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WO2025063927A1 - A bilayer tablet comprising sacubitril and valsartan - Google Patents

A bilayer tablet comprising sacubitril and valsartan Download PDF

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Publication number
WO2025063927A1
WO2025063927A1 PCT/TR2024/051041 TR2024051041W WO2025063927A1 WO 2025063927 A1 WO2025063927 A1 WO 2025063927A1 TR 2024051041 W TR2024051041 W TR 2024051041W WO 2025063927 A1 WO2025063927 A1 WO 2025063927A1
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WO
WIPO (PCT)
Prior art keywords
layer
cellulose
bilayer tablet
tablet according
sacubitril
Prior art date
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Pending
Application number
PCT/TR2024/051041
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French (fr)
Inventor
Fatih Sunel
Fadime Bilgehan ATAK
Serif KARABULUT
Alpay YUCEL
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
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Priority claimed from TR2023/011672 external-priority patent/TR2023011672A1/en
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of WO2025063927A1 publication Critical patent/WO2025063927A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K9/2072—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
    • 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
    • A61K9/2022—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 bilayer tablet comprising first layer comprising sacubitril or a pharmaceutically acceptable salt thereof, at least one filler and second layer comprising valsartan or a pharmaceutically acceptable salt thereof, at least one filler wherein the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.5 and 2.5.
  • the bilayer 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.
  • 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 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 sodium and valsartan disodium 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 bilayer tablet, which solves the problem that the present sacubitril and valsartan 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 bilayer 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 bilayer 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.
  • bilayer tablet refers to a layered tablet consisting of two layers of granulate compressed together to form a single tablet. This dosage form has the advantage of separating two incompatible substances. Each layer is fed from distinct feed frame with individual weight control.
  • layer and “layer composition” have the same meaning.
  • a bilayer tablet comprises;
  • Second layer comprising sacubitril or a pharmaceutically acceptable salt thereof and at least one filler
  • Second layer comprising valsartan or a pharmaceutically acceptable salt thereof and at least one filler
  • the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.5 and 2.5.
  • the ratio provides bilayer of sacubitril and valsartan with good dissolution profile.
  • the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.9 and 2.2, preferably it is between 1 .0 and 1 .8.
  • 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 both layers.
  • the amount of filler is 15.0% to 22.50% by weight of the total tablet.
  • valsartan or a pharmaceutically acceptable salt thereof is present valsartan disodium, sacubitril or a pharmaceutically acceptable salt thereof is present sacubitril sodium.
  • 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.
  • 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.
  • 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 both layers.
  • 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 second layer. This ratio provides the desired compressibility of the bilayer 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 both layers. This helps to provide homogeneity of each layer.
  • the disintegrant is crospovidone.
  • Crospovidone is used both layers.
  • 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.
  • the lubricant is used both layers.
  • 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 both layers.
  • the glidant is colloidal silicone dioxide.
  • the amount of glidant is 0.6% to 5.0% by weight of the total composition.
  • the bilayer tablet comprises;
  • the bilayer tablet comprises;
  • Second layer o Valsartan Disodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
  • the bilayer tablet comprises;
  • Second 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 bilayer tablet is prepared with dry granulation.
  • the dry granulation is simple and low-cost method. Since sacubitril sodium and valsartan disodium 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 sodium for a bilayer tablet comprises the following steps; a) Mixing sacubitril sodium 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 second layer comprising valsartan disodium for a bilayer tablet comprises the following steps; a) Mixing valsartan disodium 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 second layer.
  • Example 1 Bilayer 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.
  • Second layer k) Sieving valsartan disodium and talc through 0.85 mm and then mixing, l) Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone through separately 0.85 mm and then mixing, m) Sieving colloidal silicone dioxide and then adding and mixing, n) Sieving magnesium stearate and then adding and mixing, o) Compacting the mixture at step (n), p) Sieving crospovidone and adding into the mixture at step (o), q) Sieving colloidal silicone dioxide and then adding and mixing, r) Sieving talc and then adding and mixing, s) Adding magnesium stearate and mixing, t) Compressing the total mixture, and obtained second layer.

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Abstract

The present invention relates to a bilayer tablet comprising first layer comprising sacubitril or a pharmaceutically acceptable salt thereof, at least one filler and second layer comprising valsartan or a pharmaceutically acceptable salt thereof, at least one filler wherein the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.5 and 2.5. The bilayer tablet having the desired dissolution profile and a long-term stability.

Description

A BILAYER TABLET COMPRISING SACUBITRIL AND VALSARTAN
Field of the Invention
The present invention relates to a bilayer tablet comprising first layer comprising sacubitril or a pharmaceutically acceptable salt thereof, at least one filler and second layer comprising valsartan or a pharmaceutically acceptable salt thereof, at least one filler wherein the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.5 and 2.5. The bilayer 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 sodium and valsartan disodium 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 and valsartan in oral pharmaceutical dosage forms. However, despite problems of the poor flowability and stability of sacubitril and valsartan an effective formulation and method has not been disclosed.
There still remains a need in the art to provide an improved a bilayer tablet comprising sacubitril and valsartan 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 bilayer tablet, which solves the problem that the present sacubitril and valsartan 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 bilayer 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 bilayer 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 “bilayer tablet” refers to a layered tablet consisting of two layers of granulate compressed together to form a single tablet. This dosage form has the advantage of separating two incompatible substances. Each layer is fed from distinct feed frame with individual weight control. For the purposes of the invention the expressions “layer” and “layer composition” have the same meaning.
It is known that both active ingredients have poor flowability. This feature of these active agents in the same formulation causes various difficulties and stability 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 both layers. In particular, we found that the filler ratios used in both layers contributed to the desired dissolution profile.
According to this embodiment of the present invention, a bilayer tablet comprises;
- First layer comprising sacubitril or a pharmaceutically acceptable salt thereof and at least one filler,
- Second layer comprising valsartan or a pharmaceutically acceptable salt thereof and at least one filler,
Wherein the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.5 and 2.5. The ratio provides bilayer of sacubitril and valsartan with good dissolution profile.
According to this embodiment of the present invention, the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.9 and 2.2, preferably it is between 1 .0 and 1 .8.
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 both layers.
According to this embodiment of the present invention, the amount of filler is 15.0% to 22.50% by weight of the total tablet. 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.
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, each 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 both layers.
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 second layer. This ratio provides the desired compressibility of the bilayer 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 both layers. This helps to provide homogeneity of each layer.
According to an embodiment of the present invention, the disintegrant is crospovidone. Crospovidone is used both layers.
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 both layers.
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 both layers.
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 for each two 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 bilayer tablet comprises;
First layer o Sacubitril Sodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
According to this embodiment of the present invention, the bilayer tablet comprises;
Second layer o Valsartan Disodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
According to this embodiment of the present invention, the bilayer 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 Valsartan Disodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide o Talc o Magnesium Stearate
The bilayer tablet is prepared with dry granulation. The dry granulation is simple and low-cost method. Since sacubitril sodium and valsartan disodium 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 bilayer tablet is obtained by the dry granulation comprises the following steps;
Preparing first layer comprising sacubitril sodium,
Preparing second layer comprising valsartan disodium,
Compressing first layer and second layer, and obtained bilayer tablet, Coating the bilayer tablet with a film coating. According to this embodiment of the present invention, a process for preparing a first layer comprising sacubitril sodium for a bilayer tablet comprises the following steps; a) Mixing sacubitril sodium 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 second layer comprising valsartan disodium for a bilayer tablet comprises the following steps; a) Mixing valsartan disodium 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 second layer. Example 1 : Bilayer tablet
Figure imgf000009_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) Sieving valsartan disodium and talc through 0.85 mm and then mixing, l) Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone through separately 0.85 mm and then mixing, m) Sieving colloidal silicone dioxide and then adding and mixing, n) Sieving magnesium stearate and then adding and mixing, o) Compacting the mixture at step (n), p) Sieving crospovidone and adding into the mixture at step (o), q) Sieving colloidal silicone dioxide and then adding and mixing, r) Sieving talc and then adding and mixing, s) Adding magnesium stearate and mixing, t) Compressing the total mixture, and obtained second layer.
3. Pressing first layer and second layer as a bilayer, each layer of 200 mg.
4. Coating the bilayer tablets.
Example 2; Coating
Figure imgf000010_0001

Claims

1 ) A bilayer tablet comprises;
- First layer comprising sacubitril or a pharmaceutically acceptable salt thereof and at least one filler,
- Second layer comprising or a pharmaceutically acceptable salt thereof and at least one filler, Wherein the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.5 and 2.5.
2) The bilayer tablet according to claim 1 , wherein the weight ratio of filler(s) at first layer to filler(s) at second layer is between 0.9 and 2.2, preferably it is between 1 .0 and 1 .8.
3) The bilayer tablet according to claim 1 , wherein valsartan or a pharmaceutically acceptable salt thereof is present valsartan disodium, sacubitril or a pharmaceutically acceptable salt thereof is present sacubitril sodium.
4) The bilayer 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.
5) The bilayer tablet according to claim 4, wherein microcrystalline cellulose is used both layers.
6) The bilayer tablet according to claim 1 , wherein each layer further comprises the pharmaceutically acceptable excipients which are selected from the group comprising binders, disintegrants, lubricants, glidants or mixtures thereof.
7) The bilayer tablet according to claim 6, 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.
8) The bilayer tablet according to claim 7, wherein the binder is used both layers.
9) The bilayer tablet according to claim 7 or 8, wherein the binder is low-substituted hydroxypropyl cellulose.
10)The bilayer tablet according to claim 7, wherein 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 second layer. 11)The bilayer tablet according to claim 6, 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.
12)The bilayer tablet according to claim 11 , wherein the disintegrant is crospovidone.
13)The bilayer tablet according to claim 1 , wherein, the tablet comprises;
First layer o Sacubitril Sodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
14)The bilayer tablet according to claim 1 , wherein the tablet comprises;
Second layer o Valsartan Disodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide
15)The bilayer tablet according to claim 1 , wherein the 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 Valsartan Disodium o Microcrystalline Cellulose o Low Substitue Hydroxypropyl Cellulose o Crospovidone CL o Colloidal Silicone Dioxide o Talc o Magnesium Stearate
PCT/TR2024/051041 2023-09-20 2024-09-09 A bilayer tablet comprising sacubitril and valsartan Pending WO2025063927A1 (en)

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Citations (1)

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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

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* 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

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