal silica optionally, talc and/or colloidal silica; preferably with a total weight content of from 0.5 to 2.0 wt.-
  • the first granular composition comprises or essentially consists of
  • valsartan disodium salt preferably with a total weight content of from 22 to 30 wt.-%;
  • microcrystalline cellulose preferably with a total weight content of from 17 to 34 wt.-%;
  • - hydroxypropyl cellulose which is not low substituted hydroxypropyl cellulose; preferably with a total weight content of from 0.01 to 6.5 wt.-%, preferably 2.5 to 6.5 wt.-%; - low substituted hydroxypropyl cellulose and crospovidone; preferably with a total weight content of from 0.01 to 15 wt.-%, more preferably 4.0 to 15 wt.-%; and
  • talc and/or colloidal silica optionally, talc and/or colloidal silica; preferably with a total weight content of from 0.5 to 2.0 wt.-
  • the second composition which is preferably non-granular, comprises one or more diluents, one or more binders, one or more disintegrants, one or more glidants, one or more lubricants, and/or mixtures thereof.
  • the second composition which is preferably non-granular, comprises one or more disintegrants.
  • At least one of the one or more disintegrants comprised in the second composition is the same as one of the one or more disintegrants comprised in the first granular composition.
  • the second composition does not comprise hydroxypropyl cellulose, which is not low substituted hydroxypropyl cellulose.
  • the second composition comprises crospovidone.
  • the total weight content of the crospovidone in the second composi tion relative to the total weight of the formulation is at least 0.5 wt.-%, preferably at least 1.0 wt.-%, more preferably at least 1.5 wt.-%, still more preferably at least 2.0 wt.-%, yet more preferably at least 2.5 wt.-%, even more preferably at least 3.0 wt.-%, most preferably at least 3.5 wt.-%, and in particular at least 4.0 wt.-%.
  • the total weight content of the crospovidone in the second composi tion relative to the total weight of the formulation is at most 20 wt.-%, preferably at most 15 wt.-%, more preferably at most 12 wt.-%, still more preferably at most 10 wt.-%, yet more preferably at most 8.0 wt.-%, even more preferably at most 6.0 wt.-%, most preferably at most 5.0 wt.-%, and in particular at most 4.0 wt.-%.
  • the total weight content of the crospovidone in the second composi tion relative to the total weight of the formulation is within the range of from 1.2 ⁇ 0.5 wt.-%, or 1.7 ⁇ 1.0 wt.-%, or 1.7 ⁇ 0.5 wt.-%, or 2.7 ⁇ 2.0 wt.-%, or 2.7 ⁇ 1.0 wt.-%, or 2.7 ⁇ 0.5 wt.-%, or 3.7 ⁇ 3.0 wt.-%, or 3.7 ⁇ 2.0 wt.-%, or 3.7 ⁇ 1.0 wt.-%, or 3.7 ⁇ 0.5 wt.-%, or 4.7 ⁇ 4.0 wt.-%, or 4.7 ⁇ 3.0 wt.-%, or 4.7 ⁇ 2.0 wt-%, or 4.7 ⁇ 1.0 wt.-%, or 4.7 ⁇ 0.5 wt.-%.
  • the second composition comprises no crospovidone.
  • the first granular composition and the second composition comprise crospovidone.
  • the total weight content of the crospovidone in the formulation rela tive to the total weight of the formulation is at least 2.0 wt.-%, preferably at least 3.0 wt.-%, more preferably at least 4.0 wt.-%, still more preferably at least 5.0 wt.-%, yet more preferably at least 6.0 wt.-%, even more preferably at least 7.0 wt.-%, most preferably at least 8.0 wt.-%, and in particular at least 9.0 wt.-%.
  • the total weight content of the crospovidone in the formulation rela tive to the total weight of the formulation is at most 17 wt.-%, preferably at most 15 wt.-%, more pref erably at most 13 wt.-%, still more preferably at most 11 wt.-%, yet more preferably at most 9.0 wt.-%, even more preferably at most 7.0 wt.-%, most preferably at most 5.0 wt.-%, and in particular at most 3.0 wt.-%.
  • the total weight content of the crospovidone in the formulation rela tive to the total weight of the formulation is within the range of from 2.0 ⁇ 0.5 wt.-%, or 2.5 ⁇ 1.0 wt.-%, or 2.5 ⁇ 0.5 wt.-%, or 3.0 ⁇ 1.5 wt.-%, or 3.0 ⁇ 1.0 wt.-%, or 3.0 ⁇ 0.5 wt.-%, or 5.0 ⁇ 3.5 wt.-%, or 5.0 ⁇ 1.5 wt.-%, or 5.0 ⁇ 1.0 wt.-%, or 5.0 ⁇ 0.5 wt.-%, or 7.0 ⁇ 5.5 wt.-%, or 7.0 ⁇ 3.5 wt.-%, or 7.0 ⁇ 1.5 wt.-%, or 7.0 ⁇ 1.0 wt.-%, or 7.0 ⁇ 0.5 wt.-%, or 9.0 ⁇ 7.5 wt.-%, or 9.0 ⁇ 5.5 wt.-%, or 9.0 ⁇ 3.5 wt.-%, or 9.
  • the total amount of crospovidone comprised in the formulation is divided between the first granular composition and the second composition.
  • the weight ratio of the crospovidone comprised in the first granular composition to the crospovidone comprised in the second composition is within the range of from 3.0: 1.0 to 1.0:3.0, preferably 2.5: 1.0 to 1.0:2.5, more preferably 2.0: 1.0 to 1.0:2.0, still more preferably 1.5: 1.0 to 1.0: 1.5, and yet more preferably 1.1: 1.0 to 1.0: 1.1.
  • the second composition which is preferably non-granular, comprises one or more lubricants.
  • the one or more lubricants are independently of one another selected from the group consisting of
  • Ci2-2o-fatty acids and derivatives thereof preferably selected from magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, magnesium palmitate, magnesium oleate, and so dium stearyl fumarate;
  • oils preferably hydrogenated vegetable oil or hydrogenated castor oil
  • magnesium stearate preferably from magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, and mixtures thereof; more preferably sodium stearyl fumarate, magnesium stearate, and mixtures thereof.
  • the total weight content of the one or more lubricants relative to the total weight of the formulation is at least 0.9 wt.-%, preferably at least 1.2 wt.-%, more preferably at least 1.5 wt.-%, still more preferably at least 1.8 wt.-%, yet more preferably at least 2.1 wt.-%, even more preferably at least 2.4 wt.-%, most preferably at least 2.7 wt.-%, and in particular at least 3.0 wt.- %.
  • the total weight content of the one or more lubricants relative to the total weight of the formulation is at most 10 wt.-%, preferably at most 9.0 wt.-%, more preferably at most 8.0 wt.-%, still more preferably at most 7.0 wt.-%, yet more preferably at most 6.0 wt.-%, even more preferably at most 5.0 wt.-%, most preferably at most 4.0 wt.-%, and in particular at most 3.5 wt- %.
  • the total weight content of the one or more lubricants relative to the total weight of the formulation is within the range of from 2.5 ⁇ 0.5 wt.-%, or 3.0 ⁇ 1.0 wt.-%, or 3.0 ⁇ 0.5 wt.-%, or 3.5 ⁇ 2.0 wt.-%, or 3.5 ⁇ 1.0 wt.-%, or 3.5 ⁇ 0.5 wt.-%.
  • the second composition which is preferably non-granular, comprises one or more diluents.
  • at least one of the one or more diluents comprised in the second composition is the same as one of the one or more diluents comprised in the first granular composition.
  • the second composition comprises microcrystalline cellulose.
  • the total weight content of the microcrystalline cellulose in the sec ond composition relative to the total weight of the formulation is at least 1.0 wt.-%, preferably at least 2.0 wt.-%, more preferably at least 4.0 wt.-%, still more preferably at least 6.0 wt.-%, yet more prefera bly at least 8.0 wt.-%, even more preferably at least 10 wt.-%, most preferably at least 12 wt.-%, and in particular at least 14 wt.-%.
  • the total weight content of the microcrystalline cellulose in the sec ond composition relative to the total weight of the formulation is at most 30 wt.-%, preferably at most 28 wt.-%, more preferably at most 26 wt.-%, still more preferably at most 24 wt.-%, yet more preferably at most 22 wt.-%, even more preferably at most 20 wt.-%, most preferably at most 18 wt.-%, and in particular at most 16 wt.-%.
  • the total weight content of the microcrystalline cellulose in the sec ond composition relative to the total weight of the formulation is within the range of from 8.0 ⁇ 2.0 wt- %, or 10 ⁇ 4.0 wt.-%, or 10 ⁇ 2.0 wt.-%, or 12 ⁇ 6.0 wt.-%, or 12 ⁇ 4.0 wt.-%, or 12 ⁇ 2.0 wt.-%, or 14 ⁇ 8.0 wt.-%, or 14 ⁇ 6.0 wt.-%, or 14 ⁇ 4.0 wt.-%, or 14 ⁇ 2.0 wt.-%, or 16 ⁇ 10 wt.-%, or 16 ⁇ 8.0 wt.-%, or 16 ⁇ 6.0 wt.-%, or 16 ⁇ 4.0 wt.-%, or 16 ⁇ 2.0 wt.-%.
  • the first granular composition and the second composition comprise microcrystalline cellulose.
  • the total weight content of the microcrystalline cellulose in the for mulation relative to the total weight of the formulation is at least 16 wt.-%, preferably at least 20 wt.-%, more preferably at least 24 wt.-%, still more preferably at least 28 wt.-%, yet more preferably at least 32 wt.-%, even more preferably at least 36 wt.-%, most preferably at least 40 wt.-%, and in particular at least 44 wt.-%.
  • the total weight content of the microcrystalline cellulose in the for mulation relative to the total weight of the formulation is at most 74 wt.-%, preferably at most 70 wt- %, more preferably at most 66 wt.-%, still more preferably at most 62 wt.-%, yet more preferably at most 58 wt.-%, even more preferably at most 54 wt.-%, most preferably at most 50 wt.-%, and in par ticular at most 46 wt.-%.
  • the total weight content of the microcrystalline cellulose in the for mulation relative to the total weight of the formulation is within the range of from 25 ⁇ 5.0 wt.-%, or 30 ⁇ 10 wt.-%, or 30 ⁇ 5.0 wt.-%, or 35 ⁇ 15 wt.-%, or 35 ⁇ 10 wt.-%, or 35 ⁇ 5.0 wt.-%, or 40 ⁇ 20 wt.-%, or 40 ⁇ 15 wt.-%, or 40 ⁇ 10 wt.-%, or 40 ⁇ 5.0 wt.-%, or 45 ⁇ 25 wt.-%, or 45 ⁇ 20 wt.-%, or 45 ⁇ 15 wt.-%, or 45 ⁇ 10 wt.-%, or 45 ⁇ 5.0 wt.-%, or 50 ⁇ 30 wt.-%, or 50 ⁇ 25 wt.-%, or 50 ⁇ 20 wt.-%, or 50 ⁇ 15 wt.-%, or 50 ⁇ 10 wt.
  • the total amount of microcrystalline cellulose comprised in the formulation is di vided between the first granular composition and the second composition.
  • the first granular composition and the second composition both comprise microcrys talline cellulose, and wherein the weight ratio of the microcrystalline cellulose comprised in the first granular composition to the microcrystalline cellulose comprised in the second composition is within the range of from 3.0: 1.0 to 1.0:3.0, preferably 2.5: 1.0 to 1.0:2.5, more preferably 2.0: 1.0 to 1.0:2.0.
  • the second composition comprises one or more glidants.
  • At least one of the one or more glidants comprised in the second composition is the same as one of the one or more glidants comprised in the first granular composition.
  • the second composition comprises colloidal silicone dioxide.
  • the total weight content of the colloidal silicone dioxide in the second composition relative to the total weight of the formulation is at least 0.15 wt.-%, preferably at least 0.2 wt.-%, more preferably at least 0.25 wt.-%, still more preferably at least 0.3 wt.-%, yet more preferably at least 0.35 wt.-%, even more preferably at least 0.4 wt.-%, most preferably at least 0.45 wt.-%, and in particular at least 0.5 wt.-%.
  • the total weight content of the colloidal silicone dioxide in the second composition relative to the total weight of the formulation is at most 2.0 wt.-%, preferably at most 1.8 wt.-%, more preferably at most 1.6 wt.-%, still more preferably at most 1.4 wt.-%, yet more preferably at most 1.2 wt.-%, even more preferably at most 1.0 wt.-%, most preferably at most 0.8 wt.-%, and in particular at most 0.6 wt.-%.
  • the total weight content of the colloidal silicone dioxide in the second composition relative to the total weight of the formulation is within the range of from 0.3 ⁇ 0.2 wt.-%, or 0.5 ⁇ 0.4 wt.-%, or 0.5 ⁇ 0.2 wt.-%, or 0.7 ⁇ 0.6 wt.-%, or 0.7 ⁇ 0.4 wt.-%, or 0.7 ⁇ 0.2 wt.-%.
  • the first granular composition and the second composition comprise colloidal sili cone dioxide.
  • the total weight content of the colloidal silicone dioxide in the for mulation relative to the total weight of the formulation is at least 0.15 wt.-%, preferably at least 0.2 wt- %, more preferably at least 0.25 wt.-%, still more preferably at least 0.3 wt.-%, yet more preferably at least 0.35 wt.-%, even more preferably at least 0.4 wt.-%, most preferably at least 0.45 wt.-%, and in particular at least 0.5 wt.-%.
  • the total weight content of the colloidal silicone dioxide in the for mulation relative to the total weight of the formulation is at most 2.0 wt.-%, preferably at most 1.8 wt.- %, more preferably at most 1.6 wt.-%, still more preferably at most 1.4 wt.-%, yet more preferably at most 1.2 wt.-%, even more preferably at most 1.0 wt.-%, most preferably at most 0.8 wt.-%, and in particular at most 0.6 wt.-%.
  • the total weight content of the colloidal silicone dioxide in the for mulation relative to the total weight of the formulation is within the range of from 0.3 ⁇ 0.2 wt.-%, or 0.5 ⁇ 0.4 wt.-%, or 0.5 ⁇ 0.2 wt.-%, or 0.7 ⁇ 0.6 wt.-%, or 0.7 ⁇ 0.4 wt.-%, or 0.7 ⁇ 0.2 wt.-%.
  • the total amount of colloidal silicone dioxide comprised in the formulation is divided between the first granular composition and the second composition.
  • the second composition comprises or essentially consists of
  • the second composition comprises or essentially consists of
  • - sacubitril sodium salt preferably with a total weight content of from 20 to 28 wt.-%;
  • one disintegrant preferably with a total weight content of from 1.0 to 5.0 wt.-%;
  • one lubricant preferably with a total weight content of from 2.5 to 3.5 wt.-%; in each case relative to the total weight of the formulation.
  • the second composition comprises or essentially consists of
  • - sacubitril sodium salt preferably with a total weight content of from 20 to 28 wt.-%;
  • crospovidone preferably with a total weight content of from 1.0 to 5.0 wt.-%;
  • magnesium stearate preferably with a total weight content of from 2.5 to 3.5 wt.-%; in each case relative to the total weight of the formulation.
  • the formulation according to the invention does not comprise sodium lauryl sulphate, preferably no surfactant at all.
  • the formulation according to the invention comprises one or more diluents, one or more binders, and one or more glidants; and wherein the one or more diluents, the one or more binders, and the one or more glidants are comprised in the first granular composition.
  • the second composition does not comprise
  • the first granular composition comprises or essentially consists of
  • the second composition comprises or essentially consists of
  • the second composition comprises or essentially consists of - sacubitril sodium salt
  • the mixture of the formulation according to the invention additionally comprises a third composition which comprises neither valsartan disodium salt nor sacubitril sodium salt and which is preferably non-granular.
  • the second composition is preferably a second granular composition, wherein the first granular composition forms a first intragranular phase, the second granular composition forms a second intragranular phase that is admixed with the first intragranular phase, and the third composition forms an extragranular phase.
  • the third composition comprises one or more diluents, one or more binders, one or more disintegrants, one or more glidants, one or more lubricants, and/or mixtures thereof.
  • the third composition comprises or essentially consists of a disinte grant.
  • the disintegrant is crospovidone.
  • the third composition comprises or essentially consists of a lubricant.
  • the lubricant is magnesium stearate.
  • the formulation according to the invention comprises or essentially consists of
  • the valsartan disodium salt, the one diluent, the one binder, two of the three disintegrants, and the two glidants are contained in the first granular composition; wherein the sacubitril sodium salt, one of the three disintegrants, and the one lubricant are contained in the second composition, which is preferably non-granular; and wherein the formulation does not comprise sodium lauryl sulphate, preferably no surfactant at all.
  • Another aspect of the invention relates to a pharmaceutical dosage form comprising the phar maceutical formulation according to the invention.
  • the dosage form is preferably compacted or compressed.
  • the dosage form is preferably for oral administration.
  • the dosage form is preferably selected from the group consisting of tablets, minitablets, mi crotablets, coated tablets, coated minitablets, coated microtablets, pills, powders, lozenges, sachets, soft gelatin capsules, hard gelatin capsules, and suppositories; preferably tablets.
  • the dosage form is a film-coated tablet.
  • the dose of valsartan disodium salt is at least 12.9 mg, preferably at least 25.7 mg, more preferably at least 38.6 mg, still more preferably at least 51.4 mg, yet more preferably at least 64.3 mg, even more preferably at least 77.1 mg, most preferably at least 90.0 mg, and in particular at least 128.0 mg.
  • the dose of valsartan disodium salt is at most 128 mg, preferably at most 105 mg, more preferably at most 92 mg, still more preferably at most 79 mg, yet more preferably at most 66 mg, even more preferably at most 53 mg, most preferably at most 40 mg, and in particular at most 27 mg.
  • the dose of valsartan disodium salt is within the range of from 10 to 200 mg, preferably from 12 to 185 mg, more preferably from 14 to 170 mg, still more preferably from 16 to 155 mg, yet more preferably from 18 to 140 mg, even more preferably from 20 to 125 mg, most preferably from 22 to 110 mg, and in particular from 25 to 128 mg.
  • the dose of sacubitril sodium salt is at least 12.2 mg, preferably at least 24.3 mg, more preferably at least 36.5 mg, still more preferably at least 48.6 mg, yet more preferably at least 60.8 mg, even more preferably at least 72.9 mg, most preferably at least 85.1 mg, and in particular at least 97.2 mg.
  • the dose of sacubitril sodium salt is at most 126 mg, preferably at most 103 mg, more preferably at most 90 mg, still more preferably at most 77 mg, yet more preferably at most 64 mg, even more preferably at most 51 mg, most preferably at most 38 mg, and in particular at most 25 mg.
  • the dose of sacubitril sodium salt is within the range of from 10 to 200 mg, preferably from 12 to 185 mg, more preferably from 14 to 170 mg, still more preferably from 16 to 155 mg, yet more preferably from 18 to 140 mg, even more preferably from 20 to 125 mg, most preferably from 22 to 110 mg, and in particular from 24 to 100 mg.
  • the dose of valsartan disodium salt, expressed as equivalent weight of the valsartan free acid, and sacubitril sodium salt, expressed as equivalent weight of the sacubitril free acid is
  • the weight ratio of the valsartan disodium salt to the sacubitril sodium salt is within the range of from 1.5: 1.0 to 1.0: 1.5, preferably 1.4: 1.0 to 1.0: 1.4, more preferably 1.3: 1.0 to 1.0: 1.3, still more preferably 1.2: 1.0 to 1.0: 1.2, and yet more preferably 1.1: 1.0 to 1.0: 1.1.
  • Still another aspect of the invention relates to the dosage form according to the invention for use in the treatment or prevention of a condition or disease selected from the group consisting of hyperten sion, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hy pertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glo merular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders,
  • the first granular composition is prepared by wet granulation.
  • the second composition which is preferably non-granular, is a pow der.
  • the second composition comprises particles of the sacubitril sodium salt, preferably wherein at most 90 vol.-% of the particles of sacubitril sodium salt within the second composition have a particle size of at most 50 pm; more preferably at most 80 vol.-%; still more preferably at most 70 vol.-%, yet more preferably at most 60 vol.-%, even more preferably at most 50 vol.-%, most preferably at most 40 vol.-%, and in particular at most 30 vol.-%.
  • particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles, using Malvern Mastersizer MS2000 equipped with »wet « dispersion unit.
  • the particles to be subjected to the particle size measurement are preferably first suspended in appropriate dispersant such as Isoparaffin and then subjected to a size determination in a Malvern Mastersizer instrument.
  • appropriate dispersant such as Isoparaffin
  • 100-300 mg of substance is dispersed in 5-10 mL of disper sant.
  • the second composition is a second granular composition pre pared by hot-melt granulation or dry granulation, preferably dry granulation.
  • the second composition is a second granular composition prepared by wet granulation.
  • the process according to the invention preferably comprises the steps of:
  • step (b) providing a granulation mixture comprising one or more diluents, one or more disintegrants, one or more glidants, and/or one or more binders; (c) wet granulating the granulation mixture provided in step (b) with the granulation liquid provided in step (a) thereby obtaining a first granular composition; and
  • step (d) mixing the first granular composition obtained in step (c) with a second composition, which is preferably non-granular, comprising sacubitril sodium; preferably wherein the second composition is non-granular or granular; thereby obtaining a compression mixture which comprises the first granular composition obtained in step (c) and the second composition comprising the sacubitril sodium.
  • the second composition in step (d) is a non-granular powder mixture. In other preferred embodiments, in step (d) the second composition is a second granular composition, which has preferably been obtained by dry granulation, hot-melt granulation or wet granulation.
  • the second composition is a second granular composition
  • the first granular composition obtained in step (c) and the second granular composition are mixed with a third composition, which is preferably non-granular and which preferably comprises neither valsartan disodium salt nor sacubitril sodium salt.
  • the second composition is a non-granular composition (powder mixture) that additionally comprises optionally one or more disintegrants, and optionally one or more lubricants, such that the obtained compression mixture comprises the first granular composition obtained in step (c) and the second composition comprising the sacubitril sodium, the optionally present one or more disintegrants, and the optionally present one or more lubricants.
  • the second composition in step (d) is a second granular com position that additionally comprises optionally one or more disintegrants, and optionally one or more lubricants, such that the obtained compression mixture comprises the first granular composition obtained in step (c) and the second granular composition comprising the sacubitril sodium, the optionally present one or more disintegrants, and the optionally present one or more lubricants.
  • the second granular composition has been obtained by dry granulation.
  • the second granular composition has been obtained by hot-melt granulation.
  • the second granular composition has been obtained by wet granulation.
  • step (a) valsartan free acid and sodium hydroxide are provided.
  • step (a) comprises the sub-steps of:
  • the sodium hydroxide solution obtained in sub-step (a-1) has a pH value of at least 10, preferably at least 10.5, more preferably at least 11, still more preferably at least
  • the sodium hydroxide valsartan solution obtained in sub-step (a-2) has a pH value of at least 3.5, preferably at least 4.0, more preferably at least 4.5, still more preferably at least 5.0, yet more preferably at least 5.5, even more preferably at least 6.0, most preferably at least
  • the sodium hydroxide valsartan solution obtained in sub-step (a-2) has a pH value of at most 13.5, preferably at most 13, more preferably at most 12.5, still more preferably at most 12, yet more preferably at most 11.5, even more preferably at most 11, most preferably at most
  • the sodium hydroxide valsartan solution obtained in sub-step (a-2) has a pH value within the range of from 3.5 to 13.5, preferably from 4.0 to 13, more preferably from 4.5 to 12.5, still more preferably from 5.0 to 12, yet more preferably from 5.5 to 11.5, even more preferably from 6.0 to 11, most preferably from 6.5 to 10.5, and in particular from 7.0 to 10.
  • the molar ratio of the sodium hydroxide to the valsartan free acid provided in step (a) is within the range of from 3.5: 1.0 to 0.5: 1.0, preferably 3.0: 1.0 to 1.0: 1.0, more preferably 2.5: 1.0 to 1.5: 1.0, still more preferably 2.3: 1.0 to 1.7: 1.0, yet more preferably 2.1:1.0 to 1.9: 1.0, and in particular 2: 1.
  • the one or more solvents provided in step (a) comprise water and/or an organic sol vent.
  • the one or more solvents provided in step (a) are selected from the group consisting of water, acetone, ethanol, and mixtures thereof.
  • the one or more solvents provided in step (a) is water.
  • the granulation liquid provided in step (a) is a solution; preferably a clear solution.
  • the one or more binders optionally provided in step (a) are selected from the group consisting of
  • cellulose ethers preferably selected from hydroxyethyl cellulose, hydroxypropyl cellulose, and hy- droxypropyl methyl cellulose;
  • hydroxypropyl cellulose is not a low substituted hydroxypropyl cellulose; preferably polyvinylpyrrolidone.
  • the granulation mixture provided in step (b) comprises
  • lactose e.g. lactose monohydrate, anhydrous lactose, spray dried and/or granulated lactose; sucrose, fructose, dex- trates, saccharose, raffmose, trehalose, fructose, and dextrin;
  • - sugar alcohols preferably selected from xylitol, mannitol, maltitol, isomalt, and sorbitol;
  • cellulose or cellulose derivatives preferably powdered cellulose, microcrystalline cellulose, or silicified microcrystalline cellulose;
  • starch or starch derivatives preferably low moisture starch, com starch, pregelatinized starch, or low moisture pregelatinized starch;
  • magnesium aluminometasilicate such as Neusilin
  • - salts of phosphoric acid preferably calcium salts of phosphoric acid; preferably selected from calcium hydrogen phosphate anhydrous and calcium hydrogen phosphate hydrate;
  • - salts of carbonic acid preferably calcium carbonate, sodium carbonate, potassium carbonate, calcium hydrogencarbonate, sodium hydrogencarbonate, or potassium hydrogencarbonate;
  • microcrystalline cellulose preferably from microcrystalline cellulose, saccharides (preferably selected from lactose and sac charose), sugar alcohols (preferably mannitol) and mixtures thereof; more preferably mannitol, microcrystalline cellulose (such as Avicel PH101) and mixtures thereof; - one or two disintegrants independently of one another selected from the group consisting of
  • cellulose or cellulose derivatives preferably microcrystalline cellulose, low substituted hydrox- ypropyl cellulose, methylcellulose, sodium salts of carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose and salts thereof (e.g. croscar- mellose sodium and/or croscarmellose calcium);
  • starch and starch derivatives preferably native starch, pregelatinized starch, sodium starch gly- collate, or hydroxypropyl starch;
  • heteroglycanes preferably alginic acid, sodium alginate, calcium alginate, agar, or guar gum;
  • glucosamines preferably chitosan
  • one or two glidants independently of one another selected from the group consisting of colloidal silica such as Aerosil 200, talc, magnesium trisilicate, and mixtures thereof; preferably col loidal silica, talc and mixtures thereof; and
  • one binder selected from the group consisting of
  • - cellulose ethers preferably selected from hydroxyethylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose;
  • hydroxypropyl cellulose is not a low substituted hydroxypropyl cellulose; preferably hydroxypropyl cellulose.
  • the granulation mixture provided in step (b) comprises
  • microcrystalline cellulose or mannitol optionally, microcrystalline cellulose or mannitol
  • the one or more binders are provided in one of the steps (a) and (b), but not in both.
  • the wet granulation is performed by means of a granulating device.
  • the granulating device is a high shear mixer or a fluid bed dryer.
  • step (c) comprises the sub-steps of
  • step (c-1) optionally, heating the granulation mixture provided in step (b) to an elevated temperature; pref erably to a temperature within the range of from 40-43 °C, more preferably to about 40 °C;
  • step (c-2) spraying the granulation mixture provided in step (b) or the heated granulation mixture obtained in sub-step (c-1) with the granulation liquid provided in step (a) thereby obtaining wet granules; preferably at a temperature within the range of from 25-33 °C; and
  • the first granular composition has a loss on drying after 5 minutes at 105 ⁇ 2 °C of at most 7.5 wt.-%, preferably at most 7.0 wt.-%, more preferably at most 6.5 wt.-%, still more preferably at most 6.0 wt.-%, yet more preferably at most 5.5 wt.-%, even more preferably at most 5.0 wt.-%, most preferably at most 4.5 wt.-%, and in particular at most 4.0 wt.-%.
  • the loss on drying is preferably de termined in accordance with Ph. Eur. 2.2.32.
  • sacubitril is provided in step (d) in the form of sacubitril sodium salt.
  • step (d) the first granular composition is mixed with
  • cellulose or cellulose derivatives preferably microcrystalline cellulose, low substituted hydroxy propyl cellulose, methylcellulose, sodium salts of carboxymethyl cellulose, calcium salts of car- boxymethyl cellulose, cross-linked carboxymethylcellulose and salts thereof (e.g. croscarmellose sodium and/or croscarmellose calcium);
  • starch and starch derivatives preferably native starch, pregelatinized starch, sodium starch gly- collate, or hydroxypropyl starch;
  • heteroglycanes preferably alginic acid, sodium alginate, calcium alginate, agar, or guar gum; - glucosamines; preferably chitosan;
  • one lubricant selected from the group consisting of
  • Ci2-2o-fatty acids and derivatives thereof preferably selected from magnesium stea rate, calcium stearate, aluminum stearate, zinc stearate, magnesium palmitate, magnesium oleate, and sodium stearyl fumarate;
  • oils preferably hydrogenated vegetable oil or hydrogenated castor oil
  • magnesium stearate preferably from magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, and mixtures thereof; more preferably sodium stearyl fumarate, magnesium stearate, and mixtures thereof.
  • step (d) the first granular composition is mixed with
  • magnesium stearate optionally, magnesium stearate.
  • step (d) comprises the sub-steps (d) of:
  • step (d-1) mixing the first granular composition obtained in step (c) with sacubitril sodium and optionally one or more disintegrants thereby obtaining a first compression mixture;
  • step (d-2) optionally, mixing the first compression mixture obtained in sub-step (d-1) with one or more lub ricants thereby obtaining a second compression mixture.
  • the mixing is performed by means of a mixing device; preferably a con tainer mixer.
  • the second composition is prepared by wet granulation, by hot-melt granulation, or by dry granulation prior to mixing with the first granular composition in step (d).
  • Another aspect of the invention relates to a pharmaceutical formulation obtainable by the pro cess according to the invention.
  • Another aspect of the invention relates to a process for the preparation of a pharmaceutical dos age form according to the invention, the process comprising the steps of:
  • step (B) compressing the pharmaceutical formulation provided in step (A) by means of a tablet press thereby obtaining a tablet
  • step (C) optionally applying a film coating to the tablet obtains in step (B).
  • the examples are representative of the highest dose tablets.
  • the composition of the lower dose tablets is proportional to the highest dose.
  • Formulations 1 to 7 relate to mixtures of a first granular composition made by wet granulation (fluid bed granulation) and comprising valsartan disodium salt and a second non-granular composition comprising sacubitril sodium salt.
  • the first granular composition forms an intragranular phase and the second non-granular composition forms an extragranular phase.
  • the overall mixture was compacted to tablets which were subsequently film coated:
  • Formulations 8 to 10 relate to mixtures of a first granular composition made by wet granulation (fluid bed granulation) and comprising valsartan disodium salt, a second granular composition made by granulation (example 8 dry granulation by roller compaction; examples 9 and 10 wet granulation by fluid bed granulation) and comprising sacubitril sodium salt, and a third non-granular composition com prising neither valsartan disodium salt nor sacubitril sodium salt.
  • the first granular composition forms a first intragranular phase
  • the second granular composition forms a second granular phase
  • the third composition forms an extragranular phase.
  • the overall mixture was compacted to tablets which were subsequently film coated:
  • Formulations 12 and 13 relate to mixtures of a first granular composition made by wet granula tion (fluid bed granulation) and comprising valsartan disodium salt and a second non-granular compo sition comprising sacubitril sodium salt.
  • Formulation 14 relates to a mixture of a first granular compo sition made by wet granulation (fluid bed granulation) and comprising valsartan disodium salt and sacu bitril sodium salt and a second non-granular composition comprising further excipients.
  • Formulation 15 relates to a mixture of a first granular composition made by dry granulation (compaction) and comprising valsartan disodium salt and sacubitril sodium salt and a second non-granular composition compris ing further excipients.
  • first granular composition forms an intragranular phase
  • second non-granular composition forms an extragranular phase.
  • valsartan disodium salt and sacubitril sodium salt were crystalline.
  • the overall mixtures were compacted to tablets which were subsequently film coated:
  • the granulation liquid was prepared by dissolving the required amount of NaOH in an appro priate amount of water. This solution presented a clear liquid. After this, the required amount of valsartan was added during constant stirring. Valsartan dissolved completely and a clear liquid was obtained. After both NaOH and valsartan were dissolved, the pH value of the solution was measured. The pH value was between 7 and 10.
  • the Povidone K30 was also dissolved in the granulation liquid following the pH measurement.
  • the obtained solution presented a clear, slightly yellow solution, which was used as the granulation liquid.
  • Klucel EF was added to the dry mixture for granulation.
  • the Klucel EF was also added into the fluid bed dryer and not to the granulation liquid.
  • the contents in the fluid bed dryer were sprayed with the granulation liquid while being fluid ized in the fluid bed.
  • the granulation involved heating the granulate up to about 40 °C. After heating the granulate, was sprayed with the granulation liquid thereby starting to form the granules.
  • the tem perature of the granulate was maintained at about 25-33 °C to get optimal conditions for granule for mation.
  • the spraying phase was finished, the granulate was dried at a temperature of about 40 °C.
  • Example 14 sacubitril sodium was added to the first granular composition comprising valsar- tan disodium salt and prepared by wet granulation.
  • Valsartan disodium salt was dry granulated using the following composition:
  • fluid bed granulation with valsartan disodium salt in the granulation fluid i.e. wet granulation
  • fluid bed granulation with valsartan disodium salt in the granulation fluid has several unexpected advantages compared to dry granulation of valsartan disodium salt.
  • Example 15 the first granular composition comprising valsartan disodium and sacubitril so dium was prepared by dry granulation. All ingredients were mixed with one another and subsequently dry granulated using a roller compactor. After compaction the dry-granulate was sieved with a sieve with 0.6-2.0 mm openings.
  • Example 8 the second granular composition comprising sacubitril sodium was prepared by dry granulation. All ingredients were mixed with one another and subsequently dry granulated using a roller compactor. After compaction the dry-granulate was sieved with a sieve with 0.6-2.0 mm openings.
  • Example 9 the second granular composition comprising sacubitril sodium was pre pared by wet granulation. All ingredients were granulated in a fluid bed dryer. The granulating solution was prepared with water and polyvinylpyrrolidone.
  • the compression mixture for Example 1-7 was prepared by adding sacubitril sodium and the second half of crospovidone (second non-granular composition) to the first granular composition and mixing in a container mixer for approximately 15 minutes. After mixing, the lubricant was added and the mixture was mixed in a container mixer for additional 2 minutes.
  • the compression mixture for Examples 12 and 13 was prepared by adding sacubitril sodium salt, colloidal silicon dioxide and microcrystalline cellulose (second non-granular composition) to the first granular composition and mixing in a container mixer for approximately 15 minutes. After mixing, the lubricant was added and the mixture was mixed in a container mixer for additional 2 minutes.
  • the compression mixture for Examples 14 and 15 was prepared by adding the second half of crospovidone and colloidal silicon dioxide, if present, (second non-granular composition) to the first granular composition and mixing in a container mixer for approximately 15 minutes. After mixing, the lubricant was added and the mixture was mixed in a container mixer for additional 2 minutes.
  • Example 8-10 the first granular composition and the second granular composition were joined in a container mixer and additional crospovidone was added and mixed in the container mixer for approximately 15 minutes. After mixing, the lubricant was added and the mixture was mixed in a con tainer mixer for additional 2 minutes.
  • Tablet cores of Examples 1-15 were coated in automatic coating pan with water-based fdm coating suspension, prepared by suspending of ready-to-use mixture, commercially available as Opadry 85F28751 II HP white.
  • the theoretical weight of the film coated tablets is 3 % higher than the core weight.
  • Example 14 had significant impact on reaching the thera Guideic plasma concentration levels of valsartan defined with the formulations of Example 15 and En tresto ® (dry granulation), while it appears that the same changes had no influence on sacubitril bioavail- ability. Surprisingly, a broader range of Cmax could be achieved with the formulation of Example 13 (wet granulation).
  • Example 13 wet granulation
  • the absorption of valsartan diso dium in amorphous form was slowed down while at the same time not impacting the absorption of sacubitril sodium, and thus achieving a similar profile as in the reference product Entresto ® in the bioe quivalence study.
  • Raman and FT-IR imaging are techniques that generate images with both spectral and spatial information.
  • Raman/FT-IR spectra were collected from various spatial positions on the crossected tab lets, which enables the chemical identification (molecular fmgerpint) of every particle on the crossected tablets.
  • Raman and FT-IR spectra were collected for the tablets of Examples 11, 12 and 15.
  • a wet-granulated product can be distinguished from a dry granulated product by mapping.
  • the respective active ingredient (valsartan) is much more homogenously distributed. This can also be seen from the results of Raman mapping and FT-IR mapping shown in Figures 1A, IB, 2A, 2B, 3A and 3B.
  • Example 15 demonstates better homogeinity for both active ingredients than Example 11 ( Figure 1A), whereas valsartan is distributed around the excipients onto which it was sprayed in Figure 2A (Example 12). Its distribution after formulation does not look significantly different from the distribution of the sacubitril added extragranularly.

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Abstract

L'invention concerne une formulation pharmaceutique comprenant un mélange d'une première composition granulaire comprenant un sel disodique de valsartan et une seconde composition, qui est de préférence non granulaire, comprenant ou consistant essentiellement en un sel de sodium de sacubitril. La seconde composition peut être non granulaire ou granulaire. L'invention concerne en outre une forme posologique pharmaceutique comprenant une telle formulation pharmaceutique et un procédé de préparation de ladite formulation pharmaceutique.
EP22728900.6A 2021-05-14 2022-05-13 Formulation pharmaceutique de valsartan et de sacubitril Pending EP4337175A1 (fr)

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US20080152717A1 (en) * 2006-12-14 2008-06-26 Isp Investments, Inc. Amorphous valsartan and the production thereof
KR101524264B1 (ko) * 2013-01-16 2015-05-29 (주)한국파비스제약 발사르탄 함유 경구용 약학 조성물
JP6238831B2 (ja) * 2014-04-25 2017-11-29 沢井製薬株式会社 バルサルタン含有錠剤及びその製造方法
CN106309388A (zh) 2015-06-30 2017-01-11 深圳信立泰药业股份有限公司 一种用于心衰治疗的药物组合物及其制备方法
WO2017009784A1 (fr) 2015-07-14 2017-01-19 Cadila Healthcare Limited Formes à l'état solide de sel de trisodium du complexe valsartan/sacubitril et de sacubitril
EP3117823A1 (fr) 2015-07-17 2017-01-18 Quimica Sintetica, S.A. Dispersion solide amorphe comprenant un bloqueur du récepteur de l'angiotensine et d'un inhibiteur d'endopeptidase neutre
WO2017012600A1 (fr) 2015-07-20 2017-01-26 Zentiva, K.S. Composition pharmaceutique contenant du valsartan et du sacubitril et procédés de préparation et de stabilisation correspondants
CN106397249A (zh) 2015-08-03 2017-02-15 深圳信立泰药业股份有限公司 一种高稳定性lcz696结晶粉末及其制备方法
WO2017036420A1 (fr) 2015-09-06 2017-03-09 常州方楠医药技术有限公司 Composition pharmaceutique contenant du valsartan et du sacubitril, et procédé de préparation associé
WO2017042700A1 (fr) 2015-09-07 2017-03-16 Sun Pharmaceutical Industries Limited Formes solides de valsartan et de sacubitril
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
WO2019020706A1 (fr) 2017-07-28 2019-01-31 Synthon B.V. Composition pharmaceutique comprenant du sacubitril et du valsartan
EP3766484B1 (fr) 2019-07-19 2021-08-25 Zentiva, K.S. Forme posologique pharmaceutique solide comprenant du valsartan et du sacubitril

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