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WO2025063928A1 - A multilayer tablet comprising sacubitril and valsartan - Google Patents

A multilayer tablet comprising sacubitril and valsartan Download PDF

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Publication number
WO2025063928A1
WO2025063928A1 PCT/TR2024/051042 TR2024051042W WO2025063928A1 WO 2025063928 A1 WO2025063928 A1 WO 2025063928A1 TR 2024051042 W TR2024051042 W TR 2024051042W WO 2025063928 A1 WO2025063928 A1 WO 2025063928A1
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WIPO (PCT)
Prior art keywords
layer
multilayer tablet
cellulose
pharmaceutically acceptable
tablet according
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PCT/TR2024/051042
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French (fr)
Inventor
Fatih Sunel
Fadime Bilgehan ATAK
Serif KARABULUT
Alpay YUCEL
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Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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Priority claimed from TR2023/011673 external-priority patent/TR2023011673A1/en
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of WO2025063928A1 publication Critical patent/WO2025063928A1/en
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    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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

Definitions

  • the present invention relates to a multilayer tablet comprises first layer comprising sacubitril or a pharmaceutically acceptable salt thereof and second layer comprising at least one pharmaceutically acceptable excipient and third layer comprising valsartan or a pharmaceutically acceptable salt thereof wherein at least one filler is present at each layer.
  • the multilayer tablet having the desired dissolution profile and a long-term stability.
  • 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.
  • 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.
  • the existing commercial sacubitril and valsartan are unstable to hot and humid environment (for example: moisture in the air), and is extremely prone to dissociation, resulting in rapid drug absorption and metabolism or degradation. Thereby this affects the absorption after taking the medicine.
  • Valsartan and sacubitril cannot be easily processed due to their poor flowability. Moreover, the amorphous forms of valsartan and sacubitril 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 pharmaceutical composition comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, which is a multilayer tablet, which solves the problem that the present sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof is unstable to wet heat, the environment temperature and humidity requirement is strict, better controlling the product quality and reducing the production cost. So, desired stability is provided.
  • Another object of the present invention is to provide a multilayer tablet comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof with 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 process for preparing a multilayer tablet composition comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof with high stability.
  • the process is a simple, rapid, cost effective, time-saving, and industrially convenient method.
  • the process is dry granulation.
  • multilayer tablet refers to a layered tablet consisting of at least one two layers of granulate compressed together to form a single tablet. It generally consists of parallel, clear, coloured, visual distinct layers two to three or more APIs or APIs along with functional or non-functional placebo layers. Multi-layered tablet dosage forms are designed for a variety of reasons such as incompatibility problems between active agents or excipients.
  • a multilayer tablet comprises;
  • First layer comprising sacubitril or a pharmaceutically acceptable salt thereof
  • Second layer comprising at least one pharmaceutically acceptable excipient
  • Third layer comprising valsartan or a pharmaceutically acceptable salt thereof
  • At least one filler is present at each layer.
  • multilayer tablet has at least one three layer.
  • valsartan or a pharmaceutically acceptable salt thereof is present valsartan disodium, sacubitril or a pharmaceutically acceptable salt thereof is present sacubitril sodium.
  • 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.
  • microcrystalline cellulose is used at second layer.
  • microcrystalline cellulose is used at first or third layers or both. Preferably, it is used at first and third layer.
  • a multilayer tablet comprises;
  • First layer comprising sacubitril sodium
  • Second layer comprising microcrystalline cellulose
  • Third layer comprising valsartan disodium.
  • the amount of filler is 6.0% to 38.00% by weight of the total tablet.
  • the amount of filler is 2.0% to 13.00% by weight of first layer.
  • the amount of filler is 2.0% to 13.00% by weight of second layer.
  • the amount of filler is 2.0% to 13.00% by weight of third layer.
  • the amount of sacubitril or a pharmaceutically acceptable salt thereof is 18.0% to 34.0% by weight of the total core tablet.
  • the amount of valsartan or a pharmaceutically acceptable salt thereof is 18.0% to 34.0% by weight of the total core tablet.
  • first layer or third layer further comprises the pharmaceutically acceptable excipients which are selected from the group comprising binders, disintegrants, lubricants, glidants or mixtures thereof.
  • 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, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxypropyl methyl cellulose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide or mixtures thereof.
  • the binder is used at first or third layers or both.
  • the binder is low-substituted hydroxypropyl cellulose.
  • the ratio of active substances in the total tablet, even each layer, is quite high. Due to this reason as well as the characteristic features of the active ingredients, fluidity and homogeneity problems arise to.
  • the preferred binder helps to overcome provide these problems. Also, the use of the specified binder has helped to ensure stability.
  • the amount of binders is 8.0% to 17.0% by weight of the total tablet.
  • the amount of binders is 4.0% to 8.5% by weight of the first layer and the amount of binders is 4.0% to 8.5% by weight of the third layer. This ratio provides the desired compressibility of the tablet.
  • Suitable disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.
  • the disintegrant is used at first or third layers or both. This helps to provide homogeneity of layers.
  • the disintegrant is crospovidone.
  • Crospovidone is used at first or third layers or both.
  • the amount of disintegrant is 3.0% to 12.0% by weight in the total 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. According to this embodiment of the present invention, the lubricant is used at first or third layers or both.
  • 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 1.2% to 10.0% by weight of the total tablet.
  • the amount of lubricant is 3.0% to 6.0% by weight of the total tablet.
  • Suitable glidants are selected from the group comprising colloidal silicone dioxide, silicon dioxide, aluminum silicate or mixtures thereof.
  • the glidant is used at first or third layes or both.
  • the glidant is colloidal silicone dioxide.
  • the amount of glidant is 0.6% to 5.0% by weight of the total composition.
  • the multilayer tablet comprises; First layer o Sacubitril or a pharmaceutically acceptable salt thereof o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
  • the multilayer tablet comprises;
  • the multilayer tablet comprises; First layer o Sacubitril Sodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide o Talc o Magnesium Stearate
  • the multilayer tablet is prepared with dry granulation.
  • the dry granulation is simple and low-cost method. Since sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof are very hygroscopic solids, this method and the formulation prepared with the excipients mentioned below helps to provide stability.
  • a process for preparing a first layer comprising sacubitril or a pharmaceutically acceptable salt thereof for a multilayer tablet comprises the following steps; a) Mixing sacubitril or a pharmaceutically acceptable salt thereof and talc, b) Adding microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone and then mixing, c) Adding colloidal silicone dioxide and mixing, d) Adding magnesium stearate and mixing, e) Compacting the mixture at step (d), f) Adding crospovidone into the mixture at step (e), g) Adding colloidal silicone dioxide and mixing, h) Adding talc and mixing, i) Adding magnesium stearate and mixing, j) Compressing the total mixture, and obtained first layer.
  • a process for preparing a third layer comprising valsartan or a pharmaceutically acceptable salt thereof for a multilayer tablet comprises the following steps; a) Mixing valsartan or a pharmaceutically acceptable salt thereof and talc, b) Adding microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone and then mixing, c) Adding colloidal silicone dioxide and then mixing, d) Adding magnesium stearate and then mixing, e) Compacting the mixture at step (d), f) Adding crospovidone into the mixture at step (e), g) Adding colloidal silicone dioxide and then mixing, h) Adding talc and then mixing, i) Adding magnesium stearate and mixing, j) Compressing the total mixture, and obtained third layer.
  • Example 1 Multilayer tablet
  • a process for example 1 1. Preparing first layer a) Sieving sacubitril sodium and talc through 0.85 mm and then mixing, b) Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone through separately 0.85 mm and then mixing, c) Sieving colloidal silicone dioxide and then adding and mixing, d) Sieving magnesium stearate and then adding and mixing, e) Compacting the mixture at step (d), f) Sieving crospovidone and adding into the mixture at step (e), g) Sieving colloidal silicone dioxide and then adding and mixing, h) Sieving talc and then adding and mixing, i) Adding magnesium stearate and mixing, j) Compressing the total mixture, and obtained first layer.

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Abstract

The present invention relates to a multilayer tablet comprises first layer comprising sacubitril or a pharmaceutically acceptable salt thereof and second layer comprising at least one pharmaceutically acceptable excipient and third layer comprising valsartan or a pharmaceutically acceptable salt thereof wherein at least one filler is present at each layer. The multilayer tablet having the desired dissolution profile and a long-term stability.

Description

A MULTILAYER TABLET COMPRISING SACUBITRIL AND VALSARTAN
Field of the Invention
The present invention relates to a multilayer tablet comprises first layer comprising sacubitril or a pharmaceutically acceptable salt thereof and second layer comprising at least one pharmaceutically acceptable excipient and third layer comprising valsartan or a pharmaceutically acceptable salt thereof wherein at least one filler is present at each layer. The multilayer tablet having the desired dissolution profile and a long-term stability.
Background of the Invention 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.
Figure imgf000002_0001
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.
Figure imgf000002_0002
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. 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.
The existing commercial sacubitril and valsartan are unstable to hot and humid environment (for example: moisture in the air), and is extremely prone to dissociation, resulting in rapid drug absorption and metabolism or degradation. Thereby this affects the absorption after taking the medicine.
Valsartan and sacubitril cannot be easily processed due to their poor flowability. Moreover, the amorphous forms of valsartan and sacubitril 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.
In prior art, there are also several patents which disclose sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof in oral pharmaceutical dosage forms. However, despite problems of the poor flowability and stability of sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof an effective formulation and method has not been disclosed.
There still remains a need in the art to provide an improved a multilayer tablet comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof having the desired dissolution profile, excellent physicochemical properties and accordingly a desired bioavailability and a long-term stability.
Detailed Description of the Invention
The main object of the present invention is to provide a pharmaceutical composition comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, which is a multilayer tablet, which solves the problem that the present sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof is unstable to wet heat, the environment temperature and humidity requirement is strict, better controlling the product quality and reducing the production cost. So, desired stability is provided.
Another object of the present invention is to provide a multilayer tablet comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof with 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 process for preparing a multilayer tablet composition comprising sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof with high stability. The process is a simple, rapid, cost effective, time-saving, and industrially convenient method. The process is dry granulation.
The term “multilayer tablet” refers to a layered tablet consisting of at least one two layers of granulate compressed together to form a single tablet. It generally consists of parallel, clear, coloured, visual distinct layers two to three or more APIs or APIs along with functional or non-functional placebo layers. Multi-layered tablet dosage forms are designed for a variety of reasons such as incompatibility problems between active agents or excipients.
It is known that both active ingredients have poor flowability. This feature of these active agents in a single dosage form causes various difficulties and stability problems and creates homogeneity problems. In this study, we formulated them in different layers. In this way, we have overcome the problems of active substances that cause stability mentioned in the previous art, with an easy process step and formulation. Also, the flowability problem is minimized by using filler in each layer. In particular, we found that the used filler in each layer contributed to the desired dissolution profile.
According to this embodiment of the present invention, a multilayer tablet comprises;
First layer comprising sacubitril or a pharmaceutically acceptable salt thereof,
Second layer comprising at least one pharmaceutically acceptable excipient,
Third layer comprising valsartan or a pharmaceutically acceptable salt thereof,
Wherein at least one filler is present at each layer.
According to this embodiment of the present invention, multilayer tablet has at least one three layer.
According to this embodiment of the present invention, valsartan or a pharmaceutically acceptable salt thereof is present valsartan disodium, sacubitril or a pharmaceutically acceptable salt thereof is present sacubitril sodium.
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.
According to this embodiment of the present invention, the filler is microcrystalline cellulose. The filler helps to provide the desired dissolution profile.
According to this embodiment of the present invention, microcrystalline cellulose is used at second layer.
According to this embodiment of the present invention, microcrystalline cellulose is used at first or third layers or both. Preferably, it is used at first and third layer.
According to this embodiment of the present invention, a multilayer tablet comprises;
First layer comprising sacubitril sodium,
Second layer comprising microcrystalline cellulose,
Third layer comprising valsartan disodium.
According to this embodiment of the present invention, the amount of filler is 6.0% to 38.00% by weight of the total tablet.
According to this embodiment of the present invention, the amount of filler is 2.0% to 13.00% by weight of first layer.
According to this embodiment of the present invention, the amount of filler is 2.0% to 13.00% by weight of second layer.
According to this embodiment of the present invention, the amount of filler is 2.0% to 13.00% by weight of third layer.
According to this embodiment of the present invention, the amount of sacubitril or a pharmaceutically acceptable salt thereof is 18.0% to 34.0% by weight of the total core tablet.
According to this embodiment of the present invention, the amount of valsartan or a pharmaceutically acceptable salt thereof is 18.0% to 34.0% by weight of the total core tablet.
In general terms, 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. According to this embodiment of the present invention, first layer or third layer further comprises the pharmaceutically acceptable excipients which are selected from the group comprising binders, disintegrants, lubricants, glidants or mixtures thereof.
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, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxypropyl methyl cellulose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide or mixtures thereof.
According to this embodiment of the present invention, the binder is used at first or third layers or both.
According to this embodiment of the present invention, the binder is low-substituted hydroxypropyl cellulose. The ratio of active substances in the total tablet, even each layer, is quite high. Due to this reason as well as the characteristic features of the active ingredients, fluidity and homogeneity problems arise to. The preferred binder helps to overcome provide these problems. Also, the use of the specified binder has helped to ensure stability.
According to this embodiment of the present invention, the amount of binders is 8.0% to 17.0% by weight of the total tablet.
According to this embodiment of the present invention, the amount of binders is 4.0% to 8.5% by weight of the first layer and the amount of binders is 4.0% to 8.5% by weight of the third layer. This ratio provides the desired compressibility of the tablet.
Suitable disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.
According to an embodiment of the present invention, the disintegrant is used at first or third layers or both. This helps to provide homogeneity of layers.
According to an embodiment of the present invention, the disintegrant is crospovidone. Crospovidone is used at first or third layers or both.
According to an embodiment of the present invention, the amount of disintegrant is 3.0% to 12.0% by weight in the total 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. According to this embodiment of the present invention, the lubricant is used at first or third layers or both.
According to this embodiment of the present invention, 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.
According to this embodiment of the present invention, the amount of lubricant is 1.2% to 10.0% by weight of the total tablet. Preferably, the amount of lubricant is 3.0% to 6.0% by weight of the total tablet.
Suitable glidants are selected from the group comprising colloidal silicone dioxide, silicon dioxide, aluminum silicate or mixtures thereof.
According to this embodiment of the present invention, the glidant is used at first or third layes or both.
According to this embodiment of the present invention, the glidant is colloidal silicone dioxide.
According to this embodiment of the present invention, the amount of glidant is 0.6% to 5.0% by weight of the total composition.
According to this embodiment of the present invention, same excipients have been used at first and third layers. Thereof, we have minimized the interaction of excipients with each other and active agents. So, this helps to achieve an easy and practical process.
According to this embodiment of the present invention, the multilayer tablet comprises; First layer o Sacubitril or a pharmaceutically acceptable salt thereof o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
According to this embodiment of the present invention, the multilayer tablet comprises;
Third layer o Valsartan or a pharmaceutically acceptable salt thereof o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide According to this embodiment of the present invention, the multilayer tablet comprises; First layer o Sacubitril Sodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide o Talc o Magnesium Stearate
Second layer o Microcrystalline Cellulose
Third layer o Valsartan Disodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide o Talc o Magnesium Stearate
The multilayer tablet is prepared with dry granulation. The dry granulation is simple and low-cost method. Since sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof are very hygroscopic solids, this method and the formulation prepared with the excipients mentioned below helps to provide stability.
According to this embodiment of the present invention, the multilayer tablet is obtained by the dry granulation comprises the following steps;
Preparing first layer comprising sacubitril or a pharmaceutically acceptable salt thereof, Preparing first layer second layer,
Preparing third layer comprising valsartan or a pharmaceutically acceptable salt thereof, Compressing first layer and second layer, and obtained multilayer tablet, Coating the multilayer tablet with a film coating. According to this embodiment of the present invention, a process for preparing a first layer comprising sacubitril or a pharmaceutically acceptable salt thereof for a multilayer tablet comprises the following steps; a) Mixing sacubitril or a pharmaceutically acceptable salt thereof and talc, b) Adding microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone and then mixing, c) Adding colloidal silicone dioxide and mixing, d) Adding magnesium stearate and mixing, e) Compacting the mixture at step (d), f) Adding crospovidone into the mixture at step (e), g) Adding colloidal silicone dioxide and mixing, h) Adding talc and mixing, i) Adding magnesium stearate and mixing, j) Compressing the total mixture, and obtained first layer.
According to this embodiment of the present invention, a process for preparing a third layer comprising valsartan or a pharmaceutically acceptable salt thereof for a multilayer tablet comprises the following steps; a) Mixing valsartan or a pharmaceutically acceptable salt thereof and talc, b) Adding microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone and then mixing, c) Adding colloidal silicone dioxide and then mixing, d) Adding magnesium stearate and then mixing, e) Compacting the mixture at step (d), f) Adding crospovidone into the mixture at step (e), g) Adding colloidal silicone dioxide and then mixing, h) Adding talc and then mixing, i) Adding magnesium stearate and mixing, j) Compressing the total mixture, and obtained third layer.
Example 1 : Multilayer tablet
Figure imgf000010_0001
A process for example 1 ; 1. Preparing first layer a) Sieving sacubitril sodium and talc through 0.85 mm and then mixing, b) Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone through separately 0.85 mm and then mixing, c) Sieving colloidal silicone dioxide and then adding and mixing, d) Sieving magnesium stearate and then adding and mixing, e) Compacting the mixture at step (d), f) Sieving crospovidone and adding into the mixture at step (e), g) Sieving colloidal silicone dioxide and then adding and mixing, h) Sieving talc and then adding and mixing, i) Adding magnesium stearate and mixing, j) Compressing the total mixture, and obtained first layer.
2. Preparing second layer k) Mixing microcrystalline cellulose, l) Compressing the mixture, and obtained second layer.
3. Preparing third layer m) Sieving valsartan disodium and talc through 0.85 mm and then mixing, n) Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone through separately 0.85 mm and then mixing, o) Sieving colloidal silicone dioxide and then adding and mixing, p) Sieving magnesium stearate and then adding and mixing, q) Compacting the mixture at step (p), r) Sieving crospovidone and adding into the mixture at step (q), s) Sieving colloidal silicone dioxide and then adding and mixing, t) Sieving talc and then adding and mixing, u) Adding magnesium stearate and mixing, v) Compressing the total mixture, and obtained third layer.
4. Pressing first layer and second layer and third layer as a multilayer,
5. Coating the multilayer tablets.
Example 2; Coating
Figure imgf000011_0001

Claims

1 ) A multilayer tablet comprises;
First layer comprising sacubitril or a pharmaceutically acceptable salt thereof, Second layer comprising at least one pharmaceutically acceptable excipient, Third layer comprising valsartan or a pharmaceutically acceptable salt thereof, Wherein at least one filler is present at each layer.
2) The multilayer tablet according to claim 1 , wherein 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.
3) The multilayer tablet according to claim 1 , wherein the filler is microcrystalline cellulose.
4) The multilayer tablet according to claim 1 or 3, wherein microcrystalline cellulose is used at first or third layers or both.
5) The multilayer tablet according to claim 1 , wherein, the tablet comprises;
First layer comprising sacubitril sodium,
Second layer comprising microcrystalline cellulose, Third layer comprising valsartan disodium.
6) The multilayer tablet according to claim 1 or 3, wherein the amount of filler is 6.0% to 38.00% by weight of the total tablet.
7) The multilayer tablet according to claim 1 , wherein the amount of sacubitril or a pharmaceutically acceptable salt thereof is 18.0% to 34.0% by weight of the total core tablet.
8) The multilayer tablet according to claim 1 , wherein the amount of valsartan or a pharmaceutically acceptable salt thereof is 18.0% to 34.0% by weight of the total core tablet.
9) The multilayer tablet according to claim 1 , wherein first layer or third layer further comprises the pharmaceutically acceptable excipients which are selected from the group comprising binders, disintegrants, lubricants, glidants or mixtures thereof.
10) The multilayer tablet according to claim 9, wherein binders are selected from the group comprising low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, ethyl cellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxypropyl methyl cellulose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide or mixtures thereof. 11 ) The multilayer tablet according to claim 10, wherein the binder is low-substituted hydroxypropyl cellulose.
12) The multilayer tablet according to claim 10 or 11 , wherein the amount of binders is 8.0% to 17.0% by weight of the total tablet.
13) The multilayer tablet according to claim 9, wherein disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.
14) The multilayer tablet according to claim 13, wherein the disintegrant is crospovidone.
15) The multilayer tablet according to claim 13 or 14, wherein, the amount of disintegrant is 3.0% to 12.0% by weight in the total tablet.
PCT/TR2024/051042 2023-09-20 2024-09-09 A multilayer tablet comprising sacubitril and valsartan Pending WO2025063928A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008485A1 (en) * 2017-07-06 2019-01-10 Mankind Pharma Ltd Fixed dose pharmaceutical composition of valsartan and sacubitril
EP3766484A1 (en) * 2019-07-19 2021-01-20 Zentiva, K.S. Solid pharmaceutical dosage form comprising valsartan and sacubitril

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008485A1 (en) * 2017-07-06 2019-01-10 Mankind Pharma Ltd Fixed dose pharmaceutical composition of valsartan and sacubitril
EP3766484A1 (en) * 2019-07-19 2021-01-20 Zentiva, K.S. Solid pharmaceutical dosage form comprising valsartan and sacubitril

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