MX2010009129A - Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same. - Google Patents

Abstract

The present disclosure relates to pharmaceutical compositions comprising omeprazole, lansoprazole and sodium bicarbonate. Methods of using such compositions are also provided.

Description

COMPOSITION COMPRISING A COMBINATION OF OMEPRAZOL AND LANSOPRAZOL, AND A DAMAGING AGENT, AND METHODS FOR ITS USE FIELD OF THE INVENTION This application claims priority of the US Provisional Application Serial No. 61 / 030,045, filed on February 20, 2008, which is incorporated herein by reference.

Pharmaceutical compositions comprising omeprazole, lansoprazole and buffering agent are described herein. Methods for the use of these compositions are also offered.

BACKGROUND OF THE INVENTION As used herein, the term "acid labile pharmaceutical agent" refers to any pharmacologically active drug subject to acid catalyzed degradation. A class of acid-labile pharmaceutical agents is a class of antisecretory agents that do not have anticholinergic properties or histamine antagon antagonists, but that suppress the secretion of gastric acids by specific inhibition of the H +, K + -ATPase enzyme system on the surface secretory of the gastric parietal cell (hereinafter referred to as "proton pump inhibitors" or "PPIs"). These agents offer a more specific class of inhibitors of gastric acid secretion in mammals, such as humans, by blocking the final stage of acid production.

A particular class of PPIs includes compounds from substituted benzimidazoles containing a sulfinyl group which bridges substituted pyridine and benzimidazole rings. Another class of PPIs is a class of substituted aryl imidazoles, such as substituted bicyclic aryl imidazoles. The mechanism of action of the PPIs occurs when they reach parietal cells from the blood and diffuse into secretory canaliculi, where they are protonated and therefore trapped. It is believed that the protonated agent rearranges to form a sulfenic acid and a sulfenamide. It is estimated that sulfenamide, in turn, interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H +, K + -ATPase. See, for example, Hardman et al. , Goodman & Gilman's The Pharmacological Basis of Therapeutics, page 907, ninth edition (1996).

The PPI medications available today have a delay until the maximum effect is reached (for example, maintaining a gastric pH above about 3.5), so that it may take approximately 5 days to reach a steady-state effect. Therefore, it would be desirable to have a significant effect on gastric pH before 5 days, starting with the first dose of medication.

COMPENDIUM OF THE INVENTION In various embodiments, the present disclosure provides pharmaceutical compositions comprising a first proton pump inhibitor (PPI1) having a therapeutically effective portion, optionally enteric coated; a subsequent proton pump inhibitor (PPI2), which has a therapeutically effective portion, optionally with enteric coating; and one or more buffer agents.

Another embodiment discloses a pharmaceutical composition comprising omeprazole, which has an optionally enteric-coated therapeutically effective portion, lansoprazole, which has a therapeutically effective portion optionally enteric coated, and sodium bicarbonate or other buffering agents.

Methods for using these compositions for the treatment of a patient are provided, including patients with or without gastroparesis (slow emptying of the stomach), which requires therapy for various diseases and disorders, including disorders related to gastric acids, such as, for example, but not limited to these examples, severe erosive esophagitis (grade C and D of the Los Angeles classification), Barrett's esophagus and reversal of Barrett's esophagus, treatment to halt progression and encourage the reversion of esophageal metaplasia related to reflux with dysplasia of low grade or high grade, treatment for stop the progression and encourage the reversion of adenocarcinoma of the esophagus related to acid-related reflux or adenocarcinoma of the stomach, treatment of patients undergoing ablation in Barrett's esophagus to prevent recurrence, duodenal ulcer, gastric ulcer, erosions and gastric and duodenal ulcerations , acid dyspepsia, gastroesophageal reflux disease (GERD), symptomatic GERD of unsatisfactory response, acid reflux, ulcers and esophageal erosions, precancerous and cancerous esophageal lesions induced by exposure to acids, radiation-induced esophagitis or chemotherapy, acid hyper-secretion conditions, hyper- pathological gastrointestinal secretion (Such as Zollinger Ellison syndrome), ulcerative dyspepsia, eradication of Helicobacter pylori short term (H. pylori) (lower treatment 5 days with two antibiotics selected from the following group, but not limited to these examples, antibiotics penicillin type (for example amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), cefemos or cephalosporin antibiotics (for example, efixima, cefuroxime, cefuroxime axetil, cefaclor, ceftizoxime, cefotaxime, ceftazidime, etc.), macrolide antibiotic ( for example erythromycin, clarithromycin, azithromycin, telithromycin, roxithromycin, etc.), tetracycline-type antibiotic (for example tetracycline, minocycline, doxycycline, tigecycline, etc.), aminoglycoside type antibiotic (for example, gentamicin, kanamycin, netilmicin, amikacin, tobramycin, etc.), carbapenem antibiotic (for example, imipenem, meropenem, doripenem, etc. .), ester prodrug of carbapenem (eg, terbipenem pivoxil, faropenem daloxate, other oral carbapenem prodrugs including GV-118819, CS-834, L-084, DZ-2649, CL-191121, etc.), antibiotic of quinolone type (for example norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, sitafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, pazufloxacin, prulifloxacin, olamufloxacin, ganefloxacin, gemifloxacin, troxa loxacin, etc.), nitroimidazole-type antibiotic (for example metronidazole, tinidazole) , and antibiotic analogs of rifamycin or ansamycin (eg, derivatives of rifabutin, rifampin, rifampin, rifaximin, rifalazil, and rifamycin such as 3 '-hydroxy-5' - (4-propylpiperazinyl) benzoxazinorifamycin)), extraesophageal or atypical manifestations of gastroesophageal reflux disease (such as, but not limited to, eye pain, asthma, bronchitis, pneumonia, chest pain, cough, recurrent laryngitis, balloon pharyngeal, sinusitis, otalgia, otitis media, Eustachian tube dysfunction, voice change, balloon sensation, throat clearing, halitosis, sore throat, aphthous ulcers), nocturnal acid escape (NAB), sleep apnea, sleep disturbance, suspension of gastrointestinal bleeding and prevention of re-bleeding after gastrointestinal bleeding prior to endoscopic assessment of bleeding from the upper gastrointestinal tract, prevention of stress ulcer, treatment-related bleeding treatment stress, attack activity or apparent attack, Sandifer syndrome, poor development, anorexia, anorexia nervosa, weight loss, apnea, and bradycardia.

Other objects, features and advantages will be presented in the following Detailed Description, and in part will be apparent from the description or may be learned through the practice of the modalities disclosed herein. These objects and advantages will be achieved and achieved through the processes and compositions particularly specified in the written description and claims.

DETAILED DESCRIPTION OF THE INVENTION While the present invention can be incorporated in various forms, the following description of various embodiments is made on the understanding that the present disclosure should be considered as an example of the invention and should not be considered as limiting the invention to the specific embodiments illustrated. Headings are offered for convenience only and should not be construed as establishing limits to the present invention in no way. The modalities illustrated under each heading can be combined with modalities illustrated under other headings.

It has been discovered that a pharmaceutical composition comprising omeprazole and lansoprazole may offer a greater inhibition of gastric acid than the use of a single type of proton pump inhibitor, with or without a buffering agent.

A pharmaceutical composition is therefore provided herein comprising: a) a first proton pump inhibitor (PPI1) having a therapeutically effective portion optionally enteric coated; b) a second proton pump inhibitor (PPI2), which has a therapeutically effective portion optionally enteric coated; Y c) one or more buffering agents.

Also provided herein is a pharmaceutical composition comprising: a) omeprazole having an optionally therapeutically effective portion with enteric coating; b) lansoprazole, which has a therapeutically effective portion optionally enteric coated; Y c) sodium bicarbonate.

Methods are provided for using these compositions for the treatment of a patient, including patients with or without gastroparesis (slow emptying of the stomach), which requires therapy for various diseases and disorders, including gastric acid related disorders, such as, but not limited to these examples, severe erosive esophagitis (grade C and D of the Los Angeles classification), Barrett's esophagus and reversal of Barrett's esophagus, treatment to halt progression and encourage reversion of esophageal metaplasia related to reflux with grade dysplasia low or high-grade, treatment to stop progression and encourage reversal of adenocarcinoma of the esophagus related to reflux or acid-related stomach adenocarcinoma, treatment of patients undergoing ablation in Barrett's esophagus to prevent recurrence, duodenal ulcer, ulcer gastric, erosions and gastric ulcerations and duodenal, acid dyspepsia, gastroesophageal reflux disease (GERD), symptomatic GERD of unsatisfactory response, acid reflux, esophageal ulcers and erosions, precancerous and cancerous esophageal lesions induced by exposure to acids, radiation-induced esophagitis or chemotherapy, hyper-conditions -acid secretion, pathological gastrointestinal hyper-secretion conditions (such as Zollinger Ellison syndrome), dyspepsia Non-ulcerative, short-term eradication of Helicobacter pylori (H. pylori) (treatment less than 5 days with two antibiotics selected from the following group, but not limited to these examples, penicillin-type antibiotics (eg amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), cefemos or cephalosporin antibiotics (eg, efixima, cefuroxime, cefuroxime axetil, cefaclor, ceftizoxime, cefotaxime, ceftazidime, etc.), macrolide antibiotic (eg erythromycin, clarithromycin, azithromycin, telithromycin, roxithromycin , etc.), tetracycline type antibiotic (for example tetracycline, minocycline, doxycycline, tigecycline, etc.), aminoglycoside type antibiotic (for example, gentamicin, kanamycin, netilmicin, amikacin, tobramycin, etc.), carbapenem antibiotic (for example, imipenem, meropenem, doripenem, etc.), ester prodrug of carbapenem (e.g., terbipenem pivox) ilo, faropenem daloxato; other oral carbapenem prodrugs including GV-118819, CS-834, L-084, DZ-2649, CL-191121, etc.), quinolone-type antibiotic (e.g. norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, sitafloxacin, clinafloxacin, gatifloxacin , moxifloxacin, pazufloxacin, prulifloxacin, olamufloxacin, ganefloxacin, gemifloxacin, trovafloxacin, etc.), antibiotic-type nitroimidazoles (for example metronidazole, tinidazole), and antibiotic analogs of rifamycin or ansamycin (eg, derivatives of rifabutin, rifampicin, rifampin, rifaximin, rifalazil, and rifamycin such as 3 '-hydroxy-5' - (4-propylpiperazinyl) benzoxazinorifamycin)), extraesophageal or atypical manifestations of gastroesophageal reflux (as, for example, but not limited to these examples, eye pain, asthma, bronchitis, pneumonia, chest pain, cough, recurrent laryngitis, pharyngeal balloon, sinusitis, otalgia, otitis media, eustachian tube dysfunction, change of voice, balloon sensation, clearing of throat, halitosis, sore throat, aphthous ulcers), nocturnal acid escape (???), sleep apnea, sleep disturbance, suspension of gastrointestinal bleeding and prevention of re-bleeding after gastrointestinal bleeding , treatment prior to endoscopic evaluation of upper gastrointestinal bleeding, prevention of stress ulcer, treatment of bleeding related to stress, attack activity or apparent attack, Sandifer syndrome, poor development, anorexia, anorexia nervosa, weight loss, apnea, and bradycardia.

Proton Pump inhibitors Compositions of the present disclosure comprise at least one pharmaceutically acceptable acid-labile pharmaceutical agent. For example, embodiments disclosed herein comprise at least one pump inhibitor of protons H +, K + -ATPase (PPI). The term "proton pump inhibitor" or "PPI" refers to any acid-labile pharmaceutical agent that possesses a pharmacological activity as an inhibitor of H +, K + -ATPase. Classes of PPIs include, but are not limited to, these examples, substituted aryl imidazoles, substituted bicyclic aryl imidazoles, substituted benzimidazole compounds, and substituted imidazolpyridines. A PPI can be found, as desired, in any form such as for example free base, free acid, salt, ester, hydrate, anhydrate, salt hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, free acid, salt, ester, hydrate, anhydrate, salt hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or any other pharmacologically suitable derivative is therapeutically active or is subjected to conversion inside the body in a therapeutically active form. In one embodiment, illustrative PPIs are the compounds of Formula (A): where R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl; R 2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl; R3 and R5 are the same or different and each is hydrogen, alkyl, lower alkyl Ci-4 (for example, methyl, ethyl, etc.), alkoxy, amino or alkoxyalkoxy; R 4 is hydrogen, alkyl, lower alkyl Ci 4 (for example, methyl, ethyl, etc.), alkoxy which may be optionally fluorinated, or alkoxyalkoxy; Q is nitrogen, CH, or CR1; W is nitrogen, CH, or CR1; and is an integer from 0 to 4; Y Z is nitrogen, CH, or CR1; or a free base, salt, ester, hydrate, salt hydrate, amine, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.

A specific example of a PPI is tenatoprazole (TU-199, which is also known as benatoprazole), or 5-methoxy-2- [[(- methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4, 5-b] pyridine, described in EP 0254588, which is incorporated herein by reference in its entirety. An alternative IUPAC name for tenatoprazole is 3-methoxy-8 - [(4-methoxy-3,5-dimethyl-pyridin-2-yl) methylsulfinyl] -2,7,9-triazabicyclo [4.3.0] nona-2 , 4, 8, 10-tetraene. Due to its relatively long elimination profile, tenatoprazole can be used for the treatment of conditions such as gastroesophageal reflux disease, gastrointestinal bleeding and dyspepsia, in accordance with that described in French patent application 0213113, which is incorporated herein by reference in its entirety Tenatoprazole is a proton pump inhibitor that is similar to the chemical structure of omeprazole (Merck Index No. 6913; CAS No. 73590-58-6), or 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. Omeprazole is a widely used proton pump inhibitor of the class of substituted benzimidazoles. Tenatoprazole belongs to the class of substituted imidazopyridines and has an imidazo [4, 5-b] pyridine portion while omeprazole has a benzimidazole moiety.

Specific examples of suitable PPIs include esomeprazole (also known as S-omeprazole), ilaprazole (U.S. Patent No. 5,703,097), tenatoprazole (or benatoprazole), omeprazole, lansoprazole, s-lansoprazole, rabeprazole, hydroxyomeprazole, pantoprazole, pariprazol, leminoprazole, dontoprazole, habeprazole, perprazole, ransoprazole, and nepaprazole, or a free base, a free acid, a salt, hydrate, ester, salt hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug , or derivative of such compounds.

Other acid labile pharmaceutical agents include, but are not limited to, these examples, soraprazan (Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidinamine, 4- (3, -dihydro-l-methyl-2 (1H) -isoquinolinyl) -N- (4-fluoro-enyl) - 5, 6-dimethyl-monohydrochloride) (YuHan); BY-112 (Altana); SPI-447 (Imidazo (1, 2-a) thieno (3, 2-c) pyridin-3-amine, 5-methyl-2- (2-methyl-3-thienyl) (Shinnippon); 3-hydroxymethyl -2-methyl-9-phenyl-7H-8, 9-dihydro-pyran (2, -3-c) imidazo (1,2-apyridine (PCT Publication WO 95/27714) (AstraZeneca); Pharmaproj ects no. 4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyran (2, 3-c) -imidazo (1,2-a) pyridine) (AstraZeneca, discontinued) WO 95/27714; Pharmaproj ects No. 4891 (EP 700899) (Aventis); Pharmaproj ects No. 4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab); Pharmapro ects No. 3177 (Roche); BY-574 (Altana); Pharmaproj ects No. 2870 (Pfizer); AU-1421 (EP 264883 (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis); WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); nepaprazol (To a Eiyo); HN-11203 (Nycomed Pharma; OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SKAnd F-95601 (GS, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); 3337 (Aventis), RS-13232A (Roche), AU-1363 (Merck), S and F-96067 (EP 259174) (Altana), SUN 8176 (Daiichi Phama), Ro-18-5362 (Roche), ufiprazole EP 74341) (AstraZeneca) and Bay-p-1455 (Bayer), or a free base, free acid, salt, hydrate, ester, salt hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative thereof. such compounds.

Other modalities contemplated within the framework of the present invention include, but are not limited to, these modalities, the modalities described in the following U.S. Patent Nos. 4, 628, 098; 4689, 333 4,786, 505; 4, 853, 230; 4, 965, 269; 5, 021, 43.3; 5, 026, 560 5, 045, 321; 5, 093, 132; 5,430, 042; 5, 433, 959; 5, 576, 025 5, 639, 478; 5, 703, 110; 5,705, 517; 5, 708, 017; 5, 731, 006 5,824, 339; 5, 840,737; 5, 855, 914; 5,879,708; 5, 948, 773 6, 017, 560; 6, 123, 962; 6, 187, 340; 6.296, 875; 6, 319, 904 6, 328, 994; 4, 255, 431; 4, 508, 905; 4, 636, 499; 4,738, 974 5,690,960; 5,714,504 5,753,265; 5,817,338; 6,093,734 6,013,281; 6, 136,344 6, 183,776; 6, 328,994; 6, 479,075, 6, 489, 346; 6, 559, 167 6, 645,988; 6, 699,885; 7,101,573 7, 109, 161.

Other embodiments contemplated within the framework of the present invention include, but are not limited to, these examples, the modalities described in the following documents: EP 0254588; EP 0005129.

Other embodiments contemplated within the framework of the present invention include, but are not limited to, these modalities, the modalities described in the following PCT Publications: WO 94/27988; O 05/044223; WO 06/043280. Other modalities contemplated within the framework of the present disclosure include, but are not limited to, these modalities, the modalities described in the following US Applications Nos .: 20020192299; 20040131675 20040146554 20040248939 20040248942 20050003005 20050031700 20050037070 20050054682 20050249802 20050220870 20050220870 20050224800 2005024982 20050244517 20050249806 20050249811 20050266071 20050288334 20050277672 20050277673 20050277671 20060024238 20060134210 20060147522 20060159760 20060167262 20060173045; 20060204585.

The above lists of suitable acid inhibitors are for the purpose of illustrating the present invention but not they represent complete lists since a person with ordinary knowledge in the art will recognize that many other suitable acid inhibitors can be created. Inhibitors of gastric acids, including proton pump inhibitors, as well as their salts, hydrates, esters, salt hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs and derivatives can be prepared using standard procedures that a person with ordinary knowledge of the matter of synthetic organic chemistry will recognize. See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure [Advanced Organic Chemistry: Reactions, Mechanisms and Structure], 4a. Edition, (New York: Wiley-Intersciencé, 1992); Leonard et al., Advanced Practical Organic Chemistry, (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).

The terms "pharmaceutically acceptable salts" or "salts" include the salt of a proton pump inhibitor prepared from formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid , ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethane sulfonic acid, sulfanilic acid, acid cyclohexylaminosulfonic, algenic acid, beta-hydroxybutyric acid, galactárico acid and galacturónico acid.

In one embodiment, acid addition salts are prepared from the free base forms using, for example, methodologies involved in the reaction of the free base with a suitable acid. Suitable acids for the preparation of acid addition salts include both organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid , phosphoric acid, and the like.

In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the salts of The acid addition of the proton pump inhibitors are halide salts, which are prepared, for example, by the use of hydrochloric acid or hydrobromic acid. In other embodiments, the basic salts are alkali metal salts, for example, sodium salt.

Salt forms of proton pump inhibitors include, but are not limited to, these examples: a form of sodium salt, such as for example esomeprazole sodium, omeprazole sodium, tenatoprazole sodium, rabeprazole sodium, pantoprazole sodium; a magnesium salt form, such as, for example, esomeprazole magnesium or omeprazole magnesium, in accordance with that described in US Pat. No. 5,900,424; a form of calcium salt; a potassium salt form such as, for example, potassium salt of esomeparazol, in accordance with that described in US Pat. No. 6,511,996; salt hydrate forms including, but not limited to, these examples, sodium hydrate salt forms, for example, sodium tenatoprazole hydrate or omeprazole sodium hydrate; Other salts of esomeprazole are described in U.S. Patent Nos. 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are disclosed in U.S. Patent Nos. 4,758,579 and 4,628,098, respectively. The above list of suitable salts of proton pump inhibitors is intended to illustrate the present invention but is not a complete list since a A person with ordinary skill in the art could recognize that other pharmaceutically acceptable salts of the proton pump inhibitor could be created.

In one embodiment, the preparation of asters includes the functionalization of hydroxyl and / or carboxyl groups that may be present within the molecular structure of the drug. In another embodiment, the esters are acyl substituted derivatives of free alcohol groups, for example, portions derived from carboxylic acids of the formula RCOORi, wherein Ri is a lower alkyl group. Esters can be reconverted to the free acids, if desired, by using procedures that include hydrogenolysis or hydrolysis, but not limited to these procedures.

"Amides" can be prepared using techniques known to a person skilled in the art or described in the relevant literature. For example, amides can be prepared from esters, using suitable amine reagents, or can be prepared from an anhydride or acid chloride by reaction with an amine group, such as for example ammonia or a lower alkyl amine.

The "tautomers" of substituted bicyclic aryl imidazoles include, for example, omeprazole tautomers, such as those described in US Pat. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6, 316,020; 6,326,384; 6,369,087; and 6,444,689.

An "example isomer" of a substituted bicyclic aryl imidazole is the isomer of omeprazole which includes, but is not limited to, the isomers described in: Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Patent No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.

"Exemplary polymorphs" include, but are not limited to, these examples, the polymorphs described in PCT Publication No. WO 92/08716 and in US Patent Nos. 4,045,563; 4, 182, 766; 4, 508, 905; 4, 628, 098; 4, 636, 99; 4, 689, 333; 4, 758, 579; 4,783, 974; 4, 786, 505; 4, 808, 596; 4, 853, 230; 5, 026, 560; 5, 013,743; 5, 035, 899; 5, 045, 321; 5, 045, 552; 5, 093, 132; 5, 093, 342; 5, 433, 959; 5, 464, 632; 5, 536, 735; 5, 576, 025; 5, 599, 794; 5, 629, 305; 5, 639, 478; 5, 690, 960; 5, 703, 110; 5, 705, 517; 5, 714, 504; 5, 731, 006; 5, 879, 708; 5, 900, 424; 5, 948, 773; 5, 997, 903; 6, 017, 560; 6, 123, 62; 6, 147, 103; 6, 150,380; 6, 166, 213; 6, 191, 148; 5, 187.340; 6, 268, 385; 6, 262, 086; 6, 262, 085; 6.296, 875; 6, 316, 020; 6, 328, 994; 6, 326, 384; 6,369, 085; 6, 369, 087; 6, 380, 234; 6, 428, 810; 6,444,689; and 6, 462, 0577.

In one embodiment, at least one proton pump inhibitor does not present an enteric coating. In other embodiment, a portion of at least one proton pump inhibitor has optional enteric coating. In another embodiment, a therapeutically effective portion of at least one proton pump inhibitor has optional enteric coating. In another embodiment, about 5%, about 15%, about 20%, about 30%, about 40%, about 50%, or about 60%, of at least one proton pump inhibitor has optional enteric coating. In another embodiment, a portion of at least one proton pump inhibitor comprises a "thin enteric coating". The term "thin enteric coating" refers herein to a pH-sensitive coating that is applied in a manner or in an amount such that it retards the release of the coated substance in the gastrointestinal fluid over a period of time, but ultimately allows the release of a part of the coated substance before passage in the duodenum.

In one embodiment, at least one proton pump inhibitor has a particle size D90, DSQ, D70, O D5O, by weight or number, less than about 900 μ? T ?, less than about 800 μ?, less than about 700 μ ??, less than about 600 μ ?,, less than about 500 μp, less than about 400 μp, less than about 300 μ ?,, less than about 200 μ ??, less than about 150 μ? t ?, less than about 100 μ?, less than about 80?, less than about 60?, less than about 40?, less than about 35?, less than about 30. ?, less than about 25 μp ?, less than about 20 μp ?, less than about 15 and m, less than about 10 μp ?, or less than about 5] im.

In another embodiment, compositions are provided wherein a micronized proton pump inhibitor has a size that allows release of an amount greater than about 90%, greater than about 75%, or greater than about 50% of the proton pump inhibitor. from the dosage unit within about 1 hour, within about 50 minutes, within about 40 minutes, within about 30 minutes, within about 20 minutes, within about 10 minutes, or within about 5 minutes after of placement in a standard dissolution test.

In another embodiment, compositions of the disclosure comprise two PPIs in a total amount of from about 1 mg to about 3000 mg, from about 1 mg to about 2000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 750 mg , of approximately 1 mg up about 500 mg, from about 1 mg to about 300 mg, from about 5 mg to about 250 mg, from about 5 mg to about 200 mg, from about 5 mg to about 175 mg, from about 5 mg to about 120 mg, about 5 mg to about 100 mg, from about 5 mg to about 80 mg, or from about 5 mg to about 50 mg, for example about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, or approximately 200 mg mg.

In another embodiment, compositions of the present invention comprise two PPIs wherein each is present in an amount of from about 40 mg to about 160 mg, from about 50 mg to about 150 mg, from about 60 mg to about 140 mg, of about 60 mg to about 130 mg, about 60 mg to about 120 mg, from about 60 mg to about 110 mg, from about 60 mg to about 100 mg, from about 70 mg to about 100 mg, or from about 80 mg to about 100 mg.

Shock Absorbing Agent Compositions of the present invention comprise one or more pharmaceutically acceptable buffering agents. Useful buffering agents within the scope of the present disclosure include agents which possess a pharmacological activity as weak base or strong base. In one embodiment, the buffering agent, when formulated with a PPI or administered substantially simultaneously with a PPI, functions to raise the pH of the gastrointestinal fluid and consequently to prevent or substantially inhibit the acid degradation of the PPI by the gastrointestinal fluid over a period of time. of time.

In. In another embodiment, buffering agents useful in accordance with the present disclosure include, but are not limited to, these examples, a salt of a group IA metal including, for example, a bicarbonate salt of a group IA metal, a carbonate salt of a Group IA metal, an alkaline earth metal buffer, an amino acid, an alkaline salt of an amino acid, an aluminum buffer, a calcium buffer, an agent Sodium buffer, or a magnesium buffer agent. Other suitable buffering agents include carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates and the like alkali (sodium and potassium) or alkaline earths (calcium and magnesium, such as for example phosphate, citrate, borate, acetate, bicarbonate , and sodium or potassium carbonate.

Non-limiting examples of suitable buffering agents include aluminum hydroxide, magnesium, coprecipitated aluminum hydroxide / magnesium hydroxide, co-precipitated aluminum hydroxide / sodium bicarbonate, calcium acetate, calcium bicarbonate, calcium borate, carbonate calcium, calcium bicarbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphates (including calcium dihydrogen phosphate, tricalcium phosphate and the like), calcium succinate, calcium tartrate, calcium formate, calcium propionate, biphasic calcium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium acetate, magnesium aluminate metasilicate, oxide magnesium, magnesium phthalate, magnesium phosphate, magnesium silicate magnesium succinate, magnesium tartrate, • potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide , sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, tetrahydrous synthetic hydrotalcite, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and thrometarnol. (Based in part on the list provided in The Merck Index, Merck &Co. Rahway, N. J. (2001)). In addition, due to the ability of proteins or protein hydrolysates to react with stomach acids, they can also serve as buffering agents within the framework of the present embodiments. In addition, combinations or mixtures of the buffering agents mentioned above can be used in the pharmaceutical formulations described herein.

Buffering agents also include buffers or combinations of buffers that they interact with HC1 (or other acids in the environment of interest) more rapidly than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase, such as water, these buffering agents produce and maintain a pH higher than the pKa of the proton pump inhibitor.

Buffering agents also include peptides, such as for example L-carnosine. In one embodiment, a composition of the present disclosure comprises L-carnosine. In another embodiment of the present disclosure, a composition comprises L-carnosine in the ratio of greater than about 20 parts of L-carnosine to about 1 part of PPI. Other embodiments comprise L-carnosine and PPI in an amount of about 20: 1, about 25: 1, about 30: 1, about 35: 1, about 40: 1, about 45: 1, or about 50: 1.

Other embodiments of the present disclosure comprise a PPI, at least one buffering agent in an amount of about 20 parts to about 1 part of PPI, a protein component in an amount of about 20 parts to about 1 part of PPI. For example, one embodiment of the present disclosure comprises tenatoprazole, sodium bicarbonate in an amount of about 20 parts per approximately 1 part of tenatoprazole, and L-carnosine in an amount of approximately parts by approximately 1 part of tenatoprazole. Another embodiment of the present invention comprises about 40 mg of tenatoprazole, about 1600 mg of sodium bicarbonate, and about 1600 mg of L-carnosine. Another embodiment of the present invention comprises about 40 mg of tenatoprazole, about 600 mg of sodium bicarbonate and magnesium hydroxide and about 1600 mg of L-carnosine. Another embodiment of the disclosure comprises about 40 mg of omeprazole, about 600 mg of sodium bicarbonate and magnesium hydroxide, and about 1600 mg of L-carnosine.

Other embodiments of the disclosure comprise omeprazole, sodium bicarbonate in an amount of about 20 parts per about 1 part of omeprazole, and L-carnosine in an amount of about 20 parts per about 1 part of omeprazole. For example, one embodiment of the disclosure comprises about 40 mg of omeprazole, about 1600 mg of sodium bicarbonate and about 1600 mg of L-carnosine.

The above list of suitable buffering agents is illustrative but not a complete list since a person of ordinary skill in the art will recognize that other pharmaceutically acceptable buffering agents can be created.

In various other embodiments, the buffering agent is present in a total amount of about 0.1 mEq / mg to about 5 mEq / mg of the proton pump inhibitor, from about 0.5 mEq / mg to about 3 mEq / mg of the protons, from about 0.6 mEq / mg to about 2.5 mEq / mg of the proton pump inhibitor, from about 0.7 mEq / mg to about 2.0 mEq / mg of the proton pump inhibitor, from about 0.8 mEq / mg to about 1.8 mEq / mg of the proton pump inhibitor, from approximately 1.0 mEq / mg to approximately 1.5 mEq / mg of the proton-debuped inhibitor. In another embodiment, the buffering agent is present in an amount of about 0.5 mEq / mg of the proton pump inhibitor, of about 0.75 mEq / mg of the proton pump inhibitor, or about 1 mEq / mg of the pump inhibitor. protons based on dry weight.

In another embodiment, one or more buffering agents are present in a total amount of from about 0.5 mEq to about 160 mEq, from about 1 mEq to about 150 mEq, from about 10 mEq to about 150 mEq, from about 10 mEq to about 75 mEq , from about 10 mEq to about 60 mEq, or from about 10 mEq to about 50 mEq. Illustratively, a composition of the present invention may comprise about 1 mEq, about 5 mEq, about 10 mEq, about 15 mEq, about 20 mEq, about 25 mEq, about 30 mEq, about 35 mEq, about 40 mEq, about 45 mEq, about 50 mEq, about 60 mEq, about 70 mEq, about 80 mEq, about 90 mEq, about 100 mEq, about 110 mEq, about 120 mEq, about 130 mEq, about 140 mEq, about 150 mEq, or about 160 mEq of buffering agent.

In another embodiment, one or more buffering agents are present in a total amount of about 10 mEq, about 11 mEq, about 12 mEq, about 13 mEq, about 14 mEq, about 15 mEq, or at least about 16 mEq.

In another embodiment, one or more buffering agents and the mixture of the first proton pump inhibitor and subsequent proton pump inhibitors are present in a weight ratio of approximately 5: 1, approximately 7: 1, approximately 10: 1, approximately 20: 1, more than approximately 20: 1, approximately 21: 1, approximately 22: 1, approximately 23: 1, approximately 25: 1, about 30: 1, about 35: 1, about 40: 1, more than about 40: 1, about 45: 1, about 53: 3, about 11: 1, about 28: 3, about 28: 5 , approximately 23: 3, approximately 26: 1, approximately 27: 2, or approximately 31: 1.

In another embodiment, PPI1, PPI2, and one or more buffering agents are present in a weight ratio of about 2: 1: 50, about 3: 2: 50, about 2: 1:25, about 2: 1: 60, about 3 · 2 · 25 about 2: 1: 20, about 1: 1: 50, about 1: 2: 50, about 1: 1: 25, about 1: 1: 60, about 1: 2: 25, or about 1: 1: 20 In another embodiment, the amount of buffering agent present in a composition of the present invention is within a range of from about 100 to about 4000 mg, from about 200 to about 3500 mg, from about 300 to about 3000 mg, of about 400 to about 2500 mg, or from about 500 to about 2200 mg, from about 600 to about 2000 mg, or from about 700 to about 1800 mg. In other embodiments, the amount of buffering agent present in a composition of the present disclosure is about 100 mg, about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg, or about 2600 mg, or about 2700 mg, or about 2800 mg, or about 2900 mg, or about 3000 mg, or approximately 3200 mg, or approximately 3500 mg, or approximately 4000 mg.

In another embodiment, the amount of buffering agent present is in an amount of from about 100 mg to about 2000 mg, from about 200 mg to about 1750 mg, from about 300 mg to about 1500 mg, from about 400 mg to about 1250 mg , or from about 500 mg to about 1000 mg.

In another embodiment, the amount of buffered agent present is in an amount from about 100 mg to about 500 mg, from about 200 mg to 400 mg, from about 300 mg to about 400 mg, from about 100 mg to about 350 mg, from about 100 mg to about 300 mg , from about 100 mg to about 250 mg, or from about 100 mg to about 200 mg.

In another embodiment, one or more buffering agents are present in a composition of the present invention in a total amount that is greater than 800 mg, for example about 920 mg or at least about 1000 mg.

In another embodiment, the buffering agent and the mixture PPIL and PPI2 (referred to as "inhibitor mixture proton pump") are present in a composition by weight greater than 20: 1, not less than about 21: 1 , not less than about 22: 1, not less than about 23: 1, not less than about 24: 1, not less than about 25: 1, not less than about 26: 1, not less than about 27: 1, not less than about 28: 1, not less than about 29: 1, not less than about 30: 1, not less than about 31: 1, not less than about 32: 1, not less than about 33: 1, not less than about 34: 1, not less than about 35: 1, not less than about 35: 1, not less than about 37: 1, not less than about 38: 1, not less than about 39: 1, not less than about 40: 1, not less than about 41: 1 not less than about 42: 1, not less than about 43: 1, not less than about 44: 1, not less than about 45: 1, not less than about 46: 1, not less than about 47: 1, not less than about 48: 1, not less than about 49: 1, not less than about 50: 1, not less than about 53: 3, not less than about 11: 1, not less than about 28: 3, not less than about 21: 1, not less than about 28: 5, not less than about 23: 3, not less than about 26: 1, not less than about 53: 3, not less than about 27: 2, or not less than about 31: 1.

In another embodiment, there is provided a composition comprising a combination of at least two non-amino acid buffering agents, wherein the composition of at least two non-amino acid buffering agents does not substantially comprise co-precipitated aluminum hydroxide-sodium bicarbonate. In a related embodiment, if said composition comprises a poly [phosphoryl / sulfon] -ado carbohydrate, the weight ratio between poly [phosphoryl / sulfon] -ado carbohydrate and the buffering agent is less than 1: 5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05). Alternatively, the poly [phosphoryl / sulfon] -ado carbohydrate is present in the composition, if present, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg. In another embodiment, the composition does not contain poly [phosphoryl / sulfon] -ado carbohydrate.

In other embodiments, if the pharmaceutical composition comprises an amino acid buffer, the total amount of amino acid buffer present in the pharmaceutical composition is less than about mEq or less than about 4 mEq, or less than about 3 mEq.

The term "amino acid buffering agent", as used herein, includes, but is not limited to, these examples, amino acids, amino acid salts, and alkaline salts of amino acids including, for example, glycine, alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid, asparaginic acid, lysine and / or lysine glutamic acid salt, glycine hydrochloride, L-alanine, DL-alanine, L-threonine, DL-threonine, L-isoleucine, L-valine, L-phenylalanine, acid L-glutamic, L-glutamic acid hydrochloride, sodium salt of L-glutamic acid, L-asparaginic acid, sodium salt of L-asparaginic acid, L-lysine, and L-glutamic acid salt of L-lysine. The term "non-amino acid buffer" includes agents here shock absorbers in accordance with what is defined above, but does not include amino acid buffering agents.

The above list of amino acid buffering agents is for the purpose of illustrating the present invention but does not represent a complete list since a person of ordinary skill in the art will recognize that other pharmaceutically acceptable amino acid buffering agents can be created.

In another embodiment, a composition of the present invention comprises at least one non-amino acid buffer wherein the non-amino acid buffer is present in the composition in a total amount greater than 800 mg. In a related embodiment, if said composition comprises a poly [phosphoryl / sulfon] -ado carbohydrate, the weight ratio between the poly [phosphoryl / sulfon] -ado carbohydrate and the buffering agent is less than 1: 5 (0.2, less than 1:10 (0.1) or less than 1:20 (0.05) Alternatively, the poly [phosphoryl / sulfon] -ado carbohydrate is present in the composition, if present, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg.

In another embodiment, a composition comprising at least one buffer agent in a total amount of less than about 10 mEq is provided. In a related embodiment, if an amino acid buffer is present in the composition, at least one of the following conditions: (1) the proportion by weight amino acid buffering agent: mixture of proton pump inhibitors is greater than 20: 1; (2) the composition comprises at least two non-amino acid buffering agents; (3) the composition comprises at least one non-amino acid buffering agent wherein the weight ratio of the at least one non-amino acid buffering agent to the proton pump inhibitor is greater than 20: 1; and / or (4) the weight ratio of total buffering agent to mixture of proton pump inhibitors is greater than 40: 1.

In another embodiment, a composition comprising at least one buffer agent in a total amount of at least about 10 mEq is provided. In a related embodiment, if an amino acid buffer is present in the composition, at least one of the following conditions is met: (1) the weight ratio between PPI1: PPI2: amino acid buffer is about 2: 1: 50 , about 3: 2: 50, about 2: 1: 25, about 2: 1: 60, about 3: 2: 25, about 2: 1: 20, about 1: 1: 50, about 1: 2: 50, about 1: 1: 25, about 1: 1: 60, about 1: 2: 25, or about 1: 1: 20; (2) the composition comprises at least two non-amino acid buffering agents; (3) the composition comprises at least one non-amino acid buffering agent wherein the weight ratio between PPI1: PPI2: non-amino acid buffer is about 2: 1: 50, about 3: 2: 50, about 2: 1: 25, about 2: 1: 60, about 3: 2: 25, about 2: 1: 20, about 1: 1: 50, about 1: 2: 50, about 1: 1: 25, about 1: 1: 60, about 1: 2: 25, or about 1: 1: 20 and / or (4) the weight ratio between PPI1: PPI2: total buffer is about 2: 1:50, about 3: 2: 50, about 2: 1: 25, about 2: 1 : 60, approximately 3: 2: 25, approximately 2: 1: 20, approximately 1: 1: 50, approximately 1: 2: 50, approximately 1: 1: 25, approximately 1: 1: 60, approximately 1: 2: 25, or about 1: 1: 20. in other embodiments, wherein two or more buffering agents are present, the two or more buffering agents comprise at least two non-amino buffering agents, wherein the combination of at least two non-amino acid buffering agents substantially does not comprise co-precipitate of aluminum hydroxide-sodium bicarbonate.

In another embodiment, the buffering agent comprises a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, Calcium carbonate, and magnesium hydroxide are each present in an amount of about 0.1 mEq / mg of proton pump inhibitor mixture to about 5 mEq / mg of proton pump inhibitor mixture.

In another embodiment, the buffering agent comprises a mixture of sodium bicarbonate, calcium carbonate and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in an amount of about 0.1. mEq / mg of proton pump inhibitor up to about 5 mEq / mg of any proton pump inhibitor.

Also provided herein are pharmaceutical compositions comprising at least one soluble buffering agent. The term "soluble buffering agent" as used herein refers to an antacid having a solubility of at least about 500 mg / mL, or at least about 300 mg / mL, or at least about 200 mg / mL, or at least about 100 mg / mL in gastrointestinal fluid or simulated gastrointestinal fluid.

In certain embodiments, the buffering agent has a defined distribution of particle sizes. For example, in one embodiment, the particle size D50, D70, Deo or Dgo of the buffering agent, by weight or number, is not greater than about 10 μ? T ?, is not greater than about 20 μ? T ?, is not greater than about 30 μP ?, is not greater than about 40 μ? t ?, is not greater than about 50? p ?, is not greater than about 60?, is not greater than about 70? p, is not greater that approximately 80 μp ?, is not greater than approximately 90 μp ?, is not greater than approximately 100 μp? in diameter, it is not greater than approximately 200 μp? in diameter, is not greater than approximately 300 μp? in diameter, it is not greater than approximately 400 μp? in diameter, is not greater than approximately 1000 μp? in diameter, it is not greater than approximately 2000 μp? in diameter, it is not greater than approximately 3000 μ? in diameter, it is not greater than about 4000 μ ?? in diameter, it is not greater than approximately 6000 μp? in diameter, or is it not greater than approximately 9000 μp? in diameter.

The above list of suitable buffering agents is for the purpose of illustrating the present invention, but does not represent a complete list, since a person of ordinary skill in the art will recognize that other pharmaceutically acceptable buffering agents can be created.

NSIDs and Aspirins In one embodiment, compositions of the present invention comprise an NSAID. The term "NSAID" as used herein refers to compounds that act as an anti-inflammatory agent Non-steroidal as identified as such by a person with ordinary knowledge in the field.

Illustratively, the Merck Manual [Merck Manual], 16th edition, Merck Research Laboratories (1990) pages 1308-1309, provides well-known examples of NSAIDs. Exemplary NSAIDs include, but are not limited to, salicylates, indomethacin, flurbiprofen, diclofenac, ketorolaco, naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopirone, phenylbutazone, clofezone, oxifenbutazone, prexazone, apazone, benzidamine, bucolomo, cincofen, clonixin, dithrazole, epirizol, fenoprofen, floctafenin, flufenamic acid, glafenin, indoprofen, ketoprofen, meclofenamic acid, mefenamic acid, nephlumic acid, phenacetin, salidifamides, sulindac, suprofen and tolmetin. The salicylates may include acetylsalicylic acid, acetylsalicylic sodium acid, acetylsalicylic calcium acid, salicylic acid, and sodium salicylate.

In one embodiment, an NSAID, if present, is present in a total amount of from about 0.1% to about 85%, from about 0.5% to about 75%, or from about 1% to about 60%, by total weight of the composition. Illustratively, the NSAID may be present in a amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about %, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56% approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76% , about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, or about 85%, by weight of the total composition. In another embodiment, an NSAID, if present, is present in a total amount of about 1 mg to about 1500 mg, from about 1 mg to about 1200 mg, from about 1 mg to about 1000 mg, of about 1 mg a about 800 mg, or from about 1 mg to about 500 mg.

In other modalities, the NSAID is present! in a composition of the present invention in a composition of approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately. 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg.

In one embodiment, no portion of the NSAID is enteric coated. In another embodiment, at least a part of the NSAID does not present enteric coating. In another embodiment, at least one therapeutically effective portion of the NSAID does not present an enteric coating. In another embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50%, or about 60% of the NSAID does not present an enteric coating. In another embodiment, a portion of the NSAID comprises a "thin enteric coating" in accordance with that defined above.

The term "pain" includes all types of pain, including, but not limited to, chronic pain, such as arthritis-like pain (eg, pain associated with osteoarthritis and rheumatoid arthritis), neuropathic pain, post-operative pain, chronic lower back pain, cluster-type headache, herpetic neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, surgical pain, pain from bone injuries, pain during childbirth, pain resulting from burns, including sunburn, postpartum pain, migraine, pain from angina, pain related to the genitourinary tract including cystitis, the term also refers to nociceptive pain or nociception.

In other embodiments, aspirin is present in a composition of the present invention in an amount of from about 50 mg to about 400 mg, from about 60 mg to about 375 mg, from about 70 mg to about 350 mg, of about 80 mg a about 325 mg, from about 90 mg to about 300 mg or from about 100 mg to about 275 mg.

Pharmaceutical excipients Various embodiments may include, if desired, one or more pharmaceutically acceptable excipients. The term "excipient" refers herein to any substance, which is not per se a therapeutic agent, which is used as a vehicle to deliver a therapeutic agent to a subject or which is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a dosage unit of the composition. The excipients include, by way of illustration but not to limit the present invention, diluents, disintegrating agents, binding agents, adhesives, wetting agents, lubricants, slip agents, surface modifying agents, substances added to mask or counteract an unpleasant taste or odor, flavors, colorants, fragrances, and added substances to improve the appearance of the composition. Any excipient of this type can be used in any dosage form in accordance with the present invention, including liquid, solid or semi-solid dosage forms.

The excipients optionally employed in various embodiments may be solid, semi-solid, liquid, or combinations thereof. Compositions of the present invention including excipients can be prepared through various pharmaceutical techniques, such as for example the mixture of an excipient with a drug or a therapeutic agent.

In various embodiments, the compositions optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents include illustratively, without limitation, either individually or in combination, lactose, including lactose anhydrous or lactose monohydrate; starches, including directly compressible starch or hydrolyzed starches (eg, Celutab ™ and Emdex ™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose ™ 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; thinners based on sucrose; powdered sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrations; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of OI-cellulose and amorphous cellulose (e.g., Rexcel ™) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinyl pyrrolidone; and similar. Such diluents, if present, may in total amount from about 5% to about 99%, from about 10% to about 85%, or from about 20% to about 80%, of the total weight of the composition. In various embodiments, the diluent or the selected diluents may have suitable flow properties and, when tablets are desired, compressibility.

The use of extra-granular micro-crystalline cellulose (ie, micro-crystalline cellulose added to a wet granular composition after a drying step) can be used to modify or control the hardness (for tablets) and / or disintegration time .

In various embodiments, the compositions optionally comprise one or more pharmaceutically acceptable disintegrating agents as excipients, as for example in tablet formulations. Suitable disintegrating agents include, without limitation, either individually or in combination, starches, including crosslinked polyvinylpyrrolidone (crospovidone USP / NF), carboxymethylcellulose (CMC sodium), chitin, chitosan, sodium starch glycolate (e.g., ExplWab ™ from PenWest) and pregelatinized maize starches (e.g. ™ 1551, National ™ 1550, and Colocorn ™ 1500), clays (for example Veegum ™ HV), celluloses such as for example purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, and sodium carboxymethylcellulose, croscarmellose sodium (e.g. FMC Di-Sol ™), alginates, and gums such as agar, guar, xanthan, carob, karaya, pectin and tragacanth gums.

Disintegration agents can be added at any suitable step during the preparation of the composition, particularly before the granulation step or during a lubrication step prior to compression. Such disintegrating agents, if present, may in total amount from about 0.2% to about 30%, from about 0.2% to about 10% or from about 0.2% to about 5%, of the total weight of the composition.

In one embodiment, the cross-linked polyvinylpyrrolidone (crospovidone USP / NF) is an optional disintegrating agent for disintegration of tablets or capsules and, if present, may optionally constitute approximately 1% to about 5% of the total weight of the composition.

In another embodiment, chitin is an optional disintegrating agent for disintegration of tablets or capsules.

In another embodiment, chitosan is an optional disintegrating agent for the disintegration of tablets or capsules.

In another embodiment, carboxymethylcellulose (sodium CMC) is an optional disintegrating agent for the disintegration of tablets or capsules.

In another embodiment, croscarmellose sodium is a disintegrating agent for the disintegration of tablets or capsules and, if present, may optionally be from about 0.2% to about 10%, from about 0.2% to about 7%, or about 0.2. % to about 5% of the total weight of the composition.

Various embodiments described herein optionally comprise one or more pharmaceutically acceptable binders or adhesives as excipients, in particular for tablet formulations. Such binders and adhesives can provide sufficient cohesion to the powder being formed into tablets to allow normal processing operations such as size setting, lubrication, compression and packaging, but still allow the tablet to be disintegrate and that the composition is absorbed upon ingestion. Suitable binder and adhesive agents include, without limitation, either individually or in combination, acacia; tragacanth; sucrose; jelly; glucose; starches such as, but not limited to, pregelatinized starches (eg, National ™ 1511 and National ™ 1500); celluloses, for example, but not limited to these examples, methylcellulose and sodium carmellose (for example, Tylose ™); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; Bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (for example, Klucel ™); and ethylcellulose (e.g., Ethocel ™). Such binding agents and / or adhesives, sui are present, can constitute in total from about 0.5% to about 25%, from about 0.75% to about 15%, or from about 1% to about 10% of the total weight of the composition.

Compositions described herein optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants that can be used as wetting agents in various compositions include quaternary ammonium compounds, for example, benzalkonium chloride, benzethonium chloride and cetylpyridonium chloride, sodium dioctyl sulfosuccinate, polyoxyethylene alkylphenol ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene glycerides and fatty acid oils, for example monoglycerides and caprylic / capric diglycerides of polyoxyethylene (8) (for example, Labrasol ™ by Gattefossé), polyoxyethylene castor oil (35) and hydrogenated polyoxyethylene castor oil (40); polyoxyethylene alkyl ethers, for example polyoxyethylene keto stearyl ether (20), esters of polyoxyethylene fatty acids, for example polyoxyethylene stearate (40), polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (for example Tween ™ 80 from ICI), esters of propylene glycol fatty acids, for example, propylene glycol laurate (for example Lauroglycol ™ from Gattefossé), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate esters of glyceryl fatty acids, for example, glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if present, can constitute a total of about 0.25% a about 15%, from about 0.4% to about 10%, or from about 0.5% to about 5% of the total weight of the composition.

The compositions described herein optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherent and / or slip agents) as excipients. Suitable lubricants include, without limitation, either individually or in combination, glyceryl behapate (e.g., Compritol ™ 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (for example, Sterotex ™); colloidal silica; talcum powder; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (for example, Carbowax ™ 4000 and Carbowax ™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, may in total amount from about 0.1% to about 10%, from about 0.2% to about 8%, or from about 0.25% to about 5%, of the total weight of the composition.

Suitable anti-adherent agents include, without limitation, talc, corn starch, DL-leucine, sodium lauryl sulfate and metal stearates. Talc is an anti-adhesive agent or slip agent that is used for example for reduce the adhesion of the formulation on surfaces of equipment and also to reduce the static energy in the mixture. Talc, if present, may be from about 0.1% to about 10%, from about 0.25% to about 5% or from about 0.5% to about 2% of the total weight of the composition.

Sliding agents can be used with. the object of promoting the flow of the powder of a solid formulation. Suitable slip agents include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose, and magnesium trisilicate.

The compositions described herein may comprise one or more flavoring agents, sweetening agents, and / or colorants. Flavoring agents useful in the present modalities include, without limitation, acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berries, blackcurrant, butter, pecan, sugar caramel with butter, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, fresh cherry, fresh citric, cyclamate, cilamate, dextrose, eucalyptus, eufenol, fructose, fruit punch, ginger, glycyrrhinate, glycyrrhizate, syrup glycyrrhiza (licorice), grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berries, walnut, orange, peanut butter, pear , peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, swiss cream, tagatose, tangerine, thaumatin, tutti fruti, vanilla, walnut, watermelon, wild cherry, fresh mint, xylitol, and combinations thereof, for example anis-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint , honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, etc.

Sweetening agents that can be used within the framework of the present embodiments include, by way of example and not limitation, acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate, cilamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol, neohesperidin DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.

The above excipients may have multiple functions. For example, starch can serve as a filter as well as a disintegrating agent. The classification of the excipients listed here should not be construed as limiting in any way.

Pharmaceutical Dosage Forms In various embodiments, compositions can be formulated as solid, liquid or semi-solid dosage forms. In one embodiment, such compositions are in the form of discrete dose units or discrete dosage units (e.g., tablet, capsule). The terms "dose unit" and / or "dosage unit" refer herein to a portion of a pharmaceutical composition containing an amount of a therapeutic agent suitable for a single administration in order to offer a therapeutic effect. Such dosage units can be administered once a day up to a small number of times per day (i.e. from 1 to about 4 times a day), or as many times as necessary to elicit a therapeutic response. A particular dosage form can be selected so as to suit any desired frequency of administration to achieve a specified daily dose. Typically a dose unit, or a small number of dose units (i.e., up to about 4 dose units) offer a sufficient amount of active drug (eg, at least one PPI) to achieve the desired response or effect .

Alternatively, compositions of the disclosure may also be formulated for rectal, topical, or parenteral administration (e.g., subcutaneous, intramuscular, intravenous, intradermal or infusion).

In one embodiment, compositions of the disclosure are suitable for the rapid onset of the therapeutic effect, particularly in relation to PPI components. In another embodiment, upon oral administration of a composition to a subject, at least a therapeutically effective amount of the PPIs is available for absorption by the subject. As discussed above, most commercially available PPIs require an enteric coating to avoid exposure of PPI to gastrointestinal fluids (and consequent degradation of the drug) by pH-dependent coatings. Said coating, in turn, prevents a rapid absorption of PPI and a rapid onset of therapeutic action. Compositions of the present disclosure, in contrast, do not require an enteric coating to maintain drug stability in gastrointestinal fluids, and therefore offer rapid absorption and rapid onset of therapeutic effect. In fact, in one embodiment, a composition comprises at least one therapeutically effective amount of at least one PPI that does not have an enteric coating. However, other embodiments are compositions that optionally include at least part of a proton pump inhibitor that has an enteric coating.

In another modality, a single dosage unit, either solid or liquid, comprises a therapeutic and / or prophylactically effective amount. of PPIs. The term "therapeutically effective amount" or "therapeutically and / or prophylactically effective amount" as used herein refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic or / and prophylactic response, as may be required the particular context of the treatment.

It will be understood that a therapeutically and / or prophylactically effective amount of a drug for a subject depends, inter alia, on the subject's body weight. A "subject" here to which a therapeutic agent or composition thereof can be administered includes a human subject of either sex and of any age, and also includes any non-human animal, in particular a pet or pet, for illustrative purposes we may mention cat, dog or horse.

Solid Dosing Forms In various embodiments, the compositions of the present invention are in the form of solid dosage forms or solid dosage units. Non-limiting examples of suitable solid dosage forms include tablets (e.g., suspension tablets, suspension and bite tablets, fast dispersion tablets, chewable tablets, effervescent tablets, tablets of twolayers, etc.), tablets, capsules (e.g., soft or hard gelatin capsule), powder (e.g., a packaged powder, an expendable powder, or an effervescent powder), lozenges, sachets, dragees, troches, pellets, granules, micro-granules, encapsulated micro-granules, powdered aerosol formulations, or any other solid dosage form reasonably suitable for oral administration.

The tablets are an illustrative dosage form for compositions of the present invention. The tablets can be prepared in accordance with any technique used in the pharmaceutical industry. In one embodiment, tablets or other solid dosage forms can be prepared through processes employing one of the following methods with a combination of the following methods, including, without limitation, (1) dry blending, (2) direct compression, (3) crushing, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting.

Individual steps in the wet granulation process of the tablet preparation typically include cutting and screening the ingredients, mixing the dry powder, kneading in the wet state, granulating and final grinding. Dry granulation includes the compression of a mixture of powder into a crude tablet or "precompressed tablet" on a rotary press for heavy duty for tablets. The precompressed tablets are then broken into granular particles by a milling operation, usually through passage through an oscillation granulator. Individual steps include blending powders, pre-compression (slugging) and grinding (reduction of pre-compressed tablets or granulation). Typically wet binder or moisture is not included in any of the steps.

In another embodiment, solid dosage forms such as tablets can be prepared by mixing PPI1 and PPI2 with at least one buffering agent in accordance with the above described, and, if desired, with one or more optional pharmaceutical excipients for the purpose of forming a substantially homogeneous preformulation mixture. The preformulation mixture can then be subdivided and optionally further processed (eg, compressed, encapsulated, packed, dispersed, etc.) in any desired dosage form.

Compressed tablets can be prepared by compacting a powder or granulation composition of the invention. The term "compressed tablet" generally refers to a plain uncoated tablet, suitable for oral intake, prepared by simple compression or precompaction followed by a final compression. The tablets of the present disclosure may be coated or they may well be shaped differently in order to provide a dosage form that provides the advantage of improved handling and storage characteristics. In one embodiment, said coating will be selected such that it does not substantially delay the onset of the therapeutic effect of a composition when administered to a patient. The term "suspension tablets", as used herein, refers to a compressed tablet that disintegrates rapidly after placement in water.

In one embodiment, a composition comprises a multilayer tablet having a core comprising two proton pump inhibitors; the core is substantially or completely surrounded by the damping agent. The layer of buffer agent can optionally be coated with one or more coating materials. In one embodiment, the optional coating is optionally an enteric coating. In a related embodiment, the buffer agent layer completely surrounds the core. In another embodiment, the buffer agent layer partially surrounds the core. In another embodiment, the buffering agent layer is in contact with a portion of the core surface area or with the entire surface area of the core.

In another embodiment, a composition comprises a multilayer tablet having a core comprising a first proton pump inhibitor. The core is substantially or completely surrounded by a second layer comprising a buffering agent. A third comprises a subsequent proton pump inhibitor substantially or completely surrounded by the second layer comprising the buffering agent. The third layer is substantially or completely surrounded by a fourth layer comprising the same buffering agent or a different buffering agent. The fourth layer can optionally be coated with one or more coating materials. The successive layers of additional proton pump inhibitors and buffering agents can continue for any number of iterations with the same proton pump inhibitors and buffering agents or with different proton pump inhibitors and buffering agents. In one embodiment, the optional coating is optionally an enteric coating. In a related embodiment, the second layer comprises a buffering agent that completely surrounds the core. In another embodiment, the second layer comprises a buffering agent that partially surrounds the core. In another embodiment, the second layer comprising the buffering agent is in contact with part or all of the surface area of the core. In a related embodiment, the fourth layer comprising buffering agent completely surrounds the third layer comprising the inhibitor Subsequent proton pump. In another embodiment, the fourth layer comprising the buffering agent partially surrounds the third layer comprising the subsequent proton pump inhibitor. In another embodiment, the fourth layer comprising the buffering agent is in contact with a portion or all of the third layer comprising the subsequent proton pump inhibitor.

In another embodiment, a composition comprises a multilayer tablet having a core comprising either omeprazole or lansoprazole. The core is substantially or completely surrounded by a second layer comprising a buffering agent. A third layer comprising another form of PPI substantially or completely surrounds the second layer comprising the buffering agent. The third layer is substantially or completely surrounded by a fourth layer comprising the same damping agent or a different damping agent. The fourth layer can optionally be coated with one or more coating materials. The successive layers of additional proton pump inhibitors and buffering agents can continue for any number of iterations with the same proton pump inhibitors and buffering agents or with different proton pump inhibitors and buffering agents. In one modality, the Optional coating is optionally an enteric coating. In a related embodiment, the second layer comprising a damping agent completely surrounds the core. In another embodiment, the second layer comprising a buffering agent partially surrounds the core. In another embodiment, the second layer comprising a buffering agent is in contact with a portion of the surface area of the core or with the entire surface area of the core. In a related embodiment, the fourth layer comprising a buffering agent completely surrounds the third layer comprising the subsequent proton pump inhibitor. In another embodiment, the fourth layer comprising a buffering agent partially surrounds the third layer comprising the subsequent proton pump inhibitor. In another embodiment, the fourth layer comprising a buffering agent is in contact with a portion or all of the third layer comprising the subsequent proton pump inhibitor.

In another embodiment, there is one or more intermediate layers between the core and the buffering agent. The intermediate layers can comprise any pharmaceutically acceptable material, particularly inert and non-pH sensitive coating materials such as polymer-based coatings.

In another embodiment, a composition comprises a tablet of multiple layers having a core comprising a first PPI; the core is substantially or totally surrounded by the subsequent PPI and by the damping agent. Optionally, an intermediate layer may exist between the first PPI core and the subsequent PPI / buffering agent surrounding the core. In one embodiment, the optional intermediate layer is a coating layer. In another embodiment, the coating layer is optionally an enteric coating.

In another embodiment, a composition comprises a multilayer tablet having a core comprising either omeprazole or lansoprazole; the core is substantially or totally surrounded by another form of PPI and the buffering agent. Optionally, an intermediate layer may exist between the core of omeprazole or lansoprazole and the other PPI / buffering agent surrounding the core. In one embodiment, the optional intermediate layer is a coating layer. In another embodiment, the coating layer is optionally an enteric coating.

In such a mode, the buffer / PPI agent layer completely surrounds the core. In another embodiment, the buffer / PPI agent layer partially surrounds the core. In another embodiment, the buffer / PPI agent layer is in contact with a portion or the entire surface area of the core.

In another embodiment, compositions may be micro- encapsulated wherein the first PPI, subsequent PPI, and one or more buffering agents are micro-encapsulated together, for example as a modification of the description offered in U.S. Patent Publication No. 2005/0037070, which is incorporated herein by reference. totality by reference.

In another embodiment, compositions may be micro-encapsulated wherein the omeprazole, lansoprazole, and one or more buffering agents are micro-encapsulated together, for example, in accordance with the modification of the disclosure of U.S. Patent Publication No. 2005 / 0037070, which is incorporated herein in its entirety by reference.

In another embodiment, a composition comprises a first proton pump inhibitor, one or more additional proton pump inhibitors, and one or more buffering agents mixed together in powder form and optionally filled into a capsule, eg, a capsule of hard gelatin or soft gelatin or an HPMC capsule.

In another embodiment, a composition of the present invention is in the form of a molded article, for example a pellet. The term "molded article" refers herein to a discrete dosage form that can be formed by compression, extrusion, or by other processes Similar. In one embodiment, the molded article is moldable. The term "moldable" in the context of, the present invention means that it can be molded or that it can be formed manually. A moldable article in the present document will therefore have a lower hardness than a conventional pharmaceutical tablet. Said moldable article may also be chewed by an animal, for example a horse.

Said article may comprise, in addition to the PPI and the buffering agent, and in addition to other excipients described herein, a filler, a sweetener and a flavoring agent. Extrusion is a process to shape a material by pushing it to flow through an opening that has a shape in a die or other solid. The extruded material emerges in the form of an elongate article having substantially the same profile as the die opening.

In another embodiment, a composition comprises omeprazole, lansoprazole, and a number of buffering agents mixed together in powder form and optionally filled into a capsule, for example a hard or soft gelatin gelatin capsule or an HPMC capsule.

Liquid Dosage Forms In another embodiment, the compositions described herein can take the form of liquid dosage forms or dosage units. Non-limiting examples of liquid forms Suitable dosing solutions include solutions, suspensions, elixirs, syrups, liquid aerosol formulations, etc. In one embodiment, a liquid composition comprising water can be prepared. or another solvent, a first PPI, one or more additional PPIs, and a buffering agent. In another embodiment, the compositions described herein are in the form of a powder for suspension which may be suspended in a liquid vehicle before its administration to a subject. While the suspension powder itself can be in a solid dosage form of the present invention, the liquid dispersed powder also comprises a liquid embodiment of the present invention.

In another embodiment, a liquid composition comprising water or another solvent, omeprazole, lansoprazole, and one or more buffering agents can be prepared. In another embodiment, the compositions described herein are in the form of a powder for suspension which may be suspended in a liquid vehicle before its administration to a subject. While the powder for suspension itself may be in the solid dosage form of the present invention, the powder dispersed in liquid also comprises a liquid embodiment of the disclosure.

The suspension compositions comprise a first PPI, one or more additional PPIs, one or more buffering agents, a liquid medium (for example, water, water deionized, etc.), and one or more optional pharmaceutical excipients. Such compositions, when stored in a closed container maintained either at room temperature, either under refrigeration (for example, at a temperature of about 5-10 ° C), or in freezing for a period of about 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, presents approximately 90%, approximately 92.5%, approximately 95%, or approximately 97.5% of the first original PPI and / or the additional PPI or the various additional PPIs present there.

Other suspension compositions comprise omeprazole, lansoprazole, one or more buffering agents, a liquid medium (e.g., water, deionized water, etc.), and one or more optional pharmaceutical excipients. Such compositions, when stored in a closed container maintained either at room temperature, either under refrigeration (for example about 5-10 ° C), or in freezing for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, presents approximately 90%, approximately 92.5%, approximately 95%, or approximately 97.5% of the original omeprazole and / or lansoprazole present there.

Stability in Storage In one embodiment, the compositions are in the form of a powder for suspension which will be finally suspended in a liquid vehicle before its administration to a subject. Liquid compositions comprising an acid labile PPI suspended in a liquid vehicle, without further ado, would typically exhibit relatively short periods of stability, even while keeping them in refrigerated conditions. This is particularly inconvenient in the hospital environment since fresh batches of suspension are continually required. It is considered that compositions and suspensions of the disclosure exhibit improved stability during storage.

Exemplary suspension compositions comprise a first PPI, one or more additional PPIs, at least one buffering agent, water, and one or more additional pharmaceutical excipients. Such compositions, when stored in a closed container maintained at room temperature, under refrigeration (for example at a temperature of about 5 to about 5-10 ° C), or in freezing for a period of about 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, or 12 months, may present approximately 90%, approximately 92.5%, approximately 95%, or approximately 97.5% of the first original PPI and / or subsequent PPI present there.

Administration and Bioavailability In one embodiment, the compositions of the present disclosure are suitable for a rapid onset of the effect therapeutic, particularly in relation to the PPI components. In another embodiment, when a composition is orally administered to a subject, at least a therapeutically effective amount of at least one PPI is available for absorption and metabolism by the subject. The term "available for absorption" with reference to an active ingredient such as for example PPI means that the ingredient remains intact and in active form in the stomach for a sufficient length of time to allow absorption in the blood. As discussed above, most commercially available PPIs require an enteric coating to avoid exposure of the PPI to gastrointestinal fluids (and consequent degradation of the drug) by means of pH-dependent coatings. Said coating, in turn, prevents rapid absorption of the PPI and a rapid therapeutic onset of action. The compositions of the present disclosure, in contrast, do not require but may optionally include an enteric coating to maintain drug stability in gastrointestinal fluids and therefore offer rapid absorption and rapid onset of therapeutic effect. In fact, in one embodiment, a composition comprises at least one therapeutically effective amount of at least one PPI that does not have an enteric coating. Another modality offers compositions that have at least one PPI with optional enteric coating.

In another embodiment, upon oral administration of a composition described herein to a plurality of fasting adult human subjects, subjects exhibited a mean Tmax of active ingredient (e.g., at least one PPI) within about 30 seconds to about 90 minutes, within about 1 minutes to about 80 minutes, within about 5 minutes to 60 minutes, within about 10 minutes to 50 minutes, or within about 15 minutes to 45 minutes.

In another embodiment, upon administration of a composition written here to a plurality of fasting adult human subjects, the subjects had an average plasma concentration of at least one PPI of approximately 0.1 μg / ml, approximately 0.15 μg / ml, approximately 0.2 ug / ml, approximately 0.3 g / ml, approximately 0.4 g / ml, approximately 0.5 μg / ml, approximately 0.6 g / ml, approximately 0.7 μg / ml, approximately 0.8 μg / ml, approximately 0.9 g / ml, approximately 1 g / ml, approximately 1.5 μg / ml, or approximately 2.0 μg / ml at any time within approximately 90 minutes, within approximately 75 minutes, within approximately 60 minutes, within approximately 55 minutes, within approximately 50 minutes, within about 45 minutes, within about 40 minutes, within about 35 minutes, within about 30 minutes, within about 25 minutes, within about 20 minutes, within about 17 minutes, within about 15 minutes, within about 12 minutes minutes, or within approximately 10 minutes after administration.

In another embodiment, when administering a composition described herein to a plurality of fasting human adult subjects, the subjects had a plasma concentration of active ingredient (eg, at least one PPI) of approximately 0. 1 ug / ml, approximately 0. 15 Ug / ml, approximately 0.2 μg / ml, approximately 0.3 μg / ml, approximately 0.4 Ug / ml, approximately 0.5 μg / ml, approximately 0.6 μg / ml, approximately 0. 7 μg / ml, approximately 0.8 μg / ml, approximately 0.9 μg / ml, approximately 1.0 g / ml, approximately 1.5 g / ml, or approximately 2.0 μg / ml, maintained for approximately 15 minutes to about 60 minutes after administration, approximately 15 minutes after administration to approximately 90 minutes after administration, approximately 15 minutes to approximately 120 minutes after administration, or approximately 15 minutes to approximately 180 minutes after administration.

In another embodiment, upon administering a composition described herein to a plurality of fasting adult human subjects, subjects exhibited at least one of the following: a mean Cmax of PPI1 and / or PPI2 of about 500 g / ml to about 2000 μg / ml, from about 600 ug / ml to about 1900 ug / ml, or from about 700 g / ml to about 1800 ug / ml; an average Tmax of PPI1 and / or PPI2 from about 0.15 to about 2 hours, from about 0.25 to about 1.75 hours, or from about 0.3 to about 1 hour; and / or an AUC (0-average of PPI and / or PPI2 of from about 1000 to about 3000 μg * hr / ml, from about 1500 to about 2700 ug * hr / ml, or from about 1700 to about 2500 μ? * ?? G / p? 1.

In another embodiment, when administering a composition described herein to a plurality of fasting adult human subjects, the subjects presented: a mean Cmax of PPI1 and / or PPI2 of approximately 500 ug / ml to approximately 2000 ug / ml, of approximately 600 ug. / ml at approximately 1900 μg / ml, or from approximately 700 μg / ml to approximately 1800 μg / ml; an average Tmax of PPI1 and / or PPI2 of from about 0.15 to about 2 hours, from about 0.25 to about 1.75 hours, or from about 0.3 to about 1 hour; and an average AUC (o-inf) of PPI and / or PPI2 of from about 1000 to about 3000 g * hr / ml, of about 1500 to about 2700 g * hr / ml, or from about 1700 to about 2500 pg * hr / ml.

Parietal Cell Activators In one embodiment, a composition of the present invention may further include one or more parietal cell activators. Activators of parietal cells such as chocolate, calcium and sodium bicarbonate, and other alkaline substances stimulate the parietal cells and improve the pharmacological activity of the PPI administered, for the purposes of this application, "parietal cell activator" or "activator" will refer to any compound or mixture of compounds exhibiting said stimulatory effect, including, but not limited to, chocolate, sodium bicarbonate, calcium (eg, calcium carbonate, calcium bicarbonate, calcium gluconate, calcium hydroxide, calcium acetate, calcium, and calcium glycerophosphate, calcium format), peppermint oil, spearmint oil, coffee, tea and tails (even decayed), caffeine, theophylline, theobromine, and amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan) and combinations of them.

Parietal cell activators, if desired, are typically present in a composition of the disclosure in an amount sufficient to produce the desired stimulatory effect without causing deleterious side effects to the subjects. For example, chocolate, such as raw cocoa, is administered in an amount of about 5 mg to 2.5 g per 20 mg dose of omeprazole (or comparable pharmacological dose of another proton pump inhibitor). The dose of activator administered to a subject, for example a human being, in the context of the present invention, should be sufficient to result in an improved effect of a PPI over a desired time frame. Illustratively, the approximate effective ranges for several parietal cell activators per 20 mg dose of omeprazole (or affordable doses of another PPI) include, chocolate (raw cocoa) - from about 5 mg to about 2.5 g; sodium bicarbonate - from about 7 mEg to about 25 mEq; calcium carbonate - from about 1 mg to about 1.5 g; calcium gluconate - from about 1 mg to about 1.5 g; calcium lactate - from about 1 mg to about 1.5 g; calcium hydroxide - from about 1 mg to about 1.5 g; calcium acetate - from about 0.5 mg to about 1.5 g; calcium glycerophosphate - from about 0.5 mg to about 1.5 g; peppermint oil - (powder form) about 1 mg to about 1 g; Spearmint oil - (powder form) from about 1 mg to about 1 g; coffee - from approximately 20 mi to approximately 240 mi; tea - from about 20 ml to about 240 ml; tail - from about 20 mi to about 240 mi; caffeine - from about 0.5 mg to about 1.5 g; Theophylline - from about 0.5 mg to about 1.5 g; theobromine - from about 0.5 mg to about 1.5 g; phenylalanine - from about 0.5 mg to about 1.5 g; and tryptophan - from about 0.5 mg to about 1.5 g.

Gastrointestinal disos In various embodiments, the present disclosure offers a therapy for various diseases and disos. Such diseases and disos include, inter alia, gastrointestinal disos and, in particular, gastrointestinal disos related to acid. The term "acid-related gastrointestinal diso" or "acid-related gastrointestinal disease" refers in general terms to a disease or diso that occurs due to an imbalance between the production of acid and pepsin production on the one hand, which are known as aggressive factors, and production of mucosa, bicarbonate and prostaglandin on the other hand, which are known as defensive factors.

The term "therapy" as used herein refers to the treatment and / or prevention of a diso or disease, such as for example gastrointestinal diso.

The term "treat" or "treatment" as used herein refers to any treatment of a diso or disease and includes, but is not limited to, these examples, the prevention of the occurrence of diso or disease in a subject who may be predisposed to diso or disease but has not yet been diagnosed as having such diso or disease; inhibit the diso or disease, for example, by stopping the development of the diso or disease; mitigate the diso or disease, for example, cause a regression of the diso or disease; or alleviate the condition caused by the disease or diso, for example, stopping the symptoms of the disease or diso. The term "prevent" or "prevention" in relation to a diso or disease means preventing the onset of the development of gastrointestinal diso or disease if no gastrointestinal diso has already occurred, or preventing said diso or disease from developing if the diso or disease They were already present.

Compositions of the present disclosure may be in the form of a dosage unit that can be administered orally. The terms "oral administration" or "oral delivery" herein include any form of delivery of a therapeutic agent or a composition thereof to a subject, wherein the agent or composition is placed in the mouth of the subject, which the agent or the composition is swallowed or do not. Accordingly, the term "oral administration" includes buccal and sublingual as well as esophageal administration.

Chronic GERD can lead to Barrett's esophagus, dysplasia and eventually adenocarcinoma. (Devesa SS, et al., "Changing patterns in the incidence of esophageal and gastric carcinoma in the United States" [Changing patterns in the incidence of esophageal and gastric carcinomas in the United States of America], Cancer Vol. 83, pages 2049 -53 (1998)) (Epidemiology Surveillance Program and final results with age adjustment using 2000 US standard subjects from the National Cancer Institute). In fact, "The incidence of adenocarcinomas of the esophagus continues to grow rapidly in the United States of America and in Western Europe.We desperately need to detect these patients at an earlier stage and find effective ways to prevent this disease." The attack of the progression of this disease at its earliest stage will be key to preventing adenocarcinoma induced by reflux. " Tom DeMeester and Parakrama Chandrasoma, "GERD: Reflux to Esophageal Adenocarcinoma" [GERD: from Reflux to Esophageal Adenocarcinoma], Academic Press (2006).

Sampliner reported that a prolonged treatment · (years) with potent PPI drugs, omeprazole and lansoprazole, administered twice a day or more only reversed the esophagus of Barrett in 3 of 123 patients with Barrett's esophagus, with or without surgery. Sampliner, R. "Reduction of Acid Exposure and Regression of Barrett's Esophagus" [Reduction of Exposure to Acids and Regression of Barrett's Esophagus], Digestive Diseases, Vol. 18 (4), pages 203-207, (2000-2001) ).

Fackler, W., et al., Investigated the therapeutic efficacy of the addition of a histamine 2 receptor antagonist ("H2RAs") to a PPI to block nocturnal acid escape ("NAB") in 23 healthy volunteers and 20 patients with GERD. Fackler, W., et al., "Long-term Effect of H2RA Therapy on Nocturnal Gastric Acid Breakthough" [Long-Term Effect of H2RA Therapy on Nocturnal Gastric Acid Exhaust], Gastroenterology, Vol. 122 (3), pages 625-632 (2002). All subjects then received 28 days of PPI (omeprazole 20 mg) plus H2RA (ranitidine 300 mg) overnight ("QHS"), and were monitored with an ambulatory pH monitor. The results of the study found that H2RA and PPI combination therapy reduced NAB only at the beginning of therapy. Due to tolerance to H2RA, there was no difference in acid suppression between PPI twice daily and PPI twice daily + H2RA after one week of combination therapy.

Spechler SJ, et al., Evaluated the effect of dosing three times a day ("TID") of esomeprazole on esophageal acidity in patients with Barrett's esophagus. It was found that despite from. a significant reduction of gastric acidity due to treatment with high doses of esomeprazole, abnormal exposure to esophageal acid continued in 16% up to 23% of patients. Spechler SJ, et al., "Gastric and Esophageal pH in Patients With Barrett's Esophagus Treated With Three Esomeprazole Dosages: A Randomized, Double-Blind, Crossover Trial" [Gastric and esophageal pH in patients with Barrett's Esophagus treated with three Dosages of Esomeprazole: A Cross-over Trial, in Double Blind, Randomized], Am J Gastroenterol. , Vol. 101, pages 1964-1971 (2006). It is important to note that compliance with regimens with TID is significantly lower than in the case of regimens once a day. In addition, compliance continues to decrease over time, so that compliance at 14 days is greater than compliance at 30 days or 60 days. To further complicate this issue, it is recommended that delayed-release PPI medications be taken 1/2 hour before a meal to achieve optimal acid inhibition. Previous research showed that only 10% of patients comply with this recommendation. These studies illustrate that there is a need for once-a-day treatment that can sufficiently inhibit esophageal acid in patients with Barrett's esophagus in such a way that reversal of Barrett's columnar esophagus can be achieved.

Compositions of the present invention can be employed to arrest the progression and promote a reversion of esophageal metaplasia related to reflux with low grade or high grade dysplasia. Compositions of the present disclosure can also be used to arrest the progression and encourage a reversal of adenocarcinoma of the esophagus related to reflux or adenocarcinoma of the stomach related acid. In addition, compositions of the present disclosure can be used in the treatment of patients undergoing ablation in Barrett's esophagus in order to prevent recurrence. Compositions of the disclosure may also be used to treat a patient, including patients with or without gastroparesis (slow emptying of the stomach) and severe erosive esophagitis (grade C and D of the Los Angeles Classification).

Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used for their anti-inflammatory effects, analgesics and / or antipyretics. However, NSAIDs have the potential to cause gastrointestinal bleeding (GI) and / or ulceration through several mechanisms related to their topical and systemic effects. Once ulcerated, gastric acid in the stomach can cause painful irritation and stomach pain. Such bleeding and gastrointestinal ulcerations may depend on the duration of the treatment as well as the particular drug used. As As a result, many subjects who take NSAIDs, especially those subjects with chronic NSAID therapy, are at high risk of developing gastric ulcers.

Apart from the use of NSAIDs, the overproduction of gastric acid can also cause gastric ulceration and other gastrointestinal diseases and disorders. In addition, the overproduction of stomach acid can irritate particularly subjects with an irritation or gastric ulceration related to NSAIDs.

Various diseases and disorders, including disorders related to gastric acid, such as, but not limited to, severe erosive esophagitis (grades C and D of the Los Angeles Classification), Barrett's esophagus, esophageal metaplasia related to reflux with dysplasia low or high grade, adenocarcinoma of the related esophagus or adenocarcinoma of the esophagus related to acid, duodenal ulcer, gastric ulcer, erosions and gastric and duodenal ulcerations, acid dyspepsia, gastroesophageal reflux disease (GERD), symptomatic GERD of unsatisfactory response, reflux of acid, esophageal ulcers and erosions, precancerous and cancerous lesions of the esophagus induced by exposure to acids, radiation-induced esophagitis or chemotherapy, conditions of acid hypersecretion, gastrointestinal pathological hypersecretion conditions (such as example Zollinger Ellison Syndrome), non-ulcer dyspepsia, H. pylori infection, extraesophageal or atypical manifestations of gastroesophageal reflux disease (such as, but not limited to, oral pain, asthma, bronchitis, pneumonia, chest pain , cough, recurrent laryngitis, pharyngeal balloon, sinusitis, otalgia, otitis media, eustachian tube dysfunction, voice change, balloon sensation, clearing of throat, halitosis, sore throat, aphthous ulcers), nocturnal acid escape (NAB), sleep apnea, sleep disturbance, suspension of gastrointestinal bleeding and prevention of rebleeding after gastrointestinal bleeding, treatment prior to endoscopic evaluation of upper gastrointestinal bleeding, prevention of stress ulcer, treatment of bleeding related to stress, activity of attack or apparent attack, Sandifer syndrome, poor development, anorexia, anorexia nervosa, loss of weight, apnea, and bradycardia.

The above list of disorders or diseases is intended to illustrate the present invention, but are not complete lists since a person of ordinary skill in the art will be able to recognize that there are many other disorders or diseases that the embodiments of the present invention could address and / or prevent.

In one embodiment, a method is provided for treating and / or preventing a disorder or disease by administering a pharmaceutical composition comprising a first proton pump inhibitor, having a therapeutically effective portion, which optionally presents an enteric coating, a second proton pump inhibitor, having a therapeutically portion effective, which optionally has an enteric coating, and at least one buffering agent, such as, for example, sodium bicarbonate.

In another embodiment, a method for the treatment and / or prevention of a disorder or disease is provided by administration of a pharmaceutical composition comprising omeprazole, which has a therapeutically effective portion, which optionally has an enteric coating, lansoprazole, which it has an optionally therapeutically effective portion with enteric coating, and sodium bicarbonate.

In another embodiment, a method for treating and / or preventing a disorder or disease is provided by administering a pharmaceutical composition comprising about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, or approximately 100 mg of omeprazole, which has a therapeutically effective portion, whichoptionally presents an enteric coating.

In another embodiment, a method for the treatment and / or prevention of a disorder or disease is provided by administration of a pharmaceutical composition comprising about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of omeprazole, which has a therapeutically effective portion, which optionally has an enteric coating, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg lansoprazole, which has a therapeutically effective portion, which optionally has an enteric coating, and sodium bicarbonate in an amount of about 100 mg a approximately 2500 mg of sodium bicarbonate.

In another embodiment, any PPI or both PPIs may present an enteric coating in the form of tablets.

In various embodiments, pharmaceutical labile agents for the acids can be mixed together and then receive an enteric coating in the form of granules.

In another modality, tenatoprazole can receive an enteric coating in the form of granules and the other Proton pump inhibitor or the various other proton pump inhibitors can receive enteric coating in the form of granules.

Integrated Gastric Heartburn Integrated gastric acidity ("IGA") is a sensitive measurement of the inhibition of gastric acids. It is calculated as the cumulative time-weighted average of the concentration of gastric acids. IGA is sensitive to the change of the baseline for gastric acidity, while the medium or medium gastric pH has low sensitivity to detect change (ie, induced by drug) in relation to the baseline. IGA or intragastric acidity can be expressed as mmol * h / L. For example, the following values were found for IGA after a single dose of PPI (ie, Day 1). See Sercombe WJ, et al., "A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole vs. omeprazole on 24-hour intragastric acidity and gastrin concentration in young health male subjects" [A placebo-controlled trial for to evaluate the effects of 8 days of dosing with rabeprazole vs. omeprazole on intragastric acidity at 24 hours and gastrin concentration in young healthy male subjects] Aliment Pharmacol. Ther., Vol. 12, pages 1079-1089 (1998).

Placebo Raberprazole 20 Omeprazole 20 mg, of mg, of liberation release Delayed delayed IGA-24Day i 997 mmol »h / L 331 mmol'h / L. 640 mmol »h / L F.F.I. Rebecchi et al. Investigated the prognostic value of the area under the H + curve (ie, integrated acidity) in 36 healthy volunteers and 60 patients with GERD. Based on the analysis of receiver operating characteristics, the authors found that an area under the hydrogen ion activity curve above 100 mmol / L * min was very sensitive and specific (100% and 97%, respectively) for identify patients with erosive esophagitis and also had a good sensitivity and specificity (76% and 93%) to identify patients with non-erosive GERD. See F.F.I. Rebecchi et al., "Improving the analysis of esophageal acid exposure by a new parameter: area under H +" [Improved analysis of exposure to esophageal acids by a new parameter: area under H +], Ana. J. Gastroenterol. , Vol. 97, pages 568-74 (2002); J.D. Gardner et al., "Determination of the reduction in gastric acidity necessary to prevent pathological oesophageal reflux in patients with gastro-oesophageal reflux disease treated with a proton pump inhibitor" [determination of the reduction of gastric acidity necessary to prevent a pathological esophageal reflux in patients with gastroesophageal reflux disease treated with a pump inhibitor protons], Aliment. Pharmacol. Ther., Vol. 17, pages 955-64 (2003); J.D. Gardner et al., "Integrated acidity and rabeprazole pharmacology" [Integrated acidity and pharmacology of rabeprazole], Aliment Ther., Vol. 16, pages 455-64 (2002); J.D. Gardner et al., "Integrated acidity and the pathophysiology of GERD" [Integrated acidity and pathophysiology of GERD], Am J Gastroenterol. , Vol. 96, pages 1363-70 (2001).

The pharmacodynamic parameter that best demonstrates the efficacy of an agent that works by inhibiting gastric acid is the "24 hour Integrated Gastric Acidity" ("IGA-24"). The most important measurement of IGA is made in the first 24 hours after the initial dose, since PPI drugs have not routinely shown a significant effect on the inhibition of gastric acid secretion in the first 24 hours after an initial dose. Therefore, IGA-24 on Day 1 ("IGA-24Day i") is the most stringent measure of efficacy of PPI compositions. It is important to note that many studies conducted on PPI drugs concomitantly administered pentagastrin in order to artificially stimulate parietal cells to induce or artificially create efficacy on Day 1 of PPI administration. This creates an artificial effect on Day 1 and does not correlate with patients normal.

The pharmacokinetic parameter that predicts the efficacy of PPis is the area under the curve of serum concentration vs. time or area under the curve (AUC). See Cederberg et al., "Effect of omeprazole - a gastrin proton pump inhibitor - on pentagastrin stimulated acid secretion in man" [Effect of omeprazole - a proton pump inhibitor of gastrin - on the secretion of acid stimulated by pentagastrin in man ], Gut, Vol. 24, pages 270-76 (1983); Cederberg et al., "Acid inhibitory characteristics of omeprazole in man" [Characteristics inhibiting acid of omeprazole in man], Scand. J. Gastroenterol. Suppl. , Vol. 20, pages 105-12 (1985); Cederberg et al., "Comparison of once-daily intravenous and oral omeprazole on pentagastrin-stimulated acid secretion in duodenal ulcer patients" [Comparison of once daily intravenous and oral administration of omeprazole on pentagastrin-stimulated acid secretion in patients with duodenal ulcer], Digestion, Vol. 53, pages 171-78 (1985). In addition, an AUC above a micromolar of PPI (for substituted benzimidazoles) is an excellent predictor of efficacy. In addition, the time that the AUC is above 1 micromolar PPI (for substituted benzimidazoles) defines the time that the PPI is significantly efficient to bind with the proton pumps in the cell-secreting canalicular membrane parietals ("active proton pumps").

The pharmacokinetic equation to determine the AUC is presented below: (j) DOSis X ti / 2 AUC =:, 0. 693 x V where f is the bioavailability, ti / 2 is the half-life of the drug, and V is the volume of distribution of the drug. The AUC is directly proportional to ti / 2, and as ti2 rises, the AUC increases. Since the AUC is the greatest predictor of efficacy for PPI drugs, the prolongation of the half-life of the PPI (such as an increase in the AUC) directly results in an improvement in the efficacy of PPIs.

Another additional pharmacokinetic parameter that predicts efficacy is the AUC greater than the concentration required to produce a 50% inhibition (IC50), which is specific for each PPI.

The rate of conversion of PPIs in the active portion is also a determinant of efficacy, specifically since it is related to the time and the rate of onset after dosing. Therefore, it is desirable to combine two PPIs that have different half-lives in relation to activation half-lives of activation). For example, the activation half-life of lansoprazole and omeprazole complement each other with lansoprazole reaching a 90% activity at a pH of about 1 to 1.5, in 7 to 8 minutes while omeprazole achieves 90% activity, at a pH of about 1 to 1.5, in 15 to 20 minutes. The applicant unexpectedly found that when these two drugs are used together in the formulations described herein as for example 80 mg lansoprazole + 80 mg omeprazole + 1680 sodium bicarbonate), the half-life of both drugs is significantly prolonged. Normally, the elimination half-life of lansoprazole is from 1 to 1.4 hours (average of approximately 1.2 hours), and similarly for omeprazole, the elimination half-life is 0.7 to 1.2 hours (average of approximately 0.95 hour). When administered together, pharmacokinetic synergy is observed. The elimination half-life of omeprazole is prolonged to 1.9 hours (a prolongation factor of 200%), and the elimination half-life of lansoprazole is prolonged to 3.7 hours (a prolongation factor of 300%).

Pharmacokinetic synergy refers to the improvement of the action or effect of a particular drug (s) in comparison with the individual effect of the two drugs combined. As shown in the examples, combinations of omeprazole and lansoprazole have significantly longer half-lives for both drugs, as well as improved values of AUCQ-24 and IGA-24, indicating improved efficacy of the PPIs. Individual values alone can not explain the dramatic and unexpected increase in efficacy as demonstrated in the examples. Omeprazole and lansoprazole together affect and improve the efficacy of PPIs.

EXAMPLES The examples below are for the purpose of illustrating the present invention and should not be construed as posing limitations on the invention in any way.

Example 1 The following table presents a list of the half-lives of daily doses of several PPIs. Since the half-life (ti / 2) and AUC have a variability between subjects, it is important that tx be compared in the same subject under the same conditions with appropriate wash-out periods between the studies Table 1 PPI Daily Dose tí / 2 Rabeprazole 20 - 160 mg 0.8 - 1 hour Omeprazole 20 - 160 mg 0.9 - 1.5 hours Lansoprazole 15 - 160 mg 1 - 1.5 hours Tenatoprazole 40 - 160 mg 6.8 - 8 hours Pantoprazole 40 - 160 mg 1.2 · - 1.5 hours Esomeprazole 20 - 160 mg 1.1 - 1.6 hours Dexlansoprazole 15 - 160 mg 1 - 1.6 hours A list of combinations of life-sustaining drugs prolonged media, and in relation to which synergy was found, is shown in Table 2. Both PPIs can be delayed release and / or immediate release. The doses of each PPI and cimetidine may be within a range of 10 to 300 mg and 10 to 1500 mg, respectively.

Table 2 PPI1 PPI2 Cimetidine Ilaprazole Omeprazole No Ilaprazole Lansoprazole No Ilaprazole Rabeprazole No Ilaprazole Tenatoprazole No Ilaprazole Pantoprazole No Ilaprazole Esomeprazole No Ilaprazole None Yes Ilaprazole Omeprazole Si Ilaprazole Lansoprazole Si Ilaprazole Rabeprazole Si Ilaprazole Tenatoprazole Yes Ilaprazole Pantoprazole Yes Ilaprazole Esomeprazole Si Lansoprazole Omeprazole No Lansoprazole Esomeprazole No Lansoprazole Rabeprazole No Lansoprazole Tenatoprazole No Lansoprazole Pantoprazole No Lansoprazole None Yes Lansoprazole Omeprazole Si Lansoprazole Esomeprazole Si Lansoprazole Rabeprazole Si Lansoprazole Tenatoprazole Si Lansoprazole Pantoprazole Si Rabeprazole Omeprazole No Rabeprazole Tenatoprazole No Rabeprazole Pantoprazole No Rabeprazole Esomeprazole No Rabeprazole None Yes Rabeprazole Omeprazole Si Rabeprazole Tenatoprazole Si Rabeprazole Pantoprazole Si Rabeprazole Esomeprazole Si Omeprazole Tenatoprazole No Omeprazole Pantoprazole No Omeprazole Esomeprazole No Omeprazole Tenatoprazole Si Omeprazole Pantoprazole Si Omeprazole Esomeprazole Si Pantoprazole Tenatoprazole No Pantoprazole Esomeprazole No Pantoprazole Tenatoprazole Yes Pantoprazole Esomeprazole Si Tenatoprazole Esomeprazole No Tenatoprazole Esomeprazole Yes Ilaprazole None Yes Lansoprazole None Yes Rabeprazole None Yes Pantoprazole None Yes Tenatoprazole None Yes Esomeprazole None Yes The PPIs are listed as racemate and as the base form. However, this list includes the enantiomers, based on the USAN Handbook [Manual USAN], and the hydrate salt forms (examples include, but are not limited to, pantoprazole sodium, tenatoprazole sodium trihydrate, and esomeprazole magnesium) . The USAN Handbook [The USAN Handbook], Chicago, IL: US Adopted Ñames Program [US Adopted Names Program] (1999).

In one embodiment disclosed herein a solid dosage form is provided comprising all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + cimetidine hydrochloride (200 mg) + sodium bicarbonate (1680 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided which comprises all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + sodium bicarbonate (1200 mg) + calcium carbonate (400 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided comprising all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + sodium bicarbonate (1200 mg) + magnesium hydroxide (420 mg) + carboxymethylcellulose sodium (30 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided which comprises all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + sodium bicarbonate (1200 mg) + calcium carbonate (300 mg) + format of calcium (100 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). You can also add aspirin (from 80 to 325 mg) or AI It is in its normal dosages, such as naproxen (from 100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided which comprises all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + sodium bicarbonate (1200 mg) + calcium carbonate (300 mg) + format of calcium (100 mg) + sodium carboxymethylcellulose (30 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added in their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided comprising all or any of the following: omeprazole (70 mg) + lansoprazole (30 mg) + sodium bicarbonate (1200 mg) + calcium carbonate (300 mg) + format of calcium (100 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided comprising all or any of the following: omeprazole (70 mg) + lansoprazole (30 mg) + sodium bicarbonate (1200 mg) + calcium carbonate (300 mg) + format of calcium (100 mg) + carboxymethylcellulose _ sodium (30 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided comprising all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + sodium bicarbonate (1000 mg) + calcium carbonate (400 mg) + format of calcium (200 mg) + magnesium hydroxide (200 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

In one embodiment disclosed herein a solid dosage form is provided comprising all or any of the following: omeprazole (60 mg) + lansoprazole (60 mg) + cimetidine hydrochloride (400 mg) + calcium carbonate (1200 mg) + hydroxide of magnesium (200 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg). In addition, aspirin (from 80 to 325 mg) or NSAIDs can be added to their normal dosages, such as naproxen (100 to 500 mg).

A person with knowledge in the field will observe that the previous embodiments in paragraphs [00181] - [00189] could also contemplate the following ratios between omeprazole and lansoprazole: approximately 40:40, approximately 50:50, approximately 75:75, and approximately 80:80.

Example 2 1 1 A study was carried out in a crossover design, with washing period between doses. The subject received the test article after placing a Bravo pH probe in the stomach and verifying its placement with pH readings less than 2. After a baseline evaluation, to verify that the pH probe was in the the correct place for gastric acid reading in the stomach, an intravenous access was established in the subject and baseline blood was taken in order to offer evidence of absence of PPI in the blood in the baseline. The subject received one of three different formulations, and the time of administration was specified. The blood samples were taken at intervals in order to characterize the phases of absorption, distribution and elimination of the test article. From these data, the AUC was calculated. A continuous recording of gastric pH was carried out using the Bravo pH probe and radiofrequency receivers. Gastric pH values were recorded every 10 seconds. Based on these data, the IGA for the 24 hour period.

The results for three different formulations are summarized below: Example 3 A study was carried out in a crossover design, with washing period between doses. The subject received the test article after placing a Bravo pH probe in the stomach and verifying its placement with pH readings less than 2. After a baseline evaluation, to verify that the pH probe was in the the correct place for gastric acid reading in the stomach, an intravenous access was established in the subject and baseline blood was taken in order to offer evidence of absence of PPI in the blood in the baseline. The subject received one of three different formulations, and the time of administration was specified. The blood samples were taken at intervals in order to characterize the phases of absorption, distribution and elimination of the test article. From these data, the AUC was calculated. A continuous recording of gastric pH was carried out using the Bravo pH probe and radiofrequency receivers. Gastric pH values were recorded every 10 seconds. From these data, the IGA was determined for the 24-hour period.

The results for three different formulations are summarized aba or: Example 4 A study was carried out in a crossover design, with washing period between doses. The subject received the article of test after placing a Bravo pH probe in the stomach and verifying its placement with pH readings below 2. After a baseline evaluation, to verify that the pH probe was in the correct place for gastric acid reading In the stomach, an intravenous access was established in the subject and baseline blood was taken in order to offer evidence of absence of PPI in the blood in the baseline. The subject received one of three different formulations, and the time of administration was specified. The blood samples were taken at intervals in order to characterize the phases of absorption, distribution and elimination of the test article. From these data, the AUC was calculated. A continuous recording of gastric pH was made by using the Bravo pH probe and radiofrequency receptors. Gastric pH values were recorded every 10 seconds. From these data, the IGA was determined for the 24-hour period.

IR: Immediate release means that this portion of the composition is formulated in such a way that the supply starts in the stomach and there is no enteric coating or programmed release coating. The term is contemplated to refer to any formulation of PPI in which all or a portion of the PPI is in solution either before administration or immediately after administration (ie, within approximately 30 minutes). For example, with an "immediate release" formulation, oral administration results in an immediate release of the agent from the composition in the gastric fluid.

DR: Delayed release means the release of this component of the formulation that starts at a different time immediately after administration. Delayed release formulations include non-immediate release formulations, including, but not limited to, these examples, film-coated formulations, enteric-coated formulations, encapsulated formulations, sustained-release formulations, and pulse release formulations. For delayed release ormulations, the drug release rate of the dosage form is the rate of drug delivery in the target area.

The results of the different formulations are summarized Formulation 7 Formulation 8 Formulation 9 120 mg 40 mg 120 mg Omeprazole Omeprazole Rabeprazole + 200 mg + 1680 mg + 200 mg Cimetidine NaHC03 Cimetidine + 1680 mg + 1680 mg NaHC03 NaHC03 AUCo-24 12.9 g »hr / mL 2.6 g» hr / mL 7.1 g «hr / mL Omeprazole Omeprazole Rabeprazole Half-life 2.1 hours 1.1 hours 0.8 hours (tl / 2) Omeprazole Omeprazole Rabeprazole IGA-24Day i 56 mmol'h / L 202 mmol »h / L 173 mmol'h / L Formulation 10 Formulation 11 [Formulation 12] 80 mg 40 mg 120 mg Omeprazole IR Esomeprazole Omeprazole IR + 80 mg DR + 40 mg Lansoprazole 'DR Tenatoprazole + 1680 mg IR + 200 mg NaHC03 Cimetidine + 1680 mg NaHCO3 AUCo-24 7.6 pg »hr / mL 3.6 yg * hr / mL 11.8 g» hr / mL Omeprazole Esomeprazole Omeprazole 14. 7 g * hr / mL - 88.3 μg · hr / mL Lansoprazole Tenatoprazole AUCo-24 22.3 ug »hr / mL - - Combined Lansoprazole Half-life 1.6 hours 1.4 hours 1.8 hours (l / 2) Omeprazole Esomeprazole Omeprazole 2. 5 hours - 12.9 hours Lansoprazole Tenatoprazole IGA-24Day! 115 mmol'h / L 316 mmol »h / L 28.4 mmol« h / L Formulation 13 Formulation 14 Formulation 15 120 mg 100 mg 160 mg Tenatoprazole Pantoprazole IR Omeprazole IR IR + 60 mg + 1680 mg + 1680 mg Omeprazole IR + NaHC03 NaHC03 1680 mg NaHC03 AUCo-24 76.9 ug'hr / mL 22.6 ug «hr / mL 18.1 pg» hr / mL Tenatoprazole Pantoprazole Omeprazole - 2.4 g »hr / mL - Omeprazole Half-life 8.6 hours 1.5 hours 2.3 hours (tl / 2) Tenatoprazole Pantoprazole Omeprazole - 0.8 hours - Omeprazole IGA-24Day i > 400 mmol »h / L > 400 mmol-h / L > 400 mmol'h / L [Formulation Formulation Formulation 18 16] 160 mg 40 mg 60 mg Lansoprazole IR Omeprazole IR Lansoprazole IR + 1680 mg + 40 mg + 40 mg NaHCO3 Tenatoprazole Tenatoprazole GO IR + 1680 mg + 1680 mg NaHC03 NaHC03 AUCo-24 12.4 pg'hr / mL 2.3 pg * hr / mL 2.9 g «hr / mL Lansoprazole Omeprazole Lansoprazole - 56.3 g * hr / mL 48.4 g * hr / mL Tenatoprazole Tenatoprazole Half-life 2.4 hours 0.9 hours 1.6 hours (ti / 2) Lansoprazole Omeprazole Lansoprazole - 10.6 hours 7.9 hours Tenatoprazole Tenatoprazole IGA-24Day! 57 mmol »h / L > 400 mmol »h / L > 400 mmol »h / L Formulation 19 Formulation 20 Formulation 21 40 mg 60 mg 120 mg Esomeprazole Omeprazole IR Lansoprazole IR DR + 60 mg + 1680 mg + 60 mg Pantoprazole IR NaHC03 Lansoprazole IR + 1680 mg + 1680 mg NaHCO3 NaHC03 AUCo-24 2.7 μ? ·? ^ / P? 3.8 μg · hr / mL 2.7 g · hr / mL Esomeprazole Omeprazole Lansoprazole 4. 0 g-hr / mL 8.9 g-hr / mL - Lansoprazole Pantoprazole Half-life 1.1 hours 1.7 hours 2.4 hours (ti / 2) Esomeprazole Omeprazole Lansoprazole 2. 6 hours 1.1 hours - Lansoprazole Pantoprazole IGA-2 Day! > 400 mmol'h / L 109 mmol »h / L > 400 mmol »h / L Formulation 22 Formulation 23 120 mg Pantoprazole IR 120 mg Omeprazole IR + 1680 mg NaHCO 3 + 1680 mg NaHCO 3 AUCo-24 9.2 g'hr / mL 9.6 pg »hr / mL Pantoprazole Omeprazole Half-life 0.9 hours Pantoprazole 1.9 hours Omeprazole (ti / 2) IGA-24Day i > 400 mmol »h / L > 400 mmoleh / L Example 5 General: A randomized, prospective study can be performed to evaluate the regression of Barrett's esophagus in patients diagnosed with Barrett's esophagus, after treatment with Nexium® (esomeprazole) compared to the test article. Patients with Barrett's esophagus, with or without low-grade dysplasia, may be randomized to receive Nexium® 40 mg or the test article once a day. Introduction: Barrett's esophagus is related to acid reflux in the esophagus. In general, it is believed that a chronic acid reflux causes Barrett's esophagus to lead to a low grade dysplasia and then a high degree leading to adenocarcinoma of the esophagus. J W van Sandick, "Impact of biopsy surveillance of Barrett 's oesophagus on pathological stage and clinical outcome of Barrett' s carcinoma [Impact of surveillance with endoscopic biopsy of Barrett 's esophagus on the pathological stage and clinical outcome of Barrett' s carcinoma], GUT, Vol. 43 , pages 216-222 (1998) .The incidence of all these conditions is increasing in the United States of America, adenocarcinoma of the esophagus is the fastest growing cancer, patients with Barrett's esophagus are currently managed by repeated endoscopic surveillance with biopsy. / pathological evaluation If changes in the pathology of the areas undergoing biopsy are observed to involve low-grade or high-grade dysplasia, patients are monitored more frequently (low-grade dysplasia) or are evaluated for other procedures such as ablation mucosal resection or esophagectomy (high-grade dysplasia) If carcinoma is observed, An esophagectomy is often recommended. Today there is no medical treatment to reverse Barrett's esophagus to a normal squamous esophageal mucosa. In a review of prospective studies of BE treatment with proton pump inhibitors (PPIs) (with or without surgery), only 3 of 123 patients presented a complete apparent reversal of BE. Sampliner, R., "Reduction of Acid Exposure and Regression of Barrett's Esophagus" [Reduction of Exposure to Acids and Regression of Barrett's Esophagus], Digestive Diseases, Vol. 18 (4), pages 203-207 (2001).

The nocturnal acid escape (pH less than 4 for more than 60 consecutive minutes in patients treated with a PPI therapy twice a day) occurs in more than 70% of patients. Thompson, CA., "First federal comparative effectiveness review examines GI disorder." [First review of federal comparative effectiveness examines gastrointestinal disorders], Am J Health-Syst Pharm, Vol. 63, page 302 (2006). The addition of an H2 blocker at bedtime has been suggested as a method to control nocturnal acid escape, however, this has been effective only for a week, then tolerance develops and the nocturnal effects of the H2 blocker are eliminated. Janiak P, "Clinical trial: the effects of adding ranitidine at night to twice daily omeprazole therapy on nocturnal acid breakthrough and acid reflux in patients with systemic sclerosis - a randomized controlled, cross-over trial" [Clinical trial: the effects of adding ranitidine at night to a therapy with omeprazole twice a day on nocturnal acid escape and acid reflux with patients with systemic sclerosis - a controlled, randomized controlled trial], Alimentary Pharmacology Therapeutics, Vol. 26, pages 1259-1265 (2007). Esomeprazole (Nexium®) 40 mg is a potent inhibitor of proton pumps and is used Widely for acid-related disorders. The test article can be a combination of PPI developed at the University of Missouri in order to optimize the AUC (area under the curve of serum concentration vs. time) of PPI and can produce and maintain pH values at > 4 for 24 hours per day after Day 1 of treatment. Methods Null hypothesis: There will be no difference in the rate of reversion of patients with Barrett's esophagus receiving Nexium® 40 mg once a day or the test article once a day. Alternative hypothesis: There will be a difference in the rate of reversion of patients with Barrett's esophagus if they receive Nexium® 40 mg once a day or the test article once a day.

Sample size. Data from the literature suggest a 2.4% incidence of complete reversion of Barrett's esophagus after a 24-month treatment with PPI. Based on the achievement of complete pH control with pH values above 4 for 24 hours per day, a reversion rate of 50% can be expected in the arm of the test article. Based on these considerations, a sample size of 10 subjects per arm will be necessary to detect a difference of one considering a Type I error rate of 5% and a Type II error rate of 20%.

Patients can be evaluated every three months by biopsy guided by endoscopy. The pathology results will be compared at three months, six months, and nine months, to determine the presence of signs of reversion of the Barrett's esophagus or reversal of dysplastic lesions. A partial reversal and a complete reversal can be compared. Biopsy protocols that use the acetic acid test for endoscopic detection without magnification, standard biopsy areas and jumbo forceps / biopsies of four quadrants every 1 cm can be used. Vázquez-Iglesias, JL., "Acetic acid allo s effective selection of areas for obtaining biopsy samples in Barrett's esophagus" [Acetic acid allows an effective selection of areas to obtain biopsy samples in Barrett's esophagus], European Journal of Gastroenterology & Hepatology. Vol. 19 (3), pages 187-193 (2007).

The test article may comprise: omeprazole powder (80 mg) + lansoprazole powder (80 mg) + sodium bicarbonate (1680 mg) + croscarmellose sodium (25 mg) + pregelatinized starch (65 mg) + magnesium stearate (25 mg) mg).

Example 6 General: A randomized, double-blind study can be performed to compare 80 omeprazole plus 80 mg lansoprazole with Zegrid® 40 mg in normal, healthy adults. The study may include a cross design with washes between doses. Participants should fast starting at midnight on the day of the visit (Day 1). The participant can receive a Bravo pH probe in your stomach and verify its placement with pH readings less than 2. The participant may also have an intravenous access. Before the administration of PPI, the participant is offered a breakfast, after which a pre-dose blood sample of 5 mL can be collected. After the dose of one of the drugs under study, blood samples of 4 mL can be taken at 5, 15, 60, 45, 60, 75, 135, 195, 315, and 375 minutes. At noon, the participant can be provided with a lunch. IV access can be removed after the 375-minute blood draw, but the participant can keep the Bravo pH probe in their stomach for a total of 24 hours. The participant can be allowed to eat after the 375-minute blood draw. There may be a 7 day washout period. After (Day 8), the other drug under study can be tested following the same protocol as the protocol described above.

The study can measure the level of IGA, the pharmacokinetic characteristics of the drug, such as the elimination half-life (ti2), AUC and the maximum concentration (Cmax), and the level of Gastrin-17 in the bloodstream of the participant. Each of the parameters can help determine the efficacy of the drugs under study. Gastrin concentrations are directly related to the activity of parietal cells, which are responsible of the production of acid in the stomach. The PPI inhibits the proton pump and prevents the production of acid. Therefore, gastrin results, in combination with pH, can help determine the effectiveness of PPI in suppressing acid production.

Protocol Events Program This study will have two treatment periods, one for each treatment arm with the study medication. The participant will be randomized to a treatment arm. After finishing and after washing, they will be placed in the other treatment arm.

Study Less Day: The participant will sign the informed consent and HIPAA formats. All study procedures will be explained, and all questions answered. The participant will be informed of the need to be fasting starting at midnight on Study Day 1. On this visit, the concomitant medications will be recorded, as well as the relevant medical / surgical history. The inclusion / exclusion criteria will be evaluated. If the participant must complete a washout period, their Study Day 1 will be scheduled to provide the necessary wash time. Study Day 1 will also be scheduled in accordance with your personal program and in such a way that every visiting day falls from Monday to Friday.

Study Day 1: The participant must have fasted starting at midnight on the day of the visit. Concurrent medications will be reviewed and all inclusion and non-exclusion criteria must be met. The participant will receive a breakfast and lunch and will be allowed to drink only water before and during the visit. In the case of women with the potential to become pregnant, a urine sample will be taken to carry out a pregnancy test. A 20 gauge IV catheter will be inserted into the hand or arm to take approximately eleven samples of 4 mL of blood. The participant will swallow, with water, a tied Bravo pH probe that can be swallowed in his stomach under proper supervision. The cord will have a bead fixed on the lip of the participant to indicate the placement of the cord in order to keep the probe suspended in the stomach. The cord will be fixed on the cheek and the neck of the participant through two Tegaderm dressings. After having successfully swallowed the Bravo pH probe, and before taking the medication, the patient will be provided with a McDonald Egg McMuffin for breakfast. While data from the probe is being collected, the pH probe receiver will be kept within a 152.5 cm (5 ft) distance. A pre-dose blood sample of 5 mL will be collected. The participant will take the dose of the study drug. Blood samples of 4 ml will be taken at 5, 15, 30, 45, 60, 45, 60, 75, 135, 195, 315, and 375 minutes after the dose. At noon, the participant will receive a hamburger with cheese and McDonald's medium French fries for lunch. IV access will be removed after the 375-minute blood draw and the participant will keep the Bravo pH probe in the stomach for a total of 24 hours. They will be allowed to eat again after the 375-minute blood draw.

Study Day 2: The participant will return to collect the recorded data and the pH probe receiver. The participant will have two options for the removal of the probe. The cord may be cut below the fixation point of the bead so that the probe and cord pass through the digestive system. The probe can also be removed from the stomach by an appropriate staff. If resistance is found, the cord will be cut under the pearl and the appropriate personnel will be notified.

Study Day 8: The participant will enter the second treatment period and will receive the second arm of the study medication. The participant must be fasting starting at midnight on the day of the visit. You will be provided with a breakfast and a lunch and you can only drink water before and during the visit. In the case of women with pregnancy potential, a urine sample will be taken to carry out a pregnancy test. It will insert a 20 gauge IV catheter in the arm or hand for approximately 11 4 mL blood samples. The participant will swallow, with water, a Bravo pH probe that can be swallowed tied in his stomach under proper supervision. The cord will have a bead fixed on the lip of the participant to indicate the placement of the cord in order to keep the probe suspended in the stomach. The cord will be fixed on the cheek and. the neck, of the participant through two Tegaderm apposites. After having successfully swallowed the Bravo pH probe, and before taking the medication, the patient will be provided with a McDonald Egg McMuffin for breakfast. While data from the probe is being collected, the patient will maintain the pH probe receiver at all times within a distance of 152.5 cm (5 feet). A pre-dose blood sample of 5 mL will be collected. The participant will take the dose of the study drug and blood will be taken at 5, 15, 30, 45, 60, 45, 60, 75, 135, 195, 315, and 375 minutes after the dose. At noon, the participant will receive a hamburger with cheese and McDonald's medium French fries for lunch. IV access will be removed after the 375-minute blood draw and the participant will keep the Bravo pH probe in the stomach for a total of 24 hours. They will be allowed to eat again after the 375-minute blood draw.

Study Day 9: The participant will return to collect the recorded data and pH probe receiver. The participant will have two options for the removal of the probe. The cord can be cut below the fixation point of the pearl, so that the probe and cord pass through the digestive system. The catheter may also be removed from the stomach by appropriate personnel. If resistance is found, the cord will be cut under the pearl and the appropriate personnel will be notified. The participant will receive a check as compensation.

Abbreviations ?? = Adverse Event AUC = Area under the Curve b.i.d. = Twice a day CRF = Case report format FDA = Food and Drug Administration GERD = Gastroesophageal Reflux Disease IDS = Investigational Drug Services [Research Drug Services] IRB = Institutional Review Board mg = milligrams mL = milliliters NSAID = Non-Steroidal Anti-Inflammatory Drug PPI = Proton Pump Inhibitor SAE = Serious Adverse Event t.i.d. = Three Times a Day UMHC = University of Missouri Health Care [Medical Care of the University of Missouri] ZES = Zollinger-Ellison syndrome Background Information Omeprazole (the active ingredient in Zegerid and Prilosec) and lansoprazole (the active ingredient in Prevacid) are two FDA-approved drugs commonly used to treat a wide range of gastric acid-related disorders, including gastric and duodenal ulcers. Gastroesophageal reflux (GERD); and Zollinger-Ellison syndrome (ZES). They belong to a class of antisecretory compounds that are known as substituted benzimidazoles and act by inhibiting proton pumps in parietal cells (hence the term "proton pump inhibitor" which is abbreviated as "PPI"), therefore blocking the final stage of gastric acid production. In clinical studies, the mean plasma elimination half-life in healthy adults is approximately 1.5 hours in the case of lansoprazole1 and less than 1 hour in the case of omeprazole2. The acid inhibitory effect - which was measured by the reduction in basal acid production, mean gastric pH increase, and the percentage time during which the gastric pH was greater than 3 and 4 - lasted more than 24 hours in the fifth day of treatment with a dose of 30 mg of lansoprazole or with a dose of 40 mg of omeprazole in accordance with the package leaflets for Prevacid and Prilosec, respectively. The drugs also significantly reduced the production of gastric acid stimulated by food and the volume of secretion as well as the production of acids stimulated by pentagastrin on the fifth day. In the first days of treatment, however, the efficacy is usually low and the inhibition of acid rarely lasts more than 2-3 hours3'4.

It has been shown in other studies that lansoprazole is extensively metabolized in the liver in approximately equal amounts by both isoforms 2C19 and 3A4 of the enzyme Cytochrome P4505, while omeprazole is metabolized mainly by the isoform 2C196. After a single oral dose, most of the PPI detected in the urine is in the inactivated metabolized form. It was found that elimination rates were faster in pediatric patients and slower in geriatric patients, and dosage adjustment was suggested for these populations in several past studies8. No differences were reported regarding the pharmacokinetic characteristics of PPI and intragastric pH between male and female patients3'4. Patients with renal insufficiency had a shortened elimination half-life and reduced total AUC9. , while patients with liver diseases had significantly extended elimination half-lives and an increased total AUC 10 '11. More than 10,000 patients have been treated with both PPIs in Phase 2 and Phase 3 clinical trials, and each drug is used regularly in clinical environments to control various acid-related disorders.

Due to the high specificity of PPIs, the side effects are usually infrequent and mild. Omeprazole and lansoprazole are both prodrugs only converted to their active form at a pH lower than 2 and since the only physiological location that meets this requirement is the canalicular space of parietal cells, the effects of the drugs are limited to this area . Adverse effects reported in the package leaflets for each drug are presented below: Packing brochure Zegerid ™ Prevacid® packaging brochure Effect Omeprazole Placebo Lansoprazole Placebo (n = 2631) (n = 120) (n = 2768) (n = 1023) Pain 5.2 3.3 2.1 1.2 Abdominal Asthenia 1.3 0.8 < 1 N / R Constipation 1.5 0.8 1.0 0.4 Diarrhea 3.7 2.5 3.8 2.3 Headache 2.9 2.5 < 1 < 1 Table 1: Adverse effects (in terms of percentage of patients) that were found in at least 1% of patients who took any of the drugs in clinical trials3'4.

The oral administration of PPI drugs is typical. The hypothesis that will be tested in this study is that there is no difference in integrated gastric acidity of 24 hours between subjects receiving a single dose of 40 mg of Zegerid and subjects receiving a single dose of 80 mg of omeprazole plus 80 mg of lansoprazole in an immediate release formulation; the alternative hypothesis is that there is a difference in integrated 24-hour gastric acidity between subjects receiving a single dose of 40 mg of Zegerid and subjects receiving a single dose of 80 mg of omeprazole plus 80 mg of lansoprazole in a release formulation immediate Therefore, by design, a single dose will be administered.

Population to study Healthy adults, normal between 18 and 60 years old who volunteer to participate in the study.

References Below are references to literature and data that are relevant to the trial and that offer background for the trial: 1. Karol, M.D., Pharmacokinetics of lansoprazole in hemodialysis patients [pharmacokinetic characteristics of lansoprazole in patients undergoing hemodialysis]. 2. Cederberg, C, Omeprazole: pharmacokinetics and metabolism in man [Omeprazole: pharmacokinetic characteristics and metabolism in humans]. 3. Prilosec delayed-release capsules [Prolosec delayed-release capsules]. In AstraZeneca: Wilmington, DE, 2002 [Prilosec Delayed Release Capsules]. 4. Prevacid delayed-release capsules [Prevacid delayed-release capsules]. At TAP Pharmaceuticals: Lake Forest, IL. 2003 5. Pichard, L .; Curi-Pedrosa, R .; Bonfils, C.; Jacqz-Aigrain, E .; Domergue, J .; Joyeux, H., Oxidative metabolism of lansoprazole by human liver cytochromes P450 [oxidizing metabolism of lansoprazole by human hepatic cytochromes P450]. Molecular Pharmacology 1995, 47, (2), 410-8. 6. Yamazaki, H .; Inoue, K .; Shaw, P. M.; Checovich, W. J .; Guengerich, F. P .; Shimada, T., Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of these two forms in individual human samples [Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of the content of these two forms on individual human samples]. Journal of Pharmacology and Experimental Therapeutics 1997, 283, (2), 434-42. 7. Sohn, D. R .; Kobayashi, K; Chiba, K .; Lee, K. H .; Shin, S. G .; Ishizaki, T. , Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin '-hydroxylation recruited from an Oriental population [Kinetic disposition and metabolism characteristics of omeprazole in extensive and deficient metabolites of S-mephenytoin 4' -hydroxylation recruited from a population Oriental] . Journal of Pharmacology and Experimental Therapeutics 1992, 262, (3), 1195-202. 8. Phillips JO, B.J., Siddiqi SH, Bothwell M, Pediatric patients have shorter lansoprazole half-life than previously reported [Pediatric patients have a shorter half-life of lansoprazole than previously reported]. American Journal of Gastroenterology 2007, 102, (s2), S548. 9. Naesdal, J .; Andersson, T .; Bodemar, G .; Larsson, R.; Regárdh, C. G .; Skánberg, 1., Pharmacokinetics of [14C] omeprazole in patients with impaired renal function [pharmacokinetic characteristics of [14C] omeprazole in patients with impaired renal function]. Clinical Pharmacology & Therapeutics 1986, 40, (3), 344-51. 10. Delhotal-Landes, B .; Flouvat, B .; Duchier, J .; Molinie, P .; Dellatolas, F .; Lemaire, M., Pharmacokinetics of lansoprazole in patients with renal or liver diseasé of varying severity [Pharmacokinetic characteristics of lansoprazole with kidney or liver disease of variable severity]. European Journal of Clinical Pharmacology 1993, 45, (4), 367-71. 11. Yin, 0. Q. P .; Brian, T .; Albert, H. L. C; Mary, M. Y. W .; Moses, S.C., Omeprazole as a CYP2C19 marker in Chine subjects: assessment of its gene-dose effect and intrasubject variability [Omeprazole as a marker of CYP12C19 in Chinese subjects: evaluation of its gene-dose effect and intrasubject variability]. The Journal of Clinical Pharmacology 2004, 44, (6), 582-9.

Objectives and Purposes of the Assay Hypothesis: The hypothesis tested in this study is that there is no difference in integrated gastric acidity of 24 hours between subjects receiving a single dose of 40 mg of Zegerid and subjects receiving a single dose of 80 mg of omeprazole plus 80 mg of lansoprazole in an immediate release formulation; the alternative hypothesis is that there is a difference in integrated gastric acidity of 24 hours between subjects receiving a single dose of 40 mg of Zegerid and subjects receiving a single dose of 80 mg of omeprazole plus 80 mg of lansoprazole in a release formulation immediate Test Design Primary end point. The primary end point will be integrated gastric acidity over 24 hours. PH probe data will be transformed into integrated gastric acidity using the AcidipHy software.

This trial is a single-site, double-blind trial.

Measures taken to avoid / minimize bias. The study medication will be administered in double blind. A single dose of one of the medication arms under study will be provided to each treatment period for a total of 2 doses of study medication.

Duration of the Participation. The participant will participate in the trial for a minimum of 10 days. The washing required before Study Day 1 will cause the duration of participation to vary slightly among participants. The Less Study Day visit will last approximately half an hour. The Day 1 visit will last approximately 24 hours because the participant will keep the catheter in the stomach for 24 hours. The Day 2 visit will last 30 minutes. There will then be a 7-day washout period between the drugs under study. the Day 8 visit will last approximately 24 hours since the participant will keep the catheter in the stomach for 24 hours, and the Day 9 and final visit will last 30 minutes. Storage of Products in Research. The products under investigation will be provided only by the pharmacist in charge of the trials with investigational drugs. Bravo pH probes, fixation equipment, and blood collection supplies will be stored at the study site.

Assortment of Products in Research. The products under investigation will be supplied in a 50 mL centrifugation tube. Before the consumption of the study drug by the participant, 30 mL of water will be added and mixed.

Randomization codes. The maintenance of the randomization codes of the test treatment and procedures for breaking the codes shall be carried out in accordance with the following: the blind may be broken in the event of a serious adverse event. The IDS pharmacist in charge of the study drug and in charge of the randomization of the participant will have a list of participants and information about which study medication they are taking. The participant will receive a card that must be carried in which it is established that he is participating in a clinical trial, where short details of the trial are stipulated and who to call in an emergency.

Data to be registered in the CRF. the initials of the participant, their sex, date of birth, ethnicity, pregnancy status and lactation, inclusion / exclusion criteria, concomitant medications, relevant medical history, blood test data, pH probe data, time of blood sampling and time of consumption of the medication under study, any use of a prohibited medication and adverse events.

Methods Form of drug in study. The drugs under study will be in the form of a suspension consisting of powder for oral administration mixed with 30 mL of water.

Methods used to identify and recruit participants. Verbal communication.

Methods used to avoid involuntary coercion in the recruitment process. Potential participants will receive written informed consent information. Participants will be assured that they have the right not to participate.

PH Bravo probe. The Bravo pH probe will be deployed from its delivery system in such a way that the probe is separated from the delivery mechanism before being swallowed by the patient. A braided polyester brace with a diameter of 0.1 mm will be tied securely around the pin on the top of the probe in order to hold the cord on the probe. A pearl will be fixed over the cord on the patient's lip to mark the placement. Two Tegaderm dressings will be used to hold the cord on the participant's cheek.

Screening in relation to pregnancy and lactation. | Female participants with pregnancy potential will be subjected to a pregnancy test through urine.

They will be asked verbally if they are nursing.

Processes and documents of consent and assent Type of consent process: written.

Description of the consent process. The study will be explained with all the details. The participant will have time to read the consent. All questions will be answered. After providing verbal assent, the participant will sign the consent. The original will be kept with the study documents and the subject will receive a copy.

Voluntary Participation A participant may decide to participate in the study or not participate. If the participant chooses not to participate, he / she can leave the study at any time. The decision to participate will not affect the care the participant will receive from any health care provider or the medical benefits to which they are entitled. If the participant decides to withdraw from the study at a later date, we will retain the information collected up to this point but we will not ask the participant for any additional information. We will continue to use the data and samples that the participant provided until that date to unless we receive a written request from the participant signing asking us not to do so. The investigator (s) who carries out the study may also decide to withdraw the participant from the study without their consent if it is determined that the participant is not really eligible or if they can no longer comply with the study requirements.

Blood Shot All IV insertions will be done by a registered nurse or by a certified nurse practitioner who has a certification to start IVs. The objective of blood collection is to characterize the pharmacokinetics of omeprazole and lansoprazole in subjects and determine the level of Gastrin-17 during the period of blood sampling. An occasional blood sample may be taken slightly outside the scheduled time. Characterization of pharmacokinetics may allow different hours if the actual blood collection time is recorded. The scheduled time and the actual time of blood collection will be registered in the CRF. If the IV access becomes covered and another can not be started in time for the next scheduled blood draw, a butterfly-type needle will be used to obtain the required blood sample. Every effort will be made to comply with the blood collection program. In the course of the two For treatment periods, 20 samples of 4 mL of blood and two samples of 5 mL of blood will be taken, which gives a total of 90 mL of blood. After each blood draw, approximately 3-5 mL of 0.9% sodium chloride will be rinsed through the participant's IV catheter in order to avoid blockage in the IV cannula.

Conservation in blood bank. The blood will not be kept in a blood bank (preserved indefinitely), for use in other research not related to this project.

Selection and Removal of Subjects Inclusion criteria 1. Adults between 18 and 60 years of age. 2. If a woman has the potential for pregnancy, she should use an acceptable form of contraception; oral contraceptive, intrauterine device, contraceptive patch, injection, vaginal ring, double barrier method, that is, condom and spermicide, tubal ligament, abstinence, or partner, with vasectomy. 3. Ability to swallow a multi-vitamin size pill with water, without difficulty. 4. Desire and ability to comply with all study procedures.

Exclusion criteria 1. Concomitant use of any medication used to treat acid reflux. 2. Use of a drug in research within 30 days before recruitment. 3. Chronic use of PPI. 4. Use of PPI 7 days before recruitment. 5. Use of H2 receptor antagonist for 8 hours before recruitment. 6. Use of antacid 4 hours before recruitment. 7. Pregnant or lactating woman. 8. Dysphagia, or a feeling that the food "gets stuck". 9. Diabetes. 10. Liver disease. 11. Allergies to any medication under study. 12. Cheese allergy 13. Use of any pharmaceutical / herbal supplement within 5 days or 10 half-lives before Study Day 1 and study day 8 (whichever is longer) partially or totally metabolized by Cytochrome P450 2C19 or 3A4. 14. Use of any pharmaceutical / herbal supplement in the last 5 days or 10 half-lives (whichever is longer) that affects the production of gastrin.

Retirement criteria / Early termination 1. The participant withdraws his consent. 2. Vomiting caused by the placement of the probe that produces severe fluid losses (more than 1.5 liters). 3. The participant presents a serious adverse event.

Treatment of Subjects Concomitant medications. The concomitant use of the following is prohibited: The use of any medication to treat acid reflux will not be allowed during the study. The use of any pharmaceutical / herbal supplement in the five days or ten half-lives prior to Study Day 1 and Study Day 8 (whichever is longer) partially or totally metabolized by Cytochrome P450 2C19 or 3A. The use of any pharmaceutical / herbal supplement in the five days or ten half-lives prior to Study Day 1 and Study Day 8 (whichever is longer), which affects the production of Gastrin.

Treatments to administer. Omeprazole 80 mg plus lansoprazole 80 mg powder will be administered orally in the form of a suspension in 30 mL of water. It will be administered once on Study Day 1 or Study Day 8. 40 mg of Zegerid powder will also be orally administered in the form of a suspension in 30 mL of water. It will be administered once Study Day 1 or Study Day 8.

Compliance with the treatment. The procedure to monitor compliance with treatment will consist of observation by the study staff that the participant is taking the study medication. The study staff will ask the participant about the use of prohibited medications.

Evaluation of Benefits and Risks / Disturbances / Adverse Events Definition of adverse events. An adverse event is any harmful medical event in a subject receiving a pharmaceutical product. The adverse event does not necessarily have a causal relationship with the treatment. An adverse event can be any sign, symptom, or unfavorable disease and not temporarily contemplated associated with the use of a pharmaceutical product. A pre-existing condition is considered an adverse event only if there is an increase in frequency or severity or a change in nature or as a consequence of the use of mediation in a clinical trial. Any adverse event with the start date after the consent and until the completion of the study will be registered in the CRF on the appropriate page.

An adverse event does not include: * Medical or surgical procedures; The condition that leads to the procedure is the adverse event.

* Diseases or pre-existing conditions present before consent.

* Situations in which a harmful medical event has not occurred (for example, hospitalization for elective surgery, social admissions and / or comfort).

Evaluation of Adverse Events. All adverse events will be evaluated by researchers and registered CRF appropriate The recorded data will also include the beginning, resolution and result, severity, relationship with the study medication, and action taken.

Procedures to record and report adverse events. Adverse events and SAEs will be reported to the IRB in accordance with the IRB policy. Adverse events and SAEs will be recorded in the Case reports formats folder.

Risks and discomforts reasonably foreseeable for the subjects. The risks and discomforts of adverse events in the study related to omeprazole contained in Zegerid are rare and slight. Adverse events related to omeprazole and side effects related to lansoprazole and omeprazole are abdominal pain, asthenia, constipation, diarrhea and headache. Vomiting and / or nausea, cough and aspiration of fluid in the lungs are possible adverse events of swallowing and removal of Bravo pH probe. Possible adverse events of attachment are sore throat, superficial trauma to the oropharynx, intolerance and nausea. Possible adverse events of the cord used to secure the probe are cutaneous rash and superficial cutaneous trauma.

Procedures to prevent and / or minimize any risk and potential discomfort. Participants will be monitored throughout the clinical phase of this study by the staff of the I studied as to the following.

* Participants will be monitored to determine the existence of signs and symptoms of allergic reaction to the test items.

* Participants will be monitored to determine the presence of signs and symptoms of potential risks and discomfort potentially related to blood collection and swallowing of the tube.

* An experienced staff will perform and explain procedures / tests.

* The cord will be used to reduce the risk of aspiration.

The appropriate personnel will be present when the participant swallows the Bravo pH probe and when the probe is removed. Alternatively, the participant can choose to cut the cord. If resistance is encountered when removing the probe, the cord may be cut and the appropriate personnel notified.

Potential benefits of participation for the subject. For the participant there may or may not be a direct medical benefit. A participant can expect to benefit from their participation in this research to the extent that they are contributing to medical knowledge. We hope that the information obtained from this study will be beneficial for other patients who require immediate control of acid secretion in the future.

The risk / benefit ratio for the participant of this project. The risk in relation to the benefit for two reasons: (1) PPI drugs are very specific in their mechanism of action since they are only prodrugs converted into their active form at a pH below 2. Since the only physiological location that meets this requirement is the canalicular space of parietal cells, the effect of the drug is limited only to this area and (2) the subjects receive a dose of each drug separated by a lapse of time of at least a week; therefore, there is no risk of chronic exposure. The possible benefit of participating in this study is to improve treatment for patients who require immediate control of acid secretion.

Pregnancy Pregnancy test administration. A urine pregnancy test will be administered to women with pregnancy potential before their acceptance in the study and before the second dose of the study drug in the second treatment period. People who are positive in the test will be excluded from the study. Lansoprazole is in category B for pregnancy, and Omeprazole and Zegerid are in category C. In studies with rats, it was found that lansoprazole or its metabolites were excreted in the breastmilk. It is not known if omeprazole is excreted in breast milk.

Pregnancy control in the case of women with the potential to become pregnant. Acceptable methods of contraception are: * Oral contraceptive * Intrauterine device * Contraceptive injection, patch or vaginal ring * Double barrier method: that is, condom and spermicide * Tubal ligament * Partner with vasectomy * Abstinence Efficacy Evaluation Specification of efficacy parameters. The pH probe data will be used to determine the integrated gastric acidity, an accepted measure of the efficacy of PPI, using the AcidipHy software.

Methods and time frame to evaluate, record and analyze security parameters. The objective of the blood samples is to characterize the pharmacokinetics of omeprazole and lansoprazole and the levels of Gastrin-17 in the bloodstream of the participant. The concentration of omeprazole and lansoprazole in the participant's plasma will be determined and plotted on a concentration vs. time plot, which allows determining the important pharmacokinetic parameters such as elimination half-life (ti / 2), area under the drug concentration curve (AUC) and the maximum concentration (Cmax). These parameters will provide a good approximation of the amount of drug in the participant's bloodstream and the duration of or stay there; therefore, an analysis can be made of when (and to what extent) the drug is more active in the participant.

The Gastrin-17 test will be performed with each blood sample in order to determine the gastrin response to the drug and meals. High concentrations of gastrin are an indicator of increased activity of the parietal cells which are the cells responsible for the production of acid in the stomach. The gastrin concentration will be plotted on a separate graph in relation to time and will offer an improved idea of the amount of stomach acid normally produced at any given time. PPI inhibits proton pumps and prevents acid production, so that gastrin results (when combined with pH) will help determine the effectiveness of PPI in suppressing acid production.

It will be acceptable for the blood samples to be extended beyond the programmed times, since the characterization of the pharmacokinetics may allow different times than those programmed if an exact time of blood collection is observed. Every effort will be made to comply with the blood collection program.

Statistics Statistical method The statistical method used to analyze and compare the data will be the Student's T test for paired data.

Power analysis A reduction of 50 of integrated acidity is expected on Day 1 when comparing: a single dose of 40 mg of Zegerid with a single dose of 81 g of omeprazole plus 80 mg of lansoprazole. The calculation of the Power results in a sample size per arm of 13 subjects, therefore, a minimum of 26 subjects will be required for the complete study. The recruitment of a total of 30 subjects will allow the existence of subjects who leave the study, whose level is anticipated by 10%. The calculation is based on the following formula S, x (1Ó0-S,) - S2x (100-S2) Tt 5B- * > («> 0) ß (Type II Error 0. 05 0.1 0.2 0.5 0. 1 10.8 8.6 6.2 2.7 0. 05 13 10.5 7.9 3.8 (Type Error 0. 02 15.8 13 10 5.4 I) 0. 01 17.8 14.9 11.7 6.6 Use the table above to calculate the f. { a, ß) Select an a and ß and then cross-reference, Level of significance The level of significance to be used is p < 0.05 alpha p < 0.2 beta.

Procedure to post missing or unused data. It will record how and why data was lost. A calculation of pharmacokinetic parameters and integrated gastric acidity can be made with a certain loss of data. Participants to include. The participants to be included in the analyzes are healthy volunteers who complete the trial.

Costs of this Study Costs that will not be paid by participants or their insurance providers: The costs of the study are limited to: All supplies needed for blood collection and all blood tests.

Medications under study.

Bravo pH probe and study monitor.

Breakfasts and lunches.

Costs that will be paid by the participants or their insurance providers: The participant must pay for their transportation and parking and other travel costs. The use of other medications to help control side effects may result in added costs that may or may not be covered by participants' health insurance. At the end of the trial, the participant will receive up to $ 500. For the Study Day visit Less they will receive $ 20. For each of the visits of Study Days 1, 2, 8 and 9, they will receive $ 120. To receive the $ 120 in Study Days 1 and 8, the participant should make an effort to swallow the Bravo pH probe and if swallowed, to conserve the probe in his stomach and allow at least two attempts to insert a finger. IV for blood samples. Study Days 2 and 9 must successfully complete the study procedures of previous visits and return the Bravo pH probe monitor. If the participant presents an adverse event and can not continue in the study, they will receive compensation until the day of the visit in which they presented the adverse event.

Direct Access to Source / Data Documents The investigator (s) / institution will allow monitoring, auditing, IRB / IEC review and regulatory inspection (s) related to the trial by offering direct access to source data / documents. The FDA may also perform audits related to the trial and have direct access to all source / document data.

Quality Control and Quality Assurance Medications under study will be purchased from manufacturers and will be supplied by the appropriate personnel.

Compliance Statement. This trial complies with Good Clinical Practices and with all the requirements of an Institutional Review Board.

Data Security Monitoring Plan. The study data will be reviewed after each group of participants, including a review of adverse events to determine trends. Study staff will review the data and monitor patients throughout the study and will alert the appropriate staff in case of suspected adverse event. All adverse events will be reviewed by the appropriate personnel. Appropriate personnel will be present when the participant swallows the Bravo pH probe and when the probe is removed. If resistance is found, the cord will be cut and the appropriate personnel notified. Appropriate staff will be available if complications arise while the participant is in an examination room. 911 will be used as backup if they are not available. A stop cart will be available. The blood test data will be analyzed. The test results and data files will be shared among those registered with IRB as working in this study. All participant data and test results will remain protected at all times.

All references, including publications, patent applications and patents mentioned herein are incorporated by reference to the same extent as if each reference were mentioned herein individually and specifically as incorporated by reference and reproduced in its entirety herein.

The use of the terms "a" and "an" and "the" and "the" and similar terms in the context of this disclosure (especially in the context of the following claims) should be construed as encompassing both the singular and the plural, unless otherwise indicated here or unless the context clearly contradicts it. All the methods described here can be carried out in any suitable order unless otherwise indicated here or the context clearly contradicts it. The use of each and every example, or the language of the examples (eg, such as, preferably, preferably, particularly) provided herein, is contemplated simply to further illustrate the content of the disclosure and does not raise a limitation of the disclosure. scope of the claims. No expression should be interpreted in the specification as indicating that some unclaimed element is essential for the practice of the claimed invention.

Alternative embodiments of the claimed invention are described herein, which include the preferred embodiment known to the inventors to carry out the claimed invention. Among these, variations of the disclosed modalities will be apparent to people with ordinary knowledge in the matter when reading the previous disclosure. The inventors expect that persons with knowledge in the art to employ such variations as appropriate, and inventors contemplate the practice of the invention claimed in other ways than specifically described herein.

Accordingly, the claimed invention includes all modifications and equivalents of the subject matter mentioned in the appended claims as permitted by applicable law. In addition, any combination of the elements described above in all possible variations is encompassed by the claimed invention unless otherwise indicated herein or unless the context clearly contradicts it.

The use of individual numerical values is specified as approximations as if the values were preceded by the word "approximately". Similarly, the number values in the various ranges specified in this application, unless expressly stated otherwise, are set as approximations as if the minimum and maximum values within the established ranges were both preceded by the word "approximately" . In this way, variations up and down the established ranges can be used to achieve substantially the same results as the values within the ranges. As used herein, the term "about", when referring to a numerical value, will have its plain and ordinary meanings to a person with ordinary skill in the art to which the disclosed subject matter is most closely related. or the technique relevant to the rank or element in question. The amount of expansion from the strict numerical limit depends on many factors, for example, some of the factors that can be considered include the critical nature of the element and / or the effect that a given amount of variation will have on the performance of the subject claimed, as well as other considerations known by a person with knowledge in the subject. As used herein, the use of different amounts of significant digits for different numerical values is not intended to limit the way in which the use of the word "approximately" will serve to extend a particular numerical value. Therefore, in general, the term "approximately" extends the numerical value. Likewise, the disclosure of ranges is considered as a continuous range that includes each value between the minimum and maximum values plus the extension of the range allowed by the use of the term "approximately". Therefore, the fact of mentioning ranges of values here is simply intended to serve as an abbreviation method to refer individually to each separate value that falls within the range unless otherwise indicated here, and each separate value is incorporated into the specifications as if it were individually mentioned there.

It will be understood that any range, proportion and range of proportion that can be formed from any of the data disclosed herein or derived from any of the data disclosed herein represents additional embodiments of the present disclosure and is included as part of the disclosure as if presented explicitly. This includes ranges that can be formed which include or do not include an upper limit and / or finite lower limit. Therefore, a person with ordinary knowledge in the matter most closely related to a particular rank, proportion or ratio will observe; that such values can be derived unambiguously from the data presented here.

Claims (25)

1. CLAIMS 1. A pharmaceutical composition comprising a first acid labile proton pump inhibitor, a second acid labile proton pump inhibitor and at least one buffering agent. 2. The composition according to claim 1, wherein the first proton pump inhibitor and the second proton pump inhibitor have the formula (I): wherein the first proton pump inhibitor and the second proton pump inhibitor are not identical; R hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, optionally fluorinated alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R3 and R5 are the same or different and each of them is hydrogen, alkyl, alkoxy, amino or alkoxyalkoxy; R 4 is hydrogen, alkyl, optionally fluorinated alkoxy, or alkoxyalkoxy; Q is nitrogen, CH, or CR1; W is nitrogen, CH, or CR1; and is an integer from 0 to 4; Y Z is nitrogen, CH, or CR1; or a free base, salt, ester, hydrate, salt hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof. 3. The composition according to claim 1, wherein both the first proton pump inhibitor and the second proton pump inhibitor are selected from the group consisting of omeprazole, tenatoprazole (or benatoprazole), s-tenatoprazole, lansoprazole, s -lansoprazole, rabeprazole, esomeprazole (also known as S-omeprazole), hydroxyomeprazole, ilaprazole, pantoprazole, pariprazole, leminoprazole, dontoprazole, habeprazole, perprazol, ransoprazole, and nepaprazole, or a free base, a free acid, a salt, hydrate , ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative thereof. 4. The composition according to claim 1, wherein the at least one buffering agent is selected from the group consisting of: a metal salt of Group IA including, a metal buffering agent alkaline earth, an amino acid, an alkaline salt of an amino acid, a peptide, an aluminum buffer, a calcium buffer, a sodium buffer, a magnesium buffer, a potassium buffer, and a mixture thereof. 5. The composition according to claim 1, wherein the first labile proton pump inhibitor to acids is omeprazole, the second labile proton pump inhibitor is lansoprazole, and the at least one buffer is selected Within the group consisting of: sodium bicarbonate, calcium carbonate, calcium formate, magnesium hydroxide, and mixtures of the above. 6. The composition according to claim 5, wherein the omeprazole is present in an amount of about 60 mg to about 100 mg; lansoprazole is present in an amount of about 60 mg to about 100 mg; and sodium bicarbonate is present in an amount of about 100 mg to about 2000 mg. 7. The composition according to claim 5, wherein the omeprazole is present in an amount of about 80 mg to about 100 mg; lansoprazole is present in an amount of about 80 mg to about 100 mg; and the sodium bicarbonate it is present in an amount of about 700 mg to about 1800 mg. 8. The composition according to claim 6, further comprising calcium carbonate. 9. The composition according to claim 7, wherein the calcium carbonate is present in an amount of about 300 mg to about 400 mg. 10. The composition according to claim 6, further comprising calcium format. 11. The composition according to claim 10, wherein the calcium formate is present in an amount of about 100 mg. 12. The composition according to claim 6, further comprising calcium carbonate and calcium formate. The composition according to claim 12, wherein the calcium carbonate is present in an amount of about 300 mg to about 400 mg and the calcium format is present in an amount of about 100 mg. 14. The composition according to claim 1, further comprising one or more pharmaceutically acceptable excipients. 15. The composition according to claim 14, wherein the pharmaceutically acceptable excipient or the various pharmaceutically acceptable excipients are selects (n) within the group consisting of: diluents, disintegrating agents, binding agents, adhesives, wetting agents, lubricants, slip agents, surface modification agents, added substances to mask or counteract an unpleasant taste or odor, flavorings , dyes, fragrances, and added substances to improve the appearance of the composition. 16 The composition according to claim 15, wherein the disintegrating agent is selected from the group consisting of: croscarmellose sodium and sodium carboxymethylcellulose. 17 The composition according to claim 15, wherein the lubricant is magnesium stearate. 18 The composition according to claim 1, further comprising a H2-19 blocker. The composition according to claim 18, wherein the H2 blocker is cimetidine. twenty . The composition according to claim 1, further comprising aspirin. twenty-one . The composition according to claim 20, wherein the aspirin is present in an amount of about 80 mg to about 325 mg. 22 The composition according to claim 1, further comprising an NSAID. 2. 3 . The composition according to claim 22, where the NSAID is naproxen. 24. The composition according to claim 22, wherein the NSAID is present in an amount of about 1 mg to about 500 mg. 25. The composition according to claim 1, wherein the composition is in a solid dosage form selected from the group consisting of: tablets, tablets, capsules, powders, pills, sachets, dragees, troches, pellets, and granules. 25. The method for treating a subject, with or without gastroparesis, which requires therapy, said method comprises the administration to the subject of the pharmaceutical composition of claim 1, wherein the subject suffers from a condition selected from the group consisting of: esophagitis Severe erosive (grades C and D of the Los Angeles classification), Barrett's esophagus and reversal of Barrett's esophagus, esophageal metaplasia related to reflux with low or high grade dysplasia, adenocarcinoma of the esophagus related to reflux, adenocarcinoma of the stomach related to acid, patients undergoing ablation in Barrett's esophagus to prevent recurrence, short-term eradication of H. pylori, extra-esophageal or atypical manifestations of gastroesophageal reflux disease, such as eye pain, asthma, bronchitis, pneumonia, chest, cough, recurrent laryngitis, pharyngeal balloon, sinusitis, otalgia, otitis media, Eustachian tube dysfunction, voice change, balloon sensation, throat clearing, halitosis, sore throat, and aphthous ulcers, nocturnal acid escape, apnea sleep, sleep disturbance, gastrointestinal bleeding, pre-treatment before endoscopic evaluation of upper gastrointestinal bleeding, prevention of stress ulcer, bleeding related to stress, attack or apparent attack activity, Sandifer syndrome, poor development, anorexia, anorexia nervosa , weight loss, apnea, bradycardia, and esophagitis induced by radiation or chemotherapy.