Pharmaceutical composition comprising zasalprazan or pharmaceutically acceptable salt thereof for use in prevention or treatment of drug-related peptic ulcers

Abstract

The invention discloses a medicine composition for preventing or treating medicine related peptic ulcer. The medicine composition comprises zasaprazan (zasaprazan) or pharmaceutically acceptable salt of zasaprazan (zasaprazan).

Description

Technical Field

[0001] The present invention relates to the use of zastaprazan for the prevention, treatment of drug-related peptic ulcer, or prevention of recurrence of drug-related peptic ulcer. Specifically, the present invention relates to a pharmaceutical composition that can prevent, treat the peptic ulcer and prevent the recurrence of the peptic ulcer by inhibiting or delaying the onset of peptic ulcer induced by administration of non-steroidal anti-inflammatory drugs (NSAIDs) and inhibiting its recurrence. Background Art

[0002] With the continuous increase in the use of non-steroidal anti-inflammatory drugs (NSAIDs) as the main therapeutic drugs for chronic diseases, drug-induced gastrointestinal side effects such as peptic ulcer and bleeding are often observed in the first-line clinical setting. This is because, although NSAIDs have a pain-relieving effect, their long-term use makes the gastric mucosal folds more vulnerable to ulcers and damage. In past large-scale randomized controlled studies, the incidence of symptomatic peptic ulcer in the NSAID use group was reported to be 2.7% to 4.5%, and the incidence of serious complications such as bleeding or perforation was reported to be 1.0% to 1.5%.

[0003] If peptic ulcer is not treated, serious complications such as gastric or duodenal bleeding, perforation of the gastric or duodenal wall, penetration of the ulcer through the stomach or duodenum into other organs, and obstruction of the movement of food from the stomach to the duodenum may occur or recur frequently.

[0004] Ultimately, it is important to prevent and treat the onset of peptic ulcer caused by NSAIDs. In addition, after the peptic ulcer is cured, a means to safely and effectively prevent the recurrence of peptic ulcer without side effects when taking NSAIDs is urgently needed.

[0005] [Prior Art Documents]

[0006] [Patent Documents]

[0007] (Patent Document 1) Korean Patent Publication No. 10-1777971 Summary of the Invention

[0008] Technical Problem

[0009] The present inventors have recognized the need for the development of a pharmaceutical composition that can safely and effectively prevent the development of peptic ulcers, treat peptic ulcers, and further prevent their recurrence without side effects even after long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs). Accordingly, the object of the present invention is to provide a pharmaceutical composition for preventing, treating peptic ulcers induced by long-term administration of NSAIDs, and preventing the recurrence of such peptic ulcers in a safe, long-term, and effective manner without side effects, said pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0010] Technical Solution

[0011] To achieve the above object, the present invention discloses the following means.

[0012] In one aspect, the present invention discloses a pharmaceutical composition for preventing, treating peptic ulcers or preventing the recurrence of peptic ulcers, said pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein the peptic ulcers are caused by the administration of non-steroidal anti-inflammatory drugs (NSAIDs).

[0013] Beneficial Effects

[0014] The present invention relates to a pharmaceutical composition for preventing, treating peptic ulcers or preventing the recurrence of peptic ulcers, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Despite the long-term continuous and repeated administration of non-steroidal anti-inflammatory drugs (NSAIDs), the pharmaceutical composition according to the present invention can prevent the onset of peptic ulcers, treat peptic ulcers, and prevent their recurrence.

[0015] A pharmaceutical composition for preventing, treating peptic ulcers or preventing the recurrence of peptic ulcers, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, may exhibit sufficient efficacy because even when the zastaprazan of the present invention is co-administered with an NSAID, it does not affect the pharmacokinetic (PK) characteristics of each drug. Description of the Drawings

[0016] Figure 1 Shows the measurement results of ulcer area when zastaprazan and esomeprazole are co-administered in a preclinical animal model of naproxen-induced peptic ulcers.

[0017] Figure 2 and Figure 3Shows whether the co - administration of zaspirone and aceclofenac affects the pharmacokinetic (PK) profiles of the two individual drugs, and illustrates the mean plasma concentration - time curves of zaspirone citrate ( Figure 2 ) and aceclofenac ( Figure 3 ). (In Figure 2 and Figure 3 , the error bars represent standard deviation.)

[0018] Figure 4 and 5 Shows whether the co - administration of zaspirone and meloxicam affects the PK profiles of the two individual drugs, and illustrates the mean plasma concentration - time curves of zaspirone citrate ( Figure 4 ) and meloxicam ( Figure 5 ). (In Figure 4 and 5 , the error bars represent standard deviation.)

[0019] Figure 6 and 7 Shows whether the co - administration of zaspirone and naproxen affects the PK profiles of the two individual drugs, and illustrates the mean plasma concentration - time curves of zaspirone citrate ( Figure 6 ) and naproxen ( Figure 7 ). (In Figure 6 and 7 , the error bars represent standard deviation.) Figure 8 Schematically summarizes the clinical trial method in Example 3. Detailed Description

[0020] Best Mode

[0021] Hereinafter, the present invention will be described in more detail.

[0022] This is specifically explained as follows. When considering the functions in the present invention, the terms used herein are selected from the generally most widely used general terms, but they can vary according to the intentions of those skilled in the art, precedents, the emergence of new technologies, etc. In addition, in some cases, there are terms arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the corresponding parts of the detailed description of the present invention. Therefore, the terms used herein should be defined based on the meaning of the terms and the overall content of the present invention, rather than simply based on the names of the terms.

[0023] Unless otherwise defined, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries shall be interpreted as having a meaning consistent with their meaning in the context of the relevant art and shall not be interpreted in an idealized or overly formal sense unless expressly defined in this invention.

[0024] Numeric ranges include the values defined therein. Every maximum numeric limitation given throughout this specification includes every lower numeric limitation, as if such lower numeric limitations were expressly written herein. Every minimum numeric limitation given throughout this specification includes every higher numeric limitation, as if such higher numeric limitations were expressly written herein. Every numeric limitation given throughout this specification will include every better numeric range within the broader numeric range, as if the narrower numeric limitations were expressly written herein.

[0025] Hereinafter, the various descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments respectively. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0026] As used herein, unless otherwise specifically stated in the phrase or statement containing the expression, expressions such as "comprising" shall be understood as open - ended terms, meaning the possibility of including other embodiments.

[0027] The term "zaspirone" as used herein may refer to zaspirone, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof. Accordingly, a "composition comprising zaspirone" as used herein may refer to a composition comprising zaspirone, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof.

[0028] The present invention will be described in detail hereinafter.

[0029] Drug composition containing zaspirone

[0030] The present invention discloses a pharmaceutical composition comprising zaspirone.

[0031] Specifically, the present invention provides a pharmaceutical composition for preventing, treating peptic ulcer or preventing recurrence of peptic ulcer, the pharmaceutical composition comprising zaspirone, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof, wherein the peptic ulcer is caused by administration of non - steroidal anti - inflammatory drugs (NSAIDs).

[0032] For subjects who take NSAIDs continuously for a long term, the pharmaceutical composition of the present invention can prevent or treat peptic ulcers caused by the administration of NSAIDs and prevent their recurrence in a safe, long-term and effective manner without side effects.

[0033] As the number of elderly patients with chronic diseases such as musculoskeletal diseases or cardiovascular diseases increases, the number of people taking NSAIDs for a long time is also increasing. However, NSAIDs damage the gastric wall by inhibiting gastric mucosa production and stimulating gastric acid secretion, and since NSAIDs are in tablet form, most NSAIDs dissolve in the stomach and start to be absorbed, and long-term use can cause physical irritation to the gastric mucosa, leading to peptic ulcers. Even if peptic ulcers are cured, peptic ulcers may recur due to the use of NSAIDs.

[0034] The present inventors have developed a pharmaceutical composition comprising zaspirone, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof. The pharmaceutical composition can prevent peptic ulcers caused by the use of NSAIDs and at the same time prevent the recurrence of the peptic ulcers.

[0035] In the present invention, zaspirone is an example of an imidazo[1,2-a]pyridine derivative, and its chemical name is azetidin-1-yl-[8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone.

[0036] In the present invention, zaspirone is the active ingredient for preventing, treating peptic ulcers or preventing the recurrence of peptic ulcers.

[0037] In the present invention, the term "active ingredient" as used herein refers to one or a group of substances that are expected to directly or indirectly exhibit the efficacy and effects of the pharmaceutical composition through their inherent pharmacological actions, and includes the main ingredient or the active ingredient.

[0038] Zasaprazan of the present invention may exist in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed from a pharmaceutically acceptable free acid is useful. In the present invention, as used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic acid addition salt of zasaprazan that has a relatively non-toxic and harmless effect on a patient at the concentration and the side effects caused by the salt do not reduce the beneficial efficacy of zasaprazan. Organic acids and inorganic acids can be used as the free acid. Inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or tartaric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid or hydroiodic acid can be used.

[0039] The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups, and unless otherwise specified, the acidic or basic groups may be present in zasaprazan. For example, pharmaceutically acceptable salts may include sodium salts, calcium salts and potassium salts of hydroxyl groups. Other pharmaceutically acceptable salts of amino groups include hydrobromide salts, sulfate salts, bisulfate salts, phosphate salts, hydrogen phosphate salts, dihydrogen phosphate salts, acetate salts, succinate salts, citrate salts, tartrate salts, lactate salts, mandelate salts, mesylate salts (methanesulfonate salts) and tosylate salts (tosylate salts), etc., and can be prepared by methods known in the art for preparing salts.

[0040] Specifically, the pharmaceutically acceptable salt of zasaprazan may be zasaprazan citrate (azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate), but is not limited thereto.

[0041] In the present invention, the term "hydrate" as used herein refers to a hydrate formed by binding the active ingredient zasaprazan or its pharmaceutically acceptable salt to water through non-covalent intermolecular forces and containing a stoichiometric or non-stoichiometric amount of water. Specifically, based on 1 mol of the active ingredient, the hydrate may contain water in a proportion of about 0.25 mol to about 10 mol, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, etc.

[0042] In the present invention, the term "solvate" as used herein refers to a compound formed by the binding of the active ingredient zaspirone or a pharmaceutically acceptable salt thereof to a solvent through non-covalent intermolecular forces, and which contains a stoichiometric or non-stoichiometric amount of the solvent. Preferred solvents are volatile and non-toxic and can be administered to humans in very small amounts. Examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-acetate, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, and heptane, but the solvates of the present invention are not limited to these examples, and specifically, based on 1 mol of the active ingredient, the solvate may contain a proportion of the solvent in the range of about 0.25 mol to about 10 mol, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, etc.

[0043] In the present invention, the term "peptic ulcer" as used herein refers to a defect in the gastric mucosa caused by the attack of gastric acid and pepsin, and histologically, a necrotic mucosal defect occurring beneath the mucosal layer is referred to as a peptic ulcer. A peptic ulcer refers to an ulcer caused by an imbalance between the defensive factors that protect the mucosa and the attacking factors that cause mucosal damage. A peptic ulcer is a general term (superordinate term) for gastric ulcer and duodenal ulcer and is used synonymously with gastroduodenal ulcer.

[0044] In the present invention, the term "subject" as used herein refers to a mammal, and specifically, mammals including humans include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice, and more specifically, may mean a human. The subject may be a human who has developed a peptic ulcer or is at risk of developing a peptic ulcer due to continuous and / or long-term use of NSAIDs, or a human who had developed a peptic ulcer before administration of the pharmaceutical composition according to the present invention and whose peptic ulcer has since been cured.

[0045] In the present invention, the term "cured subject" as used herein refers to a mammal and means a subject who, after having developed a peptic ulcer in the past, has been confirmed by endoscopy to have no ulcers, bleeding, perforation of the gastric or duodenal wall, etc. before administration of the pharmaceutical composition according to the present invention.

[0046] In the present invention, the subject is a person who has experienced peptic ulcer at least once due to continuous and / or long-term use of NSAIDs before administration of the pharmaceutical composition of the present invention but has been cured, and the onset or complete cure of peptic ulcer in the subject can be determined by endoscopy. At this time, when bleeding or blood clot or mucosal fold concentration in the upper digestive tract (upper gastrointestinal tract) (such as the stomach or duodenum) is confirmed by endoscopy, it can be considered that peptic ulcer has occurred. Specifically, when the endoscopic examination results of the upper digestive tract in the stomach or duodenum are diagnosed as active ulcer (A1, A2) or healing ulcer (H1, H2) according to Sakita-Miwa classification, it can be considered that peptic ulcer has occurred.

[0047] In the present invention, the symptoms of peptic ulcer may include heartburn, chest tightness, pyrosis, acid regurgitation, chest pain, etc.

[0048] In the present invention, the expression "prevent recurrence of peptic ulcer" as used herein means preventing recurrence of peptic ulcer by fundamentally blocking or inhibiting the onset of peptic ulcer after at least experiencing peptic ulcer once and then being cured, and "prevent peptic ulcer" means delaying the onset of peptic ulcer. When the onset of peptic ulcer is delayed for an expected period of time, the prevention can be considered complete.

[0049] In the present invention, the NSAID may be an acetic acid-derived non-selective NSAID, an enolic acid-derived non-selective NSAID, a fenamic acid-derived non-selective NSAID, a p-aminophenol-derived non-selective NSAID, a propionic acid-derived non-selective NSAID, a salicylic acid-derived non-selective NSAID, a selective COX-2 inhibitor, or a mixture thereof.

[0050] In the present invention, the acetic acid-derived non-selective NSAID may be aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, metiazinic acid, mobenoxate, nabumetone, naproxen, oxametacin, sulindac, zomepirac, or any combination thereof.

[0051] In the present invention, the enolic acid-derived NSAID may be droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tenoxicam, or any combination thereof.

[0052] In the present invention, the fenamic acid-derived NSAID may be flufenamic acid, mefenamic acid, meclofenamic acid, tolfenamic acid, or any combination thereof.

[0053] In the present invention, the NSAID derived from p-aminophenol may be paracetamol, phenacetin, or any combination thereof.

[0054] In the present invention, the NSAID derived from propionic acid may be alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen in a pharmaceutically acceptable form, loxoprofen, oxaprozin, pranoprofen, suprofen, or any combination thereof.

[0055] In the present invention, the NSAID derived from salicylic acid may be acetylsalicylic acid, diflunisal, salsalate, or any combination thereof.

[0056] In the present invention, the selective COX-2 inhibitor may be celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, or any combination thereof.

[0057] In the present invention, the NSAID may specifically comprise one or more selected from the group consisting of naproxen, aceclofenac, meloxicam, and celecoxib, but is not limited thereto.

[0058] In the present invention, the pharmaceutical composition may be administered once a day. Specifically, the zaspirone, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof may be administered once a day for 2 weeks or longer, or 4 weeks or longer, and may be administered for 24 weeks or shorter, or 12 weeks or shorter. Specifically, the pharmaceutical composition may be administered once a day for 2 to 24 weeks, 4 to 24 weeks, 4 to 12 weeks, or 2 to 12 weeks.

[0059] In the present invention, the pharmaceutical composition may contain zaspirone in an amount of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg, calculated as zaspirone in free base form, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof. Specifically, it may contain zaspirone in an amount of about 3.3 mg, 6.6 mg, 13.1 mg, 26.2 mg or 52.4 mg, calculated as zaspirone in free base form, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof, and may contain zaspirone citrate in an amount of 5 mg to 40 mg, specifically 5 mg, 10 mg, 15 mg, 20 mg or 40 mg of zaspirone citrate, and more specifically 10 mg, 20 mg or 40 mg of zaspirone citrate. Accordingly, the pharmaceutical composition of the present invention contains a low dose of zaspirone as described above and, when administered once daily, has the advantage of effectively and safely preventing the recurrence of peptic ulcers or the onset of peptic ulcers caused by repeated long-term administration of NSAIDs.

[0060] In the present invention, the subject may be a person suffering from a potential disease such as a musculoskeletal and / or cardiovascular disease.

[0061] In the present invention, the pharmaceutical composition may contain one or more pharmaceutical additives, which are composed of excipients, disintegrants, binders and lubricants, but are not limited thereto.

[0062] In the present invention, the excipient may be one or more of microcrystalline cellulose, lactose hydrate, anhydrous lactose, sucrose, D-mannitol, starch, corn starch or light anhydrous silicic acid, but is not limited thereto.

[0063] In the present invention, the disintegrant may include starch or modified starch, such as sodium carboxymethyl starch, corn starch, potato starch or pregelatinized starch; clays, such as bentonite, montmorillonite or magnesium aluminum silicate (veegum); celluloses, such as hydroxypropyl cellulose or carboxymethyl cellulose; algins, such as sodium alginate or alginic acid; cross-linked celluloses, such as sodium cross-linked carboxymethyl cellulose; gums, such as guar gum or xanthan gum; cross-linked polymers, such as cross-linked polyvinylpyrrolidone; effervescent agents, such as sodium bicarbonate or citric acid, etc. These may be used alone or in combination of two or more, but are not limited thereto.

[0064] In the present invention, the binder may be one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silica, mannitol, lactose, polyethylene glycol, and mixtures thereof, but is not limited thereto.

[0065] In the present invention, the lubricant may be calcium stearate, glycerol monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearoyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, etc. These may be used alone or in combination of two or more, but are not limited thereto.

[0066] In the present invention, the pharmaceutical composition may be a solid oral preparation, but is not limited thereto.

[0067] In the present invention, the solid oral preparation may be any one of tablets, film-coated tablets, capsules, powders, granules, pills, lozenges, oral gels, and oral dissolving films, but is not limited thereto.

[0068] In particular, in the case of film-coated tablets, coating agents widely known in the art may be used, but are not limited thereto.

[0069] Use for preventing recurrence or onset of peptic ulcer

[0070] The present invention provides the use of a pharmaceutical composition comprising zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof for preventing peptic ulcers induced by administration of NSAIDs.

[0071] The present invention provides the use of a pharmaceutical composition comprising zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof for preventing recurrence of peptic ulcers induced by administration of NSAIDs.

[0072] Regarding the use of the present invention, the pharmaceutical composition may contain zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in an amount of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg based on zaspirone (in free base form). Specifically, it may contain zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in an amount of about 3.3 mg, 6.6 mg, 13.1 mg, 26.2 mg or 52.4 mg based on zaspirone (in free base form), and may contain zaspirone citrate in an amount of 5 mg to 40 mg, specifically 5 mg, 10 mg, 15 mg, 20 mg or 40 mg of zaspirone citrate, and more specifically 10 mg, 20 mg or 40 mg of zaspirone citrate.

[0073] Accordingly, the pharmaceutical composition of the present invention contains a low dose of zaspirone as described above, and when administered once a day, has the advantages of effectively and safely preventing the recurrence of peptic ulcers or the onset of peptic ulcers caused by repeated long-term administration of NSAIDs.

[0074] In the use for preventing the recurrence or onset of peptic ulcers, the pharmaceutical composition, subject, NSAID, peptic ulcer, etc. of the present invention can be applied in the same manner as described above, as long as they are not contradictory to each other.

[0075] Use for preparing a drug for preventing recurrence or onset of peptic ulcer

[0076] The present invention provides the use of a pharmaceutical composition for preparing a drug for preventing peptic ulcers induced by the administration of NSAIDs, wherein the pharmaceutical composition contains zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0077] The present invention provides the use of a pharmaceutical composition for preparing a drug for preventing the recurrence of peptic ulcers induced by the administration of NSAIDs, wherein the pharmaceutical composition contains zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0078] The composition of the present invention for preparing a drug can be mixed with an acceptable carrier, etc., and can further contain other reagents.

[0079] In the use of the present invention for preparing a drug for preventing the recurrence or onset of peptic ulcers, the pharmaceutical composition, subject, peptic ulcer, etc. can be applied in the same manner as described above, as long as they are not contradictory to each other.

[0080] Method for preventing recurrence or onset of peptic ulcer

[0081] The present invention provides a method for preventing the recurrence or onset of peptic ulcers induced by the administration of NSAIDs, which is implemented by administering to a subject a pharmaceutically effective amount of a pharmaceutical composition containing zaspirone, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0082] In the method, the pharmaceutical composition, subject, peptic ulcer, etc. of the present invention are substantially the same as those described above, as long as they are not contradictory to each other.

[0083] In the present invention, the term "pharmaceutically effective amount" as used herein refers to an amount effective for preventing the recurrence or onset of peptic ulcer, e.g., the amount of a pharmaceutical composition administered to a subject, which may include all amounts of a composition that prevent the onset or recurrence of peptic ulcer, relieve symptoms, inhibit direct or indirect pathological consequences, prevent metastasis, reduce the rate of progression, alleviate or temporarily relieve the disease condition, or improve the prognosis. In other words, the pharmaceutically effective amount can be interpreted to include all doses that can prevent the recurrence and / or onset of peptic ulcer by the composition.

[0084] Specifically, in the method for preventing the recurrence and / or onset of peptic ulcer according to the present invention, zafaptrazen, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof, can be administered to a subject once a day in an amount of 5 mg to 100 mg in terms of zafaptrazen (in free base form) to prevent the recurrence of peptic ulcer induced by the administration of NSAID and to prevent its onset. Specifically, zafaptrazen, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof, is administered to the subject in an amount of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg in terms of zafaptrazen (in free base form), specifically about 3.3, 6.6, 13.1, 26.2, or 52.4 mg in terms of zafaptrazen (in free base form), 5 to 40 mg in terms of zafaptrazen citrate, preferably 5 mg, 10 mg, 15 mg, 20 mg or 40 mg in terms of zafaptrazen citrate, more preferably 10 mg, 20 mg or 40 mg in terms of zafaptrazen citrate, once a day, so as to effectively and safely prevent the recurrence or onset of peptic ulcer caused by long-term continuous repeated administration of NSAID for a long time.

[0085] In the method for preventing the recurrence or onset of peptic ulcer of the present invention, by administering the pharmaceutical composition to a subject, even if NSAID is continuously / long-term administered, the recurrence and / or onset of peptic ulcer caused by the administration of NSAID can be effectively and safely prevented for a long time without side effects.

[0086] Hereinafter, the present invention will be described in more detail by preparation examples and examples. These preparation examples and examples are only intended to more specifically explain the present invention, and the scope of the present invention is not limited by these examples.

[0087] The active ingredient used in the following preparation examples and examples is zafaptrazen citrate, which is conveniently named zafaptrazen or code name JP-1366.

[0088] Preparation Examples

[0089] Preparation Example 1. Preparation of zaspirone citrate

[0090] The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate was obtained according to the following method. Specifically, the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was obtained according to the method described in Korean Patent Publication No. 10-1777971. The nuclear magnetic resonance (NMR) analysis results of the obtained azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone are as follows.

[0091] 1 H NMR (400 MHz, CDCl3); δ 7.63 (d, J = 1.2 Hz, 1H), 7.13 (dd, J = 8.4, 6.8 Hz, 1H), 7.06 - 7.04 (m, 2H), 6.42 (d, J = 1.2 Hz, 1H), 4.86 - 4.84 (m, 1H), 4.41 - 4.28 (m, 4H), 4.37 (d, J = 4.4 Hz, 2H), 3.75 - 3.69 (m, 1H), 2.43 - 2.34 (m, 13H).

[0092] Next, the obtained azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was mixed with an alcohol solvent (isopropyl alcohol, IPA), and the resulting mixture was stirred and then dried under vacuum at about 30 to 35 °C to obtain a dried product. Approximately 10 g of the dried product was taken and stirred with approximately 167 g of acetone. A solution of citric acid (approximately 5 g) dissolved in acetone (approximately 33 g) was slowly added dropwise thereto within 60 minutes, and the resulting mixture was stirred at the same temperature for one hour. The mixture was cooled to about 20 °C to 25 °C and stirred for another hour. The resulting solid was filtered, washed with acetone, and dried under vacuum to obtain azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate. The NMR analysis results of the obtained azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (zastaprazan citrate) are as follows.

[0093] 11H NMR (400 MHz, MeOD); δ 7.90 (s, 1H), 7.06 - 7.15 (m, 3H), 6.77 (s, 1H), 4.50 (t, J = 7.2 Hz, 2H), 4.45 (s, 2H), 4.24 (t, J = 7.2 Hz, 2H), 2.80 (d, J = 15.6 Hz, 2H), 2.70 (d, J = 12.0, 2H), 2.39 - 2.44 (m, 11H), 2.35 (s, 3H)

[0094] Preparation Example 2. Preparation of JP-1366 tablets 10 mg (zaspirone citrate 10 mg)

[0095] 10 mg of azetidin - 1 - yl {8 - [(2,6 - dimethylbenzyl)amino]-2,3 - dimethylimidazo[1,2 - a]pyridin - 6 - yl} methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 136.5 mg of microcrystalline cellulose, 2.3 mg of sodium stearoyl fumarate, 40.0 mg of anhydrous lactose, 6.0 mg of croscarmellose sodium, and 5.2 mg of magnesium stearate were mixed to obtain a mixture. The mixture was directly compressed to obtain tablets. Next, the tablets were coated with 8.0 mg of Opadry White to prepare film - coated tablets.

[0096] The film - coated tablets prepared as described above are referred to as "JP - 1366, 10 mg".

[0097] Preparation Example 3. Preparation of JP-1366 tablets 20 mg (zaspirone citrate 20 mg)

[0098] 20 mg of azetidin - 1 - yl {8 - [(2,6 - dimethylbenzyl)amino]-2,3 - dimethylimidazo[1,2 - a]pyridin - 6 - yl} methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 133.4 mg of microcrystalline cellulose, 6.4 mg of sodium stearoyl fumarate, 40.0 mg of anhydrous lactose, 6.0 mg of croscarmellose sodium, and 4.2 mg of magnesium stearate were mixed to obtain a mixture. The mixture was directly compressed to obtain tablets. Next, the tablets were coated with 8.0 mg of Opadry 03B54445 Pink to prepare film - coated tablets.

[0099] The film - coated tablets prepared as described above are referred to as "JP - 1366, 20 mg".

[0100] Preparation Example 4. Preparation of JP-1366 capsules 20 mg (zaspirone citrate 20 mg)

[0101] 20 mg of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 181.4 mg of D-mannitol, 12.4 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate were mixed to obtain a mixture. The mixture was filled into hard capsules No. 1 used as a capsule matrix to prepare a capsule preparation.

[0102] The capsule preparation prepared in this way is called "JP-1366 Capsule 20 mg".

[0103] Preparation Example 5. 10 mg zaspirone placebo

[0104] Except for not using the main ingredient zastaprazan citrate, zastaprazan 10 mg placebo was prepared in the same manner as Preparation Example 2. The film-coated tablets prepared in this way are called "JP-1366, 10 mg placebo".

[0105] Preparation Example 6. Preparation of lansoprazole preparation 15 mg (control drug)

[0106] In the case of lansoprazole preparation, 15 mg of Lanston Capsule (15 mg lansoprazole) from Jeil Pharmaceutical CO., LTD. was purchased and used. The purchased 15 mg Lanston Capsule is called "Lansoprazole, 15 mg".

[0107] Preparation Example 7. 15 mg lansoprazole placebo

[0108] Except for the main ingredient lansoprazole, lansoprazole 15 mg placebo was prepared in the same manner as the preparation method of Lanston Capsule by adding pharmaceutically acceptable excipients. The capsules prepared in this way are called "Lansoprazole, 15 mg placebo".

[0109] Example 1. Anti-ulcer activity evaluation of zaspirone in an animal model of naproxen-induced acute peptic ulcer Evaluation

[0110] To confirm the effect of zastaprazan in NSAID-induced peptic ulcers, the anti-ulcer activity of zastaprazan was evaluated in a rat gastric injury model induced by NSAID naproxen, and the anti-ulcer effect of zastaprazan was compared with that of esomeprazole.

[0111] 1. Test animals

[0112] Species and strain: Male Sprague-Dawley (SD) rats

[0113] Reasons for selecting the test system: The SD rats used in this test are suitable experimental animals for efficacy evaluation tests, and the reason for selecting SD rats is that: A large amount of basic test data has been accumulated on the gastric mucosal injury model, so this data can be used to interpret and evaluate the test results.

[0114] Age at acquisition: Approximately seven weeks old

[0115] Quarantine and acclimation: Approximately seven days after acquisition (only healthy animals are provided for the test)

[0116] Individual animal identification: Individual animals are identified using the tail marking method, and an individual identification card with the test number, test group, animal ID number, and sex is attached to each breeding cage.

[0117] Age at administration of the test substance: Approximately eight weeks old

[0118] Number of animals ordered: 12

[0119] Number of animals used: 12

[0120] 2. Breeding conditions

[0121] Breeding room: Clean animal room (specific pathogen free)

[0122] Ventilation frequency: At least 10 times per hour

[0123] Temperature and humidity range: 22 ± 4°C, 50% ± 20% (RH)

[0124] Lighting time and intensity: 12 hours of light (light: 08:00 to 20:00), intensity: 150 to 300 lux (Lux)

[0125] Breeding cage: Polysulfone material breeding cage

[0126] Number of animals per breeding cage: 2

[0127] Breeding management: Place autoclaved (121°C, 20 minutes) bedding (BETA Northeastern products Co., USA) at the bottom of the breeding cage to handle feces and urine, and the bedding is changed to new bedding twice a week.

[0128] Type and name of feed: Irradiated rodent solid feed (PMI 5053, USA)

[0129] Feed supply: Provided ad libitum using a feeder

[0130] Type of drinking water: Tap water sterilized by ultraviolet water sterilizer and high-pressure steam after reverse osmosis

[0131] Drinking water supply: The drinking water is changed once or twice a week to fresh drinking water, and a 500 mL special water bottle for rats is used. Wash and sterilize the water bottle before use, and use purified and ultraviolet-sterilized water as drinking water.

[0132] 3. Test methods

[0133] To induce gastric injury, naproxen was orally administered to the experimental animals once a day at a dose of 40 mg / kg for five days. The volume of the administered liquid was 5 ml / kg, and four hours after the last naproxen administration, the stomach was removed by laparotomy under anesthesia.

[0134] Specifically, naproxen 40 mg / kg was orally administered once a day to non-fasted male SD rats for five days, and the stomach was removed four hours after the last naproxen administration.

[0135] Group composition and administration volume dose setting: The test group composition and administration dose are as shown below.

[0136]

[0137] Administration site and method: The test substance (zastaprazan, JP-1366) and the control substance (esomeprazole) were administered orally in combination with naproxen. The dose for each individual was converted based on body weight before administration, and the dose was orally administered at 5 ml per kg body weight. The administration of the test substance, the control substance, and naproxen was carried out at 30-minute intervals.

[0138] Administration frequency and period: Once a day for five days (a total of 5 times)

[0139] 4. Observation and test items

[0140] A. Observation of general symptoms

[0141] Before and after the administration of the test substance, the general symptoms of each individual and the occurrence of animal death / imminent death were observed. Only individual animals showing specific symptoms were recorded (healthy individuals were not recorded).

[0142] B. Body weight measurement

[0143] Before obtaining, grouping, and before the administration of the test substance, the body weight of each individual animal was measured. The same weighing instrument was used to minimize errors in each measurement.

[0144] C. Autopsy and measurement of gastric injury area

[0145] After the experiment, the gastric damage caused by the test substance was evaluated using the ulcer index. Four hours after the last administration of naproxen, the animals were anesthetized and blood was collected, and the stomachs were removed. The removed stomachs were incised along the greater curvature, the contents were removed, the incised stomachs were washed with saline solution, spread out sufficiently with cotton swabs, fixed with needles, and then photographed. The gastric damage area and the total gastric area were measured from the photographed stomachs using an image program (Leica Application Suite V4), and the ulcer index was calculated as ulcer index (%) = damaged area (mm 2 ) / total area (mm 2 ) × 100.

[0146] D. Histopathological examination

[0147] The removed gastric tissues were fixed in 10% neutral buffered formalin solution. The fixed tissues were trimmed to a certain thickness and then paraffin-embedded through general tissue processing to produce tissue sections 4 to 5 μm thick, and then a general staining method, hematoxylin & eosin staining, was performed. Slides for hematoxylin & eosin staining (H&E staining) were prepared, and histopathological findings were obtained by requesting an external institution.

[0148] 5. Statistical processing

[0149] The experimental results were statistically analyzed by Mann-Whitney analysis using a commercial statistical processing program (IBM SPSS Statistics version 25.0).

[0150] 6. Results

[0151] Refer to Figure 1 , the group treated with the test substance zaspirone (JP-1366) showed a rapid decrease in ulcer area in the naproxen-induced peptic ulcer model, confirming that the test substance zaspirone (JP-1366) showed excellent anti-ulcer activity.

[0152] In addition, it was confirmed that the anti-ulcer efficacy of the test substance zaspirone (JP-1366) was superior to that of the control substance esomeprazole.

[0153] Therefore, it was confirmed that the test substance zaspirone (JP-1366) could prevent NSAID-induced peptic ulcers.

[0154] In addition, in Example 1, an anti-ulcer effect experiment was conducted when NSAID was administered to the subjects in a non-fasting state, which is the same as the situation of actual human administration. Therefore, it can be seen that the efficacy of preventing peptic ulcers caused by NSAID administration was also confirmed in humans.

[0155] Example 2. Evaluation of the pharmacodynamic (PK) interaction and safety of zaspirone with diclofenac, meloxicam or naproxen

[0156] Zastaprazan is a potassium-competitive acid secretion inhibitor that reversibly inhibits gastric H + or K + -adenosine triphosphatase and has a faster onset of action than proton pump inhibitors. Zastaprazan can be used not only for acid-related gastric diseases but also for preventing gastric damage caused by NSAIDs. To confirm this, the PK interaction and safety of zastaprazan with aceclofenac, meloxicam, or naproxen were clinically evaluated in healthy subjects.

[0157] - Part 1: PK interaction between zastaprazan and aceclofenac

[0158] - Part 2: PK interaction between zastaprazan and meloxicam

[0159] - Part 3: PK interaction between zastaprazan and naproxen

[0160] 1. Test drugs

[0161] A. Test drug 1 - zaspirone 40 mg

[0162] JP-1366, 2 capsules of 20 mg (40 mg of zastaprazan citrate)

[0163] B. Test drug 2 - diclofenac 100 mg

[0164] Aertal tablets (100 mg of aceclofenac)

[0165] C. Test drug 3 - meloxicam 15 mg

[0166] Mobic capsules 15 mg (15 mg of meloxicam)

[0167] D. Test drug 4 - naproxen 500 mg

[0168] Naxen-F tablets (500 mg of naproxen)

[0169] 2. Test methods

[0170] <Part 1>

[0171] Volunteer subjects in Part 1 were assigned subject numbers one day before the first clinical trial drug administration in Cycle 1 (-1d), then one aceclofenac tablet was administered on Day 1 in Cycle 1, two JP-1366 capsules were administered from Day 4 to Day 8 in Cycle 2, and two JP-1366 capsules and one aceclofenac tablet were co-administered on Day 9 in Cycle 3. Blood samples were collected from each subject at the specified times for PK assessment of the clinical trial drug, and all subjects underwent safety assessment according to the specified schedule.

[0172] All subjects who completed the clinical trial had a post-study follow-up from Day 14 to Day 20, including measurement of vital signs, physical examination, adverse reaction examination, confirmation of previous / concurrent medications, clinical laboratory tests, and electrocardiogram.

[0173] <Part 2>

[0174] Volunteer subjects in Part 2 were assigned subject numbers one day before the first clinical trial drug administration in Cycle 1 (-1d), then two JP-1366 capsules were administered from Day 1 to Day 5 in Cycle 1, one meloxicam capsule was administered from Day 15 to Day 19 in Cycle 2, and two JP-1366 capsules and one meloxicam capsule were co-administered from Day 22 to Day 26 in Cycle 3. Blood samples were collected from each subject at the specified times for PK assessment of the clinical trial drug, and all subjects underwent safety assessment according to the specified schedule.

[0175] All subjects who completed the clinical trial had a post-study follow-up from Day 31 to Day 37, including measurement of vital signs, physical examination, adverse reaction examination, confirmation of previous / concurrent medications, clinical laboratory tests, and electrocardiogram.

[0176] <Part 3>

[0177] Volunteer subjects in Part 3 were assigned subject numbers one day before the first clinical trial drug administration in Cycle 1 (-1d), then two JP-1366 capsules were administered from Day 1 to Day 5 in Cycle 1, one naproxen tablet was administered from Day 15 to Day 19 in Cycle 2, and two JP-1366 capsules and one naproxen tablet were co-administered from Day 22 to Day 26 in Cycle 3. Blood samples were collected from each subject at the specified times for PK assessment of the clinical trial drug, and all subjects underwent safety assessment according to the specified schedule.

[0178] All subjects who completed the clinical trial had a post-study follow-up from Day 31 to Day 37, including measurement of vital signs, physical examination, adverse reaction examination, confirmation of previous / concurrent medications, clinical laboratory tests, and electrocardiogram.

[0179] 3. PK analysis

[0180] Collect blood samples at specified times for PK assessment of zaspirone (JP-1366).

[0181] A. Part 1 - 22 subjects

[0182] (1) Aceclofenac 100 mg (A)

[0183] : 0 h on day 1 (before dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 h after dosing

[0184] (2) Zaspirone 40 mg (Z)

[0185] : 0 h on day 4, 0 h on day 6, 0 h on day 7, 0 h on day 8 (before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 h (0 h on day 9) after dosing

[0186] (3) Zaspirone 40 mg and aceclofenac 100 mg (Z+A)

[0187] : 0 h on day 9 (before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 h (0 h on day 10) after dosing

[0188] B. Part 2 - 22 subjects

[0189] (1) Zaspirone 40 mg (Z)

[0190] : 0 h on day 1, 0 h on day 3, 0 h on day 4, 0 h on day 5 (before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 h (0 h on day 6) after dosing, 0 h on day 15 (before dosing)

[0191] (2) Meloxicam 15 mg (M)

[0192] : 0 h on day 19 (before dosing), 1, 2, 3, 4, 5, 6, 8, 12, 24 h (0 h on day 20) after dosing

[0193] (3) Zaspirone 40 mg and meloxicam 15 mg (Z+M)

[0194] : 0 h on day 22, 0 h on day 24, 0 h on day 25, 0 h on day 26 (before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24 h (0 h on day 27) after dosing

[0195] C. Part 3 - 22 subjects

[0196] (1) Zasaprazan 40 mg (Z)

[0197] : 1 d 0 h, 3 d 0 h, 4 d 0 h, 5 d 0 h (before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 h (6 d 0 h) (after dosing), 15 d 0 h (before dosing)

[0198] (2) Naproxen 500 mg (N)

[0199] : 19 d 0 h (before dosing), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 h after dosing

[0200] (3) Zasaprazan 40 mg and Naproxen 500 mg (Z + N)

[0201] : 22 d 0 h, 24 d 0 h, 25 d 0 h, 26 d 0 h (before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 h (27 d 0 h) after dosing

[0202] 4. Results

[0203] A. Part 1 - Refer to Table 1 and Figure 2 and Figure 3

[0204] The geometric mean ratios (GMR) [90% confidence interval, CI] of the zasaprazan C max,SS and AUC T,SS of Z + A (zasaprazan 40 mg and aceclofenac 100 mg) and Z (zasaprazan 40 mg) were 1.0868 (0.9554 to 1.2362) and 0.9490 (0.9096 to 0.9902), respectively.

[0205] The geometric mean ratios (GMR) [90% CI] of the aceclofenac C max,SS and AUC T,SS of Z + A (zasaprazan 40 mg and aceclofenac 100 mg) and A (aceclofenac 100 mg) were 1.1895 (1.0429 to 1.3568) and 1.0295 (0.9803 to 1.0812), respectively.

[0206] [Table 1]

[0207]

[0208] (The above Table 1 shows the PK parameters of zasaprazan (Z) and aceclofenac (A), and the data are expressed as mean ± standard deviation.)

[0209] B. Part 3 - Refer to Table 2 and Figure 4 and Figure 5

[0210] The Cmax and AUC of Zasaprazan in Z+M (Zasaprazan 40 mg and Meloxicam 15 mg) and Z (Zasaprazan 40 mg) max,SS and AUC T,SS The GMR [90% CI] were 1.0926 (0.9387 to 1.2717) and 1.3332 (1.1494 to 1.5463), respectively.

[0211] The Cmax and AUC of Meloxicam in Z+M (Zasaprazan 40 mg and Meloxicam 15 mg) and M (Meloxicam 15 mg) max,SS and AUC T,SS The GMR [90% CI] were 1.0756 (0.9916 to 1.1668) and 1.0477 (0.9976 to 1.1002), respectively.

[0212] [Table 2]

[0213]

[0214] (The above Table 2 shows the PK parameters of Zasaprazan (Z) and Meloxicam (M), and the data are presented as mean ± standard deviation.)

[0215] C. Part 3 - See Table 3 and Figure 6 and Figure 7

[0216] The Cmax and AUC of Zasaprazan in Z+N (Zasaprazan 40 mg and Naproxen 500 mg) and Z (Zasaprazan 40 mg) max,SS and AUC T,SS The GMR [90% CI] were 0.9148 (0.7956 to 1.0518) and 1.1089 (0.9835 to 1.2503), respectively.

[0217] The Cmax and AUC of Naproxen in Z+N (Zasaprazan 40 mg and Naproxen 500 mg) and N (Naproxen 500 mg) max,SS and AUC T,SS The GMR [90% CI] were 1.0491 (1.0088 to 1.0910) and 1.0155 (0.9900 to 1.0417), respectively.

[0218] [Table 3]

[0219]

[0220] (The above Table 3 shows the PK parameters of Zasaprazan (Z) and Naproxen (N), and the data are presented as mean ± standard deviation.)

[0221] D. Summary

[0222] No clinically significant PK interactions were observed between zaspirone and aceclofenac, meloxicam, or naproxen, and there were no safety concerns.

[0223] Example 3. Evaluation of the efficacy and safety of administering zaspirone for preventing NSAID-induced peptic ulcer Assessment

[0224] 1. Subject selection

[0225] A multicenter, parallel - design, double - blind, randomized, active - controlled, non - inferiority clinical trial was designed to evaluate the efficacy and safety of zaspirone in preventing gastro - duodenal ulcers in patients with NSAID - induced peptic ulcers.

[0226] Inclusion criteria

[0227] Eligible subjects must meet all of the following criteria:

[0228] 1. Adult men and women aged 19 years or older as of the date of written consent

[0229] 2. Subjects diagnosed with musculoskeletal diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis at screening, who require continuous administration of NSAIDs (aceclofenac, meloxicam, naproxen, celecoxib) for more than 24 weeks

[0230] 3. Subjects with one or more of the following ulcer - developing risk factors at screening

[0231] 1) Age 60 years or older

[0232] 2) Subjects with a history of peptic ulcer confirmed by upper gastrointestinal endoscopy or subjects with ulcer scars confirmed by upper gastrointestinal endoscopy (performed within 10 days after randomization)

[0233] 3) Concurrent use of low - dose aspirin (aspirin < 81 mg to 325 mg / day) (however, subjects with this risk factor must continue to take low - dose aspirin during the clinical trial.)

[0234] 4) Concurrent use of prednisone at a dose of 10 mg / day or lower (or corticosteroids at an equivalent or lower dose) (however, subjects with this risk factor must maintain the administration of corticosteroids at this dose during the clinical trial.)

[0235] 4. Subjects who fully understand this clinical trial and voluntarily give written consent to participate in the clinical trial

[0236] Exclusion criteria

[0237] Eligible subjects must not meet any of the following criteria:

[0238] 1. Subjects who cannot undergo endoscopy

[0239] 2. Subjects with active ulcers (A1, A2) or healing ulcers (H1, H2) in the stomach or duodenum according to the upper gastrointestinal endoscopy findings at screening, classified according to Sakita-Miwa classification*.

[0240] *Sakita-Miwa classification

[0241] 1) Active ulcers

[0242] (1) Active stage (A1): The white exudate is thick and protrudes around certain areas. Small bleeding or clots often occur. Inflammatory symptoms such as surrounding redness, edema, and erosion are severe, and the raised edge is also large and high.

[0243] (2) Active stage (A2): The protruding white exudate disappears, and its edge becomes clear. The surrounding inflammation also becomes significantly milder, and the raised edge decreases slightly. The mucosal folds become concentrated. There is regenerative epithelium, but it is very little.

[0244] 2) Healing stage ulcers

[0245] (1) Healing stage (H1): The ulcer becomes shallower, the white exudate is clean, and the edge is smooth. The regenerative epithelium becomes clear, the main body almost disappears, and the mucosal folds reach the edge of the white exudate and concentrate.

[0246] (2) Healing stage (H2): The ulcer significantly shrinks. The white exudate thins. The width of the regenerative epithelium becomes wider.

[0247] 3) Scarred ulcers

[0248] (1) Scar stage (S1): The mucosal defect disappears, but the erythema of the regenerative epithelium still remains. Small discolored spots are common in the center. The mucosal folds slowly extend to the center.

[0249] (2) Scar stage (S2): The erythema disappears, the regenerative epithelium thickens, and the color is very similar to the surrounding mucosa. The concentration of the folds also disappears, so in some cases only the concentration of the mucosa is visible.

[0250] 3. Medical history

[0251] 1) Subjects with a history of malignant tumors within five years after screening. However, subjects with a history of digestive system malignant tumors are excluded regardless of the stage.

[0252] 2) Subjects with prodromal symptoms (dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stools, etc.) that may suggest gastrointestinal malignancies (however, subjects who are confirmed negative for malignancies by endoscopic examination and esophageal biopsy are excluded).

[0253] 3) Subjects who develop gastroesophageal varices, Barrett's esophagus (greater than 3 cm), esophageal dysplasia, esophageal stricture, ulcerative stricture, or acute gastrointestinal bleeding due to screening upper gastrointestinal endoscopy

[0254] 4) Subjects with Zollinger-Ellison syndrome or other gastric acid secretion disorders or a history of Zollinger-Ellison syndrome or other gastric acid secretion disorders

[0255] 5) Subjects with or suspected of having inflammatory bowel disease (IBD), which includes pancreatitis, primary esophageal motility disorders, irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, and Behçet's enteritis

[0256] 6) Subjects who have had or are planning to have gastrointestinal or esophageal surgery such as antisecretory surgery, gastrectomy, and endogastrectomy (excluding appendectomy, cholecystectomy, and polypectomy)

[0257] 7) Subjects who are confirmed positive for Helicobacter pylori (H. pylori) in the screening test

[0258] 8) Subjects with clinically significant diseases of the blood, liver, kidney, cardiovascular system, respiratory system, endocrine system, urinary system, neuropsychiatric system, immune system, hematologic malignancies, etc.

[0259] 9) Subjects with a history of drug or alcohol abuse within one year from the date of screening

[0260] 4. Clinical laboratory tests

[0261] 1) Subjects whose screening results meet any of the following criteria

[0262] ① The levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceed twice the upper limit of normal (ULN).

[0263] ② The total bilirubin level exceeds twice the ULN.

[0264] ③ The levels of alkaline phosphatase (ALP) or gamma-glutamyltransferase (γ-GTP) exceed twice the ULN.

[0265] 2) Subjects with any of the following results confirmed as positive: Human Immunodeficiency Virus (HIV) antigen / antibody test, Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (anti-Hepatitis C virus, anti-HCV) test, or Syphilis test (Venereal Disease Research Laboratory, VDRL)

[0266] However, the following situations may be included:

[0267] 2-1) Subjects with positive HBsAg and Hepatitis B virus (HBV)-DNA level lower than 100,000 IU / mL

[0268] 2-2) Subjects with positive Hepatitis C virus (HCV)-Ab and negative HCV-RNA

[0269] 3) Subjects with clinically significant (CS) abnormalities confirmed by electrocardiogram during the screening period

[0270] 5. Allergy and drug hypersensitivity

[0271] 1) Subjects known to have hypersensitivity to the clinical test drug and its components

[0272] 2) Subjects with a history of CS allergic diseases (excluding mild allergic rhinitis that does not require drug administration) or hypersensitivity to other drugs (NSAIDs, aspirin, antibiotics, etc.) (asthma, acute rhinitis, nasal polyps, angioedema, urticaria, anaphylaxis, etc.)

[0273] 6. Contraindicated drugs and therapies

[0274] 1) Subjects who must continue to take corticosteroids, antiplatelet drugs, and anticoagulants during this clinical trial [However, the following situations are allowed.]

[0275] ① Taking low-dose aspirin (81 mg or more to 325 mg / day) for the purpose of preventing cardiovascular diseases before participating in this clinical trial

[0276] ② Administration of prednisone at 10 mg / day (or equivalent dose or less of corticosteroids)

[0277] ③ Topical corticosteroids for the treatment of musculoskeletal diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis

[0278] 2) Subjects who are taking or need to take prohibited concomitant medications in this clinical trial (however, subjects who have taken prohibited concomitant medications can participate after a one-week wash-out period. However, depending on the half-life of the drug, subjects who have taken the following prohibited concomitant medications can participate in this clinical trial after the corresponding wash-out period.)

[0279] Drugs with a half-life exceeding 24 hours: Two weeks

[0280] When the time equivalent to 5 times the drug half-life exceeds two weeks: Five times the drug half-life wash-out period

[0281] 7. Pregnant women, lactating women, or women with a positive pregnancy test result during the screening period

[0282] 8. Contraception

[0283] 1) Subjects and their spouses (or partners) who do not use medically acceptable contraceptive measures during the clinical trial. The following methods are considered "medically acceptable contraceptive measures":

[0284] ① Use of an intrauterine device with a proven pregnancy failure rate

[0285] ② Use of a double-barrier contraceptive method (male condom and occlusive cap, diaphragm, or cervical cap), together with a spermicide

[0286] ③ Sterilization (vasectomy, tubal ligation and salpingectomy, hysterectomy)

[0287] 9. Subjects with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

[0288] 10. Subjects who participated in another clinical trial and received or applied any clinical trial drug or medical device at least once within four weeks before participating in this clinical trial

[0289] 11. Subjects who, in the opinion of the investigator, are considered ineligible to participate in this clinical trial

[0290] 2. Administration dose, administration period and administration method

[0291] The subjects receive the clinical trial drug assigned to the randomly assigned treatment group, starting from the day after the random assignment date, taking one tablet and one capsule before meals every day for 24 weeks, and orally administering them at a consistent time if possible.

[0292] [Table 4]

[0293] Administration group Administered orally once a day Test group ●△ Control group ○▲

[0294] (In Table 4 above, ● is JP-1366, 10 mg, ○ is JP-1366, 10 mg placebo, ▲ is lansoprazole, 15 mg, and △ is lansoprazole, 15 mg placebo.)

[0295] Co-administered NSAID

[0296] From the date of randomization, at the discretion of the investigator, the subject will be administered one NSAID from aceclofenac, meloxicam, naproxen, and celecoxib, and during the clinical trial, the type and dose of the co-administered NSAID must remain unchanged.)

[0297] 3. Clinical trial methods

[0298] The subject visits the clinical trial site at weeks 4, 12, and 24 from the date of randomization for efficacy and safety assessments according to the specified schedule. Efficacy assessments include confirmation of the occurrence of peptic ulcers and gastrointestinal symptoms related to NSAIDs.)

[0299] Safety assessments include collecting information on adverse events (AEs), vital signs (blood pressure, pulse, body temperature), physical examinations, and clinical laboratory tests (hematology, blood chemistry, and urine tests).)

[0300] During the clinical trial, when endoscopy confirms a peptic ulcer, clinical participation is terminated prematurely at that time point. When the ulcer is diagnosed and treatment is terminated prematurely, it is considered the end of treatment (EOT). Follow-up (F / U) is conducted after EOT.)

[0301] 4. Efficacy endpoints

[0302] A. Primary efficacy endpoint:

[0303] Cumulative proportion (%) of subjects with peptic ulcers

[0304] *Active / healing ulcers according to Sakita-Miwa classification or newly discovered scar-stage ulcers other than scars identified at screening

[0305] B. Secondary efficacy endpoints:

[0306] Proportion (%) of subjects with gastric or duodenal endoscopic bleeding**

[0307] ** Subjects corresponding to grade 1 or 2 according to Forrest classification

[0308] C. Exploratory endpoints

[0309] 1. Proportion (%) of subjects with peptic ulcer as of the 12th week

[0310] 2. Proportion (%) of subjects with bleeding** on gastric or duodenal endoscopy as of the 12th week

[0311] 3. Incidence rate (%) of peptic ulcer according to NSAID type (aceclofenac, meloxicam, naproxen, celecoxib)

[0312] 4. Incidence rate of peptic ulcer according to the items of risk factors for the onset of peptic ulcer

[0313] 5. Incidence rate of peptic ulcer according to the number of risk factors for the onset of peptic ulcer

[0314] 6. Change in serum gastrin concentration compared with the baseline

[0315] 7. Proportion (%) of gastrointestinal symptoms obtained by questionnaire survey (00) at the 4th, 12th, and 24th weeks compared with the baseline

[0316] 8. Change in blood hemoglobin (Hb) concentration at the 4th, 12th, and 24th weeks compared with the baseline

[0317] 5. Safety endpoints

[0318] - Adverse events

[0319] - Vital signs

[0320] - Physical examination

[0321] - Results of clinical laboratory tests

[0322] - Electrocardiogram

[0323] 6. Definition of analysis groups and statistical analysis methods

[0324] Definition of analysis groups

[0325] The analysis groups are divided into the following three groups. Efficacy evaluation analysis is carried out based on the full analysis set (FAS) and the per-protocol set (PPS), and FAS is the main analysis group. Safety analysis is carried out on the safety set (safety evaluation group).

[0326] 1. FAS

[0327] This refers to the group of subjects who have received at least one administration of the clinical trial drug and at least one main efficacy evaluation in this clinical trial.

[0328] 2. PPS

[0329] This refers to all subjects included in FAS who have not seriously violated the clinical trial protocol.

[0330] 3. Safety Set (Safety Assessment Group)

[0331] This refers to the group of subjects who have received the investigational drug at least once in this clinical trial.

[0332] Statistical analysis methods

[0333] A. Primary Efficacy Endpoint

[0334] Cumulative proportion (%) of subjects with peptic ulcer by week 24

[0335] : The proportion of subjects with peptic ulcer by treatment group as of 24 weeks after drug administration compared to baseline. To compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0336] In addition, logistic regression analysis is performed to confirm whether there are differences between treatment groups when adjusting the incidence of peptic ulcer at 24 weeks for the type of NSAID (aceclofenac, meloxicam, naproxen, celecoxib) administered to subjects stratified by factors (e.g., incidence of peptic ulcer at 24 weeks) and the administration (use / non-use) of aspirin or / and prednisone among ulcer risk factors.

[0337] B. Secondary Efficacy Endpoint

[0338] Proportion (%) of subjects with gastric or duodenal endoscopic bleeding by week 24

[0339] : The proportion of subjects with gastric or duodenal endoscopic bleeding by treatment group as of 12 weeks and 24 weeks after drug administration compared to baseline. To compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0340] C. Exploratory Endpoint

[0341] 1. Proportion (%) of subjects with peptic ulcer by week 12

[0342] : The proportion of subjects with peptic ulcer by treatment group as of 12 weeks after drug administration compared to baseline. To compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0343] 2. Proportion (%) of subjects with gastric or duodenal endoscopic bleeding by the 12th week

[0344] : The proportion of subjects with gastric or duodenal endoscopic bleeding by treatment group at the 12th and 24th weeks after drug administration compared to baseline. To compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0345] 3. Incidence rate (%) of peptic ulcer according to NSAID type (aceclofenac, meloxicam, naproxen, celecoxib)

[0346] 4. Incidence rate (%) of peptic ulcer according to the risk factor items for peptic ulcer onset

[0347] : The incidence rate of peptic ulcer for the risk factor items for peptic ulcer onset is presented by treatment group. To compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0348] 5. Incidence rate (%) of peptic ulcer according to the number of risk factors for peptic ulcer onset

[0349] 6. Changes in gastrin levels at weeks 4, 12, and 24 compared to baseline

[0350] Descriptive statistics (mean, standard deviation, median, minimum, maximum) of gastrin levels at weeks 4, 12, and 24 after drug administration and the changes in gastrin levels at weeks 4, 12, and 24 after drug administration relative to baseline are described. To compare whether there are differences between treatment groups, when the normality assumption is met, a two-sample t-test is performed, and when the normality assumption is not met, a Wilcoxon rank sum test is performed. In addition, when the change in the test value compared to baseline at each visit is not compared, a Wilcoxon signed-rank test is used for analysis.

[0351] 7. Proportion (%) of gastrointestinal symptoms obtained by questionnaire at weeks 4, 12, and 24 compared to baseline

[0352] Present the proportion of subjects without NSAID-related gastrointestinal symptoms (such as acid reflux, upper abdominal pain or discomfort, or dyspepsia) at 4, 12, and 24 weeks after drug administration by treatment group. And to compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0353] 8. Changes in blood hemoglobin (Hb) concentration (%) at 4, 12, and 24 weeks compared to baseline

[0354] Descriptive statistics (mean, standard deviation, median, minimum, maximum) of blood hemoglobin levels at 4, 12, and 24 weeks after drug administration and changes in blood hemoglobin levels relative to baseline up to 4, 12, and 24 weeks after drug administration are described. And to compare whether there are differences between treatment groups, when the normality assumption is met, a two-sample t-test is performed, and when the normality assumption is not met, a Wilcoxon rank sum test is performed. In addition, when not comparing the change in test values compared to baseline at each visit, a Wilcoxon signed-rank test is used for analysis.

[0355] * When the drug compliance is less than or equal to 80%, it is considered non-compliance with the investigational product (IP).

[0356] D. Safety endpoints

[0357] 1. Adverse reactions

[0358] Present the number and percentage of subjects with adverse reactions, 95% confidence intervals, and the number of occurrences by treatment group. And to compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed.

[0359] For the severity, causality, effect on the clinical trial drug, management of adverse events, and their outcomes of adverse reactions, present the number and percentage of subjects with adverse reactions, 95% confidence intervals, and the number of occurrences by treatment group. And to compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 accounts for 20% or less of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than 20% of the total, a Fisher's exact test is performed.

[0360] 2. Vital signs, physical examinations, and clinical laboratory tests

[0361] For continuous data, descriptive statistics (mean, standard deviation, median, minimum, maximum) are described for each visit, and to compare whether there are differences between treatment groups, when the normality assumption is met, a two-sample t-test is performed, and when the normality assumption is not met, a Wilcoxon rank sum test is performed. In addition, when not comparing the change in test values at each visit compared to the baseline, a Wilcoxon signed-rank test is used for analysis.

[0362] For categorical data, the frequencies and proportions for each visit are described, and to compare whether there are differences between treatment groups, when the number of cells with an expected frequency less than 5 is less than 20% of the total, a chi-square test is performed, and when the number of cells with an expected frequency less than 5 is greater than or equal to 20% of the total, a Fisher's exact test is performed. The baseline and values at each visit are classified into normal / abnormal categories, and a McNemar test is performed to test whether the normal / abnormal ratio changes before and after the administration of the clinical trial drug.

[0363] Although specific parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and the scope of the present invention is not limited thereto. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing, treating peptic ulcer or preventing recurrence of peptic ulcer, said pharmaceutical composition comprising zaspirone, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof, wherein said peptic ulcer is caused by administration of non-steroidal anti-inflammatory drugs (NSAIDs).

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of zaspirone is zaspirone citrate.

3. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises zaspirone, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof in an amount of 1 mg to 100 mg based on zaspirone.

4. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises zaspirone citrate in an amount of 5 to 40 mg.

5. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises zaspirone citrate in an amount of 10 mg.

6. The pharmaceutical composition according to claim 1, wherein the subject to whom said pharmaceutical composition is administered is a subject who has experienced a peptic ulcer caused by administration of NSAIDs.

7. The pharmaceutical composition according to claim 1, wherein the subject to whom said pharmaceutical composition is administered is a subject who has experienced the cure of peptic ulcer.

8. The pharmaceutical composition according to claim 1, wherein said NSAIDs are acetic acid-derived non-selective NSAIDs, enolic acid-derived non-selective NSAIDs, fenamic acid-derived non-selective NSAIDs, p-aminophenol-derived non-selective NSAIDs, propionic acid-derived non-selective NSAIDs, salicylic acid-derived non-selective NSAIDs, selective COX-2 inhibitors, or mixtures thereof.

9. The pharmaceutical composition according to claim 8, wherein said acetic acid-derived non-selective NSAID is aceclofenac, acemetacin, actarit, alclofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, indomethacin, ketorolac, meclofenamic acid, mobenoxaprofen, nabumetone, naproxen, oxametacin, sulindac, zomepirac, or any combination thereof; wherein said enolic acid-derived NSAID is tenoxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tenoxicam, or any combination thereof; wherein said fenamic acid-derived NSAID is flufenamic acid, mefenamic acid, meclofenamic acid, tolfenamic acid, or any combination thereof; wherein said p-aminophenol-derived NSAID is paracetamol, phenacetin, or any combination thereof; wherein said propionic acid-derived NSAID is alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen in a pharmaceutically acceptable form, loxoprofen, oxaprozin, pranoprofen, suprofen, or any combination thereof; wherein said salicylic acid-derived NSAID is acetylsalicylic acid, diflunisal, bisalicyate, or any combination thereof; and Wherein the selective COX-2 inhibitor is celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, or any combination thereof.

10. The pharmaceutical composition according to claim 1, wherein the NSAID is one or more selected from the group consisting of naproxen, aceclofenac, meloxicam, and celecoxib.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered once a day.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated as a solid oral preparation.

13. Use of a pharmaceutical composition for preventing peptic ulcers induced by administration of a non-steroidal anti-inflammatory drug (NSAID), the pharmaceutical composition comprising zaltraprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

14. Use of a pharmaceutical composition for preventing recurrence of peptic ulcers induced by administration of an NSAID, the pharmaceutical composition comprising zaltraprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

15. Use of a pharmaceutical composition for preparing a medicament for preventing peptic ulcers induced by administration of an NSAID, the pharmaceutical composition comprising zaltraprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

16. Use of a pharmaceutical composition for preparing a medicament for preventing recurrence of peptic ulcers induced by administration of an NSAID, the pharmaceutical composition comprising zaltraprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

17. A method for preventing recurrence or onset of peptic ulcers induced by administration of an NSAID, the method being implemented by administering to a subject a pharmaceutically effective amount of a pharmaceutical composition comprising zaltraprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

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