Novel enhanced pharmaceutical compositions comprising sacubitril valsartan

Abstract

The present invention comprises sacubitril or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the internal phase.

Description

[0001] DESCRIPTION NOVEL ENHANCED PHARMACEUTICAL COMPOSITIONS COMPRISING SACUBITRIL VALSARTAN Technical Field 5 The present invention comprises sacubitril or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the internal phase. Prior Art 10 Heart failure is a significant public health concern worldwide, characterized by the heart's inability to pump blood effectively, leading to symptoms such as fatigue, shortness of breath, and fluid retention. Current therapeutic strategies primarily aim to improve the heart's pumping ability, reduce symptoms, and prevent hospitalization and mortality. Among these therapeutic options, the combination of sacubitril and valsartan has 15 emerged as a particularly effective treatment. Sacubitril 20 Sacubitril is a neprilysin inhibitor that works by increasing the levels of natriuretic peptides, which help to reduce blood volume, decrease vascular resistance, and promote vasodilation. On the other hand, valsartan is an angiotensin II receptor blocker (ARB) that helps to relax blood vessels and lower blood pressure by blocking the effects of angiotensin II, a potent vasoconstrictor.

[0002] Valsartan The combination of these two agents has shown superior efficacy compared to traditional 5 therapies in reducing cardiovascular mortality and heart failure-related hospitalizations. However, the development of a stable and effective pharmaceutical composition involving these two agents presents several challenges. One key challenge is the physical and chemical stability of the active ingredients. Sacubitril, in its crystalline form, provides enhanced stability and bioavailability. In 10 contrast, valsartan, when formulated in its amorphous form, offers improved solubility and dissolution rates, which are crucial for its therapeutic effectiveness. Given these challenges, the invention described herein aims to provide a novel pharmaceutical composition that combines sacubitril in its crystalline form and valsartan in its amorphous form, with a disintegrant incorporated solely in the inner layer. This 15 specific formulation approach addresses the stability, solubility, and disintegration requirements, ultimately enhancing the therapeutic efficacy of the combination treatment for heart failure. These solutions will be described in detail. Brief Description of the Invention 20 The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the composition has inner and outer layer. The present invention provides an oral pharmaceutical composition comprising sacubitril 25 or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the inner layer. The oral pharmaceutical composition in present invention comprises the disintegrant in an amount of between 5.00 – 15.00% (w / w). The oral pharmaceutical composition can be form of film coated tablet. 5 In other aspect of the present invention a process for preparing oral pharmaceutical compositions according to claim 1, comprising the steps of a. Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof in crystal form and lubricant, b. Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof in 10 amorphous form, one or more diluent, one or more binder, one or more glidant and one or more disintegrant, c. Sieving and mixing with additional lubricant, d. Adding additional lubricant and glidant as an external layer, e. Compressing into tablets, 15 f. Coating tablets with coating materials. Detailed Description of the Invention The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof and valsartan or pharmaceutically 20 acceptable salts thereof in the treatment of symptomatic chronic heart failure. The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof and valsartan or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients. 25 The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients. The present invention relates to preparation of pharmaceutical compositions comprising 30 sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof in amorphous form and one or more pharmaceutically acceptable carriers or excipients. The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant. The present invention relates to preparation of pharmaceutical compositions comprising 5 sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof in amorphous form and one or more pharmaceutically acceptable carriers or excipients, wherein the composition has inner and outer layer. The present invention relates to preparation of pharmaceutical compositions comprising 10 sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the composition has inner and outer layer. The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan 15 or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the inner layer. The present invention relates to preparation of pharmaceutical compositions comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form and valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, 20 wherein crospovidone as disintegrant is comprised only in the inner layer. In a preferred embodiment of the present invention, the amount of disintegrant can be between 5.00-15.00 % (w / w). The aspects and disclosures according to the present invention, in particular an oral pharmaceutical composition comprising sacubitril or pharmaceutically acceptable salts 25 thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form, a disintegrant and one or more pharmaceutically acceptable excipients, defined hereinbefore and hereinafter. The aspects and disclosures according to the present invention, in particular an oral pharmaceutical composition comprising sacubitril or pharmaceutically acceptable salts 30 thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the inner layer. Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. 5 Diluents are essential components in film coated tablet compositions, serving to increase the volume of the formulation, ensuring uniform distribution of the active pharmaceutical ingredient (API), and enhancing the stability and manufacturability of the product. They help achieve consistent dosing, improve the flow properties of powders, and ensure that tablets and capsules reach a practical size for handling and administration. Diluents also 10 contribute to the appearance and taste of the final product, thereby enhancing patient compliance and acceptability. In tablet formulations, they provide the necessary bulk for compression, while in capsules, they fill the dosage unit to the desired weight and volume. Commonly used diluents in oral compositions include lactose, microcrystalline cellulose, mannitol, dibasic calcium phosphate, and starch. In a preferred embodiment of the 15 present invention, the amount of diluent can be between 10.00-30.00% (w / w). In preferred embodiment in present invention diluent can be microcrystalline cellulose. Lubricants are crucial excipients in oral pharmaceutical compositions, primarily used to reduce friction during the tablet manufacturing process. They help prevent the tablet blend from sticking to the equipment, ensuring a smooth and efficient production process. 20 Lubricants improve the flow of the tablet mixture through the machinery, enhancing the uniformity and consistency of the final product. Additionally, they aid in the ejection of tablets from the die cavity, preventing damage and ensuring the integrity of the tablets. Commonly used lubricants in oral pharmaceutical compositions include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, colloidal silicon dioxide, and 25 polyethylene glycol (PEG). In preferred embodiment in the present invention amount of diluent can be between 0.5-5.5% (w / w). In preferred embodiment in present invention lubricant can be magnesium stearate and / or talc. In preferred embodiment present invention amount of lubricant can be between 0.5-5.5% (w / w). In preferred embodiment in present invention amount of talk 30 can be between 0.50 – 3.50 (w / w) and amount of magnesium stearate can be between 0.50 – 2.00 (w / w). Commonly used binders in pharmaceutical compositions include polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) and starch. Acacia and gelatin are natural binders that provide strong adhesion, while pregelatinized starch is favored for its immediate binding capabilities. Corn syrup solids are used for their sweetness and binding properties in chewable tablets, and ethyl cellulose is commonly used in controlled-release formulations. 5 In a preferred embodiment of the present invention, the amount of binder can be between 5.00-15.00% (w / w). In a preferred embodiment of the present invention, the binder can be low-substituted hydroxypropyl cellulose. In a preferred embodiment of the present invention, the amount of low-substituted hydroxypropyl cellulose can be between 5.00-15.00% (w / w). 10 Commonly used disintegrants in pharmaceutical compositions include croscarmellose sodium, sodium starch glycolate, and crospovidone. Natural disintegrants like alginic acid and guar gum are also utilized for their rapid swelling properties, while modified starches such as pregelatinized starch are preferred for their efficiency and consistency. In a preferred embodiment of the present invention, the amount of disintegrant can be 15 between 5.00-15.00% (w / w). In a preferred embodiment of the present invention, the disintegrant can be crospovidone. In the context of internal phase and external phase utilization, the internal phase disintegrants are highly praised for their ability to provide rapid and uniform disintegration of the tablet matrix upon contact with fluids, ensuring quicker onset of 20 action. Internal phase disintegrants are incorporated within the granules, leading to a more effective breakdown from within. The inventors surprisingly have found that the pharmaceutical composition comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein 25 the disintegrant is comprised only in the inner layer represent a significant advancement in drug delivery, providing a viable alternative formulations, enhances the bioavailability of present invention compositions and develops patient-friendly therapies. In the current situation, the disintegrant is used in the inner and outer phases, which has a negative effect on the process time and process steps. Using the disintegrant only in the 30 inner phase has facilitated the process time and process steps. The inventors surprisingly have found that the formulation development result obtained as a result of using different forms for active ingredients is very efficient. By using different forms, a stable product was obtained. Commonly used glidants in pharmaceutical compositions include colloidal silicon dioxide, talc, and magnesium stearate. Colloidal silicon dioxide is particularly effective due to its high surface area and excellent flow-enhancing properties, while talc is valued for its lubricating effect. Magnesium stearate, although primarily used as a lubricant, also 5 exhibits good glidant properties. In a preferred embodiment of the present invention, the glidant can be colloidal silicon dioxide. In a preferred embodiment of the present invention, the amount of glidant can be between 0.1-1.5% (w / w). 10 Preferably the pharmaceutical composition according to the present invention may be in the form of a tablet, capsule, caplet, film-coated tablet, enteric tablet, controlled-release tablet and any similar solid oral dosage forms. The preferred dosage form according to the present invention is film-coated tablet form. Commonly available coating materials may be used for coating of tablets. 15 In one embodiment of the present invention, the oral pharmaceutical composition of the present invention comprises below: ^ 20.00% - 30.00% by weight sacubitril or pharmaceutical acceptable salts thereof, ^ 20.00% - 30.00% by weight valsartan or pharmaceutical acceptable salts thereof ^ 10.00% - 30.00% by weight diluent, 20 ^ 5.00 - 15.00% by weight binder, ^ 5.00% - 15.00% by weight disintegrant, ^ 0.25%-1.50% by weight glidant, ^ 0.50%-3.50% by weight lubricant, and ^ 0.50%-2.00% by weight lubricant. 25 In other aspect of the present invention a process for preparing oral pharmaceutical compositions according to claim 1, comprising the steps of a. Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof in crystal form and lubricant, 30 b. Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof in amorphous form, one or more diluent, one or more binder, one or more glidant and one or more disintegrant, c. Sieving and mixing with additional lubricant, d. Adding additional lubricant and glidant as an external layer, e. Compressing into tablets, f. Coating tablets with coating materials. 5 In one embodiment of the present invention, the oral pharmaceutical composition of the present invention comprises below: ^ 20.00% - 30.00% by weight sacubitril or pharmaceutical acceptable salts thereof, ^ 20.00% - 30.00% by weight valsartan or pharmaceutical acceptable salts thereof ^ 10.00% - 30.00% by weight at least one diluent, 10 ^ 5.00% - 15.00% by weight at least one binder, ^ 5.00% - 15.00% by weight crospovidone, ^ 0.25%-1.50% by weight glidant, ^ 0.50%-3.50% by weight first lubricant, and ^ 0.50%-2.00% by weight second lubricant. 15 In other aspect of the present invention a process for preparing oral pharmaceutical compositions according to claim 1, comprising the steps of a. Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof in crystal form and lubricant, 20 b. Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof in amorphous form, at least one diluent, at least one binder, at least one glidant and crospovidone, c. Sieving and mixing with additional lubricant, d. Adding additional lubricant and glidant as an external layer, 25 e. Compressing into tablets, f. Coating tablets with coating materials. In other aspect of a pharmaceutical composition of the present invention for use to reduce the risk of cardiovascular death and hospitalization for heart failure patients with chronic 30 heart failure. In one embodiment of the present invention, the oral pharmaceutical composition of the present invention comprises below: ^ Inner layer: 20.00% - 30.00% by weight sacubitril or pharmaceutical acceptable salts thereof, 20.00% - 30.00% by weight valsartan or pharmaceutical acceptable 5 salts thereof, 10.00% - 30.00% by weight at least one diluent, 5.00% - 15.00% by weight at least one binder, 0.25%-1.50% by weight glidant, 0.50%-3.50% by weight first lubricant, 5.00% - 15.00% by weight crospovidone as a disintegrant, ^ Outer Layer: 0.50%-1.50% by weight second glidant, 0.50%-2.00% by weight second lubricant. 10 In other aspect of the present invention a process for preparing oral pharmaceutical compositions according to claim 1, comprising the steps of a. Inner Layer: Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof in crystal form and lubricant, 15 Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof in amorphous form, at least one diluent, at least one binder, at least one glidant and crospovidone as a disintegrant, 20 b. Inner Layer: Sieving and mixing with additional lubricant, Adding additional lubricant and glidant as an external layer, Compressing into tablets c. Coating tablets with coating materials. 25 Experiments Stability Results The stability of the product was monitored under the following three conditions. During the stability period, the product was found to meet the specifications. 30 25°C ± 2°C / %60 RH ± %5 RH 30°C ± 2°C / %65 RH ± %5 RH 40°C ± 2°C / %75 RH ± %5 RH Result of the stability study indicates that present combination of sacubitril and valsartan composition in accordance with the present invention exhibits excellent storage stability. 5 During the stability period, the product was found to comply with specifications. Examples Example 1 In another preferred embodiment, the pharmaceutical composition according to 10 invention: Table 1: Pharmaceutical composition comprising sacubitril and valsartan and relevant excipients Ingredients Amount (w / w %) Inner Layer Sacubitril or pharmaceutical acceptable salts thereof 20.00-30.00 Valsartan or pharmaceutical acceptable salts thereof 20.00-30.00 At least one diluent 10.00-30.00 At least one binder 5.00-15.00 At least one glidant 0.25-1.00 At least one lubricant 0.50-3.50 At least one disintegrant 5.00-15.00 Outer Layer At least one glidant 0.50-1.50 At least one lubricant 0.50-2.00 Total 100.00 A process of preparing tablet composition of Example 1: a. Inner Layer: i. Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof in crystal form and lubricant, ii. Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof 5 in amorphous form, at least one diluent, at least one binder, at least one glidant and at least one disintegrant, iii. Powder compaction, b. Outer Layer: i. Sieving and mixing with lubricant, 10 ii. Adding lubricant and glidant as an external layer, iii. Compressing into tablets, iv. Coating tablets with coating materials. Example 2: 15 In another preferred embodiment, the pharmaceutical composition according to invention: Table 2: Pharmaceutical composition comprising sacubitril and valsartan and relevant excipients Ingredients Amount (w / w %) Inner Layer Sacubitril or pharmaceutical acceptable salts thereof 20.00-30.00 Valsartan or pharmaceutical acceptable salts thereof 20.00-30.00 At least one diluent 10.00-30.00 At least one binder 5.00-15.00 At least one glidant 0.25-1.00 At least one lubricant 0.50-3.50 Crospovidone 5.00-15.00 Outer Layer At least one glidant 0.50-1.50 At least one lubricant 0.50-2.00 Total 100.00 A process of preparing tablet composition of Example 2: a. Inner Layer: i. Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof 5 in crystal form and lubricant, ii. Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof in amorphous form, at least one diluent, at least one binder, at least one glidant and crospovidone, iii. Powder compaction, 10 b. Outer Layer: i. Sieving and mixing with lubricant, ii. Adding lubricant and glidant as an external layer, iii. Compressing into tablets, iv. Coating tablets with coating materials. 15

Claims

CLAIMS 1. An oral pharmaceutical composition having inner and outer layer characterized in comprising sacubitril or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a 5 disintegrant only in inner layer.

2. The oral pharmaceutical composition according to claim 1, wherein amount of disintegrant is between 5.00-15.00% (w / w).

3. The oral pharmaceutical composition according to preceding claims, wherein said composition is form of film coated tablet.

4. A process for preparing tablet compositions according to claim 1, comprising the steps of a. Sieving and mixing Sacubitril or pharmaceutically acceptable salts thereof in crystal form and lubricant, b. Sieving and mixing Valsartan or pharmaceutically acceptable salts thereof in amorphous form, one or more diluent, one or more binder, one or more glidant and one or more disintegrant, c. Sieving and mixing with additional lubricant, d. Adding additional lubricant and glidant as an external layer, e. Compressing into tablet, f. Coating tablets with coating materials.

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