Stabilization of non-peptidic pharmaceutically active agent or salt thereof

Abstract

The present invention relates to stabilization of non-peptidic pharmaceutically active agent or salt thereof. The pharmaceutical compositions comprise non-peptidic pharmaceutically active agent preferably vonoprazan or salt thereof along with glycerophosphoric acid (GPA) for the treatment of healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults.

Description

[0001] STABILIZATION OF NON-PEPTIDIC PHARMACEUTICALLY ACTIVE AGENT OR SALT THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to stabilization of a non-peptidic pharmaceutically active agent or salt thereof. The present invention relates to the stabilization of vonoprazan or a salt thereof, in the treatment of esophagitis and its associated symptoms. The present invention relates to a process of manufacturing pharmaceutical compositions comprising vonoprazan or a salt thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] The "nonpeptidic pharmaceutically active ingredient" is widely used as a pharmaceutically active ingredient for various diseases. Vonoprazan fumarate is a nonpeptidic pharmaceutically active ingredient and is a potassium-competitive acid blocker. Chemically, it is lH-pyrrole-3methanamine, 5-(2-fhrorophenyl)-N-methyl-l-(3- pyridinylsulfonyl)-, (2E)-2 -butenedioate (1 :1) with a molecular weight of 461.5 and a molecular formula of Ci7Hi6FN3O2S»C4H4O4.

[0006] The vonoprazan fumarate is represented by compound of structural formula I.

[0007] Formula I.

[0008] Vonoprazan fumarate is a white to nearly white crystals or crystalline powder. Vonoprazan fumarate is soluble in dimethyl sulfoxide, sparingly soluble in N,N- dimethylacetamide, slightly soluble in N,N-dimethylformamide, methanol and water; very slightly soluble in ethanol and practically insoluble in 2-propanol, acetone, 1 -octanol, and acetonitrile.

[0009] Vonoprazan fumarate tablets was approved in the USA on November 01, 2023 under the tradename Voquezna and is available in the strength of lOmg & 20mg. The product is used in the treatment of healing of all grades of erosive esophagitis and relief of heartbum associated with erosive esophagitis in adults, and to maintain healing of all grades of erosive esophagitis and relief of heartbum associated with erosive esophagitis in adults.

[0010] The commercially available Vonoprazan fumarate tablet under the trade name Voquezna contain Vonoprazan fumarate as the active ingredient and inactive ingredients such as ascorbic acid, croscarmellose sodium, fumaric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol 8000, titanium dioxide and ferric oxide red / yellow.

[0011] EP1803709B1 discloses compound Vonoprazan or a salt thereof.

[0012] EP1919865B1 discloses Vonoprazan or a salt thereof and its use in the treatment or prophylaxis of peptic ulcer, reflux esophagitis, symptomatic GERD, gastric cancer, stomach MALT lymphoma or for use in the eradication of Helicobacter pylori.

[0013] EP2309985B1 discloses a composition of nonpeptidic active agent along with acid. Further, said patent EP2309985B1 discloses a composition of vonoprazan or a salt thereof along with acidic compounds like fumaric acid, ascorbic acid, tartaric acid, sorbic acid, lactic acid, maleic acid, and malonic acid However, said patent does not disclose a composition of nonpeptidic active agent along with glycerophosphoric acid (GPA).

[0014] EP3329921B1 discloses a composition comprising combination of vonoprazan or a salt thereof and acetylsalicylic acid. Further, the said patent discloses a composition comprising combination of vonoprazan or a salt thereof and acetylsalicylic acid along with fumaric acid. However, said patent does not disclose a composition of nonpeptidic active agent along with glycerophosphoric acid (GPA).

[0015] EP3651735B1 discloses the composition of vonoprazan or a salt thereof along with fumaric acid, wherein said composition comprises, vonoprazan in the core followed by coating of fumaric acid and followed by a coating of a water-insoluble polymer.

[0016] The commercially available product and product known in the prior art for Vonoprazan or a salt thereof contain acid and which are selected from fumaric acid, ascorbic acid, tartaric acid, sorbic acid, lactic acid, maleic acid and malonic acid. The product known in the prior art suffers from drawbacks like release of drug from the dosage form and GIT adverse reaction like diarrhea, abdominal distension, abdominal pain, and nausea. Also, the acid used in the prior art formulation does not impart stabilization of the active agent i.e. vonoprazan fumarate sufficiently; this therefore, results in the degradation of the active agent and therefore a decrease in the bioavailability of the drug in the treatment of esophagitis and its associated symptoms. Accordingly, there is an unmet need in the art to overcome the drawbacks in the prior art; therefore, the applicant of the present invention invented a composition of a nonpeptidic pharmaceutically active agent i.e. Vonoprazan or a salt along with glycerophosphoric acid (GPA); wherein glycerophosphoric acid (GPA) stabilizes the composition.

[0017] The novel pharmaceutical compositions comprising vonoprazan and glycerophosphoric acid (GPA) is Organophosphoric acid according to the present invention provides optimum release of the drug from the dosage form and less fewer GIT adverse effects like gastritis, diarrhea, abdominal distension, abdominal pain, dyspepsia, and nausea. Also, the composition comprising vonoprazan fumarate and glycerophosphoric acid (GPA) imparts more stability, resulting in more bioavailability and patient compliance in the treatment of esophagitis and its associated symptoms.

[0018] OBJECTS OF THE INVENTION

[0019] Main object of the present invention is to provide a composition of a nonpeptidic pharmaceutically active agent i.e. Vonoprazan or a pharmaceutically acceptable salt thereof, along with glycerophosphoric acid (GPA).

[0020] Another object of the present invention is to provide a stabilized pharmaceutical composition wherein glycerophosphoric acid (GPA) an organophosphoric acid, functions as a acidifier / stabilizing agent.

[0021] Yet another object of the present invention is to provide a process for the manufacture of a pharmaceutical composition comprising a non-peptidic pharmaceutically active agent, such as vonoprazan or a pharmaceutically acceptable salt thereof, along with pharmaceutically acceptable excipients is selected from the group consisting of diluent, disintegrant, binder, acidifier / stabilizing agent, polymer, lubricant, coating agent, coloring agent, solvent or combinations thereof.

[0022] SUMMARY OF THE INVENTION

[0023] A First aspect of the present invention is to provide novel pharmaceutical composition comprising nonpeptidic active agent and glycerophosphoric acid (GPA).

[0024] The nonpeptidic active agent according to the present invention selected from Vonoprazan or a salt thereof, lH-pyrrole-3_,methanamine,5-(2-fluorophenyl)-N-methyl-l-(3 pyridinylsulfonyl), (2E)-2-butenedioate.

[0025] The Glycerophosphoric acid (GPA) is an organophosphoric acid and is colorless liquid. It has a molecular formula of C3H9O6P and a molecular weight of 172.07. Glycerophosphoric acid is a polyhydroxy acid with a phosphate group, behaving more like a biological buffer and metabolic intermediate. Glycerophosphoric acid is structurally derived from glycerol, a three-carbon triol, in which one of the hydroxyl groups is esterified with phosphoric acid. Its key functional group is the phosphate group (-PO4H2), which contributes to its chemical reactivity and acidic properties.

[0026] In another aspect, the present invention is to provide novel pharmaceutical composition comprising a nonpeptidic active agent or a salt thereof, and glycerophosphoric acid (GPA) along with one or more pharmaceutically acceptable excipient, wherein the nonpeptidic active agent is vonoprazan fumarate.

[0027] The one or more pharmaceutically acceptable excipient according to the present invention is selected from the group consisting of diluent, disintegrant, binder, acidifier / stabilizing agent, polymer, lubricant, coating agent, coloring agent, solvent or combinations thereof.

[0028] In another aspect, the present invention is to provides a novel pharmaceutical composition comprising nonpeptidic active agent wherein the composition comprises the nonpeptidic active agent and stabilizing agent of glycerophosphoric acid (GPA) an organophosphoric acid.

[0029] In another aspect, the present invention is to provide a novel pharmaceutical composition comprising a nonpeptidic active agent wherein the composition comprises the nonpeptidic active agent and acidifier / stabilizing agent of glycerophosphoric acid (GPA), wherein the nonpeptidic active agent is vonoprazan fumarate.

[0030] In another aspect, the present invention is to provide a novel pharmaceutical composition comprises a nonpeptidic active agent i.e. vonoprazan fumarate a acidifier / stabilizing agent of glycerophosphoric acid (GPA) and binder is hypromellose.

[0031] In another aspect, the present invention is to provide a novel pharmaceutical composition of vonoprazan or a salt thereof, wherein the core of the composition comprises glycerophosphoric acid (GPA) and the composition comprises vonoprazan fumarate.

[0032] In another aspect, the present invention is to provide a novel pharmaceutical composition of vonoprazan or a salt thereof, wherein the core of the composition comprises glycerophosphoric acid (GPA) and the composition comprises vonoprazan fumarate.

[0033] In another aspect, the present invention is to provide novel pharmaceutical composition of vonoprazan or a salt thereof in the form of granules, pellets, tablet, capsule.

[0034] In another aspect, the present invention is to provide a process for the manufacturing of a pharmaceutical composition of a nonpeptidic active agent wherein the nonpeptidic active agent were granulated with glycerophosphoric acid (GPA) along with one or more pharmaceutically acceptable excipients.

[0035] In another aspect, the present invention is to provide a process for the manufacturing of a pharmaceutical composition of vonoprazan or a salt thereof wherein the nonpeptidic active agent were granulated with glycerophosphoric acid (GPA) along with one or more pharmaceutically acceptable excipients.

[0036] In another aspect, of present invention is to provide process for the manufacturing of a pharmaceutical composition of vonoprazon or a salt thereof wherein the process steps comprise; i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, hypromellose and croscarmellose sodium; ii) adding the binder binder solution, such as glycerophosphoric acid into dry mix to prepare the wet granules; iii) extruding the wet granules and then spheronization to achieve the desire pellet size; iv) drying the spheronization pellets and sieving the pellets to get desired pellet size; v) coating the pellets with coating solution; vi) blending the pellets with talc; vii) filling the pellets in suitable capsule shell; and viii) packing the capsules in blister or bottle pack.

[0037] In another aspect of the embodiment, present invention is to provide a process for the manufacturing of a novel pharmaceutical composition of vonoprazan or a salt thereof, comprising the steps of: i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol and croscarmellose sodium; ii) adding the binder solution, such as hypromellose, to the dry mix to prepare the wet granules; iii) drying the wet granules and sieving the granules; iv) adding the lubricant and mixing the blend; v) compressing the granules to form tablets; and vi) coating the tablets.

[0038] In another aspect of the embodiment, present invention is to provide a process for the manufacturing of a novel pharmaceutical composition of vonoprazan or a salt thereof, comprising the steps of: i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, croscarmellose sodium and hypromellose; ii) adding the binder solution, such as glycerophosphoric acid, to the dry mix to prepare the wet granules; iii) drying the wet granules and sieving the granules; iv) adding the lubricant and mixing the blend; v) compressing the granules to form tablets; and vi) coating the tablets.

[0039] In another aspect of the present invention is to provide a novel pharmaceutical composition comprising vonoprazan or a salt thereof along with glycerophosphoric acid (GPA) in the treatment of esophagitis and its associated symptoms.

[0040] In another aspect of the embodiment, pharmaceutical composition of the present invention is provided in the form of tablets or granules. The tablets may be packaged in suitable airtight containers and moisture-proof packaging. The packaging may include, but is not limited to, high-density polyethylene (HDPE) bottles, aluminum blister packs, or aluminum-PVC blister packs. The container or packaging material is selected to ensure the stability and protection of the pharmaceutical composition from environmental factors such as moisture and air.

[0041] DETAILD DESCRIPTION OF THE INVENTION

[0042] The present invention relates to pharmaceutical composition comprising: a) a nonpeptidic active agent or a pharmaceutically acceptable salt thereof, and glycerophosphoric acid (GPA); and b) one or more pharmaceutically acceptable excipients.

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0044] The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or openended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

[0045] The term "a" and "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. The information provided in this document, and particularly the specific details of the described exemplary aspects, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood from there. The term "pharmaceutically acceptable excipients", denotes any of the components of a pharmaceutical formulation other than the active and which are approved by regulatory authorities or are generally ‘regarded as safe’ for human or animal use. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

[0046] The main embodiment of the present invention relates to a pharmaceutical composition in the form of tablets, comprising a non-peptidic pharmaceutically active agent and a acidifier / stabilizing agent.

[0047] In an aspect of the embodiment, the present invention relates to a pharmaceutical composition in the form of tablets, comprising a non-peptidic pharmaceutically active agent or salt thereof, a acidifier / stabilizing agent, and one or more pharmaceutically acceptable excipients.

[0048] The nonpeptidic active agent according to the present invention selected from Vonoprazon or salt thereof, lH-pyrrole-3_,methanamine,5-(2-fluorophenyl)-N-methyl-l-(3 pyridinylsulfonyl), (2E)-2-butenedioate.

[0049] In another aspect of the embodiment, the present invention provides a pharmaceutical composition wherein glycerophosphoric acid (GPA) is an organophosphoric acid and is colorless liquid. It has a molecular formula of C3H9O6P and a molecular weight of 172.07. Glycerophosphoric acid is a polyhydroxy acid with a phosphate group, behaving more like a biological buffer and metabolic intermediate. Glycerophosphoric acid is structurally derived from glycerol, a three-carbon triol, in which one of the hydroxyl groups is esterified with phosphoric acid. Its key functional group is the phosphate group (-PO4H2), which contributes to its chemical reactivity and acidic properties.

[0050] In another aspect of the embodiment, the present invention provides a pharmaceutical composition wherein vonoprazan may be present in the form of a pharmaceutically acceptable salt, suitable salts of vonoprazan include, but are not limited to, vonoprazan fumarate, vonoprazan L-malate, vonoprazan dihydrogen phosphate, vonoprazan hydrochloride, vonoprazan succinate, vonoprazan semi-L-tartrate, vonoprazan sulfate, vonoprazan hydrogen sulfate, and vonoprazan methane sulfonate. Preferably, vonoprazan is present in the form of its fumarate salt.

[0051] The composition comprising a non-peptidic active agent, such as vonoprazan or a pharmaceutically acceptable salt thereof, and glycerophosphoric acid (GPA) as a acidifier / stabilizing agent, according to the present invention, is intended for use in the treatment of esophagitis and its associated symptoms.

[0052] Esophagitis is the medical term for inflammation of the esophagus, the tube that connects the throat to the stomach. This inflammation can be caused by various factors and may lead to symptoms like pain, difficulty swallowing, and heartburn.

[0053] Granules are small, irregularly shaped particles formed by agglomerating powders, often used to improve flow and compressibility. Pellets are spherical or semi-spherical solid particles, typically uniform in size, used for controlled drug release and better packing in capsules. Tablets are solid dosage forms made by compressing powders or granules into a specific shape, widely used for oral drug delivery. Capsules are solid dosage forms in which the drug is enclosed in a hard or soft shell, usually made of gelatin, allowing easy swallowing and masking of taste or odor.

[0054] In another aspect of the embodiment, present invention provides a novel pharmaceutical composition comprising a non-peptidic pharmaceutically active agent and glycerophosphoric acid (GPA), wherein the active agent is vonoprazan or a pharmaceutically acceptable salt thereof. The composition is formulated in the form of granules, pellets, tablets and capsule, which are manufactured using wet granulation technology.

[0055] According to the present invention, the pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof and glycerophosphoric acid (GPA) as a acidifier / stabilizing agent is prepared in granules, pellets, tablets and capsule form by a wet granulation process. This manufacturing method ensures uniform distribution of the active ingredient and acidifier / stabilizing agent, thereby enhancing the stability and performance of the final dosage form.

[0056] The wet granulation technology for granules and pellets formation, according to the present invention, refers to a process wherein vonoprazan or a pharmaceutically acceptable salt thereof is mixed with one or more pharmaceutically acceptable excipients and subjected to wet granulation. The resulting granulated mixture is then compressed to form vonoprazan tablets, as well spheronized and form pellets and filled in capsules.

[0057] In another aspect, the present invention provides a novel pharmaceutical composition comprising a nonpeptidic active agent or a salt thereof, and glycerophosphoric acid (GPA), along with one or more pharmaceutically acceptable excipients.

[0058] The one or more pharmaceutically acceptable excipient according to present invention are selected from the group consisting of diluent, disintegrant, binder, acidifier / stabilizing agent, lubricant, coating agent, coloring agent, solvent or combinations thereof.

[0059] The formulation includes diluent. Diluents, also known as fillers, are inactive substances added to pharmaceutical formulations to increase the bulk and facilitate the manufacturing of solid dosage forms like tablets and capsules. Common examples of diluents include lactose, microcrystalline cellulose (MCC), mannitol, starch, calcium phosphates, sorbitol, and povidone (polyvinylpyrrolidone), etc.

[0060] In another aspect of the embodiment, the pharmaceutical composition comprises microcrystalline cellulose and mannitol as diluents.

[0061] Microcrystalline cellulose (MCC) and mannitol are widely used pharmaceutically acceptable diluents in solid dosage formulations due to their favorable physicochemical and mechanical properties. MCC is a purified, partially depolymerized cellulose that exhibits excellent compressibility and binding characteristics.

[0062] Mannitol provides good flow properties and helps in achieving consistent tablet weight and content uniformity. The combination of MCC and mannitol in a formulation offers synergistic benefits by balancing mechanical strength, compressibility, and palatability, thereby improving the overall manufacturability.

[0063] The formulation includes disintegrant. Super disintegrants are substances added to pharmaceutical formulations to promote rapid disintegration and dissolution of the dosage form in the gastrointestinal tract. Common examples of super disintegrant are croscarmellose sodium, crospovidone, sodium starch glycolate, sodium alginate, etc.

[0064] In another aspect of the embodiment, the pharmaceutical composition comprises croscarmellose sodium as disintegrant, in a concentration of 3% to 8% w / w.

[0065] Croscarmellose sodium is used as a disintegrant to help the tablet break apart quickly after ingestion, allowing the drug to dissolve and absorb faster. It works by swelling and drawing in water, which helps the tablet disintegrate efficiently. It is effective at low concentrations and is commonly used in both direct compression and wet granulation methods.

[0066] The formulation includes a binder, which helps hold the ingredients of the ganules together and gives it strength. Binders ensure that the tablet stays intact during manufacturing, packaging, and handling. Common examples of binders include povidone (PVP), starch paste, hypromellose, hydroxypropyl methylcellulose (HPMC), Polyethylene glycol and hydroxypropyl cellulose. In another aspect of the embodiment, the pharmaceutical composition comprises hypromellose and povidone as binder, in a concentration of 2% to 6% w / w.

[0067] Hypromellose, also known as hydroxypropyl methylcellulose (HPMC), is used as a binder in tablet formulations. It helps hold the tablet ingredients together, providing strength and stability. Hypromellose is especially useful because it is non-toxic, stable, and works well in both wet and dry granulation processes.

[0068] The formulation includes an acidifier / stabilizing agent to maintain the stability of the active ingredient and extend shelf life. An example of a stabilizer is citric acid, fumaric acid, glycerophosphoric acid (GPA), ascorbic acid, lactic acid, maleic acid, and tartaric acid which helps prevent degradation by controlling pH.

[0069] In another aspect of the embodiment, the pharmaceutical composition comprises glycerophosphoric acid (GPA) an organophosphoric acid as acidifier / stabilizing agent, in a concentration of 1% to 6% w / w.

[0070] Glycerophosphoric acid (GPA) an organophosphoric acid as an acidifier and / or stabilizing agent. In solid dosage forms, GPA plays a crucial role in maintaining the chemical stability of the active pharmaceutical ingredient by preventing degradation under varying storage conditions. Its inclusion helps ensure consistent drug potency, improves shelf life, and enhances overall formulation robustness. GPA not only helps maintain the stability of the active ingredient but also supports bioavailability by promoting better absorption of the drug in the body.

[0071] The formulation includes lubricants. Lubricants are added to formulations to reduce friction during tablet or capsule manufacturing. They help prevent sticking and ensure smooth processing during tablet compression or capsule filling. An example of lubricant includes magnesium stearate, talc, Calcium Stearate, Stearic Acid, Sodium Stearyl Fumarate.

[0072] In another aspect of the embodiment, the pharmaceutical composition comprises lubricant is magnesium stearate and talc.

[0073] Magnesium stearate is widely used as a lubricant in pharmaceutical formulations. It is a magnesium salt of stearic acid, which is a saturated fatty acid. Magnesium stearate acts as a lubricant during tablet compression or capsule filling processes. It coats the surfaces of the powder particles and the equipment, reducing friction and facilitating smooth movement of the powders. The formulation may include a coating agent, such as hypromellose (HPMC), to protect the tablet and improve appearance or taste. A coloring agent like red and yellow iron oxide can be added for identification and visual appeal. Anti-tacking agent is titanium oxide.

[0074] Solvents are substances used to dissolve or mix other ingredients without changing them. They help improve solubility, taste, stability, and consistency of the final product. Solvents can be organic or inorganic and are selected from isopropyl alcohol, dichloromethane, acetone, purified water, or their combinations.

[0075] In another embodiment, the present invention provides a process for the manufacture of a novel pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof. The process comprises the following steps: i) Preparation of a core containing vonoprazan or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients; and ii) Granulation of the core using hypromellose solution.

[0076] In another embodiment, the present invention provides a process for the manufacture of a novel pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof, wherein the process steps comprise: i) Preparation of core of vonoprazan or a salt thereof along with one or more pharmaceutically acceptable excipient; and ii) Granulation the core with glycerophosphoric acid (GPA) solution.

[0077] In another embodiment, the present invention is to provide process for the manufacturing of a novel pharmaceutical composition of vonoprazon or a pharmaceutically acceptable salt thereof. The process comprises the following steps: i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, hypromellose and croscarmellose sodium; ii) adding the binder solution such as glycerophosphoric acid into dry mix to prepare the wet granules; iii) extruding the wet granules and then spheronization to achieve the desire pellet size; iv) drying the spheronization pellets and sieving the pellets to get desired pellet size; v) coating the pellets with coating solution; vi) blending the pellets with talc; vii) filling the pellets in suitable capsule shell; and viii) packing the capsules in blister or bottle pack.

[0078] In another embodiment, the present invention is to provide process of manufacturing novel pharmaceutical composition of vonoprazan or a salt thereof, comprising the steps of: i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol and croscarmellose sodium; ii) adding the binder solution, such as hypromellose, to the dry mix to prepare the wet granules; iii) drying the wet granules and sieving the granules; iv) adding the lubricant and mixing the blend; v) compressing the granules to form tablets; and vi) coating the tablets.

[0079] In another embodiment, the present invention is to provide process of manufacturing novel pharmaceutical composition of vonoprazan or a salt thereof, comprising the steps of: i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, croscarmellose sodium and hypromellose; ii) adding the binder solution, such as glycerophosphoric acid, to the dry mix to prepare the wet granules; iii) drying the wet granules and sieving the granules; iv) adding the lubricant and mixing the blend; v) compressing the granules to form tablets; and vi) coating the tablets.

[0080] In another embodiment, the present invention provides a pharmaceutical tablet formulation comprising:

[0081] • 12.97 % w / w of vonoprazan fumarate;

[0082] • 42.78 % w / w microcrystalline cellulose as a diluent;

[0083] • 28.72 % w / w mannitol as a diluent;

[0084] • 7.28 % w / w croscarmellose sodium as a disintegrant;

[0085] • 2.91 % w / w hypromellose (HPMC) as a binder;

[0086] • 1.46 % w / w glycerophosphoric acid as a stabilizing agent; and

[0087] • 0.97 % w / w magnesium stearate as a lubricant; wherein the % w / w is with respect to total weight of the tablet.

[0088] In another embodiment, the present invention provides a pharmaceutical pellets formulation comprising:

[0089] 12.97 % w / w of vonoprazan fumarate;

[0090] 58.70 % w / w microcrystalline cellulose as a diluent;

[0091] 12.75 % w / w mannitol as a diluent; • 4.76 % w / w croscarmellose sodium as a disintegrant;

[0092] • 4.76 % w / w hypromellose (HPMC) as a binder;

[0093] • 1.42 % w / w glycerophosphoric acid as a stabilizing agent; and

[0094] • 0.97 % w / w talc as a lubricant; wherein the % w / w is with respect to total weight of the tablet.

[0095] In another embodiment, the present invention provides a stable pharmaceutical composition comprising a non-peptidic pharmaceutically active agent, such as vonoprazan or a pharmaceutically acceptable salt thereof. The composition includes a acidifier / stabilizing agent of glycerophosphoric acid and one or more pharmaceutically acceptable excipients. The pharmaceutical composition of vonoprazan or a salt was subjected to stability studies under ICH-recomm ended conditions of 40°C / 75% RH, 30°C / 75% RH, and 25°C / 60% RH. After stability study, in-vitro drug release profile, assay, related substances and other parameters found to be in the compliance; therefore, composition according to the invention is found to be stable.

[0096] In another aspect of the embodiment, the present invention is to provides a novel pharmaceutical composition comprising vonoprazan or a salt thereof along with glycerophosphoric acid (GPA) for the treatment of esophagitis and its associated symptoms.

[0097] In another embodiment, the pharmaceutical composition of the present invention is provided in the form of granules, pellets, tablets or capsules. The tablets or capules may be packaged in suitable airtight containers and moisture-proof packaging. The packaging may include, but is not limited to, high-density polyethylene (HDPE) bottles, aluminum blister packs, or aluminum-PVC blister packs. The container or packaging material is selected to ensure the stability and protection of the pharmaceutical composition from environmental factors such as moisture and air.

[0098] EXAMPLES:

[0099] Some illustrative non-limiting examples of the present invention are described below.

[0100] Table 1: formulation pellets

[0101] Note: 26.72 Vonoprazan Fumarate is equivalent to 20mg Vonoprazan base.

[0102] Manufacturing Procedure: a) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, hypromellose and croscarmellose sodium; b) adding the binder solution such as glycerophosphoric acid into dry mix to prepare the wet granules; c) extruding the wet granules and then spheronization to achieve the desire pellet size; d) drying the spheronization pellets and sieving the pellets to get desired pellet size; e) coating the pellets with coating solution; f) blending the pellets with talc; g) filling the pellets in suitable capsule shell; and h) packing the capsules in blister or bottle pack.

[0103] Table 2: formulation tablet Note: 26.72 Vonoprazan Fumarate is equivalent to 20mg Vonoprazan base.

[0104] Manufacturing Procedure: a) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol and croscarmellose sodium; b) adding the binder solution, such as hypromellose, to the dry mix to prepare the wet granules; c) drying the wet granules and sieving the granules; d) adding the lubricant and mixing the blend; e) compressing the granules to form tablets; and f) coating the tablets.

[0105] Table 3: formulation tablet

[0106] Note: 26.72 Vonoprazan Fumarate is equivalent to 20mg Vonoprazan base.

[0107] Manufacturing Procedure: a) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, croscarmellose sodium and hypromellose; b) adding the binder solution, such as glycerophosphoric acid, to the dry mix to prepare the wet granules; c) drying the wet granules and sieving the granules; d) adding the lubricant and mixing the blend; e) compressing the granules to form tablets; and f) coating the tablets. DISSOLUTION DATA:

[0108] The in-vitro release profile of the examples 1-4 has been performed in the dissolution medium of pH 4.5 acetate buffer, USP Apparatus: Type 2 (Paddle) with 900 mL of dissolution medium at a rotation speed of 50 rpm. Table 4: Dissolution study data

[0109] Table 5: Multimedia dissolution study data

[0110] Table 6: Stability study data

[0111] ND: Not detected

Claims

We Claim:1) A pharmaceutical composition comprising: a) a nonpeptidic active agent or a pharmaceutically acceptable salt thereof, and glycerophosphoric acid (GPA); and b) one or more pharmaceutically acceptable excipients.2) The pharmaceutical composition as claimed in claim 1, wherein the nonpeptidic active agent is a potassium-competitive acid blocker (PCAB) or a pharmaceutically acceptable salt thereof, and is select vonoprazan fumarate.3) The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of granules, pellets, a tablet, or a capsule.4) The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a diluent, a disintegrant, a binder, a acidifier / stabilizing agent, a lubricant, a coating agent, a coloring agent, a solvent, or combinations thereof.5) The pharmaceutical composition as claimed in claim 3, wherein the disintegrant is croscarmellose sodium in a concentration of 3% to 8% w / w.6) The pharmaceutical composition as claimed in claim 3, wherein the binder is hypromellose (HPMC) in a concentration of 2% to 6% w / w.7) The pharmaceutical composition as claimed in claim 3, wherein the acidifier / stabilizing agent is glycerophosphoric acid in a concentration of 1% to 6% w / w.8) The pharmaceutical composition as claimed in claim 3, wherein;• the diluent is microcrystalline cellulose and mannitol;• the lubricant is magnesium stearate and talc;• the coating agent is hypromellose;• the coloring agent is red iron oxide and yellow iron oxide;• the solvent is purified water; and combinations thereof.9) A process for manufacturing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof, the process comprising the steps of: i) dry mixing the vonoprazan fumarate, microcrystalline cellulose, mannitol, hypromellose and croscarmellose sodium; ii) adding the binder solution such as glycerophosphoric acid into dry mix to prepare the wet granules;iii) extruding the wet granules and then spheronization to achieve the desire pellet size; iv) drying the spheronization pellets and sieving the pellets to get desired pellet size; v) coating the pellets with coating solution; vi) blending the pellets with talc; vii) filling the pellets in suitable capsule shell; and viii) packing the capsules in blister or bottle pack.10) A process for manufacturing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof, the process comprising the steps of i) dry mixing vonoprazan fumarate, microcrystalline cellulose, mannitol, croscarmellose sodium, and hypromellose; ii) adding a binder solution comprising glycerophosphoric acid to the dry mix to prepare wet granules; iii) drying the wet granules and sieving the dried granules; iv) adding a lubricant and mixing to form a blend; v) compressing the blend to form tablets; and vi) coating the tablets.

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