Novel compositions for vonoprazan

Abstract

The present invention relates to pharmaceutical composition comprises vonoprazan or pharmaceutically acceptable salts thereof.

Description

[0001] DESCRIPTION

[0002] NOVEL COMPOSITIONS FOR VONOPRAZAN

[0003] Field of Invention

[0004] The present invention relates to pharmaceutical composition comprises vonoprazan or pharmaceutically acceptable salts thereof.

[0005] Background of the Invention

[0006] Helicobacter pylori eradication is a treatment strategy aimed at eliminating this bacterium, which is a significant public health concern worldwide. H. pylori infection is associated with serious gastrointestinal diseases such as gastritis, peptic ulcers, and gastric cancer. The primary goal of eradication therapy is to alleviate symptoms and prevent related complications. Current treatment protocols typically involve the use of two or three antibiotics in combination with proton pump inhibitors (PPls). The success of eradication depends heavily on selecting the right drug regimen and ensuring patient adherence to the treatment.

[0007] Vonoprazan fumarate is a novel potassium-competitive acid blocker (P-CAB) that suppresses gastric acid secretion by inhibiting the H+, K-i-ATPase enzyme in gastric parietal cells. Unlike traditional proton pump inhibitors (PPIs), vonoprazan offers a faster onset of action and more stable acid suppression, making it particularly effective in treating acid-related conditions. It is used for managing gastroesophageal reflux disease (GERD), peptic ulcers, and in combination regimens for Helicobacter pylori eradication. Its improved pharmacokinetics and durability provide better control over gastric acidity, especially in patients requiring long-term or high-dose acid suppression therapy. The molecule of Vonoprazan fumarate is shown below.

[0008]

[0009] Vonoprazan FumarateUS9186411B2 discloses a pharmaceutical composition or a solid preparation containing a stabilized pharmaceutically active ingredient and a stabilizing method thereof. According to the present invention, a pharmaceutical composition can be stabilized by containing a nonpeptidic pharmaceutically active ingredient having a primary or secondary amino group, an excipient and an acidic compound.

[0010] CN118344276A discloses a preparation method of a fumaric acid Vonoprazan intermediate, the chemical name of the fumaric acid Vonoprazan intermediate is 5-(2-fluorophenyl)-lH-pyrrole-3-formaldehyde, a high-yield, greener and safer posttreatment method is provided, the preparation method is used for preparing the fumaric acid Vonoprazan intermediate, and the method is suitable for industrial production. According to the method, tetrahydrofuran and water are used as crystallization solvents in post-treatment, so that the method is simple, high in yield, environment-friendly, safe and suitable for industrial production; the invention newly finds the impurities in the preparation process of the fumaric acid Vonoprazan intermediate, and by adopting the method disclosed by the invention, three impurities which are difficult to remove can be completely removed, so that the product quality is improved.

[0011] One key challenge is the physical and chemical stability of the active ingredient. To ensure the stability of the active ingredient Vonoprazan fumarate in pharmaceutical compositions, which is sensitive to hydrolysis and photolysis.

[0012] Given these challenges, the invention described herein aims to provide a novel pharmaceutical composition that comprise vonoprazan fumarate This specific formulation approach addresses the stability requirements ultimately enhancing the therapeutic efficacy. These solutions will be described in detail.

[0013] Summary of the Invention

[0014] A pharmaceutical composition comprising vonoprazan or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, characterized in that a d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is more than 80 pm. Preferably, the d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is between 80 pm and 150 pm.The oral pharmaceutical composition in present invention comprises the vonoprazan or pharmaceutically acceptable salts thereof is between 3.00 - 25.00% (w / w).

[0015] The oral pharmaceutical composition can be form of film coated tablet.

[0016] In other aspect of the present invention a process for preparing oral pharmaceutical compositions, comprising the steps of

[0017] a. Sieving and mixing Vonoprazan or pharmaceutically acceptable salts thereof and one or more diluent,

[0018] b. Obtaining granulation solution with purified water and one or more binder, c. Spraying granulation solution onto step a,

[0019] d. Obtaining granules,

[0020] e. Mixing one or more disintegrant and an antioxidant acid with step d, f. Adding and mixing one or more lubricant with step e,

[0021] g. Compressing tablets,

[0022] h. Coating with a stabilizer and coating material.

[0023] Detailed Description of the Invention

[0024] The aspects and disclosures according to the present invention, in particular an oral pharmaceutical composition comprising vonoprazan or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is more than 80 pm. Preferably, the d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is between 80 pm and 150 pm.

[0025] In preferred embodiment, vonoprazan or pharmaceutically acceptable salts thereof can be vonoprazan fumarate.

[0026] In preferred embodiment amount of vonoprazan fumarate can be between 3.0 - 25.0 % (w / w). Preferably, amount of vonoprazan fumarate can be between 6.0 - 20.0 % (w / w).

[0027] Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. Forthis reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0028] Diluents are essential components in pharmaceutical 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 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.

[0029] Commonly used diluents in pharmaceutical compositions include lactose, microcrystalline cellulose, mannitol, dibasic calcium phosphate, and starch. In a preferred embodiment of the present invention, the amount of diluent can be between 30. DO-95.00% (w / w). In preferred embodiment in present invention diluent can be mannitol and / or microcrystalline cellulose.

[0030] Lubricants are crucial excipients in 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. 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.

[0031] Commonly used lubricants in pharmaceutical compositions include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, colloidal silicon dioxide, and polyethylene glycol (PEG). In preferred embodiment in the present invention amount of lubricant can be between 0.1-3.5% (w / w).

[0032] In preferred embodiment in present invention lubricant can be magnesium stearate. In the preferred embodiment present invention amount of lubricant can be between 0.1-3.5% (w / w). Preferably, the 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.

[0033] In a preferred embodiment of the present invention, the amount of binder can be between 0.10-10.00% (w / w).

[0034] In a preferred embodiment of the present invention, the binder can be hydroxypropyl cellulose. In a preferred embodiment of the present invention, the amount of hydroxypropyl cellulose can be between 0.10-10.00% (w / w). In preferred embodiment present invention amount of hydroxypropyl cellulose can be between 0.5-5.00% (w / w).

[0035] 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.

[0036] In a preferred embodiment of the present invention, the amount of disintegrant can be between 1.00-10.00 % (w / w). In a preferred embodiment of the present invention, the amount of disintegrant can be between 2.00-6.00 % (w / w). In a preferred embodiment of the present invention, the disintegrant can be croscarmellose sodium.

[0037] In preferred embodiment, pharmaceutical composition in present invention can be comprising antioxidant as an excipient. Ascorbic acid can be selected as an antioxidant. In preferred embodiment amount of ascorbic acid can be between 0.05 - 2.0 % (w / w). Preferably can be 0.1 - 1.0% (w / w).

[0038] In preferred embodiment, pharmaceutical composition in present invention can be comprising stabilizer as an excipient. Fumaric acid can be selected as the stabilizer. In preferred embodiment amount of fumaric acid can be between 0.05 - 1.0 % (w / w). Preferably can be 0.1 - 0.5% (w / w).In preferred embodiment pharmaceutical composition in present invention further comprise coating. Preferably, the amount of coating can be between 3.0 - 5.0 % (w / w).

[0039] Vonoprazan fumarate is highly hygroscopic, meaning it absorbs moisture from the environment, which can reduce its stability. The molecule can degrade upon exposure to light, requiring protective packaging and / or coating.

[0040] The value d90 refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d90 value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, the D90 describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size.

[0041] The particle size of an active pharmaceutical ingredient (API) plays a critical role in enhancing the stability of the composition by influencing both the dissolution rate and the surface area exposed to potential degradative factors. When the particle size is optimized, the risk of API degradation due to environmental factors, such as moisture or oxygen, can be significantly minimized. Smaller particle sizes tend to increase the surface area; however, when kept within a specific range, the risk of instability caused by excessive surface exposure is mitigated. This controlled particle size distribution not only ensures the preservation of the active ingredient but also contributes to a more consistent and controlled release profile, which is essential for maintaining therapeutic efficacy over the product's shelflife.

[0042] Furthermore, the stabilization of the pharmaceutical composition through particle size optimization is essential in formulations where other excipients or additives are involved. By achieving a uniform particle size, it is possible to enhance the homogeneity of the mixture, thereby preventing segregation of components and maintaining a stable composition. This uniformity is particularly beneficial for multi-component formulations where active and inactive ingredients must remain evenly distributed to ensure consistent dosing. Consequently, the selection of a precise particle size range improves not only the physical stability but also the chemical stability of the final product, making it more resistant to unwanted reactions or degradation over time.Based on the fact that Vonoprazan fumarate active substance is Class III, i.e. high solubility, low permeability, the preferred particle size state D(90):80 microns and above was preferred. Preservation of stability is supported by the high particle size.

[0043] As the surface area increases, the contact of the active substance with the stimuli coming from the microenvironment will decrease and thus the stability is supported.

[0044] The high proportion of fillers in the pharmaceutical composition and the active substance Vonoprazan fumarate are close in particle size, which is favourable for homogeneous mixing. The risk of segregation is therefore reduced.

[0045] Another challenge in drug development of vonoprazan is achieving the desired bioavailability. Ensuring the desired in vitro and in vivo performance is crucial. This can be achieved by the methods described in our invention.

[0046] The inventors have found that the pharmaceutical composition comprising vonoprazan or pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts wherein the compositions wherein a d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is more than 80 pm, represent a significant advancement in chemical stability with providing a viable alternative formulation.

[0047] The inventors surprisingly have found that the pharmaceutical composition comprising vonoprazan or pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts wherein the compositions wherein a d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is between 80 pm and 150 pm, represent a significant advancement in chemical stability, physical stability with providing a viable alternative formulation.

[0048] 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 tablets.

[0049] The pharmaceutical composition of the present invention comprises below:

[0050] • 3.00% - 25.00% by weight vonoprazan or pharmaceutical acceptable salts thereof,• 30.00% - 90.00% by weight mannitol

[0051] • 1.00% -25.00% by weight microcrystalline cellulose,

[0052] • 0.10-10.00% by weight hydroxypropyl cellulose,

[0053] • 1.00-10.00 % by weight croscarmellose sodium,

[0054] • 0.05 - 2.0 % by weight antioxidant,

[0055] • 0.10%-3.50% by weight magnesium stearate, and

[0056] • 0.05%-1.00% by weight stabilizer.

[0057] The film coated tablet composition of the present invention comprises below:

[0058] • 3.00% - 25.00% by weight vonoprazan or pharmaceutical acceptable salts thereof, • 30.00% - 90.00% by weight mannitol

[0059] • 1.00% -25.00% by weight microcrystalline cellulose,

[0060] • 0.10-10.00% by weight hydroxypropyl cellulose,

[0061] • 1.00-10.00 % by weight croscarmellose sodium,

[0062] • 0.05 - 2.0 % by weight antioxidant,

[0063] • 0.10%-3.50% by weight magnesium stearate,

[0064] • 0.05%-1.00% by weight stabilizer, and

[0065] • 3.0 - 5.0 % (w / wj by weight coating agents.

[0066] In other aspect of the present invention a process for preparing oral pharmaceutical compositions comprising the steps of

[0067] a. Sieving and mixing Vonoprazan or pharmaceutically acceptable salts thereof and one or more diluent,

[0068] b. Obtaining granulation solution with purified water and one or more binder, c. Spraying granulation solution onto step a,

[0069] d. Obtaining granules,

[0070] e. Mixing one or more disintegrant and an antioxidant with step d,

[0071] f. Adding and mixing one or more lubricant with step e,

[0072] g. Compressing tablets,

[0073] h. Coating with a stabilizer and coating material.In preferred aspect of the present invention a process for preparing oral pharmaceutical compositions comprising the steps of

[0074] a. Sieving and mixing Vonoprazan or pharmaceutically acceptable salts thereof, mannitol and microcrystalline cellulose,

[0075] b. Obtaining granulation solution with purified water and one or more hydroxypropyl cellulose,

[0076] c. Spraying granulation solution onto step a,

[0077] d. Obtaining granules,

[0078] e. Mixing croscarmellose sodium and an antioxidant with step d,

[0079] f. Adding and mixing magnesium stearate with step e,

[0080] g. Compressing tablets,

[0081] h. Coating with a stabilizer and coating material.

[0082] In other aspect of a pharmaceutical composition of the present invention for use Helicobacter pylori eradication.

[0083] EXAMPLES

[0084] Example 1

[0085]

[0086] Vonoprazan Fumarate, mannitol and microcrystalline cellulose were sieved and mixed. Granulation solution was prepared with purified water and hydroxypropyl cellulose. Spray granulation was performed. The granules were obtained. Croscarmellose sodiumand ascorbic acid mixed with obtained granules. Magnesium stearate was added to mix. Compressing tablet was performed. Tablets were coated with fumaric acid and coating agents.

[0087] In-vitro studies

[0088] Study results of the tablet compositions comprising vonoprazan or pharmaceutically acceptable salts thereof wherein a d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof was 10 pm and 50 pm, shared below.

[0089]

[0090] In studies with Vonoprazan fumarate (d (90) = 10-50 pm), it is not an acceptable result that the mean remained at 92 at 60 minutes. As can be understood, the particle sizes that gave these results could not provide the dissolution profile that would provide the desired stability values. The use of Vonoprazan at these particle sizes is not suitable for the desired stability.

[0091] Study results of the tablet compositions comprising vonoprazan or pharmaceutically acceptable salts thereof wherein a d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof was 80 pm and 150 pm, shared below.

[0092]

[0093]

[0094] In studies with Vonoprazan fumarate (d (90) = 80-150 pm), it is an acceptable result that the mean remained at 98 at 60 minutes. As can be understood, the particle sizes that gave these results could provide the dissolution profile that would provide the desired stability values. The use of Vonoprazan at these particle sizes is suitable for the desired stability.

Claims

CLAIMS1. A pharmaceutical composition comprising vonoprazan or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, characterized in that a d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is more than 80 pm.

2. The pharmaceutical composition according to claim 1, wherein the d (90) particle size of vonoprazan or pharmaceutically acceptable salts thereof is between 80 pm and 150 pm.

3. The pharmaceutical composition according to claim 1 or 2, wherein amount of vonoprazan or pharmaceutically acceptable salts thereof is between 3.00-25.00% (w / w).

4. The pharmaceutical composition according to preceding claims, wherein said composition is in the form of film coated tablet.

5. A process for preparing tablet compositions according to claim 4, comprising the steps of;a. Sieving and mixing Vonoprazan or pharmaceutically acceptable salts thereof and one or more diluent,b. Obtaining granulation solution with purified water and one or more binder, c. Spraying granulation solution onto step a,d. Obtaining granules,e. Mixing one or more disintegrant and an antioxidant with step d,f. Adding and mixing one or more lubricant with step e,g. Compressing tablets,h. Coating with a stabilizer and coating material.

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