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WO2023211412A1 - Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche - Google Patents

Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche Download PDF

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Publication number
WO2023211412A1
WO2023211412A1 PCT/TR2023/050359 TR2023050359W WO2023211412A1 WO 2023211412 A1 WO2023211412 A1 WO 2023211412A1 TR 2023050359 W TR2023050359 W TR 2023050359W WO 2023211412 A1 WO2023211412 A1 WO 2023211412A1
Authority
WO
WIPO (PCT)
Prior art keywords
film coated
sodium
coated tablet
mixing
composition
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.)
Ceased
Application number
PCT/TR2023/050359
Other languages
English (en)
Inventor
Fadime Bilgehan ATAK
Fatih Sunel
Dilay SEZER
Akif ERDOGAN
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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
Priority claimed from TR2022/006846 external-priority patent/TR2022006846A1/tr
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of WO2023211412A1 publication Critical patent/WO2023211412A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to a film coated tablet comprising intragranular composition comprising sacubitril sodium, valsartan disodium and an extragranular composition, wherein the tablet is obtained by dry granulation.
  • Sacubitril is an antihypertensive drug used in combination with valsartan. Its chemical designation is 4-(((2S,4R)-1-([1 ,1 '-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- yl)amino)-4-oxobutanoic acid with the following chemical structure of Formula I.
  • Valsartan is a specific angiotensin II receptor antagonist, which selectively and competitively blocks AT1 -receptors and mediates the vasopressor and aldosterone effects of angiotensin II. Its chemical designation is N-(1 -oxopentyl)-N-[[2'-(1 H-tetrazol-5-yl)-[1 ,1'-biphenyl]-4- yl]methyl]-L-valine with the following chemical structure of Formula II.
  • a complex comprising valsartan, which is an angiotensin receptor antagonist, and Sacubitril, which is a neurolysin inhibitor, has been approved by US Food and Drug Administration (FDA) under the trade name ENTRESTO® by Novartis for the treatment of heart failure with reduced ejection fraction.
  • FDA US Food and Drug Administration
  • Entresto® is supplied for oral administration as immediate release film-coated tablets in three strengths: 24/26, 49/51 and 97/103 mg, containing respectively 24.3 mg sacubitril/25.7 mg valsartan, 48.6 mg sacubitril/51 .4 mg valsartan and 97.2 mg sacubitril/102.8 mg valsartan.
  • US 8101659 and US 8404744 discloses a composition comprising Valsartan and Sacubitril which are administered in combination in 1 :1 ratio.
  • US 8796331 discloses a method of treating hypertension and heart failure by administering a combination of Valsartan and Sacubitril administered in one unit dose form or in two separate unit dose forms.
  • 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.
  • Valsartan disodium and sacubitril sodium cannot be easily processed due to their poor flowability. Moreover, the amorphous forms of valsartan disodium and sacubitril sodium are very hygroscopic solids. These substances become deliquescent and sticky when exposed to air humidity. Therefore, formulation with these agents and their processing steps are crucial for tablet stability and dissolution.
  • the main object of the present invention is to provide a film coated tablet comprising sacubitril sodium and valsartan disodium with having desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
  • Another object of the present invention is to provide a film coated tablet comprising sacubitril sodium and valsartan disodium with high stability.
  • Another object of the present invention is to provide a process for preparing a film coated tablet composition comprising sacubitril sodium and valsartan disodium with high stability. The process is a simple, rapid, cost effective, time-saving, and industrially convenient method. The process is dry granulation.
  • a film coated tablet comprises;
  • an intragranular composition comprising sacubitril sodium, valsartan disodium and at least one disintegrant
  • the amount of the disintegrants is 4.0% to 15.0% by weight of the total core tablet and the tablet is obtained by dry granulation.
  • the ratio of active substances in the total tablet is quite high. Due to this reason as well as the characteristic features of the active ingredients, fluidity and homogeneity problems arise to. These problems were overcome with this preferred disintegrant ratio and dry granulation.
  • the tablet is prepared with dry granulation.
  • the dry granulation is simple and low-cost method. Since valsartan disodium and sacubitril sodium are very hygroscopic solids, this method and the formulation prepared with the excipients mentioned below provided stability.
  • the amount of sacubitril sodium is 20.0% to 30.0% by weight of the total core tablet.
  • the amount of valsartan disodium is 22.0% to 35.0% by weight of the total core tablet.
  • Suitable disintegrants are selected from the group comprising crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose, sodium alginate, corn starch, sodium glycine carbonate or mixtures thereof.
  • the disintegrant is crospovidone.
  • crospovidone is used both an intragranular composition and an extragranular composition. This provides the desired dissolution profile. Furthermore, this helps to achieve an effective and an easy process.
  • the amount of disintegrant is 5.0% to 10.0% by weight of the total core tablet.
  • the dry granulation comprises the following steps;
  • composition comprising sacubitril sodium, valsartan disodium and at least one pharmaceutically acceptable excipient
  • excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
  • the formulations should have no physicochemical incompatibility between the active agents and the excipients.
  • each composition further comprises the pharmaceutically acceptable excipients which are selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, pregelatinized starch, mannitol, dicalcium phosphate, lactose monohydrate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, cellulose acetate, ethylcellulose, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sugar sphericals or mixtures thereof.
  • the filler is microcrystalline cellulose.
  • the filler helps to provide the desired dissolution profile. Also, it helps to provide the desired stability.
  • the amount of filler is 15.0% to 25.0% by weight of the total core tablet.
  • binder addition is especially valuable for a poorly soluble formulation. Binder can lead to processing problems such as rapid over granulation, tablet hardness increases and dissolution concert diminish.
  • Suitable binders are selected from the group comprising low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, ethyl cellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
  • the binder is low-substituted hydroxypropyl cellulose. Especially, using low-substituted hydroxypropyl cellulose provides the desired dissolution profile and the desired stability.
  • the amount of binders is 8.0% to 15.0% by weight of the total core tablet.
  • Suitable lubricants are selected from the group comprising talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, magnesium lauryl sulfate, sodium oleate, polyethylene glycol, sodium lauryl sulphate or mixtures thereof.
  • the lubricant is magnesium stearate or talc or mixtures thereof. It improves the powder processing properties. Also, it enhances powder flow by reducing the inter-particle friction.
  • the amount of lubricant is 0.8% to 11 .5% by weight of the total composition.
  • Suitable glidants are selected from the group comprising silica colloidal anhydrous, silicon dioxide, aluminum silicate or mixtures thereof.
  • the glidant is silica colloidal anhydrous.
  • the amount of glidant is 0.2% to 5.0% by weight of the total composition.
  • the film coated tablet comprises;
  • the film coated tablet comprises;
  • a process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
  • the present invention relates to a process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
  • the formulation solves the sticking problem of the tablet in the preparation process.
  • the preparation process also solves problems of degradation of the preparation due to hygroscopicity and improves stability of the tablet.
  • Example 1 Example 2: Example 3: Coating agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un comprimé pelliculé comprenant une composition intragranulaire renfermant du sacubitril sodique, du valsartan disodique et une composition extragranulaire, le comprimé étant obtenu par granulation à sec.
PCT/TR2023/050359 2022-04-26 2023-04-17 Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche Ceased WO2023211412A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/006846 TR2022006846A1 (tr) 2022-04-26 Kuru granülasyon yöntemi̇yle hazirlanan sakubi̇tri̇l ve valsartan i̇çeren bi̇r tablet
TR2022006846 2022-04-26

Publications (1)

Publication Number Publication Date
WO2023211412A1 true WO2023211412A1 (fr) 2023-11-02

Family

ID=88519461

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2023/050359 Ceased WO2023211412A1 (fr) 2022-04-26 2023-04-17 Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche

Country Status (2)

Country Link
GE (1) GEAP202416631A (fr)
WO (1) WO2023211412A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018069937A1 (fr) * 2016-10-13 2018-04-19 Mylan Laboratories Limited Dispersions solides de sacubitril/valsartan trisodique et procédé de leur préparation
WO2018211479A1 (fr) * 2017-05-19 2018-11-22 Lupin Limited Compositions stabilisées d'inhibiteurs de l'angiotensine ii et d'inhibiteurs de l'endopeptidase neutre, et leur procédé de préparation
WO2019020706A1 (fr) * 2017-07-28 2019-01-31 Synthon B.V. Composition pharmaceutique comprenant du sacubitril et du valsartan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018069937A1 (fr) * 2016-10-13 2018-04-19 Mylan Laboratories Limited Dispersions solides de sacubitril/valsartan trisodique et procédé de leur préparation
WO2018211479A1 (fr) * 2017-05-19 2018-11-22 Lupin Limited Compositions stabilisées d'inhibiteurs de l'angiotensine ii et d'inhibiteurs de l'endopeptidase neutre, et leur procédé de préparation
WO2019020706A1 (fr) * 2017-07-28 2019-01-31 Synthon B.V. Composition pharmaceutique comprenant du sacubitril et du valsartan

Also Published As

Publication number Publication date
GEAP202416631A (en) 2024-12-25

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