WO2020022974A2

WO2020022974A2 - A pharmaceutical composition comprising prucalopride and a proton pump inhibitor

Info

Publication number: WO2020022974A2
Application number: PCT/TR2018/000132
Authority: WO
Inventors: Mahmut Bi̇lgi̇ç
Original assignee: Neutec Ar-Ge Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2017-12-29
Filing date: 2018-12-28
Publication date: 2020-01-30
Also published as: WO2020022974A3; TR201723047A2

Abstract

The present invention is misted to a pharmaceutical composition comprising prucalopride and a proton pump inhibitor to be used in treating helicobacter pylori eradication, NSAID sourced ulcer prophylaxis, Zolliger-EIllison syndrome, dyspepsia, duodenum ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), pyrosis, systemic mastocytosis, multiple endocrine adenoma syndrome, and esophagitis.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING PRUCALOPRIDE AND A PROTON PUMP

INHIBITOR

The present invention is related to combinations of suitable active agents selected from prucalopride and proton pump inhibitor groups and the usage of these combinations and pharmaceutical salts comprising these combinations in treating heiicobacter pylori eradication, NS AH) sourced ulcer prophylaxis, Zollinger-Ellison syndrome, dyspepsia, duodenum ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), pyrosis, systemic mastocytosis, multiple endocrine adenoma syndrome, and esophagitis. Particularly the invention is related to pharmaceutical compositions comprising a) prucalopride or pharmaceutically acceptable derivative thereof and b) proton pump inhibitor selected from omeprazole, esomeprazole, lansoprazole, dexlansoprazote, rabeprazole, dexrabeprazole, pantoprazole or pharmaceutically acceptable derivatives thereof.

The chemical name prucalopride is "4-amjno-5 chloro*2,3-dihydro-N- [ 1 -(3-methoxypropy 1>4- piperidylH- bcnzofurancarboxarmdc", which is a selective serotonin (5«HT4) antagonist having prokinetic features that has been described for the first time with the application numbered W09616060. Following oral application it can be nqpidly absorbed and the plasma concentration reaches its maximum point within 2*3 hours.

Prucalopride is sold in 1 mg and 2mg film coated tablet forms. The chemical name is 5-Methoxy-2-(4-mcthoxy»3,5-dmicthyl-2-pndmylmethyl- sul½yl)benzimidazole, which is a proton pump inhibitor which reduces gastric acid secretion that has been described for the first time with the application numbered US4255431. It is a strong and effective drug. It can also be used as «omeprazole which is an S-isomer. In said document omeprazole has been described to be used in treating peptic ulcer.

The chemical name of Lansoprazole is 2-({3-Mdhyl-4«(2,2_>2-trifiuoroethoxy>2 pridinyl} sulfinyt benzimidazole, which is a proton pump inhibitor which inhibits foe enzyme system of gastric parietal cells and gastric add secretion and has been described for the first time with the application numbered US4628098. It can also be used as dexlansoprazole which is an R-enantiomer. It has been described in said document that lansoprazole is effective in treating ulcers.

The chemical name of rabeprazole is 2_*[([4^3«methoxypropoxy)-3-methyl-2-pridinyl]- methyi]suifmy l]- 1 H-betizimidazoie and it is a proton pump inhibitor having a substituted benzimidazole structure which inhibits gastric add secretion and has been described for foe first time in the application numbered EPG2689S6. It has been described in said document that rabeprazole is effective in treating gastric ulcers. It is a mixture of Rabeprazole Rf+) and S(-) isomers.

The chemical name of Pantoprazo!e is “5-(Di{!orometoksi)-2-f((3,4 dimetoksi-2- pridil)metU]siUfmil)benzimidazor which is a proton pump inhibhor having a substituted benzimidazole structure which suppresses gastric acid secretion by inhibiting the adenosine triphosphatase enzyme pump and has been described for the first time with the patent application numbered EPO 166287. In said patent it has been described to be used in treating gastrointestinal diseases and increased gastric acid secretion.

It has been surprisingly discovered that an unexpected therapeutic benefit, particularly synergistic therapeutic benefits could be obtained in the treatments of helicobacter pylori eradication, NSAID sourced ulcer prophylaxis, Zollinger-Eilison syndrome, dyspepsia, duodenum ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), pyrosis, systemic mastocytosis, multiple endocrine adenoma syndrome, and esophagitis where prucalopride and a proton pump inhibitor is used. It is possible for said therapeutic benefit to be according to the following, when it is used in treatments in combinations in comparison to what required when only prucalopride or a proton pump inhibitor is used in treatments;

• Reducing the required dosage in order to obtain the required therapeutic effect and/or

• Reducing undesired adverse effects and/or

• Observing therapeutic effect in a short period of time and/or

• Observing therapeutic effect for a tong period of time and-'or

• Providing a more effective treatment. Accordingly the present invention is & pharmaceutical composition comprising an active agent or pharmaceutically acceptable derivatives thereof selected from the prueaiopride and proton pump inhibitor group as active agent.

In another aspect it can be said that the pharmaceutical composition in which prueaiopride and a proton pump inhibitor is used simultaneously or together shows higher therapeutic benefits in comparison to compositions which use these two agents separately.

The invention owners have discovered as a result of the studies they have carried out. in patients that showed gastroesophageal reflux disease (GERD) symptoms and chronic reflux symptoms, that these patients experienced significant decrease in reflux cases and alleviation of symptoms when prueaiopride was used in combination with a proton pump inhibitor even though they did not experience any alleviation in the disease symptoms when they had been using any kind of proton pump inhibitor for a long period of time.

The patient groups on which the studies have been carried out have stated that they felt a significant amount of improvement in their daily life quality when they took prueaiopride together with a proton pump inhibitor rather than only using a proton pump inhibitor.

Accordingly the invention is related to a pharmaceutical composition comprising the following as active agents: a) Prueaiopride or pharmaceutically acceptable derivative and b) Omeprazole or pharmaceutically acceptable derivative.

On the other hand the invention is related to a pharmaceutical composition comprising the following as active agents; a) Prueaiopride or pharmaceutically acceptable derivative and b) Esomepraaole or pharmaceutically acceptable derivative. On the other hand the invention is related to a pharmaceutical composition comprising the following as active agents; a) Prueaiopride or pharmaceutically acceptable derivative and b) Lansoprazole or pharmaceutically acceptable derivative. On tiie other band the invention is related to a pharmaceutical composition comprising foe following as active agents; a) Prucalopride or pharmaceutically acceptable derivative and b) Dexlansoprazole or pharmaceutically acceptable derivative. On foe other hand foe invention is related to a pharmaceutical composition comprising foe following as active agents; a) Prucalopride or pharmaceutically acceptable derivative and b) Rabepntzso!e or pharmaceutically acceptable derivative.

On the other hand the invention is related to a pharmaceutical composition comprising the following as active agents; a) Prucalopride or pharmaceutically acceptable derivative and b) Dcxrabeprazoie or pharmaceutically acceptable derivative.

On foe other hand the invention is related to a pharmaceutical composition comprising foe following as active agents; a) Prucalopride or pharmaceutically acceptable derivative and b) P&ntoprazole or pharmaceutically acceptable derivative.

According to another aspect, the combined usage of the active agents inside foe pharmaceutical composition subject to the invention ensures to see the therapeutic effect in a short period of time and ensures that tins effect is stronger in comparison to these two active agents being used separately. By this means it is possible to provide a more effective treatment. interestingly, these positive effects can be seen in combinations when these two active agents arc given sequentially and said positive effects can be seen when these two active agents are given inside a dosage form at the same time or inside independent dosage forms simultaneously. High therapeutic benefits can also be observed as long term effects. Accordingly the present invention is related to pharmaceutical compositions that comprise both active agents together in the same dosage form in order to be given at foe same time or inside separate dosage forms to be given simultaneously for said agents to be used sequentially in separate dosage forms. If the compositions are in separate dosage forms said dosage forms can be the same as each other or thev can he different from each other According to another aspect the present invention describes a pharmaceutical formulation which is used in treating Helicobacter pylori eradication, NSAID sourced ulcer prophylaxis, Zollmger-Eliison syndrome, dyspepsia, duodenum ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), pyrosis, systemic mastocytosis, multiple endocrine adenoma, syndrome, and esophagitis by giving effective amounts of a proton pump inhibitor selected from the group of omeprazole, esomeprazole, lansoprazole dexlansopr&zole, rabeprazole, dexrabcprazolc and pantopsazole in addition to prucalopride.

Accenting to an aspect the present invention is related to pharmaceutical compositions that comprise at least one pharmaceutically acceptable excipient in addition to the active agents. in pharmaceutical compositions that comprise pmca!opride and a proton pump inhibitor suitable to (he invention the expression“derivative” means pharmaceutically acceptable salts of prucalopride and a proton pump inhibitor, hydrates, solvates, esters, enantiomers, diastereomers, racemates and/or any polymorphic forms such as amorphous crystals or combinations thereof.

The pharmaceutical compositions according to fee invention can be prepared in any form such as tablets, effervescent tablets, effervescent granules, effervescent dty powder, film coated tablet, enteric coaled tablet, dry powder, granule, capsule, delayed release tablet, modified release tablet, prolonged release tablet, orodispersible tablet or chewing tablets. The pharmaceutical compositions accenting to the subject matter of the invention can have any kind of dosage forms together, and said compositions am be in any dosage form if the active agents are stored in dosage forms separate from each other. In other words, compositions that comprise combinations suitable to 6» invention can have any kind of dosage forats mentioned above, or a combination of said dosage forms or a treatment package form formed of said combinations.

The pharmaceutical compositions suitable to the invention additionally comprises at least an excipient selected from the group comprising a dispersant, a diluent, a glidant, a lubricant, a binder, an effervescent pair formed of at least an acidic agent and at least a basic agent, a colorant, a pH adjuster agent, a surfactant, a stabilizer, a sweetener and/or a flavoring agent and an aromatic agent.

The dispersant feat can be used inside the pharmaceutical compositions suitable to the invention can be selected from the group comprising carboxymethyl cellulose, carboxymethyi cellulose calcium, carboxymethyl cellulose sodium, croscarmetiose sodium, crospovidone, hydroxypropyl cellulose, macrocrystalline cellulose, methyl cellulose, chitosan, starch and sodium glyco!ate.

The diluent that can be used in the pharmaceutical compositions suitable to the invention can be selected from the group comprising calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate, calcium sulphate, microerystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maitodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xy!itol.

The giidant that can be ased inside the pharmaceutical compositions according to the invention can be selected from the group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium Iauril sulphate, talc, stearic acid and zinc stearate.

The lubricant that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicatc and talc.

The binder that may be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising carboxymcthyi cellulose sodium, ethyl cellulose, gelatin, hydroxycthyl cellulose, Hydroxymethyl cellulose, hydroxypropyi cellulose, hypermellosc, magnesium aluminum silicate, maitodextrin, methyl cellulose, povidone and starch.

The acidic agent that forms the effervescent pair formed of at least an acidic agent and at least a basic agent that can be used inside the pharmaceutical compositions according to the invention can be selected from a group formed of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid and from a group comprising basic agent; sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.

The pH adjuster agent that can be used inside the pharmaceutical compositions according to the invention can be selected from citrate, phosphate, tartarate, ftmtantte, acetate and amino acid salts. The surfactant that can be used inside the pharmaceutical compositions according to the invention can be selected from sodium iauril sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and other similar agents.

The stabilizer that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.

The sweetener and/or flavoring agent that can be used inside the pharmaceutical compositions according to the invention can be selected from the group comprising acesuifame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol and sodium chloride.

The aromatic agent that can be used inside the pharmaceutical compositions according to the invention can be selected from aromas such as menthol, lemon, orange, vanilla, strawberries, raspberries and caramel. 0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight pmcalopride is available inside the pharmaceutical compositions according to die invention.

0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight omeprazole is available inside the pharmaceutical compositions according to the invention. 0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight esoraeprazoie is available inside the pliarmacexitical compositions according to (he invention.

0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight lansoprazole is available inside the pharmaceutical compositions according to the invention.

0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight dexlansoprazolc is available inside the pharmaceutical compositions according to the invention.

0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight rabeprazole is available inside the pharmaceutical compositions according to the invention.

0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by weight dexrabeprazo!e is available inside the pharmaceutical compositions according to the invention.

0.1 to 99% by weight in ratio, preferably 1 to 98% in ratio, particularly preferably 5 to 95% in ratio by- weight pantoprazo!e is available inside the pharmaceutical compositions according to die invention.

Pmcalopride is available inside the pharmaceutical composition according to the invention within the range of 0.1 mg to 5 mg per unit dosage fonn, preferably within the range of 0.2 mg to 4.5 mg, especially preferably within the range of 0.5 mg to 4 mg.

Omeprazole is available inside the pharmaceutical composition according to the invention within the range of 5 mg to 80 mg per unit dosage form, preferably within the range of 5 mg to 75 mg, especially preferably within the range of 5 mg to 70 mg.

Esomeprazolc is available inside the pharmaceutical composition according to die invention within the range of 5 rag to 80 mg per unit dosage form, preferably within the range of 5 mg to 75 mg, especially preferably within the range of 5 mg to 70 mg.

Lansoprazole is available inside the pharmaceutical composition according to the invention within die range of 3 mg to 50 mg per unit dosage form, preferably within the range of 5 mg to 45 mg, especially preferably within the range of 8 mg to 40 mg. Dexiansoprazole is available inside the pharmaceutical composition according to the invention within the range of 10 mg to 100 mg per unit dosage form, preferably within the range of 12 mg to 90 mg, especially preferably within the range of 15 mg to 80 mg.

Rabeprazoie is available inside the pharmaceutical composition according to the invention within the range of 1 mg to 100 mg per unit dosage form, preferably within the range of 2 mg to 90 mg, especially preferably within the range of 3 mg to 80 mg.

Dembeprazoie is available inside the pharmaceutical composition according to the invention within the range of l mg to 50 mg per unit dosage form, preferably within the range of 2 mg to 45 mg, especially preferably within the range of 3 mg to 40 mg. Pantoprazole is available inside the pharmaceutical composition according to the invention within the range of 1 mg to 80 mg per unit dosage form, preferably within the range of 2 mg to 75 mg, especially preferably within the range of 5 mg to 70 mg.

A third active agent can be optionally included in addition to the active agents already available inside the pharmaceutical compositions according to the invention. The third active agent can be selected from anti acid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antioobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiloci, antiseptic, antiacne, antibacterial, antimicotic, antiviral, antineop!astic, antiarrhythmic, antiadrenergic, antiepileptic anti-parkinson, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulfonamide, imidazole, corticosteroid, thiozoiidinedione, biguanide, immuoostimulant, immunosuppressant, muscle relaxant, analgesic, psyeholeptic, psychoanaicptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; aipha-glucosidase inhibitors, aidozreductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin B;, vitamin C, vitamin E, vitamin B*, vitamin Bz, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium. The pharmaceutical composition according to the invention can be obtained by;

• Homogeneous mixing of active agents and, if necessary, addition of at least one of the above- mentioned excipients or

• Granulating the active agents with a granulation solution containing at least one of the excipients and then homogeneously mixing with the other excipients or

• Granulating the mature comprising at least one of the excipients mentioned above and the active agents with a granulation solution and then homogeneously mixing with the other excipients or • Mixing the active agents with at least one of the excipients mentioned above and granulating it with a granulation solution comprising at least an excipient or

• In tiie case that the active agents are prepared in two separate compositions, the methods mentioned above can be obtained by using the methods separately for the active agent compositions and by combining the resulting compositions or storing than in different dosage forms.

The obtained pharmaceutical composition or compositions may be brought into die form of any of the above-mentioned dosage forms. In the case that tablet form is obtained, the tablets may be treated with film coating agents, for example, with sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents, or coating compositions comprising any of the combinations thereof.

Saccharose can be used alone as the sugar based coating agent or it can be used optionally with agents such as tale, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arable, polyvinylpyrrolidone and puliuian or a combination thereof. The water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl acetal diethyiammoacetaie, aminoalky! methacrylate copolymers and polyvinyl pyrrolidone and polysaccharides such as puliuian or combinations thereof.

Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid derivatives such as methacrylic add copolymer L, methacrylic add copolymer LD and methacrylic acid copolymer S and natural agents such as shellac or combinations thereof.

Delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose, acrylic acid derivatives such as aminoalky! methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsions or combinations thereof.

The pharmaceutical composition according to the invention can be used in treating Helicobacter pylori eradication, NSAID sourced ulcer prophylaxis, Zollinger-Ellison syndrome, dyspepsia, duodenum ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), pyrosis, systemic mastocytosis, multiple endocrine adenoma syndrome, and esophagitis.

Claims

1. A pharmaceutical composition comprising an active agent or pharmaceutically acceptable derivatives thereof selected from the prucalopride and proton pump inhibitor group as active agent.

2. A pharmaceutical composition according to claim 1, characterized by the proton pump inhibitor is selected from the group comprising omeprazole, esomepruzoie, lansoprazole, dexlansoprazole, rabeprazo!e, dexrabeprazok, pantopraznie or pharmaceutically acceptable derivatives thereof.

3. A pharmaceutical composition according to claim 2, characterized by comprising omeprazole or pharmaceutically acceptable derivatives thereof m combination with prucalopride or pharmaceutically acceptable derivatives thereof.

4. A pharmaceutical composition according to claim 2, characterized by comprising esomeprazole or pharmaceutically acceptable derivatives thereof in combination with prucalopride or pharmaceutically acceptable derivatives thereof.

5. A pharmaceutical composition according to claim 2, characterized by comprising lansoprazole or pharmaceutically acceptable derivatives thereof in combination with prucalopride or pharmaceutically acceptable derivatives thereof.

6. A pharmaceutical composition according to claim 2, characterized by comprising dexlansoprazole or pharmaceutically acceptable derivatives thereof in combination with prucalopride or pharmaceutically acceptable derivatives thereof.

7. A pharmaceutical composition according to claim 2, characterized by comprising rabeprazole or pharmaceutically acceptable derivatives thereof in combination with prucalopride or pharmaceutically acceptable derivatives thereof.

8. A pharmaceutical composition according to claim 2, characterized by comprising dexrabeprazole or pharmaceutically acceptable derivatives thereof in combination with prucalopride or pharmaceutically acceptable derivatives thereof

9. A pharmaceutical composition according to claim 2, characterized by comprising pantoprazok or pharmaceutically acceptable derivatives thereof in combination with prucalopride or pharmaceutically acceptable derivatives thereof

10. A pharmaceutical composition that comprises prucalopride and a proton pump according to claim 1 - 2 characterized in that it is in the form of pharmaceutically acceptable salts of prucalopride and proton pump inhibitor, hydrates, solvates, esters, enantiomers, diastereomers, and/or any of polymorphic forms such as amorphous crystals or combinations thereof,

11. A pharmaceutical composition according claim 1, characterized in that it can be in any form such as tablets, effervescent tablets, effervescent granules, effervescent dry powder, film coated tablet, enteric coated tablet, (by powder, granule, capsule, delayed release tablet, modified release tablet, prolonged release tablet, orodispersible tablet or chewing tablets.

12. A pharmaceutical composition according to any of the preceding claims characterized in that it comprises at least a pharmaceutically acceptable excipient besides the active agents.

13. A pharmaceutical composition according to claim 12, characterized in that besides the active agents, it comprises at least an excipient selected from the group comprising a dispersant, a diluent, a lubricant, a gljdant, a binder, an effervescent pair formed of at least an acidic agent and at least a basic agent, a colorant, a pH adjuster agent, a surfactant, a stabilizer, a sweetener and/or a flavoring agent and an aromatic agent.

14. A pharmaceutical composition according to any of the preceding claims, characterized in that it optionally comprises a third active agent in addition to the active agents it comprises which can be selected from anti acid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrhcal, antioobesity, antithrombotic, antifibrtnolytic, antianemic, antihypertensivc, antifungal, antipruritic, antipsortatic, antibitoci, antiseptic, antiacnc, antibacterial, antimicotic, antiviral, antineoplastic, antianhythmic, antiadrenergic, «ntiepi!eptic anti-parkinson, antiprotozoal, anthelmintic, antiuiflammatory, diuretic, laxative, sulfonamide, imidazole, corticosteroid, thiozolidinedione, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha· g!ucosidase inhibitors, aldozreductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin Bt, vitamin C, vitamin E, vitamin B». vitamin B_?., vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.

15. A pharmaceutical composition according to claim 1 , characterized by being used in treating hclicobacter pylori eradication. NSAID sourced ulcer prophylaxis, Zoilmger-EUison syndrome, dyspepsia, duodenum ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), pyrosis, systemic mastocytosis, multiple endocrine adenoma syndrome, and esophagitis.