MXPA05008804A - A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained supression of gastric acid. - Google Patents

Abstract

The present invention is directed to methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease, or the symptoms associated with, or related to a gastrointestinal disorder or disease in a subject in need thereof. In one aspect, the present invention provides a pharmaceutical composition comprising a proton pump inhibiting agent and a buffering agent for oral administration and ingestion by a subject. Upon administration, the composition contacts the gastric fluid of the stomach and increases the gastric fluid pH of the stomach to a pH that substantially prevents or inhibits acid degradation of the proton pump inhibiting agent in the gastric fluid and allows a measurable serum concentration of the proton pump inhibiting agent to be absorbed into the blood serum of the subject.

Description

A NOVEL FORMULATION, OMEPRAZOLE ANTI-RELEASE COMPLEX FOR IMMEDIATE RELEASE FOR QUICK AND SUSTAINED SUPPRESSION OF GASTRIC ACID REFERENCE CROSSED TO RELATED APPLICATIONS This application claims priority of the US patent application. Serial No. 10 / 938,766, filed September 10, 2004, which claims priority of the US patent application. Serial No. 10 / 783,871, filed on February 20, 2004, which claims priority of the provisional patent application of the US. Serial No. 60 / 448,627, filed on February 20, 2003, each of which are fully incorporated herein by reference. TECHNICAL FIELD The present invention relates to combinations of a proton pump inhibiting agent and a buffering agent, which have been found to possess improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other properties. improved pharmacokinetics, pharmacodynamics, chemical and / or physical. The present invention is directed to methods, equipment, combinations and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disease or disorder, or the symptoms associated with, or related to, a gastrointestinal disorder or disease, in a subject who requires BACKGROUND OF THE INVENTION Omeprazole is a substituted benzimidazole, 5-methoxy-2- [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole, which inhibits the secretion of gastric acid. Omeprazole belongs to a class of antisecretory compounds called proton pump inhibitory agents ("PPIs" = proton pump inhibiting agents) that do not exhibit anti-cholinergic or histamine antagon antagonist properties. Drugs of this class suppress the secretion of gastric acid by the specific inhibition of the proton pump H +, K + -ATPase on the secretory surface of the gastric parietal cell. Typically, omeprazole, lansoprazole and other proton pump inhibitors are formulated in an enteric coating solid dosage form (either as a capsule or a delayed release tablet) or as an intravenous solution (as a product for reconstitution), and are prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, in gastroesophageal reflux disease (GERD), severe erosive esophagitis, gastroesophageal reflux disease with a deficient response and pathological hypersecretory conditions such as Zollinger syndrome Ellison These conditions are caused by an imbalance between the production of acid and pepsin, called aggressive factors, and production of mucosa, bicarbonate and prostaglandin, called defensive factors. These aforementioned conditions commonly arise in healthy or critically ill patients and may be accompanied by significant upper gastrointestinal bleeding. Anta Antagonists, antacids, and sucralfate, are commonly administered to minimize pain and complications related to those conditions. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the above-mentioned conditions and / or produce adverse side effects, such as mental confusion, constipation, diarrhea and thrombocytopenia. H2 antagonists such as ranitidine and cimetidine are relatively expensive modes of therapy, particularly in NPO patients, which frequently require the use of automated infusion pumps for continuous intravenous infusion of the drug.

It is considered that omeprazole (Prilosec), lansoprazole (Prevacid ^), and other proton pump inhibitors reduce the production of gastric acid by inhibiting H +, K + -ATPase from the parietal cell-the final common pathway for gastric acid secretion (Fellenius et al., Substituted Benzimidazoles Inhibit Gastric Acid Secretion by Blocking HF ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between Gastric Acid Secretion and Gastric X-ATPase Activity, J. Biol. Chem., 260: 13681-13684 (1985); Fryklund et al., Function and Structure of Parietal Cells After H +, K + -ATPase Blockade, Am. J. Physiol., 254 (3 pt 1); G399-407 (1988)). Some proton pump inhibitors contain a sulfinyl group in a bridge between substituted benzimidazole and a pyridine as illustrated below.

A neutral H, omeprazole, lansoprazole and other proton pump inhibitors are weak bases, chemically stable, soluble in liquids and lacking inhibitory activity. When delivered in an enteric coating form, these neutral weak bases are considered to reach parietal blood cells and diffuse into the secretory canaliculi, where the drugs are protonated and thus trapped. The protonated agent is rearranged to form a sulphonic acid and a sulfenamide. Sulfenamide interacts covalently with sulfhydryl group at critical sites in the extracellular (luminal) domain of membrane-spanning H +, K + -ATPase (Hardman et al., Goodman &Gilman's The Pharmacological Basis of Therapeutics, p.907 (9th ed., 1996)). Omeprazole and lansoprazole, therefore are prodrugs that must be activated to be effective. The specificity of the effects of proton pump inhibitors also depends on: (a) the selective distribution of H +, K + -ATPase; (b) the requirement for acidic conditions to catalyze the generation of the reactive inhibitor; and (c) entrapment of the protonated drug and cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme (Hardman et al., 1996). Proton pump inhibitors are acid labile and therefore have been formulated as enteric coating dosage forms, to avoid acid degradation. Examples include, omeprazole (Prilosec "11), lansoprazole (Prevacid11 *), esomeprazole (NexiumMR), rabeprazole (Aciphex ™), pantoprazole (Protonix), pariprazole and leminoprazole Prilosec (omeprazole) is formulated as enteric coating granules in capsules of Gelatin Prevacid ™ (lansoprazole) is available as enteric coating granules in gelatin capsules and as steric coating microspheres, for use as a liquid suspension.Nexium1411 (esomeprazole magnesium), are enteric coating granules in gelatin capsules. drugs are stable at alkaline pH, they are destroyed rapidly as the pH drops (for example by gastric acid) .Therefore, if the enteric coating is interrupted (for example by grinding to formulate a liquid or by chewing), the forms Dosage of the prior art will be exposed to degradation by gastric acid in the stomach. Labile acid pharmaceutical compound should be protected from contact with acidic stomach secretions to maintain its pharmaceutical activity. In this manner, compositions with enteric coatings have been designed to dissolve at a pH to ensure that the drug is released in the proximal region of the small intestine (duodenum), not in the stomach. However, due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as well as intra- and intra-subject variability, are key aspects to use steric coating systems for controlled release of a drug. To ensure that the enteric coatings dissolve or disintegrate rapidly at the target site in the intestine, which is close to a neutral pH, the enteric coatings have been designed to generally dissolve at about pH 5. However, at this pH, the Most acid-labile pharmaceutical agents are still susceptible to acid degradation depending on the particular pKa of the agent. Since an acid-labile compound to be ingested must be transferred in intact form, ie a reaction form not degraded or reacted with acid, to the duodenum, while the pH is close to or above its pKa, the enteric coating must be resistant to dissolution and disintegration in the stomach, this is impermeable to gastric fluids while it resides in the stomach. Additionally, the initiation or therapeutic activation of an enteric coating dosage form is substantially dependent on the gastric emptying time. In most subjects, gastric emptying is usually an all-or-nothing process, and generally ranges from approximately 30 minutes to several hours after ingestion. Thus, for a period of time after ingestion, an enteric coating dosage form resides in the low pH environment of the stomach, before passing into the duodenum. During this time, the enteric coating may begin to dissolve, or imperfections or cracks may arise in the coating, allowing gastric acid to penetrate the coating and prematurely release the drug into the stomach instead of the small intestine. In the absence of buffering agent, an acid-labile drug that is exposed to this gastric acid degrades rapidly and becomes therapeutically ineffective. The dosage forms of enteric coating are also generally taken on an empty stomach with a glass of water. This reduces the time of exposure to gastric fluid, since it ensures a gastric emptying within about 30 minutes and the delivery of the dosage form from the stomach to the duodenum. Once in the duodenum, there are optimal conditions for the enteric coating to dissolve and release the drug into the bloodstream where the absorption of a drug not degraded with acid occurs. If food is ingested contemporaneously with the administration of an enteric coating dosage form, not only gastric emptying is slowed but there are also increases in the stomach pH from about pH 1 to about 5 in the following several hours, depending on the general health of the subject and the composition that is administered. When the pH begins to approach 5, the enteric coating begins to dissolve, resulting in premature release of the drug into the stomach. This is a particular problem in older people who already have a high gastric acid pH, since as they get older there is a general decline in the secretion of gastric acid in the stomach. Also, when fat-containing food is ingested, gastric emptying can be delayed for up to 3 to 6 hours or more, since fat in any form will combine with bile and pancreatic fluids, strongly inhibiting gastric emptying. Thus, as a general rule, enteric coating dosage forms should only be digested on an empty stomach with a glass of water, to provide optimal conditions for dissolution and absorption. In addition, the effects of currently commercially available delayed release enteric proton pump inhibitor formulations can not be seen until several hours after dosing, requiring administration of the enteric coating formulation to a patient several hours before ingestion of a meal. (for example to a patient in "fast") so that the patient experiences relief of the gastrointestinal symptoms that arise when eating. Thus, administration of a delayed-release formulation for a patient either with food or after the initiation of ingestion of a meal (eg, a "fed" patient) will not result in any immediate relief of symptoms induced by the patient. food, and in fact may result in the patient continuing to suffer for several hours after ingesting the offending food. In addition, a patient may not always anticipate the time of their ingestion of a food such that the delayed-release formulation can be administered in time for it to take effect before the meal begins, or even that a meal causes symptoms that require treatment with a proton pump inhibitor. As such, it is desirable to have a proton pump inhibitor formulation that can be administered to a fed patient (i.e. with food, shortly after the start of food ingestion, or at any time within the period after initiation of ingestion). of food, where the symptoms that require the administration of the formulation arise), in an immediate release formulation, such that the patient is treated in a timely manner after the initiation of the ingestion of a meal. SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition comprising a proton pump inhibitory agent and a buffering agent, for oral administration and ingestion by a subject. In one embodiment, upon administration to a fed subject, the composition contacts the gastric fluid of the stomach and increases the gastric pH of the stomach at a pH that prevents or inhibits the acid degradation of the proton pump inhibitory agent in the gastric fluid of the stomach and allows a measurable concentration in the serum of the proton pump inhibitory agent to be absorbed into the subject's blood serum, such that pharmacokinetic and pharmacodynamic parameters can be obtained using test procedures known to those skilled in the art. Pharmaceutical compositions that include: (a) a therapeutically effective amount of at least one inhibitor of labile acid protons and (b) at least one buffering agent, in an amount sufficient to increase the pH of gastric fluid, at a pH that avoids acid degradation of at least some of the proton pump inhibitor in the gastric fluid. Methods for treating disorders related to gastric acid are provided using the pharmaceutical composition of the present invention. Proton pump inhibitors include but are not limited to, omeprazole, hydroxymeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, periprazol, ransoprazole, pariprazole, leminoprazole.; or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph or prodrug thereof. In one embodiment, the proton pump inhibitor is omeprazole or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph or prodrug thereof. Compositions may contain between about 5 mgs and about 500 mgs of proton pump inhibitor, specifically about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mgs, or about 60 mgs of the pump inhibitor. protons Compositions are provided wherein the proton pump inhibitor is micro-encapsulated with a material that improves the shelf life of the pharmaceutical composition. The material that improves the shelf life of the pharmaceutical composition includes, but is not limited to, cellulose hydroxypropyl esters, low substituted hydroxypropyl ethers, hydroxypropyl methyl ethers of cellulose, polymers of methyl cellulose, ethyl cellulose and mixtures thereof, polyvinyl alcohol, hydroxyethylcelluloses, carboxymethylcelluloses, salts of carboxymethylcelluloses, polyvinyl alcohol, polyethylene glycol copolymers, monoglycerides, triglycerides, polyethylene glycols, modified food starch, acrylic polymers, acrylic polymer blends with cellulose ethers, cellulose acetate phthalate, sepifilms, cyclodextrin and mixtures thereof. The hydroxypropyl ether cellulose can be, but is not limited to Klucelg, Nisswo HPC or PrimaFlo HP22. Hydroxypropyl methyl ether cellulose can be but is not limited to Seppifilm-LC, Pharmacoat1®, Metolose SR, Opadry YS, PrimaFlo, ?? 3295 ?, Benecel P82, or BenecelMP843. The mixture of methylcellulose and polymers of hydroxypropyl and methyl cellulose can be but is not limited to Methocelg, Benecel-MC, or Metolose. "11 Ethylcellulose or its mixture can be, but is not limited to, Ethocel" 11, BenecelM043, Celacal, Cumibak NC, and E461. Polyvinyl alcohol can be but is not limited to Opadry AMB. A composition may include a mixture wherein the hydroxyethyl cellulose is Natrosol1 * 1, the carboxymethylcellulose is Aqualon®-CMC, the copolymer of polyvinyl alcohol and polyethylene glycol is Kollicoat IR1®, and the acrylic polymers are chosen from Eudragits ™ 1 EPO, Eudragits ™ 1 RD100, and Eudragits1111 E100. The material that improves the shelf life of the pharmaceutical composition may also include an antioxidant, a plasticizer, a buffering agent or mixtures thereof. Compositions are provided which include (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor, wherein at least some of the proton pump inhibitor is coated, and (b) at least one buffering agent, in one sufficient amount to increase the pH of the gastric fluid to a pH that prevents acidic degradation of at least some of the proton pump inhibitor of the gastric fluid. Compositions are provided which include (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor and (b) at least one buffering agent in an amount sufficient to increase the pH of gastric fluid to a pH that prevents acidic degradation. of at least some of the proton pump inhibitor in the gastric fluid, wherein the buffering agent is an alkali metal salt or a metal of the group ?? selected from a metal bicarbonate salt of group IA, a carbonate salt of a metal group IA. The buffering agent can be, but is not limited to, an amino acid, an acid salt of an amino acid, an alkaline salt of an amino acid, aluminum hydroxide, co-precipitated aluminum hydroxide / magnesium carbonate / calcium carbonate, magnesium aluminum hydroxide, co-precipitated aluminum hydroxide / magnesium hydroxide, co-precipitated aluminum hydroxide / sodium bicarbonate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, phosphate sodium dibasic, hydrogen phosphate di-potassium, dipotassium phosphate, sodium hydrogen phosphate, sodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, carbonate magnesium, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium aluminate metasilicate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, magnesium acetate potassium, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, pyrophosphate of potassium, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, phthalate sodium, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, pyrophosphate tetrasodium, dipotassium phosphate, trisodium phosphate, trometamol, and mixtures thereof . In particular, the buffering agent can be sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide and mixtures thereof. Compositions are provided as described herein, wherein the buffering agent is sodium bicarbonate, present at about 0.1 mEq / mg of proton pump inhibitor up to about 5 mEq / mg of proton pump inhibitor. Compositions are provided, as described herein, wherein the buffering agent is a mixture of sodium bicarbonate and magnesium hydroxide, and each buffering agent is present at about 0.1 mEq / mg of proton pump inhibitor at about 5 mEq / mg of proton pump inhibitor. Compositions are provided as described herein, wherein the buffering agent is a mixture of sodium bicarbonate, calcium carbonate and magnesium hydroxide, and each buffering agent is present at about 0.1 mEq / mg of proton pump inhibitor at about 5. mEq / mg of proton pump inhibitor. Compositions are provided as described herein, wherein the buffering agent is present in an amount of about 0.1 mEq / mg to about 5 mEq / mg of the proton pump inhibitor, or about 0.5 mEq / mg to about 3 mEq / mg of the proton pump inhibitor, or about 0.8 mEq / mg to about 2.5mEq / mg of the proton pump inhibitor, or about 0.9 mEq / mg to about 2.0mEq / mg of the proton pump inhibitor, or about 0.9 mEq / mg to approximately 1.8 mEq / mg of the proton pump inhibitor. Compositions are provided as described herein, wherein the buffering agent is present in an amount of at least 1.0 mEq / mg to about 1.5 mEq / mg of the proton pump inhibitor, or at least about 0.4 mEq / mg of the pump inhibitor. of protons. Compositions are provided as described herein, including about 200 to 3000 mg of buffering agent, or about 500 to about 2500 mg of buffering agent, or about 1000 to about 2000 mg of buffering agent, or about 1500 to about 2000 mg of buffering agent. . Compositions are provided such that, when administered to a subject before a food, the gastric pH is maintained at about 4.0 by at least about one hour after feeding. Compositions are provided such that when administered to a subject prior to a food, the gastric pH is maintained above about 4.2 by at least about 1 hour after the food. Compositions are provided such that when administered to a subject before a food, the gastric pH is maintained at about 4.5 by at least about 1 hour after feeding. Compositions are provided such that when administered to a subject before a food, the gastric pH of the subject is increased to at least about 3 within about 1 hour after administration. Compositions are provided such that when administered to a subject prior to a food, the gastric pH of the subject is increased at least to about 3 within about 45 minutes after administration. Compositions are provided such that when administered to a subject before a food, the gastric pH of the subject is increased to at least about 3 within about 30 minutes after administration. Compositions are provided such that when administered to a subject before a food, the gastric pH of the subject is increased to at least about 3 within about 15 minutes after administration. Compositions are provided such that when administered to a subject before a food, the gastric pH of the subject is increased to at least about 4 within about 1 hour after administration. Compositions are provided such that when administered to a subject prior to a food, the gastric pH of the subject is increased to at least about 4 within about 45 minutes after administration. Compositions are provided such that when administered to a subject prior to a food, the gastric pH of the subject is increased to at least about 4 within about 30 minutes after administration. Compositions are provided such that when administered to a subject before a food, the gastric pH of the subject is increased to at least about 4 within about 15 minutes after administration. Compositions are provided wherein a therapeutically effective amount of the proton pump inhibitor is absorbed in about 1 hour after administration. Compositions are provided wherein a therapeutically effective amount of the proton pump inhibitor is absorbed within 45 minutes after administration. Compositions are provided wherein a therapeutically effective amount of the proton pump inhibitor is absorbed within about 30 minutes after administration. Compositions are provided such that the maximum gastric pH is reached in about 45 minutes after administration of the composition. Compositions are provided such that the maximum gastric pH is reached in about 30 minutes after administration of the composition. Compositions are provided such that the maximum gastric pH is reached within about 15 minutes after administration of the composition. Compositions are provided such that the maximum gastric pH is reached within about 10 minutes after administration of the composition. Compositions are provided such that the gastric pH is greater than about 4.0 at least about 50 percent of the time. Compositions are provided such that the gastric pH is greater than about 4.0 at least about 60 percent of the time. Compositions are provided such that the gastric pH is greater than about 4.0 at least about 70 percent of the time. Compositions are provided such that the gastric pH is greater than about 4.0 or at least about 80 percent of the time. Compositions are provided wherein, orally administered to the subject, the composition provides a pharmacokinetic profile such that at least about 50 percent of the total area ba or the time curve serum concentration (AUC) for the proton pump inhibitor occurs in about 2 hours after the administration of a single dose of the composition to the subject. Compositions are provided where, before oral administration to the subject, the area under the curve of serum concentration per time (AUC) for the proton pump inhibitor in the first 2 hours is at least about 70 percent of the total area. Compositions are provided wherein the area under the serum concentration time curve (AUC) for the proton pump inhibitor in the first 2 hours is at least about 70 percent of the total area. Compositions are provided wherein at least about 50 percent of the total area under the serum concentration time curve (AUC) for the proton pump inhibitor, occurs from about 1.75 hours after administration of a single dose of the composition to the subject. Compositions are provided wherein at least about 50% of the total area under the serum concentration by time curve (AUC) for the proton pump inhibitor occurs within about 1.5 hours after administration of a single dose of the composition to the subject . Compositions are provided wherein at least about 50 percent of the total area under the serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 1 hour after administration of a single dose of the composition to the suj eto. Compositions including (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor, and (b) at least one buffering agent, in an amount sufficient to increase the pH of gastric fluid to a pH that prevents acidic degradation. of at least some of the proton pump inhibitor in the gastric fluid, wherein the composition is in a selected dosage form of a powder, a tablet, a bile-disintegrating tablet, a chewable tablet, a capsule, an effervescent powder , a rapid disintegration tablet or an aqueous suspension produced from the powder. Compositions as described above are provided, which also include one or more excipients, including but not limited to, parietal cell activators, erosion facilitators, flavoring agents, sweetening agents, diffusion facilitators, antioxidants and carrier materials selected from binders, agents of suspension, disintegrating agents, fillers or fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, anti-adherents and anti-foaming agents. Also provided are compositions wherein at least some of the proton pump inhibitor is micronized. Compositions comprising (a) an amount of at least one labile acid proton pump inhibitor are provided.; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor, such that when the composition is administered to a subject prior to a food, the composition causes a increase in gastric pH above 3.0 within 30 minutes after administration. Compositions comprising (a) an amount of at least one labile acid proton pump inhibitor are provided; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor, such that when the composition is administered to a subject prior to a food, the composition causes a increase in gastric pH to about 3.0 within about 1 hour after administration. Compositions comprising (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor are provided; and (b) at least one buffering agent and an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor by gastric fluid, wherein the composition is in an amount effective to reduce or inhibit higher GI bleeding after of administration to the subject. Compositions are provided wherein the composition is administered in a liquid formulation and reduces mortality or nosocomal pneumonia due to upper GI bleeding, or a complication associated with upper GI bleeding. Compositions comprising (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor are provided; and at least one buffering agent is provided in an amount sufficient to inhibit or reduce the degradation of at least some of the proton pump inhibitor by gastric fluid, for the treatment of disorders related to gastric acid. Disorders related to gastric acid include, but are not limited to duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, symptomatic gastroesophageal reflux disease with poor response, pathological gastrointestinal hypersecretory disease, Solinger syndrome, heartburn, esophageal disorder, or acid dyspepsia. Methods are provided for preventing or inhibiting interruption of pH control in the meantime, by administering a compound comprising: (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and (b) at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of a proton pump inhibitor by gastric fluid, wherein the subject has previously been administered a compound within the last two at approximately 22 hours that increases in gastric pH to approximately 3, thus preventing or inhibiting the interruption of pH control. Methods are provided so that the composition useful for preventing or inhibiting the interruption of pH control is administered before going to sleep. Methods are provided so that the composition useful for preventing or inhibiting the interruption of pH control is administered to treat or prevent nocturnal heartburn. Methods are provided such that the gastric acidity integrated in a subject is reduced by at least about 25% to about 500%. Here methods are provided for treating or preventing nocturnal GERD symptoms in a patient requiring it, by administering a pharmaceutical composition comprising: (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and (b) at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor. In some embodiments, the pharmaceutical composition is administered once a day. In other embodiments, the pharmaceutical composition is administered twice a day. Still in other modalities, the pharmaceutical composition is administered before going to sleep. Methods for treating or preventing nocturnal GERD symptoms are provided herein wherein after administration of the pharmaceutical composition, the average pH for a nighttime period of 8 hours is greater than 3. In some embodiments, the average pH for a nighttime period of 8 hours is greater than 4. Still in other embodiments, the average pH for a nighttime period of 8 hours is greater than 5. Here methods are provided for treating or preventing nocturnal GERD symptoms wherein 24 hours after administration of the pharmaceutical composition, the Gastric pH is greater than 4 at least 40% of the time. In some embodiments, 24 hours after administration of the pharmaceutical composition, the gastric pH is greater than 4 at least 50% of the time. In some embodiments, the pharmaceutical composition is administered twice a day and wherein the gastric pH is greater than 4.0 at least about 40% of a time period of up to eight hours after administration of the second dose. In other embodiments, the pharmaceutical composition is administered twice a day and wherein the gastric pH is greater than 4.0 at least about 50% of a time period of up to eight hours after administration of the second dose. In still other embodiments, the pharmaceutical composition is administered twice daily and wherein the gastric pH is greater than 4.0 at least about 70% of a time period of up to eight hours after administration of the second dose. In still other embodiments, the pharmaceutical composition is administered twice daily and wherein the gastric pH is greater than 4.0 at least about 90% of a time period of up to eight hours after administration of the second dose. Here methods are provided for reducing nocturnal gastric acidity in a subject by administering a composition comprising: (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and (b) at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor. In some embodiments, the average blood serum concentration of the proton pump inhibitory agent is at least about 1.0 g / ml in the subject within about 30 minutes after administering the pharmaceutical composition to the subject. In other embodiments, the pharmaceutical composition is administered once or twice a day. In other embodiments, the pharmaceutical composition is administered once or twice a day, for two or more consecutive days. Here methods are provided wherein the pharmaceutical composition is administered before going to sleep. In some embodiments, the pharmaceutical composition is administered less than about 2 hours before sleep. In other embodiments, the pharmaceutical composition is administered at least twice a day, for two or more consecutive days. Here methods are provided for rapidly reducing the production of gastric acid in a subject by administering a composition comprising: (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce degradation of at least some proton pump inhibitor by gastric fluid. Also provided herein are methods for treating food-induced gastric acid disorder by administering compositions comprising (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce the degradation of at least some of the proton pump inhibitor by gastric fluid. Here are provided methods for treating a food-induced gastric acid-related disorder in a subject when administered to the subject within about 4 hours after ingestion of the food, a composition comprising: (a) at least one proton pump inhibitor labile acid; and (b) at least one buffering agent in an amount sufficient to inhibit or reduce the degradation of at least some of the proton pump inhibitor, such that the amount of proton pump inhibitor is effective to reduce or inhibit one or more symptoms of the disorder related to gastric acid in the subject. Methods are provided for treating a critically ill subject who has or is at risk of having upper GI bleeding or a symptom associated with upper GI bleeding, comprising administering to a subject a liquid formulation comprising at least one proton pump inhibitor. labile acid, and at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor, such that an amount of proton pump inhibitor is effective to reduce or inhibit proton pump bleeding. Upper GI or the symptom associated with upper GI bleeding in a critically ill patient. Methods are provided for treating a critically ill subject who has or is at risk of having upper GI bleeding or a symptom associated with upper GI bleeding, such that the subject has a naso-gastric (NG) tube or tube. gastric. Methods to reduce the incidence, severity, duration or frequency of upper GI bleeding or one or more symptoms associated with upper GI bleeding in the subject are also provided herein. Methods to reduce mortality or nosocomal pneumonia associated with upper GI bleeding in the subject are provided. Methods for treating a patient having a gastric acid related disorder or having the risk of having a gastric acid related disorder, wherein the subject has difficulty swallowing a pill, capsule, tablet or coated tablet (caplet), by administering to the subject a liquid formulation comprising at least one labile acid proton pump inhibitor and at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor. Also provided herein are methods for treating a patient suffering from heartburn or at risk of suffering from heartburn, by administering a pharmaceutical composition comprising (a) a therapeutically effective amount of at least one labile acid proton pump inhibitor.; and (b) at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor by gastric fluid. BRIEF DESCRIPTION OF THE DRAWINGS Other advantages of the present invention will be readily appreciated as it is better understood with reference to the following detailed description, when considered in connection with the accompanying drawing in which: Figure 1 is a line graph illustrating the omeprazole concentrations in average plasma, measured during the time period of 6 (six) hours after administration of 40 mg of immediate release formulation of omeprazole / antacid (OAC-IR = omeprazole / antacid immediate-release) and 40 mg of delayed-release formulation of omeprazole (OME-DR = omeprazole delayed-release) to fasting subjects. Figure 2 is a line graph illustrating average plasma omeprazole concentrations for 40 mg of omeprazole plus sodium bicarbonate administered after nighttime fasting and for 40 mg of Prilosec administered after overnight fasting. Figure 3 is a line graph illustrating plasma omeprazole concentrations averaged at day 7 for 40 mg of omeprazole plus sodium bicarbonate administered after overnight fasting and for 40 mg of Prilosec ™ 1 administered after an overnight fast. Figure 4 (a) illustrates the gastric acidity integrated in baseline (untreated) and on days 1 and 7 of 40 mg of omeprazole plus sodium bicarbonate administered after overnight fasting. Figure 4 (b) illustrates gastric acidity integrated in baseline (untreated) and days 1 and 7 of 40 mg of Prilosec ™ 1 administered after overnight fasting. Figure 5 (a) illustrates the phase changes in gastric acid concentration produced by the ingestion of food with administration of 40 mg of omeprazole plus sodium bicarbonate administered after the overnight fast on days 1 and 7; Baseline values (untreated) are also presented. Figure 5 (b) illustrates phase changes in gastric acid concentration produced by ingestion of food with administration of 40 mg of Prilosec after overnight fasting on days 1 and 7; Baseline values are also presented (untreated). Figure 6 (a) illustrates the average gastric pH measured on day 1 after administration of 40 mg of omeprazole plus sodium bicarbonate, after nocturnal fasting and the average gastric pH measured after administration of Prilosec1 * 11 mg after a nighttime fast Figure 6 (b) illustrates the mean gastric pH measured on day 7 after administration of 40 mg of omeprazole plus sodium bicarbonate after overnight fasting and the gastric pH measured after administration of 40 mg Prilosec1111 after an overnight fast. Figure 7 (a) illustrates values from day 1 showing the time when the gastric pH was < 4 with administration of 40 mg of omeprazole plus sodium bicarbonate after nighttime fasting and the time when the gastric pH was < 4 with administration of 40 mg of Prilosec1® after an overnight fast. Figure 7 (b) illustrates values from day 7 showing the time when the gastric pH was < 4 with administration of 40 mg of omeprazole plus sodium bicarbonate after nighttime fasting and the time when the gastric pH was < 4 with administration of 40 mg of Prilosec administered after an overnight fast. Figures 8 (a) and 8 (b) are line graphs summarizing the average proportions and confidence intervals for pharmacokinetic and pharmacodynamic parameters after 7 days of daily administration of omeprazole plus sodium bicarbonate and Prilosec ™ 1. Figure 8 (b) shows parameters calculated after 7 days of daily administration of 20 mg of omeprazole plus sodium bicarbonate after an overnight fast and 20 mg of Prilosec "11, each of which is administered after an overnight fast. Figure 8 (b) presents parameters calculated after 7 days of daily administration of 40 mg of omeprazole plus sodium bicarbonate and 40 mg of Prilosec "11, each of which is administered after an overnight fast. Figure 9 is a line graph illustrating average concentrations of omeprazole in plasma on day 7 for 40 mg of omeprazole plus sodium bicarbonate administered prior to feeding and after nighttime fasting; and illustrates the average concentration of omeprazole in plasma on day 8 for 40 mg of omeprazole plus sodium bicarbonate administered post-food. Figure 10 is a line graph illustrating the average concentrations of omeprazole in plasma of fasted subjects, following the administration of: 40 mg of omeprazole plus antacid in the SAN-15 powder formulation; 40 mg of omeprazole plus antacid in the SAN-15 chewable tablet formulation; and 40 mg of Prilosec ™ in a delayed release formulation (enteric coating). Figure 11 is a line graph illustrating: the bioavailability of 40 mg of omeprazole plus sodium bicarbonate in the formulation of SAN-15 chewable tablets administered 30 minutes before feed; and the bioavailability of 40 mg of Nexium "11 administered 30 minutes prior to feeding Figure 12 is a bar graph illustrating cumulative integrated gastric acidity after administration of different formulations of omeprazole, apinex chewable tablet formulations"; suspension formulation Acitrel1 ^; and Prilosec ™ 1 delayed release formulation. Figure 13 is a line graph illustrating the effect on gastric pH of administering: 40 mg of omeprazole as the formulation of SAN-15 (40 mg of omeprazole plus sodium bicarbonate) administered either 30 or 60 minutes before feeding; Nexium1 ^ 30 minutes before feeding; Prilosec ^ 30 minutes before feeding; and shows the gastric pH of untreated subjects.

Figure 14 is a bar graph illustrating the effect of integrated gastric acidity to be administered: 40 mg of omeprazole plus sodium bicarbonate in the SAN formulation "-15 either 30 or 60 minutes pre-food; Nexium ™ 1 and without omeprazole (control) Figure 15 (a) is a line graph illustrating the pH of average gastric acid over time after administration of 40 mg of omeprazole plus sodium bicarbonate in the SAN-15 formulation, control values representing the pH of gastric acid from its untreated ethos Figure 15 (b) is a line graph illustrating the pH of average gastric acid over time after administration of 80 mg of omeprazole plus sodium bicarbonate in the SAN-15 formulation control values that represent the pH of gastric acid of untreated subjects Figure 15 (c) is a linear graph illustrating the pH of average gastric acid over time after administration of 120 mg of omepraz ol more sodium bicarbonate in the SAN-15 formulation; Control values represent the gastric acid pH of untreated subjects.

Figure 16 is a line graph illustrating the concentration of omeprazole in plasma after administration of 40 mg of omeprazole plus sodium bicarbonate in the SAN-15 formulation, comparing administration results to fed subjects, 1 hour post-feed administration. Figure 17 is a line graph illustrating the average concentration of omeprazole in plasma after 2 doses of 40 omeprazole in the OSB-IR formulation, administered spaced 6 hours apart. Figure 18 (a) is a line graph illustrating the average gastric pH for 24 hours after administration of 40 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation on day 1 of the qA treatment. Figure 18 (b) is a line graph illustrating the average gastric pH for 24 hours after administration of 40 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation on day 7 of the qAM treatment. Figures 19 (a) and 19 (b) are bar graph illustrations of the integrated gastric acidity of subjects treated with 20 omeprazole plus sodium bicarbonate in the OSB-IR formulation, on day 1 and day 7. Figure 19 (a) presents gastric acidity during the day.

Figure 19 (b) shows nocturnal gastric acidity. In each Figure, results for untreated subjects are presented as baseline values. Figures 20 (a) and 20 (b) are illustrations of bar graphs of the integrated gastric acidity of subjects treated daily with 40 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation, on day 1 and day 7. Figure 20 (a) shows gastric acidity during the day. Figure 20 (b) shows nocturnal gastric acidity. In each Figure, results for untreated subjects are presented as baseline values. Figures 21 (a) and 21 (b) are line graphs illustrating the pH of medium gastric acid at day 7 over time after administration of 20 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation (Figure 21). (a)) or 40 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation (Figure 21 (b)); Results for untreated subjects are presented as baseline values. Figure 22 is a bar graph illustrating the postprandial integrated gastric acidity after each of the three daily foods, on day 1 and day 7 of the daily administration (qAM) of 20 mg of omeprazole plus sodium bicarbonate in the formulation OSB-IR; Results for untreated subjects are presented as baseline values. Figure 23 is a bar graph illustrating the postprandial integrated gastric acidity after each of the three daily foods, day 1 and day 7 of the daily administration (qAM) of 40 mg of omeprazole plus sodium bicarbonate in the formulation OSB-IR; Results for untreated subjects are presented as baseline values. Figures 24 (a) and 24 (c) are line drawings illustrating the medium gastric pH for 24 hours on day 7 of daily administration (qAM) of 40 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation (Figure 24). (to) ); the average graphical pH for 24 hours on day 7 of the daily administration (qAM) of 20 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation (Figure 24 (b)), - and the medium gastric pH for 24 hours a day 8, wherein the second dose of 20 mg of omeprazole plus sodium bicarbonate in the OSB-IR formulation (Figure 24 (c)) is administered at the time of sleep. Figure 25 is a bar graph illustrating the number of critically ill patients in a population treated with cinitidine and the number of critically ill patients in a population treated with omeprazole (OSB-IR) that has the following: A lower pH value to 4 in 2 successive aspirates; any evidence of bleeding; and clinically significant bleeding. Figure 26 is a line graph illustrating pre-dose and post-dose pH values in critically ill patients dosed during the first two days of treatment with three doses of a 40 mg suspension of omeprazole (OSB-IR formulation) , or with intravenous (IV) cimetidine 1200 mg / day. Figure 27 is a line graph illustrating medium gastric pH for 14 days in critically ill patients dosed with either a 40 mg suspension of omeprazole (OSB-IR formulation), with intravenous (IV) cimetidine 1200 mg / day. Figure 28 is a noninferiority analysis for the difference in bleeding velocity, illustrating the difference between OSB-IR bleeding velocity and the bleeding velocity of cimetidine. Figure 29 is a line graph illustrating nocturnal midnight gastric pH over a period of 8 hours on the sixth day of administering the suspension of OME-IR to one group of patients and Protonix® to the other group of patients. Figures 30A and 30B are linear graphs illustrating nocturnal median gastric pH over a period of 8 hours on the seventh day of administration of two doses of OME-IR suspension (20 mg or 40 mg) to a group of patients (n = 15 or 17, respectively) and Protonix® to the other group of patients. Figure 31 are circular sector diagrams illustrating the proportion of patients who experienced nocturnal acidity (NAB) on days 1, 6 and 7 of administration of the OME-IR suspension to one group of patients and Protonix® to the other group of patients. Figure 32 is a diagram illustrating the percent of time that the gastric pH was greater than 4 during the night for patients treated with either the OME-IR or Protonix® suspension. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to methods, equipment, combinations and compositions for treating a condition or disorder wherein treatment with an inhibiting agent of H +, K + -ATPase or inhibitor, such as for example an inhibitory agent, is indicated. of proton pump. Methods, kits, combinations and compositions are also provided to treat, prevent or reduce the risk of developing a gastrointestinal disorder or disease or the symptoms associated with or related to a gastrointestinal disorder or disease in a subject that requires it. While the present invention can be incorporated in many different forms, several specific embodiments are discussed herein, it being understood that the present disclosure will be considered only as an exemplification of the principles of the invention and is not intended to limit the invention to the illustrated embodiments. For example, when the present invention is illustrated herein with particular reference to omeprazole, hydroxyomeprazole, esomeprazole, tenatopropazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, periprazole, ransoprazole, pariprazole, or leminoprazole, it will be understood that any other pump inhibiting agent of protons, if desired, can be substituted totally or partially by these agents in the methods, equipment, combinations and compositions described herein. GLOSSARY To further facilitate the understanding of the invention and its referred modalities the meanings of terms used herein will be apparent from the context of this specification., in view of the common use of various terms and the explicit definitions of other terms that are provided in the glossary below or in the following description. As used herein, the terms "comprise", "includes," and "such as" are used in that open, non-limiting sense. The use of the term "approximate" in the present description means "approximately" and illustratively, the use of the term "approximate" indicates that values slightly outside the quoted values can also be effective and safe, and these doses are also encompassed for the scope of the present claims. As used herein, the phrase "acid-labile pharmaceutical agent" refers to any pharmacologically active drug subject to centralized acid degradation. "Anti-adherent", "slip agents" or "anti-adhesion" prevent components of the formulation from being added or adhered and improves the material flow characteristics. These compounds include, for example, silicon dioxide such as Cab-o-sil "11 tribasic calcium phosphate, talc, corn starch, DL-leucine, um lauryl sulfate, magnesium stearate, calcium stratum, um stearate, kaolin, micronized amorphous silicon dioxide (Syloid) and the like. "Anti-foaming agents" reduce foaming during processing, which can result in coagulation of aqueous dispersions, bubbles in the determined film or in general, deteriorate processing Exemplary antifoaming agents include emulsions of silicon or sesquiolate of sorbxtan. "Antioxidants" includes, for example, butylated hydroxytoluene (BHT), um ascorbate, and tocopherol. "Binders" impart cohesive qualities and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocell ^) hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ^ 1), ethylcellulose (e.g., Ethocel ™), and microcrystalline cellulose (e.g., Avicel101); microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymers; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (eg, Dipac "11), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg, Xylitab), and lactose; a natural or synthetic gum such as acacia, tragacanth, gum ghatti, mucilage of isapol shells, polyvinylpyrrolidone (for example, Polividone * CL, Kollidon "CL, Polyplasdone ™ 1 XL-10), larch arabogalactan, polyethylene glycol, waxes, sodium alginate and the like. "Bioavailability" refers to the extent to which an active portion (drug or metabolite) is absorbed in the general circulation and is available at the site of action of the drug in the body. The term "bioequivalence" or "bioequivalent" means that two drug products do not differ signficantly when the two products are administered in the same dose under similar conditions. A product that is bioequivalent to a second product can be considered if there is no significant difference in the speed and extent in which the active ingredient or active portion is available at the site of action of the drug when the product is administered in the same molar dose as the second product under similar conditions in an appropriately designed study. Two products with different absorption rates can be considered equivalent if the difference in the speed at which the active ingredient or portion is available at the site of action of the drug is intentional and is reflected in the proposed labeling, it is not essential to achieve the Effective drug concentrations in the body in chronic use and is considered medically insignificant for the drug. It can be considered bioequirement when, for example, the 90% confidence interval is between 87% and 120% for the objective parameters (for example Cmax and AUC). "Carrier materials" include any excipients commonly employed in pharmaceutical products and should be selected based on compatibility with the proton pump inhibitor and the release profile properties of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, like diluents. "Carrier materials" include any excipients commonly used in pharmaceutical and should select pathways for compatibility with the proton pump inhibitor and the release profile properties of the desired dosage form. Exemplary carrier materials include for example binders, suspending agents, disintegrating agents, fillers or fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents and the like. "Pharmaceutically compatible carrier materials" may comprise, for example, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, bad odextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate. , dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch and the like. See, for example, The Science and Practice ofPlaarnaacy, ninth edition (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999). The term "controlled release" includes any formulation of non-immediate release, including but not limited to formulations of enteric coating and formulations of sustained release, delayed release and pulsed release. The term "delayed release" includes any non-immediate release formulation, which includes but is not limited to film-coated formulations, enteric coating formulations, encapsulated formulations, sustained release formulations and pulsed-release formulations. See "The Science and Practice Pharmacy," (20th ed. 2000). As discussed above, immediate and non-immediate (or controlled release) release can be defined kinetically by reference to the following equation: K K Way of ^ Bank of 3 Dosage .... Absorption, drug absorption Target elimination area The bank or collection of absorption represents a solution of the drug administered at a particular absorption site and Kr, a and Ke are constants of first order speed for: (1) drug release from the formulation; (2) absorption, and (3) elimination, respectively. For immediate release dosage forms, the rate constant for drug release Kr is generally equal to or greater than the absorption rate constant of a. For controlled release formulations, the opposite is generally true, this is Kr < < Ka, such that the rate of drug release from the dosage form is the limiting step in the rate at which the drug is delivered to the target area. "Diffusion facilitators" and "dispersing agents" include materials that control the diffusion of an aqueous fluid through coating. Exemplary dispersing facilitators / dispersing agents include, for example, hydrophilic polymers, electrolytes, TweenMa 60 or 80, PEG and the like. Combinations of one or more erosion facilitators with one or more diffusion facilitators may also be employed in the present invention. "Diluents" increase the volume of the composition to facilitate compression. These compounds include, for example, lactose; starch, mannitol; sorbitol; microcrystalline cellulose such as Avicel "; dibasic calcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; dried lactose per layer; pregelatinized starch; compressible sugar, such as Di-PacMR (Amstar); mannitol; hydroxypropylmethylcellulose; sucrose-based diluents, confectionery sugar, calcium sulphate monobasic monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolysed cereal solids, amylose, powdery cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite; and similar. The term "disintegrate" includes both dissolution and dispersion of the dosage form, when contacted with gastric fluid. "Disintegration agents" facilitate the breakdown or disintegration of a substance. Examples of disintegrating agents include a starch, for example a natural starch such as corn starch or potato starch, a pre-gelatinized starch such as National 1551 or Amijel "11, or sodium starch glycolate such as Promogel1111 or Explotab ™ 1; a cellulose such as wood product, methylcrystalline cellulose, for example Avicel ^, Avicel1 ^ PH101, Avicel ™ 1 PH102, Avicel1® PH105, Elcema1 ^ P100, Emcocel ™; Vivacel1;, MingTiare, and Solka-Floc "; methylcellulose, croscarmellose, or an interlaced cellulose such as an interlaced sodium carboxymethylcellulose (Ac-Di-Sol ^), interlaced carboxymethylcellulose, or cross-linked croscarmellose; an interlaced starch such as sodium starch glycolate; an interlaced polymer such as crospovidone; an interlaced polyvinylpyrrolidone; alginate such as alginic acid or an alginic acid salt such as sodium alginate; a clay such as Veegum ™ HV (magnesium aluminum silicate); a gum such as agar, guar, carob, Karaya, pectin, or tragacanth; Sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation exchange resin; citrus pulp, sodium lauryl sulfate; Sodium lauryl sulfate in combination with starch and similar. "Drug absorption" or "absorption" refers to the process of movement from the site of administration of a drug into the systemic circulation. "Drug elimination" or "elimination" refers to the sum of the body's loss of drug processes. "Erosion Facilitators" includes materials that control the erosion of a particular material in gastric fluid. Erosion facilitators are generally known to those with ordinary skill in the specialty. Exemplary erosion facilitators include, for example, hydrophilic polymers, electrolytes, proteins, peptides and amino acids. "Fillers or fillers" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose; dextrations; dextran, starches, pre-gelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like. "Flavoring agents" or "sweeteners" employed in the pharmaceutical compositions of the present invention, include for example acacia syrup, acesulfame K, alitame, .anis, apple, aspartame, banana, Bavarian cream, berry, mild buttery flavor caramel , calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, chewing gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, refreshing cherry, refreshing citrus, cyclamate, cilamate, dextrose , eucalyptus, eugenol, fructose, fruit punch, ginger, gliciretinate, licorice syrup or glycyrrhiza (licorice), grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, mono ammonium glyceride (MagnaSweet "11), maltol, mannitol, maple, marshmallow, tnentol, mint cream, mixed berries, neohesperidina DC, neotame, orange, pear, peach, mint, mint cream, prosweetm powder, raspberry, root beer, rum, saccharin, safrol, sorbitol, mint green, mint cream rde, strawberry, strawberry cream, stevia, sucralose, sucrose, saccharine sodium, saccharin, aspartame, acesulfame potassium, mannitol, talin, sorbitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, taumantine, tutti-fruti. vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, for example anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime , lemon-mint, menthol-eucalyptus, cream-orange, vanilla-mint and their mixtures. The terms "therapeutically effective amount" and "effective amount" mean in relation to the amount of proton pump inhibitory agent, consistent with considerations known in the art, the amount of effective proton pump inhibiting agent to produce a pharmacological effect. or therapeutic effect (including but not limited to, elevation of gastric pH, elevation of pH in the esophagus, reduce gastrointestinal bleeding, reduce need for blood transfusion, improve survival rate, faster recovery, inhibition or improvement of H +, K + -ATPase or elimination of symptoms, and other indicators as appropriate measures are chosen by those with skill in the art) without undue adverse side effects. "Effective amount" in the context of a buffering agent means an amount sufficient to prevent acidic degradation of PPI totally or partially, either in vivo or in vitro.

An "enteric coating" is a substance that remains substantially intact in the stomach, but that dissolves and releases at least some of the drug, once it reaches the small intestine. In general, the enteric coating comprises a polymeric material that prevents release into the environment of low pH in the stomach, but ionizes at a slightly higher pH, typically a pH of 4 or 5, and thus dissolves sufficiently in the small intestine, for gradual release of the active ingredient there. "Fasting adult human object" or "fasting subject" refers, for example, to any patient who has abstained from food for a period of time, for example a patient who has not eaten a food during the night (for example 8 hours), a patient who has not eaten a food in several hours, a patient on an empty stomach who does not suffer from any food-related symptoms, who can be treated with a proton pump inhibitor, or any patient who has not ingested a food such that the most recently ingested food is digested and the patient does not suffer from any food-related symptoms, which can be treated with a proton pump inhibitor. "Adult human subject fed" or "subject fed", refers for example to a patient who initiates the ingestion of a food, a patient who has initiated the ingestion of a food shortly before the administration (for example approximately 10 minutes before , approximately 30 minutes before, approximately 45 minutes before, approximately 60 minutes before, or approximately 90 minutes before), a patient who has initiated the ingestion of a food a short time before administration and continues to ingest food after administration, a patient who has recently finished eating a food, or a patient who has finished eating a food and who experiences symptoms related to the ingestion of that food. The phrase "gastrointestinal disorder" or "gastrointestinal disease" generally refers to a disorder or disease that occurs in a mammal due to an imbalance between acid production and pepsin, termed aggressive factors, and production of mucosa, bicarbonate and prostaglandin, called defensive factors. In mammals, such disorders or diseases include, but are not limited to duodenal ulcer, gastric ulcer, acid dyspepsia, gastroesophageal reflux disease (GERD), severe erosive esophagitis, gastroesophageal flow disease symptomatic of poor response, heartburn, other esophageal disorders , irritable bowel syndrome and gastrointestinal pathological hypersecretory condition, such as Zollinger Ellison syndrome. The treatment of these conditions is achieved by administration to a subject, of a therapeutically effective amount of a pharmaceutical composition according to the present invention. The phrase "gastrointestinal fluid" or "gastric fluid" refers to the fluid of secretions from the stomach of a subject or its equivalent. An equivalent stomach secretion includes for example an in vitro fluid, which has a similar content and / or pH of stomach secretions. The content and pH of a particular stomach secretion is generally a subject specific in general, and depends, among other things, on the weight, sex, age, diet or health of a particular subject. These particular stomach secretions may for example be limited or replicated by those skilled in the art, for example those found in in vivo models used to study the stomach. Such a model is commonly referred to as the "acid kinetics neutralization model", and can be used to study or experimentally determine the release kinetics (eg, immediate release against controlled release) of a component of the compositions of the present invention. , under predetermined experimental conditions; or acid degradation of a pharmaceutical agent of the compositions described herein under predetermined experimental conditions. "Half-life" refers to the time required for the concentration of the drug in the plasma or the amount in the body to decrease 50% of its maximum concentration. The use of the term "highly acidic pH" in the present description means a pH in the range of from about 1 to about 4. The term "immediate release" is intended to refer to any PPI formulation, wherein everything other than PPI is in solution either before administration or immediately (ie within approximately 30 minutes) after administration. For example, with an "immediate release" formulation, oral administration results in immediate release of the agent from the composition in the gastric fluid. For delayed release formulations, the opposite is generally true, the rate or rate of release of the drug from the dosage form is the rate limiting step in the delivery of the drug to the target area.

"Integrated acidity" is calculated as the cumulative cumulative time-weighted average gastric acid concentration. The integrated gastric acidity is expressed in mmoles x hr / L and is calculated from gastric pH data obtained (approximately every 8 seconds) using a pH probe (electrode). In other words, integrated gastric acidity can be calculated from time-weighted average hydrogen ion concentrations during a 24-hour recording recording period. The "acid kinetic neutralization model" is an in vitro model used to study the subject. Briefly, in the kinetic acid neutralization model, the synchronized acid neutralization of a quantity of buffering agents or agents, for example a representative amount of calcium carbonate and / or sodium bicarbonate, can be evaluated. While not intended to be bound by any other theory, it is generally considered that a healthy human stomach adds HCl to the contents of the stomach at a rate of 30 mL per hour. The kinetic acid neutralization model uses a glass flask (in the form of a 100 mL or 200 mL solution flask, for example) to contain 0.1 mL hydrochloric acid (HCl) (to simulate stomach acidity in the state). of fasting).

Fifty mL is considered the volume of acid that is usually found in a fasting stomach, but for experimental convenience, the model can for example use 100 mL (double the volume in the usual fasting stomach). A higher agitator keeps RPM constant, controlled and reproducible, stirring the contents in the flask. For pH analysis, for example, an Orion pH meter (model 720A) equipped with an Orion pH electrode (PerpHeot Ross probe / semimicro-electrode combination) can be used. The acid kinetic neutralization model can be added by means of a peristaltic pump (Watson / Marlow Multichannel PumpPro model with acid resistant tubing), 200 mL per hour of 0.05 N HCl. This expense compensates for the duplication of the initial volume of 0.1 N HCl of 50 to 100 mL. To simulate emptying of the stomach, fluid can be withdrawn from the flask at the same expense, and by the same peristaltic pump, keeping the volume of 100 mL constant. This kinetic acid neutralization model combines the concepts of USP < 301 > , Acid Neutralization Capacity Test, and the concepts of USP < 724 > , the Flow Through Cell for Drug Release Test, which are incorporated herein by reference. Illustratively, the pH of the initial acid in the flask can be measured as a function of time.

At time zero, the buffering agent is added to the flask, and the pH of the contents is measured, starting at one minute intervals, and advancing at convenient time intervals, until the pH falls below a predetermined level, for example a value of 3 or less. When a controlled release dosage form of the present invention is tested in this model, the amount of the agent released from the dosage form in the gastric fluid and / or the acid degradation of the agent, can be determined for example by liquid chromatography of High performance (HPLC). The use of the term "pH less acidic to basic" means a pH between about 4 to about 8.0. "Lubricants" are compounds that prevent, reduce or inhibit the adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid; calcium hydroxide; talcum powder; sodium stearyl fumarate; a hydrocarbon such as a mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex °); higher fatty acids and their alkali and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glxcerol, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, sodium, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax ™, sodium oleate, glyceryl behenate, polyethylene glycol, sodium lauryl sulfate or magnesium, colloidal silica such as Silooid ™, Carb-0-Sile, a starch such as corn starch, silicone oil, a surfactant and the like. "Food" refers, for example, to any amount of food, for example a snack, a food ration, several servings of a food, one or several servings of each of different foods or any amount of foods that induce symptoms that require treatment with a proton pump inhibitor. The term "measurable serum concentration" means the concentration in serum (typically measured in mg, g / n or ng of the therapeutic agent per mi, di, or 1 · of blood serum) of a therapeutic agent, absorbed into the bloodstream. after administration. Illustratively, the serum concentration of a proton pump inhibitory agent of the present invention corresponding to a measurable serum concentration for an adult subject is greater than about 5 ng / ml. In another embodiment of the present invention, the concentration in the serum of the proton pump inhibitor agent corresponding to a measurable serum concentration for an adult human is less than about 10 ng / ml. In yet another embodiment of the present invention, the serum concentration of the proton pump inhibitory agent corresponding to a concentration in the serum measurable for an adult human is from about 100 ng / ml to about 500 ng / ml. In yet another embodiment of the present invention, the serum concentration of the proton pump inhibitory agent corresponding to a measurable serum concentration for a human adult is from about 250 ng / ml to 2500 ng / ml. "Metabolism" refers to the process of chemical alteration of drugs in the body. "Parietal cell activators" or "activators" stimulate the parietal cells and improve the pharmaceutical activity of the proton pump inhibitor. Parietal cell activators include, for example, chocolate; alkaline substances such as sodium bicarbonate; calcium such as calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate; mint oil, spearmint oil; coffee; tea and colas (even decaffeinated); caffeine; theophylline; theobromine; amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan), - and combinations thereof.

The term "pharmaceutically acceptable" is used herein as an adjective to mean that the modified name is appropriate for use in a pharmaceutical product. "Pharmacodynamics" refers to the factors that determine the biological response observed with respect to the concentration of drug at the site of action. "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of the appropriate concentration of drug in a site of action. The term "pharmacologically active drug" and its equivalents, includes at least one of any prophylactically and / or pharmacologically and physiologically beneficial therapeutic active substance, or mixtures thereof, that is delivered to a living subject, to produce a desired, usually therapeutic, effect. More specifically, any drug that is capable of producing a pharmacological, localized or systemic response, regardless of whether it is diagnostic or prophylactic therapeutic in nature, particularly in mammals, is contemplated by the invention. "Plasma concentration" refers to the concentration of a substance in the blood plasma or blood serum of a subject. It is understood that the plasma concentration of a therapeutic agent must vary many times between subjects, due to the variability regarding the metabolism of therapeutic agents. According to one aspect of the present invention, the plasma concentration of proton pump inhibitors and / or non-spheroidal anti-inflammatory drug can vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum serum concentration (Tmax), or area under the curve of maximum serum concentration (AUC) may vary from subject to subject. Because of this variability, the amount needed to constitute "a therapeutically effective amount" of proton pump inhibitor, non-spheroidal anti-inflammatory drug or other therapeutic agent, may vary from subject to subject. It is understood that when average plasma concentrations are described for a population of subjects, these average values may include substantial variation. The term "avoid" or "prevention", in relation to a gastrointestinal disorder or disease, does not mean the development of gastrointestinal disorder or disease if it has not occurred, and without further development or gastrointestinal disease if the gastrointestinal disorder or disease had already developed. . The ability to avoid some or all of the symptoms associated with the gastrointestinal disorder or disease is also considered. "Solubilizers" include compounds such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate and the like. "Stabilizers" include compounds such as any antioxidant, buffers, acids and the like. "Suspending agents" or "thickening agents" include compounds such as polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol, for example, polyethylene glycol can have a molecular weight of from about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; carboxymethylcellulose sodium; methylcellulose; hydroxypropylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gums such as, for example, gum tragacanth and acacia gum; guar gum; xanthans, including xanthan gums; sugars; cellulosics, such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose; polysorbate-80; sodium alginate; sorbitan. polyethoxylated monolaurate; sorbitan polyethoxylated monolaurate; povidone and similar. "Surfactants" include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, for example, Pluronics (BASF); and similar. As used here, the terms "Suspension" and "solution" are interchangeable with each other and generally mean a solution and / or suspension of the substituted benzimidazole in an aqueous medium. The term "sustained release" is used in its conventional sense to refer to a drug formulation that provides for the gradual release of a drug over a prolonged period of time, and occasionally, although not necessarily, results in substantially increased blood levels. constants of a drug over a prolonged period of time. "Therapeutic window" refers to the range of plasma concentrations, or the range of levels of therapeutically active substance at the site of action, with a high probability of producing a therapeutic effect.

The term "treat" or "treatment" as used herein, refers to any treatment of a disorder or disease associated with gastrointestinal disorder, and includes, but is not limited to, preventing the occurrence of the disorder or disease in a mammal, which may have a predisposition to disorder or disease, but has not yet been diagnosed as having the disorder or disease, inhibiting the disorder or disease, for example slowing the development of the disorder or disease, alleviating the disorder or disease, for example causing regression of the disorder or disease; or alleviate the condition caused by the disease or disorder, for example stop the symptom of the disease or disorder Proton Pump Inhibitors For the purposes of this application, the term "proton pump inhibitor" or "PPI" "or" proton pump inhibiting agent "means any agent that possesses pharmacological activity as an inhibitor of H ÷, K + -ATPase.The definition of" PPI " , "or" proton pump inhibitor "or" proton pump inhibiting agent ", as used herein, may also mean that the agent possesses pharmacological activity as an inhibitor of H +, + -ATPase may if desired to encompass all the related chemical forms, which may be in the form of a free base, free acid, a salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a polymorph, a prodrug, a derivative or the like , provided that said forms are pharmacologically suitable, that is, effective in the present methods, combinations, equipment and compositions. After oral administration to the subject and absorption of the proton pump inhibitory agent (or intravenous administration), the agent is delivered through the serum to various tissues and cells of the body, including the parietal cells. Not pretending to be bound by any theory, the research suggests that when the proton pump inhibiting agent is in the form of a weak base and is not ionized, it passes freely through physiological membranes, including the cell membranes of the parietal cell. It is considered that the non-ionized proton pump inhibiting agent moves in the acidic secretory portion of the parietal cell, the secretory canicle. Once in the acidic medium of the secretory canicle, the proton pump inhibitory agent is apparently protonated (ionized) and converted to the active form of the drug. In general, ionized proton pump inhibitor agents are membrane impermeable and form covalent disulfide bonds with cysteine residues in the alpha subunit of the proton pump. These active forms are included within the definition of "PPI", "proton pump inhibitor", or "proton pump inhibiting agent" as used herein. A class of proton pump inhibiting agents useful in the methods, kits, combinations and compositions of the present invention are substituted benzimidazole (including for example substituted benzimidazoles wherein the benzimidazole ring itself is substituted with nitrogen to form a six-membered pyridine ring connected to the imidazole ring). In one embodiment, the substituted benzimidazole of the formula (I) wherein R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoyloalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl; R 2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl; R3 and R5 are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy; R 4 is hydrogen, alkyl, alkoxy which may be optionally fluorinated, or alkoxyalkoxy; y y is an integer from 0 to 4; or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or its prodrug. Illustratively, a substituted benzimidazole of interest that can be employed in the methods, kits and combinations and compositions of the present invention, includes but is not limited to omeprazole, hydroxymeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, esomeprazole (also known as -omeprazole or perprazole), tenatoprazole, habeprazole, ransoprazole, pariprazole, and leminoprazole; or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds. (Based in part on the list provided in The Merck Index, Merck &Co. Rahway, N.J. (2001)). Examples of salt forms of proton pump inhibitors include, for example, a sodium salt form, such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form, such as esomeprazole magnesium or omeprazole magnesium, as described in U.S. Pat. No. 5,900,424; or a form of calcium salt; or a potassium salt form, such as the potassium salt of esomeprazole, as described in the co-pending US patent application. Serial No. 2002/0198239, and U.S. Patent No. 6,511,996. Other salts of esomeprazole are described in U.S. Patent No. 4,738,974 and U.S. Patent No. 6,369,085, for example. Included in the methods, equipment, combinations and pharmaceutical compositions of the present invention are the isomeric and tautomeric forms of the disclosed compounds and their pharmaceutically acceptable salts. Examples of substituted benzimidazole tautomers useful in the present invention include tautomers of omeprazole, as described in U.S. Pat. Nos. 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; and the publication of Patent Application No. 02/0156103, all by Whittle et al. Examples of substituted benzimidazole isomers useful in the present invention include an isomer of omeprazole. For example, the compound 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole, which has the generic name omeprazole, as well as its therapeutically acceptable salts , are described in EP 5129. Single-crystal X-ray data and molecular structure derived from a crystalline form of omeprazole, are described by Oishi et al., Acta Cryst. (1989), C45, 1921-1923. This crystal form of omeprazole is referred to as omeprazole form B. Another crystalline form of omeprazole referred to as omeprazole form A is described in U.S. Pat. No. 6,150,380, and the publication of the US patent application, No. 02/0156284, by Lovgvist et al. Still another crystalline form of omeprazole is described in WO 02/085889, by Hafner et al. Examples of suitable polymorphs are described, for example, in U.S. Patents. Nos. 4,045,563; 4,182,766; 4,508.905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; , 093, 132; 5, 093, 342; 5,433,959; 5,464, 632; 5, 536, 735; .576, 025; 5,599, 794; 5, 629, 305; 5, 639, 478; 5, 690, 960; , 703, 110; 5,705,517; 5,714,504; 5,731, 006; 5, 879, 708; ,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 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; and 6,444, 689. Illustrative pharmaceutically acceptable are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulphonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethane sulfonic, sulphanilic, cyclohexylaminosulfonic, algic, b-hydroxybutyl, galactárico and galacturonics: Pharmaceutically acceptable cations include metal ions and organic ions Illustratively, metal ions include, but are not limited to, appropriate alkali metal salts (Group IA), alkaline earth metal salts (Group IIA) and others Acceptable physiological metal ions Exemplary ions include aluminum, calcium, lithium, magnesium or, potassium, sodium and zinc in their usual valencies. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part trimethylamine, diethylamine, α, β-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, acid gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like. Also in the methods, equipment, combinations and pharmaceutical compositions of the present invention, the prodrugs of the described compounds and their pharmaceutically acceptable salts are included. Prodrugs in general, are considered drug precursors that, after administration to a subject and subsequent absorption, are converted to an active species or a more active species through some process, such as a metabolic process. Other products of the conversion process are easily eliminated by the body. Prodrugs generally have a chemical group present in the prodrug, which makes them less active and / or confers solubility or some other property to the drug. Once the chemical group has been separated from the prodrug, the most active drug is generated. Prodrugs can be designed as reversible drug derivatives and used as modifiers to improve drug transport to site-specific tissues. The design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound to target in regions where water is the main solvent. For example, Fedorak et al., Am. J. Physiol, 269: 6210-218 (1995), describes dexamethasone-beta-D-glucuronide. McLoed et al., Gastroenterol. , 106: 405-413 (1994), describes dexamethasone-succinate-dextrans. Hochhaus et al., Biomed. Chrom. , 6: 283-286 (1992), describes sodium dexamethasone-21-sulfobenzoate and dexamethasone-21-isonicotinate. Additionally, J. Larsen and H. Bundgaard [Int. J. Pharmaceutics, 37, 87 (1987)] describe the evaluation of N-acylsulfonamides as potential prodrug derivatives. J. Larsen et al., [Int. J. Pharmaceutics, 47, 103 (1988) 1 also describes the evaluation of N-methylsulfonamides as potential prodrug derivatives. Prodrugs are also described, for example, by Sinkula et al., J. Pharm. Sci. , 64: 181-210 (1975). Other substituted benzitnidazole compounds and their hydrate salts, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs and derivatives, can be prepared using standard procedures known to those known in the synthetic organic chemistry art and described for example by J. arch. , Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Edition (New York: iley-Interscience, 1992). Combinations and mixtures of the aforementioned proton pump inhibiting agent can be used in the methods, equipment, combinations and compositions described herein. Salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs and derivatives of the proton pump inhibiting agent, can be prepared using standard procedures known to those skilled in the synthetic organic chemistry art and described for example in J March, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4a. Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methodology, and involve reaction with a convenient acid. In general, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added. The resulting salt either precipitates or can be removed from solution by the addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, for example acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, acid citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulonic acid, salicylic acid and the like, as well as inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar. An acid addition salt can be reconverted to the free base by treatment with a convenient base. In one embodiment, the acid addition salts of the active agents present are halide salts, such as can be prepared using hydrochloric or hydrobromic acids. In yet another embodiment, the basic salts herein are alkali metal salts, for example sodium salt and copper salts. Preparation of esters involves the functionalization of hydroxyl and / or carboxyl groups that may be present within the molecular structure of the drug. The esters are typically acyl-substituted derivatives of free alcohol groups, that is, portions that are derived from carboxylic acids of the formula RCOOH, wherein H is replaced with a lower alkyl group. Esters can be reconverted to free acids, if desired, by using conventional hydrogenolysis or hydrolysis processes. Amides can also be prepared using techniques known to those skilled in the art or described in the relevant literature. For example, amides can be prepared from esters, using convenient amine reagents, or they can be prepared from an anhydride or acid chloride by reaction with ammonia or a lower alkyl amine. As used herein, the term "acyl", alone or in combination, means a radical that is provided by the residue after removal of hydroxyl from an organic acid. Examples of these acyl radicals include alkanoyl and aroyl radicals. Examples of these alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl and the like. The term "alkoxy" or "alkyloxy", alone or in combination, means an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The "alkoxy" radicals may also be substituted with one or more halo atoms, such as fluorine, chlorine or bromine, to provide haloalkoxy radicals. Illustratively, haloalkoxy radicals are "haloalkoxy" radicals having one to six carbon atoms and one or more halo radicals. Examples of these radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "alkoxyalkyl", alone or in combination, means an alkyl radical having one or more alkoxy radicals connected to the alkyl radical, that is to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" radicals may also be substituted with one or more halo atoms, such as fluorine, chlorine or bromine, to provide haloalkoxy radicals.

The term "alkyl", alone or in combination, means a straight or branched chain alkyl radical containing one to about twelve carbon atoms, preferably one to about ten carbon atoms, and more preferably one to about six carbon atoms . Examples of these radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term "alkylsulfinyl", alone or in combination, means a radical containing a linear or branched alkyl radical of one to ten carbon atoms, connected to a divalent radical -S (= 0) -. Illustratively, alkylsulfinyl radicals are radicals having alkyl radicals of one to six carbon atoms. Examples of these alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "alkylsulfonyl", alone or in combination, means an alkyl radical connected to a sulfonyl radical, wherein alkyl is as defined above. Illustratively, alkylsulfonyl radicals are alkylsulfonyl radicals having from one to six carbon atoms. Examples of these alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The radicals "alkylsulfonyl" may also be substituted with one or more halo atoms, such as fluorine, chlorine or bromine, to provide haloalkylsulfonyl radicals. The term "alkylthio", alone or in combination means a radical containing a linear or branched alkyl radical, from one to about ten carbon atoms connected to a divalent sulfur atom. Illustratively, alkylthio radicals are radicals having alkyl radicals of one to six carbon atoms. Examples of these alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthioalkyl", alone or in combination, means a radical containing an alkylthio radical connected through the divalent sulfur atom with an alkyl radical of one to about ten carbon atoms. Illustratively, alkylthioalkyl radicals are radicals having alkyl radicals of one to six carbon atoms. Examples of these alkylthioalkyl radicals include methylthiomethyl, methylthioethyl, ethylthioethyl and ethylthiomethyl. The term "amino", alone or in combination means an amine or group -NH2, while the term mono-substituted amino, alone or in combination, means a substituted amine group -N (H) (substituent), wherein one atom of hydrogen is replaced with a substituent and disubstituted amine means an -N (substituent) 2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups. Amines, amino groups and amides are compounds that can be designated as primary (Io), secondary (IIo) or tertiary (IIIo) or unsubstituted, mono-substituted or?,? -disubstituted, depending on the degree of substitution of the amino nitrogen. Quaternary amine (IVo) means a nitrogen with four substituents [-N + (substituent) 4] that has a positive charge and is accompanied by a counter ion, while N-oxide means a substituent is oxygen and the group is represented as [-N + (substituent) 3-0 ~]; this is the charges are internally compensated. The term "aminoalkyl", alone or in combination, means an alkyl radical substituted with amino radicals. Aminoalkyl radicals having alkyl portions with one to six carbon atoms are preferred. Examples of these radicals include aminomethyl, aminoethyl, and the like. The terms "arylalkyl" or "aralkyl" alone or in combination, mean an alkyl radical as defined above, wherein a hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, 2-phenylethyl and the like. The aryl in the aralkyl can be additionally substituted with halo, alkyl, alkoxy, halcoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term "aryl", alone or in combination means a five- or six-member carboxylic aromatic ring containing portion, or a five or six member carbocyclic aromatic system containing two or three rings, wherein these rings are connected together in a secondary form, or a fused ring system containing two or three rings that have all carbon atoms in the ring; that is, a carbocyclic aryl radical. The term "aryl" embraces aromatic radicals such as phenyl, indenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted with one or more substituents including alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.

The terms "carbonyl" or "oxo", alone or in combination, this is used in other terms such as "alkoxycarbonyl", means a group -C (= 0) - where two remaining bonds (valences) can be independently substituted. The term "carbonyl" is also intended to encompass a hydrated carbonyl group -C (OH) 2-. The terms "carboxy" or "carboxyl", whether employed alone or in combination, that is, with other terms, such as "carboxyalkyl", mean a -C02H radical. The term "carboxyalkyl", alone or in combination, means an alkyl radical substituted with a carboxy radical. Illustratively, carboxyalkyl radicals have alkyl radicals as defined above and may be further substituted on the alkyl radical with halo. Examples of these carboxyalkyl radicals include carboxymethyl, carboxyethyl, carboxypropyl and the like. The term "cyano", alone or in combination, means a group -C-triple bond-N (-C = N). The term "cycloalkyl", alone or in combination, means a cyclic alkyl radical containing three to about twelve carbon atoms. Illustratively, cycloalkyl radicals are cycloalguyl radicals having three to about eight carbon atoms. Examples of these radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "derivative" refers to a compound that is produced from another compound of similar structure by replacing the substitution of one atom, molecule or group with another. For example, a hydrogen atom of a compound can be substituted by alkyl, acyl, amino, hydroxyl, halo, haloalkyl, etc., to produce a derivative of this compound. The term "halo" or "halogen", alone or in combination, means halogen such as fluorine, chlorine, bromine or iodine. The term "haloalkyl", alone or in combination, means an alkyl radical having the meanings defined above, wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for example, may have either an iodine, bromine, chlorine or fluorine atom, within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. In some embodiments, the haloalkyl radicals are haloalkoxy radicals having one to six carbon atoms and one or more halo radicals. Examples of these haloalkyl radicals include chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. The term "heteroaryl", alone or in combination means a five- or six-member aromatic ring-containing portion or a fused ring (radical) system, which contains two or three rings having carbon atoms and also one or more heteroatoms in The ring (s) such as sulfur, oxygen and nitrogen. Examples of these heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (for example, imidazol-4-yl, l-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl. , furyl, tetrahydrofuryl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, l-oxido- 2-quinolinyl and the like), isoquinolinyl (for example, 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (for example, 1, 2, 3, 4-tetrahydro-2-quinolyl, and the like), 1, 2, 3, 4-tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydro-l-oxo-isoquinolinyl, and the like), quinoxalinyl, beta-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals. The term "heterocycle" embraces ring-shaped radicals containing saturated, partially unsaturated and unsaturated heteroatoms, wherein the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocycle radicals include three to six membered heteromonocyclic group containing one to four nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated three to six membered heteromonocyclic groups containing one to two oxygen atoms and one to three nitrogen atoms (e.g., morpholinyl, etc.); saturated three to six membered heteromonocyclic group containing one to two sulfur atoms and one to three nitrogen atoms (eg, thiazolidinyl, etc.). Examples of partially unsaturated heterocycle radicals include dihydrothiophene, di-propyran, dihydrofuran and dihydrothiazole. A (heterocyclic) heterocyclic portion of a heterocyclocarbonyl, heterocycloxycarbonyl, heterocycloalkoxycarbonyl or heterocycloalkyl group or the like is a monocyclic, bicyclic or tricyclic saturated or partially unsaturated heterocycle containing one or more hetero atoms selected from nitrogen, oxygen and sulfur. Heterocycle compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane. Said portion may be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo and the like, and / or on a secondary nitrogen atom (ie, -NH-) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or at a tertiary nitrogen atom (ie = N-) by oxide and which is connected by a carbon atom. The tertiary nitrogen atom with three substituents can also be connected to form an N-oxide group [= N (0) ~]. The term "heterocycloalkyl", alone or in combination means a saturated and partially unsaturated heterocycle-substituted alkyl radical such as pyrrolidinylmethyl and substituted heteroaryl alkyl, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl and quinolylethyl. The heteroaryl in the heteroaralkyl may be further substituted with halo, alkyl, alkoxy, halcoalkyl and haloalkoxy. The terms "hydride" or "hydrogen", alone or in combination, mean a single hydrogen atom (H). This hydride radical can be connected, for example, to an oxygen atom to form a hydroxyl radical or two hydride radicals can be connected to a carbon atom to form a methylene radical (-CH2-) - The term "hydroxyalkyl", alone or in combination means a linear or branched alkyl radical having one to about ten carbon atoms, any of which may be substituted with one or more hydroxyl radicals. Preferred hydroxyalkyl radicals have one to six carbon atoms and one or more hydroxyl radicals. Examples of these radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The term "hydroxyl", alone or in combination means an -OH group. The term "nitro", alone or in combination means a group -NO2 - The term "prodrug" refers to a drug or compound in which the pharmacological action results from the conversion by metabolic processes within the body.

Prodrugs in general are drug precursors that, after administration to a subject and subsequent absorption, are converted to an active or more active species by some process, such as conversion by a metabolic route. Some prodrugs have a chemical group present in the prodrug that makes them less active and / or confers solubility or some other property to the drug. Once the chemical group has been cleaved and / or modified from the prodrug, the active drug is generated. Prodrugs can be designed as reversible drug derivatives, to be used as modifiers to improve drug transport to site-specific tissues. The design of prodrugs to date has been to increase the effective solubility in water of the therapeutic compound to target in regions where water is the main solvent. See, for example Fedorak, et al., Am. J. Physio.l, 269: G210-218 (1995); McLoed, and collaborators, Gastroenterol. , 106: 405-413 (1994); Hochhaus, and collaborators, Biomed. Chrom. , 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci. , 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. The term "sulfone", alone or in combination, means a group -S02- wherein the two remaining bonds (valencies) illustrated can be substituted independently. The term "sulfonyl", alone or in combination, this is linked to other terms such as alkylsulfonyl, means a group -SO2- wherein the two remaining bonds (valences) illustrated, can be independently substituted. The term "sulfoxide", alone or in combination means an -SO- group in which the two remaining bonds (valencies) can be independently substituted. The term "thiol" or "sulfhydryl", alone or in combination, means a -SH group. The term "thio" or "aunt", alone or in combination, means a thiatheric group; This is an ether group where the oxygen ether is replaced by a sulfur atom. Shock-absorbing Agents The terms "cushioning agent" or "buffer" mean any pharmaceutically acceptable weak base or strong base (and mixtures thereof) which, when formulated or delivered before, during and / or after the proton pump inhibiting agent, function to substantially prevent or inhibit the acid degradation of the proton pump inhibitory agent by sufficient gastric acid to preserve the bioavailability of the administered proton pump inhibitory agent. The pharmaceutical compositions of the invention comprise one or more buffering agents. A class of buffering agents useful in the present invention includes, but is not limited to, buffering agents that possess pharmacological activity as a weak base or a strong base. In one embodiment, the buffering agent, when formulated or delivered with a proton pump inhibiting agent, functions to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastric fluid for a period of time, for example by a enough time to conserve the bioavailability of the administered proton pump inhibitor. The buffering agent can be supplied before, during and / or after delivery of the proton pump inhibitor. In one aspect of the present invention, the buffering agent includes a metal salt of Group IA (alkali metal), including for example a metal bicarbonate salt of Group IA, a metal carbonate salt of Group IA; an alkaline earth metal buffering agent (Group IIA metal); an aluminum buffering agent; a calcium buffering agent; or a magnesium buffering agent. Other buffering agents suitable for the present invention include, for example alkali metal (Group IA metal including but not limited to lithium, sodium, potassium, rubidium, cesium and francium) or alkaline earth metal (Group IIA metal including but not limited to beryllium, magnesium, calcium, strontium, barium , radio) carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrate, succinates and the like, such as sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate. In various embodiments, a buffering agent includes an amino acid, an alkali metal salt of an amino acid, aluminum hydroxide, co-precipitated aluminum hydroxide / magnesium carbonate / calcium carbonate, magnesium aluminum hydroxide, co-precipitated aluminum hydroxide / magnesium hydroxide, co-precipitated aluminum hydroxide / sodium bicarbonate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, glycerophosphate calcium, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, hydroxide gel dry aluminum, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate esio, magnesium hydroxide, magnesium lactate, magnesium aluminate metasilicate, magnesium oxide, 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, carbonate sodium, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, tartrate sodium, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate and trometamol. . { See, for example, lists that are provided in Merck Index, Merck &; Co. Rahway, N.J. (2001)). Certain proteins or protein hydrolysates that rapidly neutralize acids can serve as buffering agents in the present invention. Combinations of the aforementioned buffering agents can be employed in the pharmaceutical compositions described herein. Buffering agents useful in the present invention also include buffers or combinations of buffering agents that interact with HC1 (or other acids in the environment of interest) faster than the proton pump inhibitor that interacts with the same acids. When placed in a liquid phase, such as water, these buffering agents produce and maintain a higher pH than the pKa of the proton pump inhibitor. In various embodiments, the buffering agents are chosen from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide and mixtures thereof. In another embodiment, the buffering agent is sodium bicarbonate and is present at about 0.1 mEq / mg of proton pump inhibitor at about 5 mEq / mg of proton pump inhibitor. In yet another embodiment, the buffering agent is a mixture of sodium bicarbonate and magnesium hydroxide, wherein the sodium bicarbonate and magnesium hydroxide are each present in about 0.1 mEq / mg of proton pump inhibitor at about 5 mEq / mg of proton pump inhibitor. In still another embodiment, the buffering agent is a mixture of at least two buffers selected from sodium bicarbonate, calcium carbonate and magnesium hydroxide, wherein each buffer is present at about 0.1 mEq / mg proton pump inhibitor at about 5 mEq / mg of proton pump inhibitor. Compositions are provided as described herein, wherein the buffering agent is present in an amount of about 0.1 mEq / mg to about 5 mEq / mg of the proton pump inhibitor, or about 0.25 mEq / mg to about 3 mEq / mg of the proton pump inhibitor, or about 0.3 mEq / mg to about 2.5 mEq / mg of the proton pump inhibitor, or about 0.4 mEq / mg to about 2.0 mEq / mg of the proton pump inhibitor, or about 0.5 mEq / mg to approximately 1.5 mEq / mg of the proton pump inhibitor. Compositions as described above are provided, wherein the buffering agent is present in an amount of at least 0.25 mEq / mg to about 2.5 mEq / mg of the proton pump inhibitor, or at least about 0.4 mEq / mg of the pump inhibitor. of protons. In one aspect of the invention, compositions are provided wherein the buffering agent is present in the pharmaceutical compositions of the present invention, in an amount of about 1 mEq to about 160 mEq per dose, or about 5 mEq, or about 10 mEq, or about 11 mEq, or about 12 mEq, or about 13 mEq, or about 15 mEq, or about 19 mEq, or about 20 mEq, or about 21 mEq, or about 22 mEq, or about 23 mEq, or about 24 mEq, or about 25 mEq, or about 30 mEq, or about 31 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq, or about 80 mEq , or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150 mEq, or approximately 160 mEq per dose. In another aspect of the invention, compositions are provided wherein the buffering agent is present in the composition in an amount on a weight to weight (w / w) basis, of more than about 5 times, or more than about 10 times, or more than about 20 times, or more than about 30 times, or more than about 40 times, or more than about 50 times, or more than about 60 times, or more than about 70 times, or more than about 80 times, or more than about 90 times, or more than about 100 times, the amount of the proton pump inhibiting agent. In another aspect of the invention, compositions are provided wherein the amount of buffering agent present in the pharmaceutical composition is between 200 and 3500 mg. In some embodiments, the amount of the buffering agent present in the pharmaceutical composition is 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 about 3200 mg, or about 3500 mg. Combination Therapy The phrase "combination therapy" means the administration of a composition of the present invention in conjunction with another pharmaceutical agent. The therapeutic compounds that constitute the combination therapy can be a combined dosage form or in separate dosage forms intended for substantial simultaneous administration. The therapeutic compounds that constitute the combination therapy can also be administered sequentially, either with a therapeutic compound administered by a regimen requiring two-step administration. Substantially simultaneous administration can be achieved, for example by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple single capsules or tablets, for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route. In this manner, a regimen may require sequential administration of the therapeutic compounds with spaced administration of the active agents, separated. The period of time between the multiple administration steps may be in the range for example from a few minutes to several hours to days, depending on the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending on the effect of food ingestion and the age and condition of the subject. The circadian variation of the target molecular concentration can also determine the optimal dose range. The therapeutic compounds of the combination therapy, whether administered simultaneously, substantially simultaneously or sequentially, may involve a regimen requiring administration of a therapeutic compound by oral route or other therapeutic compound by an oral route, a percutaneous route, an intravenous route , an intramuscular route or by direct absorption through mucous membrane tissues, for example. Whether the therapeutic compounds of the combination therapy are administered orally, by inhalation spray, rectally, topically, orally (for example, sublingually), or parenterally (for example subcutaneous, intramuscular, intravenous and intradermal injections or infusion techniques) ), separately or in combination, each therapeutic compound will be contained in a suitable pharmaceutical formulation or excipients, pharmaceutically acceptable diluents or other components of formulations. The combination therapy includes, for example, administration of a composition of the present invention in conjunction with another pharmaceutical agent, as part of a specific treatment regimen, intended to provide a beneficial effect of the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action, which results from the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically carried out over a defined period of time (usually substantially simultaneously, minutes, hours, days, weeks, months or years depending on the selected combination). For example, the present methods, equipment and compositions can be used in combination with another pharmaceutical agent that is indicated to treat or prevent a gastrointestinal disorder, such as for example an antibacterial agent, an alginate, a prokinetic agent, a antagon -antagonist, a antacid or sucralfate, which are commonly administered to minimize pain and / or complications related to this disorder. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the above-mentioned conditions and / or produce adverse side effects, such as mental confusion, constipation, diarrhea and thrombocytopenia. Anta Antagonists, such as ranitidine and cimetidine, are relatively expensive modes of therapy, particularly in NPO patients (unable to eat or drink), who frequently require the use of automated infusion pumps for continuous intravenous infusion of the drug. However, when used in conjunction with the present invention, this is in combination therapy, many if not all of these unwanted side effects can be reduced or eliminated. The profile of reduced side or side effects of these drugs is generally attributed, for example, to the reduced dose necessary to achieve a therapeutic effect with the combination administered. In another example, the present methods, equipment and compositions can be used in combination with other pharmaceutical agents, including but not limited to: NSAIDs including but not limited to aminoarilcarboxylic acid derivatives such as enfenamic acid, ethofenomate, flunfenamic acid, isonixin, meclofenamic acid , mefenamic acid, niflumic acid, talnifluminic acid, terofenemate, and tolfenamic acid; arylacetic acid derivatives such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclonic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac, metyazinic acid , mofezolac, oxametacine, pyrazolac, proglumetacin, sulindac, thiaramide, tolmetin, tropesin, and zomepirac, arylbutyl acid derivatives such as bumadizon, butibufen, fenbufen, xenbucin; arylcarboxylic acids such as clidanac, ketorolac, tinoridine; arylpropionic acid derivatives such as alminoprofen, benoxaprofin, bermoprofen, bucilloxic acid, carpro in, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinic acid, suprofen, acid thiaprofen, ximoprofen, and zaltoprofen; pyrazoles such as diphenamizole, and epirozole; pyrazolones such as apazone, benzpiperilone, feprazone, mofebutazone, morazone, oxifenbutazone, phenylbutazone, pipebuzone, propifenazone, prostaglandins, ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives such as acetaminosalol, aspirin, benorilate, bromosaligenin, calcium acetylsalicylate, diflunisal, ethersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine; thiazinecarboxamides such as ampiroxicam, droxicam, isoxicam, lomoxicam, piroxicam, and tenoxicam; cyclooxygenase-II inhibitors ("COX-II") such as Celebrex (Celecoxib), Vioxx, Relafen, Lodina, and Voltaren and others, such as epsilon-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrinea, benzadac, benzidamine, alpha-bisabolol, bucololoma, diphenpiramide, ditazole, emorfazone, fepradinol, guayazulene, nabumetone, nimesulide, oxaceprol, paraniline, perisoxal, proquazone, tenidap and zilenton; sleep aids that including but not limited to a hypnotic benzodiazepine, hypnotic non-benzodiazepine, hypnotic antihistamine, hypnotic antidepressant, herbal extract, barbiturate, hypnotic peptide, triazolam, brotizolam, loprazolam, lormetazepam, flunitrazepam, flurazepam, nitrazepam, quazepam, estazolam, temazepam, lorazepam, oxazepam, diazepam, halazepam, prazepam, alprazolam, chlordiazepoxide, clorazepate, a hypnotic of imidazopyridine or pyrazolopyrimidine, zolpidem or tartarate zolpidem, zopiclone, eszopiclone, zaleplon, indiplone, diphenhydramine, doxylamine, phenyltoloxamine, pyrilamine, doxepin, amtriptiline, trimipramine, trazodon, nefazodone, buproprion, bupramityiptilin, an herbal extract such as valerian extract or amentoflavone, a hormone such as melatonin, or gabapeptin; mobility agents; including but not limited to 5-HT inhibitors such as cisapride, domperidone, and metoclopramide, and agents useful for treating irritable bowel syndrome. Compositions The present invention provides pharmaceutical compositions comprising a proton pump inhibitory agent and a buffering agent for oral administration and ingestion by a subject. The composition may comprise any convenient proton pump inhibitory agent, for example omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, esomeprazole (also known as s-omeprazole or perprazole), habeprazole, perprazole, ransoprazole, pariprazole, and Leminoprazole; or a free base, free acid or salt, hydrate, ester, amide, enantiomer, isomer, trimer, polymorph per drug or derivative of these compounds. The composition may comprise any convenient buffering agent, which when formulated or delivered before, during and / or after the proton pump inhibitory agent, functions to prevent or substantially inhibit the acid degradation of the proton pump inhibitory agent by gastric acid sufficient to preserve the bioavailability of the administered proton pump inhibiting agent such as, for example, sodium salts, potassium salts, magnesium salts, salts calcium, aluminum hydroxide, coprecipitated aluminum hydroxide / sodium bicarbonate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer and a mixture of an alkaline salt of an amino acid or buffer and a suitable agent or mixture of buffering agents, the present invention relates to a pharmaceutical composition comprising a proton pump inhibitory agent, a buffering agent and optionally a parietal cell activator. The therapeutic agents of the present invention can be formulated as a single pharmaceutical composition or as multiple independent pharmaceutical dosage forms. Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, buccal (for example sublingual), or parenteral (e.g., intravenous) administration, although the most convenient route in any given case will depend on the nature and severity of the drug. the condition to be treated and the nature of the particular compound used. The therapeutic agents can be formulated in any convenient dosage forms, such as, for example, tablets including chewable tablets, coated tablets, powders, suspensions, capsules or any other convenient dosage form known in the art. In another embodiment of the present invention, the composition of the present invention comes in the form of a kit containing one or more of the compositions or therapeutic agents of the present invention. The composition containing the composition or therapeutic agent can be packaged in the form of a packet or in a packet in which doses per hour, day, week or month or other periodicals are arranged (for an adequate, sequential or simultaneous administration. invention further provides a kit containing a plurality of dose units adapted for a successive daily administration, each dose unit comprising at least one of the compositions or therapeutic agents of the present invention.This drug delivery system can be employed to facilitate the administration of any of the various embodiments of the compositions and therapeutic agents of the present invention In one embodiment, the system contains a plurality of doses that are to be administered on a daily basis or as required for symptomatic relief. agents used in combination therapy to facilitate an adequate administration of ation of the dosage forms. The equipment may also contain a set of instructions for the subject. The pharmaceutical composition of the present invention can be prepared in any convenient dosage form. Suitable dosage forms include, but are not limited to, a tablet, a coated tablet, a powder, a suspension tablet, a chewable tablet, a capsule, an effervescent powder, an effervescent tablet, a seed, a granule, a bead, a microcapsule, a mini tablet, a spheroid, a micro sphere, an agglomerate, a granule or any other forms of multiple particles manufactured by conventional pharmacological techniques. In one embodiment of the present invention, the compositions comprise a dry formulation, or a solution and / or suspension of the proton pump inhibiting agent. These dry formulations, solutions and / or suspensions may also include for example a suspending agent (eg, gums, xanthates, cellulosics and sugars), a humectant (eg, sorbitol), a solubilizer (e.g., ethanol, water, PEG and propylene glycol), a surfactant (for example, sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), a preservative, an antioxidant, (for example, parabens and vitamins E and C), a anti-cake agent, a coating agent, a chelating agent (e.g., EDTA), a stabilizer, an antimicrobial agent, an antifungal or antibacterial agent (e.g., parabens, chlorobutanol, phenol, sorbic acid) an isotonic agent (for example, example, sugar, sodium chloride) a thickening agent (for example, methyl cellulose), a flavoring agent, an antifoaming agent (for example, simethicone, Mylicon3), a disintegrant, a flow aid, a lubricant, an adjuvant, a excipient, a dye, a diluent, a wetting agent, a preservative, a pharmaceutically compatible carrier or a parietal cell activator. Flavoring agents that may be employed in the present invention include aspartame, talmantine, dextrose, chocolate, vanilla, root beer, pepper, green pepper, sucrose, cocoa, or watermelon and the like. Other flavoring agents that can be used include: banana, camphor, cinnamon, ginger, grape, lemon, orange, pear, apple, rum, wintergreen, acacia syrup, wild cherry, strawberry, anise, blackcurrant, grapefruit, caramel, raspberry, maple, soft butter flavored candy, glycyrrhiza syrup (licorice) citrus, walnut, lemon, tutti frutti, cinnamon, eucalyptus, lime, orange, calcium chloride, menthol, eugenol, cilamate, cilitol, safrol, mixed berries, fruit punch, fresh cherry, fresh citrus, cream bavaria, green mint cream, cherry cream, mint cream, citrus cream, strawberry cream, Swiss cream, lemon cream, mint cream, citrus punch, cola, tangerine , berry, honey or any combination of these flavoring ingredients, for example,. chocolate-mint, orange-cream, cherry-anise, lemon-mint, vanilla-mint, anis-menthol, honey-lemon, cherry-cinnamon, menthol-eucalyptus, cinnamon-orange or lemon-lime. In general, colorants and flavoring agents, for example cherry red, coffee for chocolate, should coincide. Also effervescence can mask the salty taste of a drug. In one embodiment of the present invention, the total amount of flavoring agent may be in the range of about 0.10 mg to about 50 mg / dose form. In some embodiments, the pharmaceutical composition is substantially free of sucralfate. In other embodiments of the present invention, the pharmaceutical composition is free of sucralfate. In other embodiments, the pharmaceutical composition is substantially free of amino acids. In still other embodiments, the pharmaceutical composition is free of amino acids. In another embodiment of the present invention, the composition is in the form of a freeze-dried dose that rapidly disintegrates (e.g., in less than about 10 seconds) upon contact with an aqueous medium, such as when contacted with saliva in the mouth or gastric fluid. In general, a freeze-dried dosage form provides a fast-dissolving agent by freeze-drying a liquid suspension containing a uniformly suspended agent or agent such as a labile acid pharmaceutical agent and / or a buffering agent. The basic teachings of the dry dose or freeze forms are set forth in US Pat. Nos. 4,371,516; 4,305,502; 4,758,598; and 4,754,597. Other examples of freeze-dried dosage forms that can be used in the present invention are described in the following patents: E.U.A. E.U.A. E.U.A. E.U.A. E.U.A. 4, 749,790 4, 894,459 4, 946, 684 5, 021, 582 5, 046, 618 E.U.A. E.U.A. E.U.A. E.U.A. E.U.A. , 064, 946 5, 075,114 8,178, 867 5, 188, 825 5,206, 025 E.U.A. E.U.A. E.U.A. E.U.A. E.U.A. ,206, 072 5,215,756 5,275, 823 5,457, 895 5, 631, 023 EP GB 1548022 GB 2111423 GB 211440 GB 2119246 90143667 GB In one embodiment of the present invention, the general manufacturing method employed to prepare a dry dose form by freezing utilizes a previously prepared liquid composition that includes a solvent, an agent and a carrier material containing gelatin. The liquid composition is placed in one or more depressions formed in a tray or mold, to define depressions filled with liquid composition. The liquid composition in the filled depressions is frozen, then the liquid composition of the liquid composition is sublimed, to define a solid drug tablet. Trays filled with solid medications are then collected. In another embodiment of the present invention, xanthan gum is added to the liquid composition which is then stirred, before the freezing step. It is contemplated that xanthan gum behaves synergistically with gelatin as a flocculating agent, to improve the ability of the liquid composition to suspend relatively large particles during the manufacturing process. It is also contemplated that xanthan gum has the ability to improve the suspension qualities of the liquid composition without degrading the dissolution and texture qualities of the tablet in the mouth. Examples of suitable gelatin include simple gelatin and gelatin which is partially hydrolyzed, for example when heating gelatin in water. Examples of other suitable carrier materials that can be combined with gelatin are those inert and pharmaceutically acceptable for use in preparing pharmaceutical dosage forms. These carrier materials include polysaccharides such as dextran and polypeptides. In one embodiment of the present invention, the agent employed in a freeze-dried dose form, includes a buffering agent having an average particle size in the range of about 1 μt? at approximately 400 μ ?? Any particulate agent that remains at least partially in the solid state of the matrix of the carrier material can be employed in the present invention. In yet another embodiment of the present invention, the freeze-dried dosage form contains an enteric coating labile acid pharmaceutical agent, such as a proton pump inhibiting agent. In yet another embodiment, the proton pump inhibiting agent is lyophilized to obtain a freeze-drying of an aqueous solution of the agent, for inclusion in a composition of the present invention. A freeze-drying technique such as may be employed in the present invention is described, for example, in US patent application. Serial No. 2003/0003058, which describes lyophilized pantoprazole, ethylenediamine tetraacetic acid and / or its convenient salt, and sodium hydroxide and / or sodium carbonate. In yet another example, a pharmaceutical formulation is prepared by mixing enteric coating granules of a proton pump inhibitor with one or more buffering agents (eg, granules of omeprazole 20 mg, plus sodium bicarbonate 500 mg, and calcium carbonate). 500 mg) in a solid dosage form. Anti-oral administration, the buffering agents raise the gastric pH in such a way that all or part of the enteric coating dissolves in the gastric fluid (instead of, for example, in the upper pH environment of the duodenum), and omeprazole is available for immediate release in the gastric fluid for absorption into the bloodstream. Many variations in this type of formulation (ie, higher or lower amounts of inhibitory agent and / or buffering agent can be employed in the present invention.) The pharmaceutical composition of the invention comprises a buffering agent., which may be any convenient buffering agent which, when formulated or supplied before, during and / or after the proton pump inhibiting agent, functions to substantially prevent or inhibit the acid degradation of at least some of the proton pump inhibitory agent by sufficient gastric acid to preserve the bioavailability of the administered proton pump inhibitory agent. Suitable buffers include, for example, buffers as described herein, such as sodium salts, potassium salts, magnesium salts and calcium salts or any other suitable buffering agent or buffering agent mixture. The buffering agent is administered in an amount sufficient to prevent or substantially inhibit the acid degradation of at least some of the proton pump inhibitory agent by sufficient gastric acid to preserve the bioavailability of a therapeutically effective amount of the administered proton pump inhibitory agent, in this way preserving the ability of the proton pump inhibiting agent to produce a therapeutic effect. Therefore, the amount of buffering agent of the compositions of the present invention, when in the presence of the biological fluid of the stomach, should only raise the pH of these biological fluids sufficiently to achieve adequate bioavailability of the drug to achieve the action therapy.

In one embodiment, the buffering agent is present in the methods, equipment, combinations and compositions of the present invention, in an amount of about 0.05 mEq to about 10.0 mEq per mg of proton pump inhibiting agent. In another embodiment of the present invention, the buffering agent is present in an amount of about 0.2 mEq to about 5 mEq per mg of the proton pump inhibiting agent. Illustratively, the amount of the buffering agent in the composition is about 0.2 mEq, or about 1 mEq, or about 2 mEq, or about 3 mEq, or about 5 mEq, or about 10 mEq, or about 11 mEq, about 12.5. mEq, or about 13 mEq, or about 15 mEq, or about 19 mEq, or about 20 mEq, or about 21 mEq, or about 22 mEq, or about 23 mEq, or about 24 mEq, or about 25 mEq, or about 30 mEq, or about 31 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 55 mEq, or about 60 mEq, or about 65 mEq, or about 70 mEq, or about 75 mEq, 80 mEq, or about: 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150 mEq Eq, or approximately 160 mEq per dozen. In yet another embodiment of the present invention, the buffering agent is present in an amount of at least 10 mEq. In yet another embodiment of the present invention, the buffering agent is present in an amount of about 5 mEq to about 70 mEq. In yet another embodiment, the buffering agent is present in an amount of about 20 mEq to about 40 mEq. And still in another embodiment of the present invention, the amount of the buffering agent is present in an amount greater than about 20 times, or more than 22 times, or more than 25, or more than about 30 times, or more than 35 times, or more than about 40 times the amount of the proton pump inhibiting agent, on a weight-to-weight basis in the composition. The mEq specific amounts of buffer may vary, for example from about 0.01% to about 20% or more, depending on the application and desired therapeutic result. In another aspect of the invention, compositions are provided wherein the amount of buffering agent present in the pharmaceutical composition is between 200 and 3500 mg. In some embodiments, the amount of buffering agent present in the pharmaceutical composition is 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 about 3200 mg, or about 3500 mg. One embodiment of the present invention, buffering agent is sodium carbonate and is present in the methods, equipment, combinations and compositions in an amount of at least about 250 mg. In another embodiment, the sodium carbonate is present in an amount of at least about 700 mg. In yet another embodiment, sodium carbonate is present in an amount of about 250 mg to about 4000 mg. Still in another modality, sodium carbonate is present in an amount of about 1000 mg to about 2000 mg. And still in another embodiment, the sodium carbonate is present in an amount from about 1250 mg to about 1750 mg. Illustratively, the amount of buffering agent in a composition of the present invention is about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, or 1750 mg. These specific amounts may vary, for example, from about 0.01% to about 20% or more, depending on the application and desired therapeutic result. In one embodiment of the present invention, the buffering agent is calcium carbonate and is present in the methods, equipment, combinations and compositions in an amount of at least about 250 mg. In another embodiment, calcium carbonate is present in an amount of at least about 700 mg. In yet another embodiment, calcium carbonate is present in an amount from about 250 mg to about 4000 mg. And in yet another embodiment, calcium carbonate is present in an amount of about 500 mg to about 1500 mg. Illustratively, the amount of buffering agent in a composition of the present invention is about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, or 1750 mg. These specific amounts may vary, for example from about 0.01% to about 20% or more, depending on the application and desired therapeutic result. In one embodiment of the present invention, the buffering agent is sodium bicarbonate and calcium carbonate present in the methods, equipment, combinations and compositions in an amount totaling at least about 250 mg. In another embodiment, the sodium bicarbonate and calcium carbonate are present in an amount that totals at least about 700 mg. In yet another embodiment, the sodium bicarbonate and calcium carbonate are present in an amount which totals from about 250 mg to about 4000 mg. In yet another embodiment, sodium bicarbonate is present in an amount from about 1000 mg to about 2000 mg. And still in another embodiment, the sodium bicarbonate is present in an amount from about 1250 mg to about 1750 mg. Illustratively, the amount of buffering agent in a composition of the present invention is about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, or 1750 mg. These specific amounts may vary, for example, from about 0.01% to about 20% or more, depending on the application and desired therapeutic result. Compositions are provided as described herein, wherein the buffering agent is present in an amount of about 0.1 mEg / mg to about 5 mEq / mg of the proton pump inhibitor or about 0.25 mEq / mg to about 3 mEq / mg of the inhibitor of proton pump, or about 0.3 mEq / mg to about 2.5 mEq / mg of the proton pump inhibitor, or about 0.4 mEq / mg to about 2.0 mEq / mg of the proton pump inhibitor, or about 0.5 mEq / mg a approximately 1.5 mEq / mg of the proton pump inhibitor. Compositions are provided as described herein, wherein the buffering agent is present in an amount of at least 0.25 mEq / mg to about 2.5 mEq / mg of the proton pump inhibitor, or at least about 0.4 mEq / mg of the pump inhibitor. of protons. Microencapsulation and Coatings All or part of the proton pump inhibitor of the present invention, may or may not be enteric coated or in a sustained release or delayed release form, depending on the context in which the proton pump inhibitory agent is used. In one embodiment of the present invention, the proton pump inhibitory agent does not have an enteric coating or a sustained release or delayed release coating. In yet another embodiment, the enteric coating proton pump inhibitor is either coated with a sustained release or delayed release coating. And in another embodiment, the composition may contain both an enteric coating proton pump inhibiting agent and a non-enteric proton pump inhibiting agent. Said composition is contemplated wherein both an immediate release of the proton pump inhibiting agent in the gastric fluid, for example a collection of absorption of a subject is desired as well as a delayed release of a proton pump inhibitory agent, providing an effect prolonged therapy In some embodiments of the present invention, all or part of the proton pump inhibitor is microencapsulated with a material that improves the shelf life or storage of the pharmaceutical compositions. Exemplary microencapsulation materials useful for improving the shelf life of pharmaceutical compositions comprising a proton pump inhibitor, include but are not limited to: cellulose hydroxypropyl ethers (HPC) such as Klucel ° or Nisso HPC; low substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Sepifilm-LC, Pharmacoats, Metolose SR, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel ° and Metolose °; Ethylcelluloses (EC) and their mixtures such as E461, Ethocel °, Aqualon ° -EC, Surelease °; polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol °; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon ° -CMC; polyvinyl alcohol and polyethylene glycol copolymers such as ollicoat IR °; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified edible starch; acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit EPO, Eudragit RD100, and Eudragit0 El00; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins; and mixtures of these materials. In other embodiments, some or all of the antacid is microencapsulated with a material that improves the life in the storage of the pharmaceutical composition. In various embodiments, a buffering agent such as sodium bicarbonate is incorporated into the microencapsulation material. In other embodiments, an antioxidant such as BHT is incorporated into the microencapsulation material. Still in other embodiments, plasticizers such as polyethylene glycols, for example, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid and triacetin are incorporated into the microencapsulation material. . In other embodiments, the microencapsulation material useful for improving the shelf life of the pharmaceutical compositions is from USP or the National Formulary (NF). In some embodiments, all or some of the proton pump inhibitor is coated. In other modalities, all or some of the antacid is coated. The coating useful in the present invention can be for example a gastric resistant coating such as an enteric coating, a controlled release coating, an enzymatically controlled coating, a film coating, a sustained release coating, an immediate release coating or a delayed release coating. According to another aspect of the invention, the coating can be useful for improving the stability of the pharmaceutical compositions of the present invention. Various techniques can be employed to determine whether a pharmaceutical composition has an improved shelf life. For example, a pharmaceutical composition of the present invention can have an improved storage life stability if the pharmaceutical composition contains less than about 5% total impurities after approximately 3 years of storage, or after approximately 2.5 years of storage or approximately 2 years of storage, or approximately 1.5 years of storage, or approximately 1 year of storage, or after 11 months of storage, or after 10 months of storage, or after 9 months of storage, or after 8 months of storage , or after 7 months of storage, or after 6 months of storage, or after 5 months of storage, or after 4 months of storage, or after 3 months of storage, or after 2 months of storage, or after 1 month of storage. Micronized Proton Pump Inhibitor The particle size of the proton pump inhibitor can affect the solid dose form in numerous ways. Since the decreased particle size increases in surface areas (S), the reduction in particle size provides an increase in dissolution rate (dM / dt) as expressed in the Noyes-Whitney equation below: dM / dt = dS / h (Cs-C) M = dissolved drug mass; t = time; D = diffusion coefficient of the drug; S = effective surface area of drug particles; H = stationary layer thickness; Cs = concentration of solution in saturation; and C = concentration of solution at time t. Because omeprazole, as well as other proton pump inhibitors, have poor water solubility, to aid in rapid absorption of the drug product, various embodiments of the present invention utilize micronized proton pump inhibitor in the formulation of the drug product.

In some embodiments, the average particle size of at least about 90% of the micronized proton pump inhibitor is less than about 40 μt ?, or less than about 35 μt., or less than about 30 μt ?, or less than about 25 μt ?, or less than about 20 μ ??, or less than about 15 μ ??, or less than about 10 μt ?. In other embodiments, at least 80 percent of the micronized proton pump inhibitor has an average particle size of less than about 40 μt ?, or less than about 35 μt ?, or less than about 30 μt ?, or less than about 25 μp ?, or less than about 20 μp ?, or less than about 15 μt ?, or less than about 10 μp ?. Still in other embodiments, at least 70 percent of the micronized proton pump inhibitor has an average particle size of less than about 40 μt ?, or less than about 35 μ ??, or less than about 30 μt ?, or less of about 25 μ ??, or less than about 20 μ ??, or less than about 15 μp ?, or less than about 10 μ? t ?. Compositions are provided wherein the micronized proton pump inhibitor is of a size that allows more than 75 percent of the proton pump inhibitor to be released within approximately 1 hour or within approximately 50 minutes, or within approximately 40 minutes , or within approximately 30 minutes, or within approximately 20 minutes, or within approximately 10 minutes or within approximately 5 minutes of dissolution test. In another embodiment of the invention, the micronized proton pump inhibitor is of a size that allows more than 90 percent of the proton pump inhibitor to be released within approximately 1 hour or within approximately 50 minutes, or within approximately 40 minutes, or within approximately 30 minutes, or within approximately minutes, or within approximately 10 minutes or within approximately 5 minutes of the dissolution test. Administration The present invention provides a pharmaceutical composition comprising a proton pump inhibitory agent and a buffering agent for oral administration to a subject. In one embodiment, upon administration to a fed subject, the composition contacts the gastric fluid of the stomach and increases the gastric pH of the stomach to a pH that prevents or inhibits acid degradation of the proton pump inhibitory agent in the gastric fluid of the stomach and allows that a measurable serum concentration of the proton pump inhibitory agent be absorbed into the subject's blood serum, so that pharmacokinetic or pharmacodynamic parameters can be obtained using test procedures known to those skilled in the art. The present invention also provides a pharmaceutical composition comprising a proton pump inhibitory agent and a buffering agent for oral administration and ingestion by a subject, which exhibits increased bioavailability of omeprazole when administered to a fed subject, as compared to the administration of a subject fasting, the first day of administration. The present invention further provides pharmaceutical compositions exhibiting bioavailability of lowered omeprazole when administered to a fed human subject, as compared to administration to a fasted adult human subject on the seventh consecutive day of daily administration. Thus, the present invention provides a pharmaceutical composition comprising a proton pump inhibitory agent and a buffering agent for oral administration and ingestion by a subject. The pharmaceutical compositions can be administered to a subject at any time, in relation to the ingestion of food, for example to a subject fed or to a fasted subject. A subject fed may for example be a subject initiating the ingestion of a food, a subject who has initiated the ingestion of a food a short time before administration (e.g., approximately 10 minutes before, approximately 20 minutes before, approximately 30 minutes before , approximately 45 minutes before, approximately 60 minutes before, or approximately 90 minutes before, or approximately 120 minutes before), a subject who has initiated ingestion of a food a short time before administration and continues to ingest food after administration, a subject who recently finished eating a food, or a subject who finished eating a food and who experiences symptoms related to ingestion of this food. A food can be any amount of food, for example, a snack, a ration of food, several servings of a food, one or several servings of each of different foods or any amount of food that induces symptoms that require treatment with an inhibitor of proton pump.

Pharmaceutical compositions of the present invention can also be administered to a fasted subject. A fasting snack can be any subject who has abstained from food for a period of time, for example a subject who has not ingested a food overnight (for example 8 hours), a subject who has not ingested a food in several hours, a subject on an empty stomach that does not suffer from any symptoms related to food, can be treated with a proton pump inhibitor or any subject who has not eaten a food such that the food most recently ingested is digested and the subject does not suffer from any symptoms related to foods that can be treated with a proton pump inhibitor. In a modality, before administration to a fed subject, the composition contacts the gastric fluid of the stomach and increases the gastric pH of the stomach to a pH that prevents or inhibits acidic degradation of the proton pump inhibitory agent in the gastric fluid of the stomach and allows a concentration in the stomach. measurable serum of the proton pump inhibitory agent is absorbed into the subject's blood serum, so that pharmacokinetic and pharmacodynamic parameters can be obtained using test procedures known to those skilled in the art.

In one embodiment, the pharmaceutical composition of the invention exhibits increased bioavailability of omeprazole, when administered to a fed subject compared to administration to a fasted subject on the first day of administration. In another embodiment, the pharmaceutical composition exhibits a lowered bioavailability of omeprazole, when administered to a fed human subject, compared to administration to a fasted adult human subject, on the seventh consecutive day of daily administration. The present invention is also directed to methods for treating a condition or disorder by administering the pharmaceutical composition of the invention wherein treatment with an H + inhibitor, K + -ATP asa is indicated. The condition or disorder can be for example, a gastrointestinal disorder caused by acid such as for example heartburn, duodenal ulcer disease, gastric ulcer disease, a gastroesophasic reflux disease, erosive esophagitis, a symptomatic gastroesophageal reflux disease of poor response, pathological gastrointestinal hypersecretory disease, Zollinger Ellison syndrome or acid dyspepsia. A pharmaceutical formulation of the proton pump inhibiting agents used in the present invention can be administered orally or internally to the subject. This can be achieved, for example, by administering the solution through a nasogastric tube (ng) or other resident tubes placed in the GI tract. In one embodiment of the present invention, in order to avoid the disadvantages associated with administering large amounts of sodium bicarbonate, the proton pump inhibitor solution of the present invention is administered in a single dose that does not require further administration of bicarbonate , or another buffer, after administration of the proton pump inhibitor solution, nor does it require a large amount of bicarbonate or buffer in total. That is, unlike the proton pump inhibitor agent solutions and administration protocols set forth above in the Background of the Invention section, a formulation of the present invention is delivered in a single dose, which does not require administration of bicarbonate and either before or after administration of the proton pump inhibitory agent. The present invention eliminates the need for pre- or post-dose with additional volumes of water and sodium bicarbonate. The amount of bicarbonate delivered by the administration of a single dose of the present invention is less than the amount of bicarbonate administered as illustrated in the aforementioned references. Modalities of the present invention also provide pharmaceutical compositions wherein a therapeutically effective dose of the proton pump inhibitor is in the patient's blood serum within about 45 minutes, or within about 30 minutes, or within about 25 minutes, or within about 20 minutes, or within about 15 minutes, or within about 10 minutes, or within about 5 minutes after ingestion of the pharmaceutical composition. In various embodiments of the present invention, the pH of the stomach is increased to a pH of about 3, or a pH over 3.5, or a pH over 4, or a pH over 4.5, or a pH over 5, or a pH over 5.5. , or a pH above 6, or a pH above 6.5, or a pH at about 7 within about 45 minutes after administration of the pharmaceutical composition. In other embodiments of the present invention, the stomach pH is increased to a pH of about 3, or a pH over 3.5, or a pH over 4, or a pH over 4.5, or a pH over 5, or a pH over 5.5. , or a pH above 6, or a pH above 6.5, or a pH above 7 within about 30 minutes after administration of the pharmaceutical composition. In still other embodiments, the pH of the stomach is increased to a pH of about 3, or a pH above 3.5, or a pH above 4, or a pH above 4.5, or a pH above 5, or a pH above 5.5, or a pH above 6, or a pH above 6.5, or a pH above 7 within about 15 minutes after administration of the pharmaceutical composition. Dosage The proton pump inhibitory agent is administered and dosed according to good medical practice, taking into account the clinical condition of the individual patient, the site and method of application, administration schedule and other factors known to medical practitioners. In human therapy, it is important to provide a dosage form that delivers the required therapeutic amount of the drug in vivo, and makes the drug bioavailable in a fast manner. In addition to the dosage forms described herein, the dosage forms described by Phillips, in U.S. Pat. Nos. 5,840,737; 6,489,346; and 6,645,988, incorporated herein by reference. In addition to being useful for human treatment, the present invention is also useful for veterinary treatments of mammals, reptiles, birds, exotic animals and farm animals, including mammals, rodents and the like. In one embodiment, mammals include a primate, for example a human, a monkey, a lemur, a horse, a dog, a pig or a cat. In another modality, the rodent includes a rat, a mouse, a squirrel or a guinea pig. In one embodiment of the present invention, the composition is administered to a subject in a therapeutically effective amount, ie the composition is administered in an amount that achieves a therapeutically effective dose of a proton pump inhibitory agent in the blood serum. of a subject, for a period of time to produce a desired therapeutic effect. Illustratively, the composition is administered to achieve a therapeutically effective dose of a proton pump inhibitory agent in the blood serum of a subject within about 5 minutes after administration of the composition. In another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject within about 10 minutes from the time of administration of the composition to the subject. In another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject within about 20 minutes from the time of administration of the composition to the subject. In yet another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject within about 30 minutes from the time of administration of the composition to the subject. In still another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject within about 40 minutes from the time of administration of the composition to the subject. In one embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject within about 20 minutes to about 12 hours from the time of administration of the composition to the subject . In another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject at about 20 minutes to about 6 hours from the time of administration of the composition to the subject. Still in the embodiment of the present invention, a therapeutically effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject from about 20 minutes to about 2 hours from the time of administration of the composition to the subject. In still another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject at about 40 minutes up to about 2 hours from the time of administration of the composition to the subject . And in yet another embodiment of the present invention, a therapeutically effective dose of the proton pump inhibitory agent is achieved in the blood serum of a subject of about 40 minutes to about 1 hour from the time of administration of the composition to the subject. In general, a composition of the present invention is administered at a suitable dose to provide an average serum concentration in the blood of a proton pump inhibitory agent of at least about 1.0 μg / ml in a subject, over a period of about 1 hour after administration. Contemplated compositions of the present invention, provide a therapeutic effect as proton pump inhibitory agent medicaments over a range of about 5 minutes to about 24 hours after administration, allowing if desired, one administration once a day or twice a day. In one embodiment of the present invention, the composition is administered at a suitable dose to provide an average concentration in blood serum of a proton pump inhibitory agent of at least about 1.0 μg / ml in a subject of about 10. minutes, or approximately 20 minutes, or approximately 30 minutes, or approximately 40 minutes after administration of the composition to the subject. In one embodiment of the present invention, the composition is administered in an amount to achieve a serum concentration for measuring the proton pump inhibitory agent greater than about 0.1 μg / L within about 15 minutes after administration after the composition. In another embodiment of the present invention, the composition is administered in an amount to achieve a measurable serum concentration of the proton pump inhibitory agent greater than about 0.1 g / ml within about 30 minutes after administration of the composition. In other embodiments contemplated by the present invention, the composition is administered in an amount to achieve a measurable serum concentration of the proton pump inhibitory agent, greater than about 0.1 μg / ml within about 45 minutes after administration of the composition. In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibitory agent, greater than about 0.1 μg / ml from about 15 minutes to about 6 hours after administration of the composition. In yet another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibitory agent greater than about 0.15 μg / ml from about 15 minutes to about 1.5 hours after administration of the composition. In still another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibitory agent greater than about 0.2 / g / ml within about 15 minutes after administration of the composition. In one embodiment, substantially all doses of the pharmaceutical agent are released from the composition of the present invention in gastric fluid in less than about 120 minutes, or within about 1 minute to about 120 minutes, or between about 2 minutes, or within about 5 minutes, or within about 10 minutes, or within about 20 minutes, or within about 30 minutes, or within about 40 minutes, or within about 80 minutes, or within about 120 minutes. In one embodiment, the pharmaceutical composition comprises an amount of buffering agent, sufficient to increase the pH of the gastric fluid at a target pH, for a period of time. When the gastric fluid is from the stomach of a subject, the period of time is generally sufficient for the pharmaceutical agent to be absorbed into the bloodstream. Illustratively, the pH is from about 3 to about 8, or greater than about 3, or about 3. 5, or about 4, or about 4, 5, or about 5, or about 5, 5, or about 6, or about 6, .5, or about 7, or about 7.5, or about 8. The particular target pH may depend, among other things, on the particular pharmaceutical agent employed in the composition and its labile acid characteristics (e.g., its pKa).

In yet another embodiment, the pH of the gastric fluid is maintained for a period of time that substantially dissolves an enteric coating that covers some or all of the proton pump inhibitor. Illustratively, the time period is approximately less than about 120 minutes, or about 30 seconds to about 120 minutes, or greater than about 1 minute, or greater than about 2 minutes, or greater than about 5 minutes, or greater than about 10 minutes, or greater than about 15 minutes, or greater than about 20 minutes, or greater than about 30 minutes, or greater than about 40 minutes, or greater than about 50 minutes, or greater than about 60 minutes, or greater than about 90 minutes minutes, or greater than approximately 120 minutes. In order to measure and determine the effective amount for disease or gastrointestinal disorder of a proton pump inhibitory agent to be delivered to a subject, concentrations of proton pump inhibitory agent in serum can be measured, using standard assay techniques. The necessary amount of therapeutic agent to produce a therapeutic effect can be determined experimentally based for example on the absorption rate of people in people's serum, the bioavailability of the agent and the amount of proteins that bind the agent. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular patient depend on a variety of factors including the activity of the specific compound employed, age, but body, general health, sex and diet of the patient. subject (including for example if the subject is in a fasted or fed state), the time of administration, the rate of excretion, the combination of drugs and the severity of the particular disorder being treated and the manner of administration. The fed state generally refers to the period of time of initial ingestion of food by a subject through approximately 30 minutes to approximately 4 hours after completing a food. Treatment doses can usually be titrated to optimize safety and efficacy. Typically, dose-effect relationships of in vitro and / or in vivo tests may initially provide useful guidance at doses suitable for administration to the subject. Animal model studies can generally be employed for guidance regarding effective doses for treatment of gastrointestinal disorders or diseases according to the present invention. In terms of treatment protocol, it will be appreciated that the dose to be administered will depend on several factors, including the particular agent being administered, the route administered, the condition of the particular subject, etc. Generally speaking, it would be desirable to administer a quantity of the compound that is effective to achieve a serum level proportional to the concentrations that are effective in vitro for a period of time effective to produce a therapeutic effect. Thus, when a compound is found to demonstrate in vitro activity, for example at 10 ng / ml, it would be desirable to administer the amount of the drug that is effective, to provide at least about a 10 ng / ml concentration in vivo. for a period of time that produces a desired therapeutic effect, for example raising the gastric pH, reducing gastrointestinal bleeding, reducing the need for blood transfusion, improving the survival rate, faster recovery, activation of parietal cells and inhibition or improvement or elimination of symptoms of H +, K + -ATPase, and other indicators as appropriate measures are chosen by those skilled in the art. The determination of these parameters is well within the skill in the art. These considerations are well known in the art and are described in standard textbooks. It will be understood that the amounts of proton pump inhibitory agent and / or buffering agent that are administered to a subject, depends for example on sex, general health, diet and / or body weight of the subject. Illustratively, when the agent is a substituted benzimidazole, such as for example omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, pariprazole, or leminoprazole, and the subject for example is a child or a small animal (e.g., a dog) , a relatively low amount of the agent in the dose range of about 1 mg to about 60 mg, will likely provide blood serum concentrations consistent with therapeutic effectiveness. When the subject is an adult human or a large animal, for example a horse (achieving these serum concentrations of the agent's blood will probably require dose units containing a relatively greater amount of the agent, for example a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 80 mg, 85 mg, 90 mg, 95 mg , 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg for a human adult or a dose of 150 mg, 200 mg, 400 mg, 800 mg, or 1000 mg for an adult horse The solid compositions herein invention are generally in the form of discrete unit doses such as tablets (e.g., a suspension tablet, chewable tablet, coated tablet or effervescent tablet), pills, powders (e.g., a sterile packing powder, powder for dispensing, powder effervescent), capsule (for example a soft or hard gelatin capsule), pellet, wafer, troche, granule or nodule. unit dose typically contain about 1 mg to about 1000 mg of the proton pump inhibiting agent, or about 5 mg to about 240 mg, or about 10 mg to about 160 mg, or about 15 mg to about 120 mg, or about 20 mg to about 8 mg.

Approximately 2 mg, or approximately 5 mg, or approximately 10 mg, or approximately 15 mg. or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 55 mg, or about to 60 mg. or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 85 mg, or about 90 mg, or about 95 mg, or about 100 mg, or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or approximately 200 mg, or approximately 220 mg, or approximately 240 mg of a proton pump inhibitory agent. In one embodiment, the buffering agent is present in compositions of the present invention, in an amount of about 0.05 mEq to about 10.0 mEq per mg of the proton pump inhibitory agent or about 0.1 mEq to about 2.5 mEq per mg of the inhibitory agent of proton pump, or about 0.4 mEq to about 1.0 mEq per mg of the proton pump inhibitory agent. These dose units can be provided at least one, two, three or four times a day, or as many times as required to produce a therapeutic response. A particular unit dosage form can be selected to achieve the desired frequency of administration used to obtain a specified area dose.

Pharmacokinetic and Pharmacodynamic Measures The present invention provides a pharmaceutical composition comprising a proton pump inhibitory agent and a buffering agent for oral administration and ingestion by a subject. In one embodiment, upon administration to a fed subject, the composition contacts the gastric fluid of the stomach and increases the gastric pH of the stomach to a pH that prevents or inhibits acidic degradation of the proton pump inhibitory agent in the gastric fluid of the stomach and allows that a measurable serum concentration of the proton pump inhibitory agent is absorbed into the subject's blood serum, such that the composition exhibits a pharmacokinetic or pharmacodynamic profile component. The present invention also provides a pharmaceutical composition comprising a proton pump inhibitory agent and a buffering agent for oral administration and ingestion by a subject exhibiting bioavailability of increased omeprazole when administered to a fed subject as compared to administration to a subject fasting on the first day of administration, such that the composition exhibits a component of a pharmacokinetic or pharmacodynamic profile. The present invention further provides a pharmaceutical composition that exhibits a decreased bioavailability of omeprazole when administered to a fed human subject as compared to administration to a fasted adult human subject on the seventh consecutive day of daily administration, such that the composition exhibits a component of a pharmacokinetic or pharmacodynamic profile. In one embodiment, the solid pharmaceutical composition of the present invention comprises an amount for gastrointestinal disorder of at least one proton pump inhibitory agent and at least one buffering agent, and upon oral administration to a human subject fed, exhibits at least one component of a pharmacokinetic profile of proton pump inhibitory agent and / or a pharmacodynamic profile of proton pump inhibitory agent. In one embodiment, the pharmacokinetic profile of proton pump inhibitory agent has at least one of (i) a Cmax not less than about 880 ng / ml; (ii) a Tmax not greater than approximately 1.5 hours; (iii) an AUC (0-inf) not less than about 3860 ng x hr / ml; or (iv) a concentration of proton pump inhibitory agent in plasma of about one hour after administration not less than about 750 ng / ml. In yet another embodiment, the pharmacodynamic profile of proton pump inhibitory agent has at least one of (i) an integrated acidity not greater than about 0 mmol x hr / L; (ii) an integrated acidity not greater than about 11.1 mmol x hr / L; (iii) an integrated acidity not greater than about 41.5 mmol x hr / L; or (ii) an increased pH of about 4.0 by at least about 4 hours to about 5 hours after ingestion of a food at about 160 minutes after oral administration. In still another embodiment of the present invention, a pharmaceutical composition comprises omeprazole and sodium bicarbonate, wherein the composition is orally administered to a fed adult human subject, and exhibits a bioavailability of omeprazole AUC (o-inf) at least about 45. % to about 75% greater than the bioavailability of omeprazole exhibited by administering either omeprazole without the sodium bicarbonate to an adult human fasted on the first day of administration of the amount of dose to the fasted subject, or oral administration of a capsule delayed release of enteric coating omeprazole to a fasted adult human subject on the first day of administration of the capsule to the fasted subject. In yet another embodiment of the present invention, a pharmaceutical composition comprises omeprazole and sodium bicarbonate, wherein the composition is orally administered to a fed adult human subject, and exhibits a pharmacokinetic profile of omeprazole having at least one AUC parameter. (0-inf) described and / or Cmax. In one embodiment, AUCo-inf) is at least about 18 percent less than an AUC (0-inf) exhibited by oral administration of omeprazole without sodium bicarbonate to a fasting adult human subject and / or by oral administration of a capsule enteric coating with delayed release of omeprazole to a fasted adult human fascia. In yet another embodiment, Cmax is at least about 45 percent to about 55 percent less than Cmax exhibited by oral administration of omeprazole without sodium bicarbonate to an adult human fasted fasting and / or by oral administration of a release capsule. delayed omeprazole with enteric coating, to a fasted adult human subject. In still another embodiment of the present invention, there is provided a method for preparing an oral dosage form by dry blending at least one proton pump inhibitory agent and at least one buffering agent to form a mixture in the oral dosage form . The dosage form, when administered orally to a fed human subject, exhibits at least one component of a proton pump inhibitory pharmacokinetic profile and / or a pharmacodynamic profile of a proton pump inhibitory agent. In one embodiment, the pharmacokinetic profile of proton pump inhibitory agent has at least one of (i) a Cmax not less than about 880 ng / ml; (ii) a Tntax no greater than about 1.5 hours; (iii) an AUC (o-inf) not less than about 3860 ng x hr / ml; or (iv) a concentration of proton pump inhibitory agent in plasma about one hour after administration, not less than about 750 ng / ml. In yet another embodiment, the phonathamnamic profile of proton pump inhibiting agent has at least one of (i) an integrated acidity not greater than about 0 mmol x hr / L; (ii) an integrated acidity not greater than about 11.1 mmol x hr / L; (iii) an integrated acidity not greater than about 41.5 mmol x hr / L; or (ii) an increased pH above 4.0 by at least about 4 hours to about 5 hours after ingestion of a food at about 160 minutes after oral administration. The pharmacokinetic and pharmacodynamic data can be met by techniques known in the art. Due to the variation inherent in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects, appropriate pharmacokinetic and pharmacodynamic profile components that describe a particular composition may vary. Typically, pharmacokinetic and pharmacodynamic profiles are based on the determination of the "average" parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable to determine a representative average for example, 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The "average" is determined by calculating the average of all the measurements of the subjects for each parameter measured. The pharmacokinetic parameters may be any suitable parameters to describe the present composition. For example, Cmax can be not less than approximately 500 ng / ml; not less than about 550 ng / ml; not less than about 600 ng / ml; not less than about 700 ng / ml; not less than approximately 800 ng / ml; not less than about 880 ng / ml, not less than about 900 ng / ml; not less than approximately 100 ng / ml; not less than about 1250 ng / ml; not less than about 1500 ng / ml, not less than about 1700 ng / ml, or any other suitable Cmax to describe the pharmacokinetic profile of proton pump inhibitory agent. The Tmax may be no greater than about 0.5 hours, no greater than about 1.0 hours, no greater than about 1.5 hours, no greater than about 2.0 hours, no greater than about 2.5 hours, no greater than about 3.0 hours, or any other Tmax. appropriate to describe the pharmacokinetic profile of proton pump inhibitory agent. AUC (0-inf) can be for example not less than about 590 ng x hr / ml, not less than about 1500 ng x hr / ml, not less than about 2000 ng X hr / ml, not less than about 3000 ng X hr / ml, not less than about 3860 ng X hr / ml, not less than about 4000 ng X hr / ml, not less than about 5000 ng / ml, not less than about 6000 ng x hr / ml, not less than about 7000 ng x hr / ml, not less than about 8000 ng x hr / ml, not less than about 9000 ng x hr / ml, or any other AUC (o-inf) to describe the pharmacokinetic profile of proton pump inhibitory agent of the composition of the invention. The concentration of omeprazole in plasma about one hour after administration can be, for example, not less than about 140 ng / ml, not less than about 425 ng / ml, not less than about 550 ng / ml, not less than about 640 ng / ml. ml, not less than about 720 ng / ml, not less than about 750 ng / ml, not less than about 800 ng / ml, not less than about 900 ng / ml, not less than about 1000 ng / ml, not less than about 1200 ng / ml, or any other concentration of proton pump inhibitor in plasma suitable to describe the composition of the invention. The pharmacodynamic parameters can be any suitable parameters to describe the present composition. For example, the pharmacodynamic profile can exhibit an integrated acidity no greater than, for example, about 20 mmol x hr / L, about 30 mmol x hr / L, about 41.5 mmol x hr / L, about 50 mmol x hr / L, about SO mmol x hr / L, or any other integrated acidity appropriate to describe the composition of the invention. The photodynamic profile can exhibit an increased pH above 4.0, for example at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 4 to about 5 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours or more after ingestion of a food. The food can be administered for example at about 75 minutes, about 90 minutes, about 120 minutes, about 160 minutes, about 240 minutes, or at any time after the appropriate oral administration to demonstrate increased pH of about 4.0 with the administration of the present composition. Studies can be conducted to evaluate the bioavailability of compositions of the present invention, using a cross-over, randomized, compensated, open-label, single-dose design. A study, for example, can be done using 12 healthy male and / or female volunteers between the ages of 18 and 35. Blood samples are removed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 , 15 and 25 hours. Except for the "feeding" treatment where subjects receive a standard high-fat breakfast, no food is allowed until a standard lunch is served 4 hours after the dose is administered. The data from each point of time are used to derive pharmacokinetic parameters such as area under the plasma-time concentration curve ("AUC"), including AUC (0-t), AUC (0_nf), average peak plasma concentration (Cmax) and time for average peak plasma concentration (Tmax) - The data can be used to confirm that the composition of the present invention provides the characteristics of appropriate release. The compositions of the present invention can also be evaluated under a variety of dissolution conditions, to determine the effect of medium pH, agitation and apparatuses. For example, dissolution tests can be performed using a USP Type II or III device (Van the Bio-Dis II). Effects of pH, agitation, polarity, enzymes and bile salts can also be evaluated. For brevity, all patents and other references cited herein are incorporated by reference in their entirety. EXAMPLES The present invention is further illustrated by the following examples, which are not to be considered as limiting in any way. The practice of the present invention will employ, unless otherwise indicated, conventional pharmacology and pharmaceutical techniques, which are within the skill in the art. The experimental procedures for generating the data shown are discussed in more detail below. The invention has been described in an illustrative form, and it will be understood that the terminology employed is intended in the nature of description rather than limitation. Example 1; Abbreviations, Standards and Reagent Sources This example describes abbreviations, standards, sources of reagents and various pharmacokinetic and pharmacodynamic parameters described here. SAN-05 / OSB-IR (powder for suspension): Omeprazole (20 mg or 40 mg) with sodium bicarbonate 1680 mg (20mEq), for immediate release, reconstituted to a total volume of 20 mL of water at 1 or 2 mg / mL. SAN-10 / OME-IR (capsule): Omeprazole (20 mg or 40 mg) with an antacid complex for immediate release. Antacid complexes include: sodium bicarbonate alone; sodium bicarbonate with magnesium hydroxide; and sodium bicarbonate with calcium carbonate. SAN-15 / OME-IR (chewable tablet): Omeprazole (20 mg or 40 mg) with an antacid complex for immediate release. Antacid complexes include: sodium bicarbonate alone; sodium bicarbonate with magnesium hydroxide; and sodium bicarbonate with calcium carbonate. OME-DR (enteric coating): Omeprazole (20 mg or 40 mg) with enteric coating for delayed release.

Pharmacokinetic parameters described here include: (1) parameters that are obtained directly from the data without interpolation, including concentration of omeprazole in plasma, peak concentration of omeprazole in plasma (Cmax), and time to peak concentration of ometrazole in plasma (Tmax); (2) terminal elimination rate (kei) constant, determined from a log-linear regression analysis of plasma omeprazole terminal concentrations; (3) terminal elimination half-life (ta / 2) calculated as 0.693 / kei; (4) area under the omeprazole concentration curve in plasma-time, from time zero to time "t" (AUC0-t), calculated using the trapezoidal rule with the plasma concentration at time "t" which is the last concentration measure; (5) area under the omeprazole concentration curve in plasma-time, from time zero to infinite time (AUC0-iuf) calculated as AUC0-t + Ct / ei, where C is the last measured plasma concentration and kei is the rate constant or terminal elimination rate defined above. Pharmacodynamic parameters described herein include: (1) average concentration of gastric acid; (2) time of onset of gastric pH increase; (3) gastric pH over time; (4) Time duration of gastric pH is > 4; (5) percent (%) of gastric pH time is pH time > 4 (in Figures as "percent of pH time> 4"); (6) Medium gastric pH; and (7) integrated gastric acidity, which is expressed as mM acid x time, (m moles of acid x hr / L) is calculated as the cumulative time-weighted average of the average concentration of gastric acid, as follows: Concentration of acid (mM) - 1000 x 10-pH Acidity (mmol.hr/L) = (acid in mM at time "t" + acid in mM at time "tl") / 2 x (t - t-1) Values for acidity add up cumulatively. Definitions used for convenience: (1) onset of action, the time earlier than the value with active treatment was significantly different from the corresponding baseline; (2) duration of action, the later time when the value with active treatment was significantly different from the corresponding baseline; (3) a magnitude of the effect, maximum value of a given post-dose interval. Standardized breakfast foods: two large eggs, two strips of bacon, two slices of white / toasted bread, 10 grams of butter, 113.4 g (4 ounces) of grated "hash brown" potatoes, one cup of whole milk, and 177.4 ml ( 6 fluid ounces) of cold orange juice. Lunch of high standardized fat content: 240 grams of potatoes (fried potatoes), thin cut, frozen, fried in a mixture of oils, 225 grams of cod, breaded, fried in a mixture of oils; 70 grams of peas or pea, frozen, boiled in salted water; 120 grams of custard made with whole milk; 110 grams of sponge pudding, with ham; and 200 ml of whole milk. Reagents Chewable antacid tablets (Murty Pharmaceuticals, Inc., Lexington, KY) containing 1260 mg of NaHCO 3 and 750 mg of CaCO 3, as well as common excipients. Omeprazole bulk USP grade was obtained from commercial sources. In some experiments, omeprazole powder was mixed with powdered pepper flavor and Equal141 'sweetener prior to administration. Prilosec ° capsules containing enteric coated omeprazole granules (40 mg) and Nexium1"1 capsules containing enteric coated esomeprazole granules (40 mg) marketed by MR AstraZeneca Abbreviations Acitrel °: 20 mg omeprazole powder suspension, formulation OSB-IR AE: Adverse event ALT: (SGPT) Alanine aminotransferase AST: (SGOT) Aspartate aminotransferase AUCÍo-inf): Area under the drug concentration curve in plasma calculated from time 0 extrapolated to infinity AUC (ot ): Area under the plasma drug concentration curve calculated from time 0 to last time evaluated BUN: Blood urea nitrogen Cma: Maximum plasma concentration of the measured drug Ct: Concentration of plasma in a given time H2: H2 receptor histamine Kei: Constant elimination rate LC-MS: Liquid chromatography mass spectroscopy NaHC03: Sodium bicarbonate OSB-IR PWD F / S: Sodium bicarbonate Omeprazole, immediate release powder for PK suspension: Pharmacokinetics PPI: Proton pump inhibitor qAM: Every morning Rapinex®: Chewable tablet formulation SAN-15 SAS: Program for SOS statistical analysis: Solution / suspension of simplified omeprazole Tmax: Time in which Cmax T¾ is observed: Average life of drug elimination Earmacokinetic and pharmacodynamic measures Blood samples (10 mL) taken in 30 minutes prior at the dose and up to 12 hours after the dose; for example, after the dose at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 minutes, and up to 12 hours in some studies. Baseline gastric pH data were collected from each subject in a supervisory visit prior to the trial periods. Baseline data were collected using a single ambulatory disposable catheter and pH recording system. The electrode was calibrated at 37 ° using standard polyelectrolyte solutions at pH 1.07 and pH 7.01. The location of the lower esophageal sphincter (LES = lower esophageal sphincter) of the subject was located manometrically and the distance from the lower edge of the nostrils or nostrils to the upper edge of the SLE was recorded. Example 2: Test Protocols This example describes several test protocols used to obtain results described here. Test Protocol SAN-15 - C01 This test protocol is designed as a single-dose crossover study, wherein each subject receives one or two chewable pH tablets administered concomitantly with omeprazole powder during each treatment period, for up to six treatment periods. Each period was followed by a drag of 7 to 14 days. The same treatment was administered to all subjects in each testing period. Period 1: one (1) antacid tablet (1: 3 formulation) plus 40 mg of omeprazole powder administered in a fasted state. Period 2: 20 mEq of sodium bicarbonate plus 40 mg of omeprazole powder as an aqueous suspension administered in the fasted state. Period 3: Prinosec, 40 mg delayed-release capsule, administered in fasting state. Period 4: one (1) antacid tablet (formulation 1: 3) plus 40 mg of omeprazole powder administered one hour after starting a food. Period 5: one (1) antacid tablet (1: 1 formulation) plus 40 mg of omeprazole powder administered in a fasted state.

Period 6; two (2) antacid tablets (formulation 1: 1) plus 40 mg of omeprazole powder, administered one hour after starting a food. For periods that include administration of omeprazole plus tablet powder, the subject received omeprazole powder administered directly in the dorsal mid-part. Immediately afterwards, the subjects were given a chewable antacid tablet, which they began to chew. The subject continues to chew the tablet while chewing it with the omeprazole powder and carefully avoided swallowing immediately. One minute after starting the chewing (and after completely swallowing the test drugs) each subject drank 120 ml of water, clicking the oral contents, before swallowing. The gastric pH was continuously monitored for up to 6 hours after each determined treatment dose, and blood samples were obtained for determination of omeprazole concentrations in plasma, on the days of control and active treatment. Pharmacodynamic evaluations may include measures of gastric acidity integrated by average pH; and percent of pH time > 3, percent pH time > 4, and percent of pH time > 5. Pharmacokinetic evaluations include concentration of omeprazole in plasma at each time of sampling; and plasma omeprazole Cmax, Tmax, kel, AUC (0-t) and AUC (0_inf). This test estimated the pharmacokinetics and gastric acidity of omeprazole / antacid as an immediate release formulation of omeprazole. Test protocol SAN-15 - C01 This test protocol is designed as a cross-over study in a single dose, where each subject received an oral antacid formulation with an omeprazole / antacid formulation, omeprazole alone or Prilosec powder in each period, for 6 treatment periods. Each period was followed by a wash of 7 to 21 days. The same treatment was administered to all subjects in each trial period: Period 1: one antacid tablet (30 mEq of a 1: 1 formulation of sodium bicarbonate and calcium carbonate) plus 40 mg of omeprazole powder, administered one hour before ingestion of standardized breakfast. Period 2: one antacid tablet (30 mEq of a 1: 1 formulation of sodium bicarbonate and calcium carbonate) plus 40 mg of omeprazole powder, administered for 30 minutes before standardized breakfast ingestion. Period 3: one antacid tablet (30 mEq of a 1: 1 formulation of sodium bicarbonate and calcium carbonate) plus 40 mg of omeprazole powder, administered for 3 hours before standardized breakfast ingestion. Period 4; a Nexium ™ tablet (40 mg esomeprazole) given for 30 minutes before ingesting a standard breakfast. Period 5: one antacid tablet (30 mEq of a 1: 1 formulation of sodium bicarbonate and calcium carbonate) plus 60 mg of omeprazole powder, administered for 4 hours after the start of ingestion of a standard breakfast. Period 6: a 40 mg capsule of Prilosec "11 administered 30 minutes before ingestion of a standard breakfast." For periods that included administration of omeprazole plus tablet powder, the subject received the omeprazole powder administered directly in the dorsal midsection Immediately afterwards, the subjects were given a chewable antacid tablet, which they began to chew.The subject began to chew the tablet while mixing it with the omeprazole powder and carefully avoiding swallowing the powder immediately. Minute after starting chewing (and after completely swallowing the test drugs) each subject drank 120 ml of water, clicking the oral contents before swallowing.For periods requiring a feed, subjects who fasted for at least 10 hours during night, and they were allowed water ad libitum until two hours before administration.The standardized breakfast was ingested in 30 minutes. period 1, they were also given 120 ml of water one hour before the start of food ingestion. For period 2, 120 ml of water were also given half an hour before eating the food. For six hours after each dose of a finished treatment, the gastric pH was monitored and blood samples were obtained to determine the plasma omeprazole concentration. Pharmacodynamic evaluations may include measurements of gastric pH over time; start time of gastric pH increase; and the extension and duration of pH increase (over pH 3 or 4). Pharmacokinetic evaluations include concentration of omeprazole in plasma at each time of sampling; and Cmax, Tmax, kei, AUC (o-t) and AUC (o-inf) of omeprazole in plasma. SAN-15 is an omeprazole chewable antacid tablet that provides faster pH control and relief of gastric symptoms than currently commercially available proton pump inhibitors. In this formulation, omeprazole is protected by a mixture of antacids, thus limiting the exposure of omeprazole to gastric acid. Cmax is higher and occurs before the first dose than after the first dose of Prilosec. This allows the omeprazole and antacid formulation to be administered in close proximity to foods that often induce or are associated with symptoms related to gastric acid. This trial estimated pharmacokinetics and gastric acidity under these conditions, indicating that the combination of omeprazole plus antacid may be useful for treating food-induced or food-associated heart attacks. Test Protocol SAN-15-C01C This test protocol is designed as a single-dose crossover study; each healthy volunteer subject received an oral antacid formulation with omeprazole; omeprazole powder alone; Prilosec capsule (US formulation) and Nexium capsule (US formulation) in each period. Each dose was followed by a 7 to 14 day wash. The same treatment was administered to all subjects in each trial period. Period 1: A single oral dose of 80 mg of omeprazole powder administered with a chewable antacid tablet (1260 mg of NaHCO3 and 750 mg of CaCO3) administered 90 minutes before a standardized breakfast. Period 2: A single 40 mg oral dose of omeprazole powder administered on an empty stomach. Period 3: A single oral dose of 40 mg of omeprazole powder administered with a chewable antacid tablet (1260 mg of NaHCO3 and 750 mg of CaCO3) administered 90 minutes after a standardized breakfast. Period: A single 40 mg oral dose of a Nexium ™ capsule (esomeprazole, US formulation) administered 90 minutes after a standardized breakfast. Period 5: A simple oral dose of 40 mg of omeprazole powder administered 90 minutes after a standardized breakfast. Period 6: A single oral dose of 120 mg of omeprazole powder administered with a chewable tablet (1260 mg of NaHCO3 and 750 mg of CaCO3) administered 90 minutes after a standardized breakfast. For periods that include administration of omeprazole powder plus tablet, the subject received the omeprazole powder administered directly to the dorsal part of the tongue. Immediately afterwards, the subjects were given a chewable antacid tablet, which they began to chew. The subject continues to chew the tablet while mixing it with the omeprazole powder, and carefully avoids swallowing the powder immediately. One minute after starting the chewing (and after completely swallowing the test drugs) each subject drank 120 ml of water, clicking the oral contents before swallowing. For periods requiring a feed, subjects who fasted for at least 10 hours, and were allowed water ad limitum up to two hours before administration. Supervision of gastric pH was recorded for up to 11 hours starting at time 0. In standardized breakfasts, it was ingested in 30 minutes starting at 90 minutes after the beginning of pH monitoring. For periods that include doses after food, subjects fasted for at least 10 hours. On day 0, 90 minutes of monitoring with a pH probe, was initiated before starting the ingestion of the standardized breakfast, which was ingested in 30 minutes. The pH monitoring continues for 9.5 hours after starting the breakfast ingestion. For periods 1 and 2, a subsequent period, 120 mL of water was only administered 90 minutes after starting the standard breakfast ingestion.

On day 1, after fasting during the night for at least 10 hours, 90 minutes of monitoring with a pH probe is initiated before starting the ingestion of the standardized breakfast, which was ingested in 30 minutes. The pH monitoring continued for 9.5 hours after starting the breakfast ingestion. The test medications were administered 90 minutes after starting the standardized breakfast ingestion. Pharmacokinetic evaluations include concentrations of omeprazole and esomeprazole in plasma over time; and Cmax, Tmax, kei, T1 / 2, AUC (0-t), AUC (0-inf) d omeprazole and esomeprazole in plasma. Pharmacodynamic evaluation may include the time of onset of gastric pH increase, gastric pH over time and percent of time pH > . Cmax of omeprazole is higher and occurs before or after the first dose with antacid than after the first dose of Prilosec or Wexium. The omeprazole / antacid formulations can be administered in close proximity to foods that are often associated with acid-related symptoms, thereby treating for example food-associated or food-induced acesias. The SA-15-C01C test estimates pharmacokinetics and gastric pH under these conditions. Test SAN-15-C01D This test is a single-dose, open-label, cross-test, and each subject received up to ten different oral formulations of omeprazole, one in each of ten treatment periods. It was followed by at least 7 days of washing. Omeprazole (40 mg) was administered with up to 1680 mg of sodium bicarbonate and / or up to 600 mg of magnesium hydroxide and / or up to 750 mg of calcium carbonate. Formulations of SA-15 (Patheon Pharmaceuticals Inc., Cincinnati, Ohio) contain 40 mEq of one or more antacids plus 40 mg of omeprazole (with or without incorporation in a chewable tablet), and capsules of SA-10 (Pharm. ., Phillipsburg, New Jersey) contain = 40 mEq of one or more antacids and 40 mg of omeprazole. All formulations were administered with 120 mL of water after an overnight fast and 1 hour before a standardized high-fat breakfast. Within a period of completion treatment, the same treatment was administered to all subjects. Omeprazole was supplied either as Prilosec or as an immediate release formulation (without enteric coating). It was formulated as uncoated granules or microencapsulated in a loose powder, as powder in a capsule, in a chewable tablet, or in a swallow tablet. The antacid was administered concomitantly as antacid tablets or the omeprazole and antacid were combined in a tablet or capsule. Pharmacokinetic evaluations were as previously described. When omeprazole powder plus the tablet was administered, the subject received omeprazole powder administered directly to the dorsal mid-part of the tongue. Immediately afterwards, the subjects were given a chewable antacid tablet that they began to chew. The subjects continued to chew the tablet while mixing it with the omeprazole powder, carefully avoiding swallowing the powder immediately. One minute after starting the chewing (and after completely swallowing the test drugs), each subject drank 120 mL of water, clicking the oral contents before swallowing. Administering omeprazole plus antacid formulations in close proximity with foods that are often associated with acid-related symptoms may be useful for treatment, eg, of food-induced heartburn. Test Protocols OSB-IR-C02 and OSB-IR-C06 Both tests are randomized cross-tests, where each healthy subject received seven consecutive daily doses of either Prilosec1 ™ 40 mg or OSB-IR 40 mg (0SB-IR-C02). ) or Prilosec ™ 20 mg or OSB-IR 20 mg (OSB-IR-C06) administered qAM one hour before starting the ingestion of a standardized breakfast: for Period 1; an eighth dose of OSB-IR (20 or 40 mg) was administered at the end of a standardized food on day 8 for those subjects who received OSB-IR in Period 1. A 10-14 day wash occurred before the beginning of Period 2 The alternate dose form was then administered once daily for seven days (Period 2). Period 1: 40 mg or 20 mg of omeprazole (OSB-IR-C02 or OSB-IR-COS, respectively) either as OSB-IR or Prilosec administered by seven consecutive single daily doses, fasting; (plus Dosage 8 with food only for subjects who received OSB-IR). Pharmacokinetics of twelve (12) hours and pH of 24 hours supervised after Doses 1 and 7; 12-hr PK supervised after Dosage 8. Period 2: 40 mg or 20 mg of omeprazole (the formulation alternates to that used in Period 1) (OSB-IR-C02 or 0SB-IR-C06, respectively) for seven consecutive single daily doses; fast. Pharmacokinetics of twelve (12) hours and pH of 24 hours supervised after Doses 1 and 7. For both tests 0SB-IR-C02 and 0SB-IR-C06, gastric pH in baseline was recorded before dosing on Day 1 Periods 1 and 2. For 24 hours after each dose of a given treatment on Days 1 (Dose 1) and 7 (Dose 7) in each period, the gastric pH was monitored and blood samples were obtained for plasma omeprazole determination . Doses 2 to 6 were administered after an overnight fast with water ad libitum. One hour postdose, the subjects were allowed to consume food and non-alcoholic beverages ad libitum. Subjects who received OSB-IR in Period 1 only continued on Dose 8 of OSB-IR on Day 8, administered after the 24 hour monitoring period after Dose 7 and upon completion of a standardized breakfast. After the washout period, the procedures set forth above for Period 1 (except without Dose 8) were repeated for the alternate dose form (Period 2). For the 0SB-IR-C06 test, subjects receiving OSB-IR in Period 2 only continue for Dosage 8 of OSB-IR on Day 8 administered after completing the monitoring period 24 hours after Dose 7 and one hour before starting a standardized breakfast on Day 8. These subjects consumed standardized foods at 1300 and 1800 hours after Dosage 8 and did not consume any additional food on Day 8. At 2200 hours, subjects took another dose of OSB- IR 20 mg (Dosage 9). These subjects were monitored for pH 24 hours after Dosage 8, continuously. Pharmacokinetic evaluations may include concentration of omeprazole in plasma over time; and Ti / 2, AUC (o-t) / and AUC (o-inf) of omeprazole in plasma. Pharmacodynamic evaluation may include integrated gastric acidity, average acid concentration, gastric pH time > 4, gastric pH time < 4 and average gastric pH. OSB-IR allows delivery of omeprazole as a suspension, where omeprazole is protected from gastric acid by the sodium bicarbonate contained in the formulation. A liquid form of omeprazole towards the drug available to patients for whom the solid dose form is unsatisfactory, for example the very young, the elderly, the neurologically affected and those with nasogastric tubes (NG). The bioavailability (AUC) and pharmacodynamics (suppression of gastric acid) of OSB-IR and Prilosec were estimated and found to be equivalent in stable state. These tests also determined the effect of food on OSB-IR pharmacokinetics. This test of 0SB-IR-C06 further revealed that the formulation of omeprazole plus antacid administered before sleep is useful to reduce nighttime gastric acidity and therefore potentially to heartburn. OSB-IR-C05 This test is designed as a single period, with an open label. Two doses of 40 mg immediate release suspension of omeprazole sodium bicarbonate (OSB-IR) were administered to healthy subjects under fasting conditions on the first Day of therapy, with an interval between doses of six hours. Blood samples were collected over a total of 18 hours. Omeprazole supplied as the liquid dosage form (OSB-IR suspended in water before administration) was protected against gastric acids by sodium bicarbonate contained in the formulation. OSB0-IR-CO3 Test This was a comparison of an immediate-release oral suspension of Omeprazole plus sodium bicarbonate with intravenous cimetidine to prevent upper gastrointestinal bleeding in critically ill patients. The OSB-IR suspension (40 mg of omeprazole plus 1680 mg of sodium bicarbonate) was administered to half of the patients and cimetidine was administered (bolus of 300 mg, followed by 50 mg / hr) to the other half. Gastric aspirates were estimated by bleeding and pH. Clinically significant bleeding was bright red blood for 5-10 minutes, Days 1-14, or ground coffee positive Gastroccult material for 8 consecutive hours on Days 1-2, or 2-4 hours, Days 3-14 (after start enteral feeding). 359 critically ill patients were treated. Administering omeprazole plus antacid formulations to patients who have upper GI bleeding or at risk of developing upper GI bleeding (IGU) may be useful to prevent bleeding, as well as to reduce or avoid associated complications (eg death).

Example 3; Omeprazole absorbs well and absorbs quickly in the presence of antacid This example describes results indicating that omeprazole is well absorbed in the presence of antacid, and that a single oral dose of omeprazole-antacid complex is rapidly absorbed (see Example 8 for the effects of the omeprazole antacid complex on gastric acidity). To compare the pharmacokinetic characteristics of immediate release of omeprazole plus antacid to omeprazole alone, studies were performed as described in test protocol 0SB-IR-C01C. The pharmacokinetic profiles of omeprazole powder plus chewable antacid tablets, omeprazole powder alone, Prilosec ™ 5 capsules (omeprazole), and Nexium ™ capsules (esomeprazole magnesium) in the context of different dosing regimens with respect to food intake, were performed as described in the test protocol SAN-15-C01C. These results of the SAN-15-C01C test are summarized in Table 3.A). Table 3.A.

Powder Pharmacokinetics of Omeprazole (40 mg) Administered With or Without Antacid (Pre-food) Number of Cmax ng / mL AUC (o-t) ng Subjects (Medium) x hr / mL (Medium) Control 10 - - Powder Omeprazole 10 186.4 225 Administered 1 hour Pre-food Omeprazole Powder Plus 10 911.5 965.7 Number of Cmax ng / mL AUC (o-t) ng Substitutes (Medium) x hr / mL (Medium) mEq of Antacid Administered 1 hour P e-food AUC (o-inf) media for omeprazole immediate release of omeprazole antacid complex, 966 ng. hr / mL, was significantly higher (P = 0.0355) than omeprazole alone, AUC (o-inf) 225 ng. hr / mL. These results indicate that omeprazole without concomitant antacid is weakly absorbed (low bioavailability). The pharmacokinetic results of the study illustrated in Figure 10 indicate that when administered to fasted subjects, the omeprazole powder with antacid (either as a suspension or as a chewable antacid tablet) is absorbed more rapidly than omeprazole supplied as Prilosec101 release delayed (enteric coating). Figure 11 indicates that a single pre-food dose of 40 mg of omeprazole powder plus 30 mEq of antacid delivered 30 minutes before a food is absorbed more rapidly than Nexium "11 40 mg delivered 30 minutes before a meal.

Example 4; Omeprazole plus antacid formulation has faster absorption and comparable bioavailability than the delayed-release omeprazole formulation This example describes results indicating that the antacid omeprazole complex has a faster absorption and comparable bioavailability than the delayed release omeprazole formulation. To compare the immediate release composition of the omeprazole antacid complex with enteric coating granules of omeprazole relative to PK and gastric pH, a cross-over test was performed on 10 fasted subjects receiving a single 40 mg capsule of enteric coating granules of omeprazole (delayed release of omeprazole), and 7 received 40 mg of omeprazole powder plus a chewable tablet of 1260 mg of aHC03 and 750 mg of CaC03 (immediate-complex release or to omeprazole antacid). Plasma concentration of omeprazole was measured during a 6-hour post-dose period (Figure 1) and the gastric pH was measured 1 hour before and 6 hours after the dose. Absorption of omeprazole from OAC-IR was faster (T (max) 25 min; C (raax) 1019 ng / mL) than from the delayed release formulation of omeprazole (T (niaX) 127 min; C (max) 544 ng / mL). The bioavailability of the antacid complex omeprazole-immediate release (AUC (0-inf) 1120 ng x hr / mL) and OME-D (AUC (0-inf) 1170 ng x hr / mL) were similar (P = 0.96). Integrated gastric acidity during the 6-hour post-dose period was 43% less with the immediate-release omeprazole antacid complex than with the delayed release omeprazole (P = .071, median for all subjects). When compared with a commercial formulation of omeprazole delayed release, the immediate release omeprazole antacid complex has a more rapid absorption, with similar pharmacodynamic effect. The immediate release antacid omeprazole complex will be effective in relieving existing and recurrent, with the antacid that produces immediate relief and omeprazole that prevents the recurrence, severity or duration of subsequent episodes. Example 5; Bioavailability of Omeprazole plus sodium bicarbonate compared to Prilosec "1 This example describes studies that indicate that omeprazole / sodium bicarbonate and Prilosec ^ are bioequivalent after one Day and after 7 Days of administration as established by the requirements of the FDA.

To compare the pharmacokinetic and pharmacodynamic characteristics of omeprazole / immediate release antacid with enteric coating omeprazole, studies were performed as described in the 0SB-IR-C02 and 0SB-IR-C06 tests with omeprazole (40 mg or 20 mg, respectively ) plus 1680 mg of sodium bicarbonate administered as an aqueous suspension. Pharmacokinetic parameters can include AUC (0-inf) for the first and seventh doses of each omeprazole formulation, Cmax for the first and seventh doses of each omeprazole formulation and Tmax, Kel, / / 2, AUC (0-t) for the first and seventh doses of each omeprazole formulation. The results of omeprazole pharmacokinetic parameters between administration of omeprazole plus pre-food sodium bicarbonate and administration of Prilosec® pre-food are summarized in Tables 5.A., 5.B. and 5.C. Table 5.A.

Concentration of Omeprazole in Plasma Omeprazole / Sodium Bicarbonate 40 mg against Prilosec "40 mg (Day 1) Omeprazole / BicarbonaPrilosec ^ 40 mg 90%% Sodium 40 mg (Fast) Cl Pro (Fast) Average portion ParameN Average SD N Average SD tros ArithmeticArritimetic C-max 32 1412 616.2 32 1040 579.1 - - (ng / mL) Tmax (hr) 32 0.44 0.19 32 2.34 2.40 - - AUC (ot) 32 2180 2254 32 2460 2546 (ng x hr / mL) AUC (o-inf) 32 2228 2379 31 2658 2888 (ng x hr / mL) T1 / 2 (hr) 32 1.00 0.63 31 1.21 0.73 - - the 32 0.89 0.38 31 0.73 0.30 - - (1 / hr) ) ln (Cmax) 32 7.15 0.47 32 6.74 0.74 124.0- 151.1 184.1 After one dose, 40 mg of omeprazole plus 1680 mg of sodium bicarbonate and Prilosec (40 mg) were bioeguivalent with respect to AUC (Table 1). The average ratio for omeprazole plus sodium bicarbonate to Prilosec ™ was 87.9% for AUC (0-inf) with the limits of 90% CI within 80% and 125% compared to Prilosec® 111. Graph of average concentrations of omeprazole in plasma versus time for day 1, is illustrated in Figure 2.

Table 5.B.

Concentration of Omeprazole in Plasma Omeprazole / Sodium Bicarbonate 40 mg against Prilosec 40 mg (Day 7) Omeprazole / Bicarb - Prilosec ^ 40 mg 90% Cl% Sodium Pronate 40 mg (Fast) by (Fast) Average ParameN PromeSD N PromeSD tros gave ArithmeticArhythmics C-max 31 1954 654.0 31 1677 645.5 - - (ng / mL) Ima 31 0.58 0.23 31 1.77 0.90 - - (hr) AUC (ot) 31 4555 2586 31 4506 2522 (ng) x hr / mL) AUC (0-31 4640 2741 31 4591 2640 inf) (ng X | hr / mL) Table 5. C.

Concentration of Omeprazole in Plasma Omeprazole / Sodium Bicarbonate 20 mg against Prilosec1® 20 mg (Day 7) Omeprazole / Bicarbo- Prilosec "40 mg 90%% Sodium Nation 40 mg (Fast) Cl Pro (Fast) Average ParameN PromeSD N PromeSDs gave Arithmetic Arithmetic 31 902 31 573 - - (ng / mL) AUC (o-inf) 31 1446 31 1351 (ng x hr / mL) ln (Cmax) 142 157 174 Ln [AÜC (0- 100 107 inf)] 114 The extreme point of primary bioequivalence was AUC (o-inf) at steady state (Dia 7). The 40 mg of omeprazole plus 1680 mg of sodium bicarbonate and the 40 mg of Prilosec1511 administered once a day in the morning were bioequivalent (Table 2a). The average AUC (0-inf) · proportion was 101.9% with a 90% confidence interval (CI) of 95.3% to 109.0%. Cmax for the solution of omeprazole plus sodium bicarbonate in stable state was slightly higher than for Prilosec ^ with an average ratio of 119.5% and 90% CI from 107.2% to 133.2%. Average concentrations of plasma omeprazole versus time for Day 7 are illustrated in Figure 3. The average Tmax for Prilosec101 tends to decrease over time (2.34 hours for Day 1 versus 1.77 hours for Day 7). The average Tmax for omeprazole plus sodium bicarbonate does not change significantly with time (0.44 hour for Day 1 versus 0.58 hour for Day 7). The average half-life values were similar for omeprazole plus sodium bicarbonate and Prilosec "11 (1.0 hour and 1.2 hours, respectively) for Day 1. Example 6: Omeprazole plus sodium bicarbonate is pharmacodynamically equivalent to Prilosec ^.

This example describes results indicating that omeprazole plus sodium bicarbonate and Prilosec1 were pharmacodynamically equivalent to 24-hour suppression in the steady state of integrated gastric acidity.

Studies also indicate that omeprazole plus sodium bicarbonate and Prilosec "11 are equally effective in suppressing gastric acid production, but that the omeprazole plus sodium bicarbonate formulation provides a rapid increase in gastric pH compared to Prilosec®. performed the studies as described in the test protocols 0SB-IR-C02 and 0SB-IR-C06 After the drug was administered, the gastric pH levels were measured for 24 hours after the administration of the study treatment. subjects on Days 1 and 7. The primary analysis focused on Day 7 dosing, since the pharmacodynamic effects are maximal by the seventh day of daily consecutive dosing (stable state) The pharmacodynamic profiles of both omeprazole plus sodium bicarbonate As Prilosec1411 were estimated as previously described, integrated gastric acidity was selected as the primary pharmacodynamic parameter. Aryo for bioequivalence, because it is equally sensitive to change over the entire range of values obtained. In contrast, mean gastric pH and gastric pH time was < 4 have lower sensitivity to detect drug-induced change of the baseline in gastric acidity.

Differences in pharmacodynamic effects measured by integrated gastric acidity and gastric pH time 4 were estimated using an ANOVA model. Pharmacodynamic equivalence with respect to these parameters was stated if the upper and lower limits of the 90% confidence intervals for the ratio of omeprazole plus sodium bicarbonate to Prilosec "11 were within 80% to 125%." Pharmacodynamic data for administration of omeprazole plus sodium bicarbonate pre-food and administration of Prilosec "11 pre-food are summarized in Table 6.A. Table 6.A.

Evaluation of Pharmacodynamic Equivalence Between Omeprazole plus Sodium Bicarbonate and Prilosec (ANOVA) Decrease 40 mg Prilosec ^ (40 90% CI% Omeprazole plus mg) Rate Percentage 1680 mg of Prode Line Bicarbonate of Me¬ Base in Sodium gave Acidity N PromeSD N GASTRIC PROMISE gave Integrated ArithmeticArm 24 24 Hours a day 1 24 62.34 34.8 24 61.79 39. 85.56- 99.3 Decrease40 mg Pr losec "(40 90% CI Omeprazole plus mg) Rate Percentage 1680 mg of Prode Line Bicarbonate of Me¬ Base in Sodium gave Acidity N PromeSD N GASTRIC PROMISE gave Integrated ArithmArhythmics 24 Hours attic 4 22 115.38 6 Day 7 24 83.33 17.0 24 85.11 19. 87.35- 101. 7 74 118.49 74 Omeprazole plus sodium bicarbonate was pharmacodynamically equivalent to Prilosec ™ in steady state (Day 7) with respect to the percentage decrease in baseline in integrated gastric acidity (Table 3). The 90% CIs borders were between 80% and 125%. As illustrated in Table 6.B., Day 1, omeprazole plus sodium bicarbonate and Prilosec1411 decreased the integrated gastric acidity by 70% and 76%, respectively. With increased bioavailability of omeprazole on Day 7, the corresponding decrements were 84% and 93%. The average of the rates per subject (omeprazole plus sodium bicarbonate / Prilosec1'111) of the decrease in the baseline of integrated gastric acidity was 100%. Table 6.B.

Gastric acidity integrated with Omeprazole plus Sodium Bicarbonate and Prilosec1 Integrated Gastric Acid Omeprazole plus (mmol x hr / L) Bicarbonate Evaluates40 mg Prilosec * 6 (40 Sodium / Prilosec1 ization omeprazole plus mg) (%) Median of 1680 mg of Fees for Sodium Bicarbonate Line 2194 2061 -Base (1421-2943) (1358-2763) Day 1 557 538 - (202-1218) (169-1262) Day 7 319 145 - (26-512) (21-558) Percent of Baseline Decrease to: Day 1 70 76 98 (52-89) (46-90) (83-104) Day 7 84 93 100 (74-99) (74-99) (91-105) As illustrated by wide interquartile intervals both at baseline and after treatment with omeprazole plus sodium bicarbonate and Priloseclt®, there was substantial inter-subject variation in integrated gastric acidity. This degree of variation is characteristic of gastric acid secretion before and after treatment. AUC (o-inf) and percent decrease in baseline in integrated gastric acidity for omeprazole plus sodium bicarbonate, bioequivalent to Prilosec "11 on Days 1 and 7, indicate that the two treatments were not bioequivalent with respect to Cmax, with the upper border of the confidence interval around the average rate slightly above the upper boundary defined for steady-state bioequivalence.The difference in Cmax had no apparent effect on the pharmacodynamics of the omeprazole plus sodium bicarbonate solution During the baseline period , integrated gastric acidity increased at a lower rate, when food was consumed (hours 0 to 12) than during fasting (hours 13 to 24.) Figure 4a illustrates the effect of 40 mg of omeprazole plus 1680 mg of sodium bicarbonate, Days 1 and 7 after 3 foods that are provided during hours 0 to 12. Figure 4 also illustrates that on both Days 1 and 7, the time course setting for acidity Integrated gastric with omeprazole plus sodium bicarbonate, was similar to that with Prilosec ™ * (Figure 4b). In particular, both treatments decreased gastric acidity close to zero during the initial 15 hours of the recording or 24-hour recording period. The values for average gastric acid concentrations are equivalent to 24-hour integrated gastric acidity divided by 24 and are shown in Table 6.C. Table 6.C.

Concentration of Average Gastric Acid with Omeprazole plus Sodium Bicarbonate and Pril Average Gastric Acid Concentration Evaluation (TIIM) 40 mg omeprazole plus Prilosec "(40 1680 mg bicarbonate mg) sodium Baseline 92 (59-123) 86 (57-115) Day 1 24 (9-51) 23 (8-53) Day 7 13 (1-22) 6 (1-24) Figure 5 illustrates the phase changes in baseline on Days 1 and 7 of gastric acid concentration , which are produced by ingestion of food. At hours 1, 5, and 10, the concentration of acid in the baseline decreased because the food neutralized the gastric acid. This decrease was then followed by an increase in gastric acid concentration produced in part by the secretion of gastric acid stimulated by food. At hour 16, there was a characteristic increase, but without explanation, in the concentration of acid in the baseline. On Days 1 and 7, omeprazole plus sodium bicarbonate and Prilosec1 decreased the gastric acid concentration close to zero during the daytime period from hours 0 to 14 (Figure 5). With each treatment, however, there was a nocturnal increase in acid concentration from hours 14 to 19 and the magnitude of this increase was lower on Day 7 than on Day 1. Median gastric pH is illustrated in Table 6.D. Table 6.D.

Average Gastric pH with Omeprazole plus Sodium Bicarbonate and Prilosecm Average Gastric pH (Intervals) Interquartile Evaluation) 40 mg omeprazole plus Prilosec "(40 mg) 1680 mg sodium bicarbonate Baseline 1.10 1.16 (0.96-1.42) (1.01-1.51) Day 1 3.86 4.33 (2.20-5.39) (2.81-5.21) Day 7 5.20 5.20 (4.14-5.49) (4.84-5.59) Table 6.D. illustrates that a substantial increase in baseline gastric pH occurred on Days 1 and 7 for both treatments. For both treatments, an increase in baseline greater than 3 pH units was observed on Day 7, which represents an average decrease in gastric acid concentration greater than 99.9%. Medium gastric pH for omeprazole plus sodium bicarbonate, baseline and for Prilosec ^ over time is illustrated in Figure 6. On Day 1, there was an increase in mean gastric pH during the first hour after dosing with omeprazole plus sodium bicarbonate , but not with Prilosec "11 (Figure 6a) This reflected the neutralization of gastric acid by sodium bicarbonate in the treatment of omeprazole plus sodium bicarbonate Figure 6a also shows that on Day 1 there was a greater decrease in gastric pH during each of the three postprandial periods with omeprazole plus sodium bicarbonate than with Prilosec ™ 1. However, on Day 7 the time course for medium gastric pH with omeprazole plus sodium bicarbonate was the same as with Prilosec "11 ( Figure 6b). In particular, there was no decrease in gastric pH less than 4 for any of the three postprandial periods for either omeprazole plus sodium bicarbonate or Prilosec. · The average percentage of time in which the gastric pH was < 4, Day 1 for omeprazole plus sodium bicarbonate was somewhat higher than for Prilosec1111, but Day 7 was the same, as shown in Table 6.E. following.

Table 6.E.

Percent of Gastric pH Time < _ 4 For 24 Hours with Omeprazole plus Sodium Bicarbonate and Prilosec ™ 1 In the diagram of Figure 7a and Figure 7b, the amount of time that the gastric pH was </ i> is plotted. 4 for omeprazole plus sodium bicarbonate and Prilosec1 ^. A compendium comparison of pharmacokinetic and pharmacodynamic parameters between omeprazole (20 mg and 40 mg) plus sodium bicarbonate (1680 mg) and Prilosec® (20 mg and 40 mg) after 7 days is presented in Figure 8a and Figure 8b .

Example 7; Effect of food ingestion in bioavailability of omeprazole plus sodium bicarbonate This example describes studies that indicate that food intake reduces the bioavailability of omeprazole plus sodium bicarbonate, compared to bioavailability, when fasting. The studies were carried out as described in the 0SB-IR-C02 test protocol. Subjects who received omeprazole plus sodium bicarbonate in Period 1 received an eighth dose of omeprazole plus sodium bicarbonate given after a high-fat meal. The administration of 40 mg of omeprazole with 1680 mg of sodium bicarbonate at one hour of steady state after the start of a high-fat food, reduces the bioavailability [AUC (0-inf)] to 73% compared to administration after an overnight fast (pre-food). The post-feed Cmax was 40% of the pre-food Cmax. The food delayed the average Tmax by 55 minutes. Although there was a reduction in bioavailability of omeprazole plus sodium bicarbonate post-feed on Day 8 compared to pre-feed on Day 7, Day 8 AUC (o-inf) post-feed, of omeprazole plus sodium bicarbonate (3862 ng) x hr / ml) was substantially greater than AUC (o-inf) pre-food of omeprazole plus sodium bicarbonate or Prilosec "11 for all subjects on Day 1 (2228 and 2658 ng x hr / mL, respectively). they are summarized in Table 7.A. Table 7.A. Plasma omeprazole concentration 40 mg omeprazole plus 1680 mg sodium bicarbonate (ost-food) 40 mg of 40 mg of 90% Cl Q, omeprazole plus omeprazole plus Pro¬ 1680 mg of 1680 mg sodium bicarbonate sodium bicarbonate (Post-sodium (Post-Food) Food) average rate ParaN · Average S N Average SD meters arithmetic arithmetic nax 16 880.6 3 16 2133 695 - - (ng / mL) 7 .4 8 Plot of plasma omeprazole concentrations in steady state average for administration of omeprazole plus sodium bicarbonate pre-saw food (Day 7) and post-feed (Day 8) against time is illustrated in Figure 9. Example 8; Extension and duration of increase in gastric pH after administration of omeprazole plus sodium bicarbonate This example describes studies that indicate that omeprazole plus antacid is effective to increase and maintain pH over 4.0 for several hours, and that increasing doses of omeprazole plus antacid increases the duration of acid suppression. Pharmacodynamic parameters were compared for administration of 40 mg of omeprazole powder alone and 40 mg of omeprazole plus sodium bicarbonate (SA -15-C01C). The results are summarized in Table 8.A. Table 8.A. Pharmacodynamics of omeprazole powder (40 mg) Administered with or without antacid (Pre-food) Gastric acid number Its integrated mean values 0-210 min. Post-food (mmoles x hr / L) Control 10 44 Powder Omeprazole 10 35 administered one hour Pre-food Omeprazole powder plus 10 0.5 30 mEq of antacid administered one hour pre-food Omeprazole powder with antacid is considerably more effective for suppressing gastric acid, compared to omeprazole powder alone (Table 8.B.). Figure 13 shows that a single pre-food dose of 40 mg of omeprazole powder plus 30 mEq of chewable antacid tablet, given 30 minutes before a meal causes a greater decrease in gastric acidity (increased pH) and has a suppressive effect more Prolonged in food-induced acid secretion than Nexium (study SA -15-C01B). The data shown in Figure 13 can also be analyzed as illustrated in Figure 1. A single dose of 40 mg of omeprazole powder plus 30 mEq of chewable antacid tablet administered at 60 minutes pre-food resulted in a 95% reduction in mean gastric acidity during 210 minutes after a meal (study SAN-15-C01B) . A single 40 mg dose of omeprazole powder plus 30 mEq of this acid administered at 30 minutes pre-food resulted in an 81% reduction in mean gastric acidity, whereas a single dose of Nexium ™ * (40 mg) administered at 30 minutes pre-food resulted in only a 52% reduction in medium gastric acidity. In this way omeprazole / antacid is more effective than Nexium ™ to reduce post-food integrated gastric acidity, when pre-food is administered. The SAN-15-C01C study showed that a single post-food dose of 40 mg to 120 mg of omeprazole powder plus 30 mEq of antacid delivered 90 minutes after breakfast is effective to increase the pH above 4.0 for 4-5 hours after lunch (Figures 15 (a) -15 (c)). An effect of the dose range with increasing amounts of omeprazole powder greater than 30 mEg of antacid was observed with respect to increase in acid suppression (Figures 15 (a) -15 (c)). The dose interval results in Figure 15 are summarized numerically in Table 8.B. Table 8.B. % time with pH > 4 after ingestion of a standard lunch with administration of a single dose of Omeprazole powder plus antacid 90 minutes after a standardized breakfast.

A Acidity% integrated half-time with pH > mmoles x hr / L 4 Control 65.9 39.0% 40 mg powder 41.5 52.6% omeprazole administered with antacid 80 mg powder 11.1 71.4% omeprazole administered with antacid 120 mg powder 0 99.0% omeprazole administered with antacid Example 9. Effect of multiple doses of omeprazole plus sodium bicarbonate in bioavailability and suppression of gastric acid.

This example describes studies that indicate that omeprazole plus sodium bicarbonate delivered multiple times exhibits increased bioavailability and increased and sustained suppression of gastric acidity. To evaluate pharmacokinetics of omeprazole (omeprazole in plasma) and pharmacodynamics (gastric pH and integrated gastric acidity) for multiple dose administrations, studies were performed as described in the test protocols 0SB-IR-C02, 0SB-IR-C05 and 0SB -IR-C06. Omeprazole in plasma after two doses of 40 mg OSB-IR administered with 6-hour separation, is illustrated in Figure 17 (OSB-IR-C05). These results indicate that a subsequent administration of omeprazole may exhibit greater bioavailability than a previous administration. As demonstrated in Figure 2 and Figure 3, plasma levels and systematic exposure of omeprazole from 40 mg of omeprazole plus antacid increases from a single dose to 7 days of dosing once a day. The duration of medium gastric pH increase over the baseline on day 7 although most of the pH day was > 4. Fig. 19 and F g. illustrate diurnal gastric activity (9:00 a.m. to 10:00 p.m.) against nocturnal gastric activity (22:00 a.m. to 9:00 p.m.) for doses of omeprazole 20 mg and 40 mg (plus antacid). The results in Fig. 19 and Fig. 20 indicate that the average integrated gastric acidity increases over the baseline during the day as well as at night (nocturnal) when the baseline gastric acidity in the larger one. These data also indicate that there is a greater suppression of gastric acidity on day 7 compared to day 1. As illustrated in Fig. 21 and Fig. 23, the pH of average gastric pH is higher as the dose of omeprazole is increased ( supplied with antacid). For example, a greater cumulative effect is observed at the 40 mg dose than 20 mg (compare Fig. 21a and Fig. 21b). However, the suppressive effect of the 20 mg dose is still present throughout the day and night. Fig. 22 and Fig. 23 present the effects of omeprazole 20 mg and omeprazole 40 mg, respectively, in postprandial (post-food) gastric acidity. There is a decrease related to dose in integrated gastric acidity, and this effect is greater after 7 days of dose once a day than on day 1. As illustrated in the previous figures, repeated doses once a day of omeprazole plus antacid over time, they provide a cumulative relationship in gastric acidity that lasts throughout the day and night. Due to the cumulative effect observed after food consumption, repeated doses of omeprazole plus antacid may be useful to reduce or avoid the occurrence (frequency), duration or severity of food induced arousal. Example 10; Effect of omeprazole on the nocturnal sensation of acid This example describes the study OSB-IR-C06, indicating that a dose of 20 mg of omeprazole with antacid before sleep, after repeated doses of omeprazole once a day, may suppress nocturnal gastric activity (Fig. 24 (b) and Fig. 24 (c)). It is also illustrated in Fig. 24 (a) to Fig. 24 (c) that two doses of 20 mg (one before going to sleep) of omeprazole plus antacid are better than a dose of 40 mg in the morning, to suppress the nocturnal gastric acidity. The results demonstrate that omeprazole with antacid administered before going to sleep may be useful to treat one or more symptoms associated with nocturnal gastric acidity such as nocturnal heartburn. Example 11; Effect of omeprazole on upper GI bleeding.

This example describes the study (0SB-IR-C03) indicating that a daily dose of 40 mg of omeprazole with antacid, prevents or reduces bleeding of the upper GI in patients typically sick and was not inferior to cimetidine to avoid or reduce bleeding of the GI superior (Fig. 28). As illustrated in Figure 25, the results indicate that fewer patients had gastric aspirates with a lower pH 4 in the OSB-IR group. than in the cimetidine group. Fewer patients treated with OSB-IR suspension exhibited bleeding (both no evidence and typically significant amounts) than in the group treated with cimetidine. The results in Fig. 26 illustrate the median gastric pH of critically ill patients treated during the first two days and indicated that OSB-IR (40 mg of omeprazole) provides a statistically significant greater increase in gastric pH in OSB-IR patients than in cimetidine patients. The results in Figure 27 illustrate medium gastric pH for each of the 14 days of the study, and indicate that OSB-IR (40 mg of omeprazole) provide a statistically significant higher increase in pH on all study days in OSB-IR patients than in patients treated with cimetidine.

Example 12: Oral suspension of omeprazole with immediate release is more effective than pantoprazole delayed release capsules, to reduce nocturnal gastric acidity in GERD patients.

This example describes studies that indicate that the nocturnal dosing of oral suspension of immediate release of omeprazole at once and twice daily regimens is more effective than nocturnal doses of pantoprazole to reduce nocturnal gastric acidity. This study also indicates that omeprazole is more effective than delayed-release proton pump inhibitors such as Protonix to control nocturnal GERD symptoms when they are delivered at night. A group of 32 GERD patients with nocturnal symptoms was given a dose of 40 mg of Protonix at 2200 hrs (when sleeping) on day 1 and before snack on days 2-6. On day 7, this group was given Protonix ° one hour before breakfast and again at 2200 hrs. The second group of 32 GERD patients with nocturnal symptoms was given OME-IR suspension at 2200 hrs on days 1-6. On day 7, the 17 patients of the second group were given 40 mg of OME-IR suspension, one hour before breakfast and again at 2200 hrs; The remaining 15 patients of the second group were given 20 mg of OME-IR suspension one hour before breakfast and again at 2200 hrs. A 24-hour continuous gastric pH monitoring (Medtronic) was performed on days 1, 6 and 7 for all groups. Mean gastric pH, percent of time in which pH was higher at pH, and the proportion of patients with sensation (NAB) was determined for the night period (2200-0600 hrs). See Figures 31 and 32. The nocturnal acid sensation is approximately greater than one continuous hour at pH < . Mid-night gastric pH for 8 hours (day 6) is shown in Figure 29. During this 8-hour period, the percent of mean time at which pH > 4 was higher for patients on OME-IR, 55% compared to patients on Protonix®, 27% (p <0.001). The mean pH was 4.7 for patients on OME-IR and 2.0 for patients on Protonix ° (p <0.001). In addition, NAB occurred in a few patients treated with OME-IR (17 of 32 patients) than patients treated with Protonix ° (25 of 32 patients) (p = 0.005). See Fig. 31. Average night pH for 8 hours after two doses per day (day 7) is shown in Figure 30. During this 8-hour period, the average percent of time at which pH > 4 was higher for patients of 40 and 20 mg of OME-IR than for patients on Protonix ° (40 mg OME-IR Protonix®: 6.5 vs. 1.5 and 20 mg OME-IR vs. Protonix18: 5.8 vs. 1.9, p <0.001 each). NAB also occurred in fewer patients treated with OME-IR than in patients treated with Protonix *. (40 mg OME-IR vs.

ProtonixS: 2.17 vs. 12/17 and 20 mg OME-IR vs. Protonix®: 7/15 vs. 12/15, p = 0.025 each). See Fig. 31. This study demonstrates that the suspension of OME-IR is more effective in reducing nocturnal gastric acidity than Protonix °. These results suggest that OME-IR may also be more effective than delayed-release proton pump inhibitors such as Protonix to control nocturnal GERD symptoms when taken before bedtime. The invention has been described in an illustrative form and it will be understood that the termology employed is intended in nature and description rather than limitation. All patents and other references cited herein are incorporated by reference in their entirety. Obviously, many equivalent modifications and variations of the present invention are possible in light of the above teachings. Therefore, it will be understood that within the scope of the appended claims, the invention may be practiced differently than as specifically described.

Claims (58)

1. CLAIMS 1. A method for treating or preventing nocturnal GERD symptoms in a patient requiring it, by administering a pharmaceutical composition comprising: a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and b) at least one buffering agent in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor.
2. 2. Method of compliance with the claim 1, characterized in that the average blood serum concentration of the proton pump inhibitory agent is at least about 1.0 μg / ml in the patient within about 30 minutes after administration of the pharmaceutical composition to the subject. Method according to claim 1, characterized in that the pharmaceutical composition is administered once a day. 4. Method according to claim 1, characterized in that the pharmaceutical composition is administered twice a day. Method according to claim 1, characterized in that the pharmaceutical composition is administered at least once a day for two or more consecutive days. 6. Method according to claim 1, characterized in that the pharmaceutical composition is administered at least twice a day for two or more consecutive days. 7. Method of compliance with the claim 1, characterized in that the pharmaceutical composition is administered before going to sleep. Method according to claim 1, characterized in that the pharmaceutical composition is administered less than 2 hours before going to sleep. Method according to claim 1, characterized in that after the administration of the pharmaceutical composition, the average gastric pH for a night period of 8 hours is greater than approximately 3. Method according to claim 1, characterized in that after the administration of the pharmaceutical composition the average gastric pH for a night period of 8 hours is greater than approximately 4. 11. Method according to claim 1, characterized in that after the administration of the pharmaceutical composition the average gastric pH for a night period of 8 hours is greater than approximately 5. 12. Method according to claim 1, characterized in that during a night period of 8 hours after administration of the pharmaceutical composition, the gastric pH is greater than about 4 at least about 40% of the time. 13. Method according to claim 1, characterized in that during a night period of 8 hours after administration of the pharmaceutical composition, the gastric pH is greater than about 4 at least about 50% in time. 14. Method according to claim 1, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is higher at about 4.0 at least about 40% of a night period of 8 hours. 15. Method according to claim 1, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater about 4.0 at least about 50% of a night period of 8 hours. 16. Method according to claim 1, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater about 4.0 at least about 70% of a night period of 8 hours. 17. Method according to claim 1, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater about 4.0 at least about 90% of a night period 8 hours Method according to claim 1, characterized in that the nocturnal GERD symptom is acedia. 19. Method of conformance with IB claim 1, characterized in that at least some of the proton pump inhibitory agent in the pharmaceutical composition has no enteric coating. 20. Method according to claim 1, characterized by the amount of The proton pump inhibiting agent present in the pharmaceutical composition is about 20 mg. 21. Method according to claim 1, characterized by the amount of proton pump inhibitor present in the The pharmaceutical composition is approximately 40 mg. 22. Method according to claim 1, characterized in that the proton pump inhibiting agent comprises omeprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, derivative or its prodrug. 23. Method according to claim 1, characterized in that the proton pump inhibiting agent comprises lansoprazole, or a free base, free acid, salt, ester hydrate, amide, enantiomer, isomer, tautomer, polymorph, derivative or its prodrug. Method according to claim 1, characterized in that the proton pump inhibiting agent comprises esomeprazole, or a free base, free acid, salt, ester hydrate, amide, enantiomer, isomer, tautomer, polymorph, derivative or its prodrug. Method according to claim 1, characterized in that the inhibiting agent comprises one or more buffering agents selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium hydroxide and magnesium oxide. 26. Method according to claim 1, characterized in that the buffering agent comprises from about 200 to about 2000 mg of buffering agent. 27. Method according to claim 1, characterized in that the pharmaceutical composition comprises at least about 5 mEq of buffering agent. 28. Method according to claim 1, characterized in that the pharmaceutical composition comprises at least about 10 mEq of buffering agent. 29. Method according to claim 1, characterized in that the pharmaceutical composition is in the form of a powder, a tablet, a disintegrating tablet when biting, a chewable tablet, a coated tablet, a capsule, an effervescent powder, a tablet of rapid disintegration or an aqueous suspension or emulsion. 30. Method for reducing nocturnal gastric acidity in a subject by administration of a composition, comprising: a) a therapeutically effective amount of at least one labile acid proton pump inhibitor; and b) at least one buffering agent, in an amount sufficient to inhibit or reduce degradation of at least some of the proton pump inhibitor. 31. Method according to claim 30, characterized in that the average blood serum concentration of the proton pump inhibitory agent is at least about 1.0 / xg / ml in the patient within about 30 minutes after administration of the pharmaceutical composition. to the subject. 32. Method according to claim 30, characterized in that the pharmaceutical composition is administered once a day. 33. Method according to claim 30, characterized in that the pharmaceutical composition is administered twice a day. 34. Method according to claim 30, characterized in that the pharmaceutical composition is administered at least once a day for two or more consecutive days. 35. Method according to claim 30, characterized in that the pharmaceutical composition is administered at least twice a day for two or more consecutive days. 36. Method according to claim 30, characterized in that the pharmaceutical composition is administered before going to sleep. 37. Method according to claim 36, characterized in that the pharmaceutical composition is administered less than about 2 hours before retiring to sleep. 38. Method according to claim 30, characterized in that after administration of the pharmaceutical composition, the average gastric pH for a night period of 8 hours is greater than approximately 3. 39. Method according to claim 30, characterized in that after administration of the pharmaceutical composition, the average gastric pH for a night period of 8 hours is greater than about 4. 40. Method according to claim 30, characterized in that after administration of the pharmaceutical composition, the average gastric pH for a night period of 8 hours is greater than about 5. 41. Method according to the claim 30, characterized in that during a night period of 8 hours after administration of the pharmaceutical composition, the gastric pH is greater than about 4 at least about 40% of the time. 42. Method according to claim 30, characterized in that during a night period of 8 hours after administration of the pharmaceutical composition, the gastric pH is greater than about 4 at least about 50% of the time. 43. Method according to claim 30, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater than about 4.0 at least 40% of a night period of 8 hours . 44. Method according to claim 30, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater than about 4.0 at least 50% of a night period of 8 hours . 45. Method according to claim 30, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater than about 4.0 at least 70% of a night period of 8 hours . 46. Method according to claim 30, characterized in that the pharmaceutical composition is administered twice a day and where after administration of the second dose, the gastric pH is greater than about 4.0 at least 90% of a night period of 8 hours. 47. Method according to claim 30, characterized in that the nocturnal GERD symptom is acedia. 48. Method according to claim 30, characterized in that at least some of the inhibited proton pump agent in the pharmaceutical composition does not have enteric coating. 49. Method according to claim 30, characterized in that the amount of proton pump inhibitor present in the pharmaceutical composition is about 20 mg. 50. Method according to claim 30, characterized in that the amount of proton pump inhibitor present in the pharmaceutical composition is about 40 mg. 51. Method according to claim 30, characterized in that the proton pump inhibiting agent comprises omeprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, derivative or its prodrug . 52. Method according to claim 30, characterized in that the proton pump inhibiting agent comprises lansoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, derivative or its prodrug . 53. Method according to claim 30, characterized in that the proton pump inhibiting agent comprises esomeprazole, or its free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, derivative or prodrug thereof . 54. Method according to claim 30, characterized in that the buffering agent comprises one or more buffering agents selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium hydroxide and magnesium oxide. 55. Method according to claim 30, characterized in that the buffering agent comprises about 200 to about 2000 mg of buffering agent. 56. Method according to claim 30, characterized in that the pharmaceutical composition comprises at least about 5 mEq of buffering agent. 57. Method according to claim 30, characterized in that the pharmaceutical composition comprises at least about 10 mEq of buffering agent. 58. Method according to claim 30, characterized in that the pharmaceutical composition is in the form of a powder, tablet, a disintegrating tablet when biting, a chewable tablet, a coated tablet, a capsule, an effervescent powder, a fast disintegrating tablet or an aqueous suspension or emulsion.