# Patent

## Title
Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

## Abstract

The present invention relates to pharmaceutical formulations comprising at least one acid-labile proton pump inhibiting agent and at least one antacid, which have improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. 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.

## Background
This application claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/574,646, filed May 25, 2004 and U.S. Provisional Application No. 60/574,663, filed May 25, 2004, the contents of which are fully incorporated by reference herewith.


FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations in solid oral dosage form comprising at least one acid-labile proton pump inhibiting agent and at least one antacid, which have improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. Also described herein are pharmaceutical formulations comprising at least one proton pump inhibiting agent and about 5 mEq to about 11 mEq of antacid, which have similar bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties to similar combinations comprising greater than 11 mEq of antacid.
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.
BACKGROUND OF THE INVENTION
Upon ingestion, most acid-labile pharmaceutical compounds must be protected from contact with acidic stomach secretions to maintain their pharmaceutical activity. To accomplish this, compositions with enteric-coatings have been designed to dissolve at a neutral pH to ensure that the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach. However, due to the pH-dependent attributes of these enteric-coated compositions and the uncertainty of gastric retention time, in-vivo performance as well as both inter- and intra-subject variability are all major set backs of using enteric-coated systems for the controlled release of a drug.
In addition, Phillips et al. has described non-enteric coated pharmaceutical compositions. These compositions, which allow for the immediate release of the pharmaceutically active ingredient into the stomach, involve the administration of one or more antacids with an acid labile pharmaceutical agent, such as a proton pump inhibitor. The antacid is thought to prevent substantial degradation of the acid labile pharmaceutical agent in the acidic environment of the stomach by raising the pH. See, e.g., U.S. Pat. Nos. 5,840,737 and 6,489,346.
A class of acid-labile pharmaceutical compounds that are administered as enteric-coated dosage forms are proton pump inhibiting agents. Exemplary proton pump inhibitors include, omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole. The drugs of this class suppress gastrointestinal acid secretion by the specific inhibition of the H+/K+-ATPase enzyme system (proton pump) at the secretory surface of the gastrointestinal parietal cell. Most proton pump inhibitors are susceptible to acid degradation and, as such, are rapidly destroyed as pH falls to an acidic level. Therefore, if the enteric-coating of these formulated products is disrupted (e.g., trituration to compound a liquid, or chewing the capsule or tablet) or the antacid fails to sufficiently neutralize the gastrointestinal pH, the drug will be exposed to degradation by the gastrointestinal acid in the stomach.
Omeprazole is one example of a proton pump inhibitor which is a substituted bicyclic aryl-imidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, that inhibits gastrointestinal acid secretion. U.S. Pat. No. 4,786,505 to Lovgren et al. teaches that a pharmaceutical oral solid dosage form of omeprazole must be protected from contact with acidic gastrointestinal juice by an enteric-coating to maintain its pharmaceutical activity and describes an enteric-coated omeprazole preparation containing one or more subcoats between the core material and the enteric-coating.
Proton pump inhibitors are typically prescribed for short-term treatment of active duodenal ulcers, gastrointestinal ulcers, gastro esophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These above-listed conditions commonly arise in healthy or critically ill patients of all ages, and may be accompanied by significant upper gastrointestinal bleeding.
It is believed that omeprazole, lansoprazole and other proton pump inhibiting agents reduce gastrointestinal acid production by inhibiting H+/K+-ATPase of the parietal cell the final common pathway for gastrointestinal acid secretion. See, e.g., Fellenius et al., Substituted Benzimidazoles Inhibit Gastrointestinal Acid Secretion by Blocking H+/K+-ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between Gastrointestinal Acid Secretion and Gastrointestinal H+/K+-ATPase Activity, J. Biol. Chem., 260: 13681-13684 (1985); and Fryklund et al., Function and Structure of Parietal Cells After H+/K+-ATPase Blockade, Am. J. Physiol., 254 (1988).
Proton pump inhibitors have the ability to act as weak bases that reach parietal cells from the blood and diffuse into the secretory canaliculi. There, the drugs become protonated and thereby trapped. The protonated compound can then rearrange to form a sulfenamide, which can covalently interact with sulfhydryl groups at critical sites in the extra cellular (luminal) domain of the membrane-spanning H+/K+-ATPase. See, e.g., Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 907 (9th ed. 1996). As such, proton pump inhibitors are prodrugs that must be activated to be effective. The specificity of the effects of proton pump inhibiting agents is also dependent upon: (a) the selective distribution of H+/K+-ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. See, e.g., Hardman et al.
SUMMARY OF THE INVENTION
The present invention is directed to pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor, and (b) at least one antacid sufficient to increase gastric pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid, wherein upon oral administration to a patient, a therapeutically effective amount of the proton pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained within about 75 minutes after administration. In alternative embodiments, Tmax of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.
In one embodiment, pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor; (b) a sufficient amount of sodium bicarbonate to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; and (c) less than about 3% of disintegrant, wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained within about 75 minutes after administration are described. In other embodiments, the pharmaceutical formulations comprise less than about 2% or less than about 1% of disintegrant. In alternative embodiments, Tmax of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.
Stable pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor, and (b) at least one antacid in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid, wherein the pharmaceutical formulation does not comprise a binder; and wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained within about 75 minutes after administration are also provided herein. In some embodiments, the antacid is present in an amount of greater than about 5 mEqs. In other embodiments, the antacid is present in an amount of about 5 mEq to about 30 mEq, or about 5 mEq to about 20 mEq, or about 8 mEq to about 15 mEq, or about 10 mEq to about 15 mEq. In still other embodiments, the antacid is present in an amount of about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq, or about 12 mEq, or about 13 mEq, or about 14 mEq, or about 15 mEq, or about 16 mEq, or about 17 mEq, or about 18 mEq, or about 19 mEq, or about 20 mEq, or about 22.5 mEq, or about 25 mEq, or about 27 mEq, or about 30 mEq, or about 35 mEq. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.
Stable pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor, (b) at least about 5 mEq of antacid, wherein the antacid is a combination of at least two different antacids, and (c) between about 3% to about 11% of a disintegrant, wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained within about 75 minutes, are also provided herein. In some embodiments the pharmaceutical formulation comprises about 4% to about 8% disintegrant. In other embodiments, the pharmaceutical formulation comprises about 5% to about 7% disintegrant. In alternative embodiments, Tmax of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.
Also provided herein are stable pharmaceutical formulations in a single capsule dosage form comprising (a) at least one acid-labile proton pump inhibitor, (b) about 5 to about 15 mEq of sodium bicarbonate, and (c) less than about 3% of a disintegrant, wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained within about 75 minutes. In some embodiments, the pharmaceutical formulation comprises about 8 mEq to about 15 mEq of sodium bicarbonate. In other embodiments, the pharmaceutical formulation comprises about 10 mEq to about 15 mEq of sodium bicarbonate. In yet other embodiments, the pharmaceutical formulation comprises about 13 mEq of sodium bicarbonate. In still other embodiments, Tmax of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration.
Stable pharmaceutical formulations in a solid oral dosage form comprising (a) omeprazole or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof, (b) at least about 5 mEq of sodium bicarbonate, and (c) less than about 3% of a disintegrant, wherein the pharmaceutical formulation does not comprise a binder; and wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained within about 75 minutes after administration are also provided herein. In some embodiments, the pharmaceutical formulation comprises between about 5 mEq to about 20 mEq, or between about 5 mEq to about 15 mEq, or between about 10 mEq to about 15 mEq of sodium bicarbonate. In other embodiments, the pharmaceutical formulation comprises less than about 2% sodium bicarbonate. In yet other embodiments, Tmax of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.
Also provided herein are stable pharmaceutical formulations in single capsule dosage form comprising (a) at least one acid-labile proton pump inhibitor, and (b) about 5 to about 30 mEq of antacid wherein the antacid is selected from magnesium hydroxide, magnesium oxide, sodium carbonate, sodium bicarbonate, and calcium carbonate, wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered; and Tmax of the proton pump inhibitor is obtained within about 75 minutes. In other embodiments, Tmax of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration.
Also provided herein are pharmaceutical compositions in solid oral dosage forms wherein the wt-% of disintegrant is at least as great as the wt-% of binder. In some embodiments, the pharmaceutical formulation is substantially free of a binder. In other embodiments, the solid oral dosage form is a tablet (such as a caplet) and the binder is present in an amount of less than about 20 wt%, or less than about 10 wt-%, or less than about 5 wt-%. In other embodiments, the solid oral dosage form is a capsule and the binder is present in an amount of about 0 wt-% to about 5 wt-%.
The present invention provides a pharmaceutical composition comprising a proton pump inhibiting agent and about 5 mEq to about 11 mEq of antacid for oral administration and ingestion by a subject.
Pharmaceutical formulations are included that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein upon oral administration to a subject, the oral bioavailability of the proton pump inhibitor is at least 25% and the maximum serum concentration of the proton pump inhibitor is obtained within about 75 minutes after administration. In other embodiments, the maximum serum concentration is obtained within about 60 minutes, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes after administration of the pharmaceutical formulation. In still other embodiments, the oral bioavailability of the proton pump inhibitor is about 25% to about 60%, or about 30% to about 50%, or at least about 30%, or at least about 35%, or at least about 40%.
Pharmaceutical formulations that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the pharmaceutical formulation is bioequivalent to a pharmaceutical formulation comprising (a) at least one acid-labile proton pump inhibitor, and (b) greater than 11 mEq of antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 11 mEq of antacid. In other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±10% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 11 mEq of antacid. In still other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when administered with greater than 11 mEq of antacid.
Pharmaceutical formulations that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the pharmaceutical formulation is bioequivalent to a pharmaceutical formulation comprising (a) at least one acid-labile proton pump inhibitor, and (b) greater than 15 mEq of antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15%, or within about ±10%, or within about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 15 mEq of antacid.
Pharmaceutical formulations that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the pharmaceutical formulation is bioequivalent to a pharmaceutical formulation comprising (a) at least one acid-labile proton pump inhibitor, and (b) greater than 20 mEq of antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15%, or within about ±10%, or within about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 20 mEq of antacid.
Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid wherein the pharmaceutical formulation is bioequivalent to a proton pump inhibitor product. In some embodiments, the pharmaceutical formulation is bioequivalent to Priolosec®, Nexium®, Prevacid®, Protonic®, and Aciphex®. In other embodiments, the maximum concentration of the proton pump inhibitor for the pharmaceutical formulation is within about 80% and about 120% of the maximum concentration (Cmax) for the proton pump inhibitor product. In some embodiments, the maximum concentration of the proton pump inhibitor for the pharmaceutical formulation is within about 80% and about 120% of the maximum concentration (Cmax) for the proton pump inhibitor product when the pharmaceutical formulation and proton pump inhibitor product are administered to the same patient.
Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided herein, wherein upon oral administration to a subject, the pharmaceutical composition has an area under the serum concentration time curve (AUC) for the proton pump inhibitor that is equivalent to an area under the serum concentration time curve (AUC) for the proton pump inhibitor when an enteric form of the proton pump inhibitor is delivered without antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±20% of the area under the serum concentration time curve for the proton pump inhibitor when an enteric form of the proton pump inhibitor is delivered without antacid. In still other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15%, or within about ±10%, or with about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when an enteric form of the proton pump inhibitor is delivered without antacid.
Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided herein, wherein a therapeutic dose of the proton pump inhibitor is delivered as a single capsule, tablet, or caplet.
A pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered; the antacid increases the gastric pH to at least about 3.5 for no more than about 30 minutes measured by a simulated stomach model such as Fuchs kinetic in-vitro pH model; and the maximum concentration of the proton pump inhibitor is obtained within about 75 minutes are also provided herein. In some embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 30 minutes, or less than about 25 minutes, or less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes. In other embodiments, the maximum concentration of the proton pump inhibitor is obtained within about 60 minutes.
Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided herein, wherein the formulation comprises about 5 mgs to about 200 mgs of the proton pump inhibitor. In other embodiments, the pharmaceutical formulation comprises about 10 mgs, or about 20 mgs, or about 30 mgs, or about 40 mgs, or about 50 mgs, or about 60 mgs, or about 80 mgs, or about 120 mgs of the proton pump inhibitor. In yet other embodiments, the pharmaceutical formulation comprises about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq of antacid.
Compositions are provided such that an initial serum concentration of the proton pump inhibitor is greater than about 100 ng/ml at any time within about 30 minutes after administering the formulation. Initial serum concentration of the proton pump inhibitor can be greater than about 100 ng/ml at any time within about 15 minutes. Initial serum concentration of the proton pump inhibitor can be greater than about 200 ng/ml at any time within about 1 hour after administration, greater than about 300 ng/ml at any time within about 45 minutes after administration.
Compositions are provided such that a serum concentration of greater than about 100 ng/ml can be maintained from at least about 30 minutes to about 1 hour after administration of the composition. Compositions are provided such that a serum concentration of proton pump inhibitor greater than about 100 ng/ml can be maintained from at least about 15 minutes to about 30 minutes after administration. Compositions are provided such that a serum concentration of greater than about 100 ng/ml can be maintained from at least about 30 minutes to about 45 minutes after administration. Compositions are provided such that a serum concentration of greater than about 250 ng/ml can be maintained from at least about 30 minutes to about 1 hour after administration. Compositions are provided such that a serum concentration of greater than about 250 ng/ml can be maintained from at least about 30 minutes to about 45 minutes after administration. Compositions are provided such that a serum concentration of greater than about 250 ng/ml can be maintained from at least about 15 minutes to about 30 minutes after administration.
Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 150 ng/ml from about 15 minutes to about 1 hour after administration. Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 150 ng/ml from about 15 minutes to about 1.5 hours after administration. Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 100 ng/ml from about 15 minutes to about 1.5 hours after administration. Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 150 ng/ml from about 15 minutes to about 30 minutes after administration.
Compositions of the invention can be administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 150 ng/ml at any time from about 5 minutes to about 30 minutes after administration. Compositions of the invention can be administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 150 ng/ml at any time within about 30 minutes after administration.
Compositions are provided wherein, upon oral administration to the subject, the composition provides a pharmacokinetic profile such that at least about 50% of total area under serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 2 hours after administration of a single dose of the composition to the subject. Compositions are provided wherein, upon oral administration to the subject, the area under the serum concentration time curve (AUC) for the proton pump inhibitor in the first 2 hours is at least about 60% 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% of the total area.
Compositions are provided wherein at least about 50% of total area under the serum concentration time curve (AUC) for the proton pump inhibitor occurs within 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 total area under the serum concentration 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% of 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 subject.
Compositions and methods are provided wherein, upon oral administration to the subject, the composition provides a pharmacokinetic profile such that the proton pump inhibitor reaches a maximum serum concentration within about 75 minutes after administration of a single dose of the pharmaceutical formulation. In yet other embodiments the maximum serum concentration is reached within about 60 minutes after administration, or within about 45 minutes after administration of the pharmaceutical formulation. In still other embodiments, the maximum serum concentration is reached within about 30 minutes after administration of the pharmaceutical formulation.
Methods are provided for treating a gastric acid related disorder including, but not limited to duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison syndrome, heartburn, esophageal disorder, and acid dyspepsia. Method are provided wherein the proton pump inhibitor treats an episode of gastric acid related disorder.
In some embodiments, the proton pump inhibitor is a substituted bicyclic aryl-imidazole. In other embodiments, the proton pump inhibitor is selected from the group consisting of omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, ransoprazole, pariprazole, leminoprazole; or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof. In still other embodiments, the proton pump inhibitor is selected from lansoprazole, tenatoprazole, esomeprazole, rabeprazole and pantoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof.
Pharmaceutical formulations of the present invention comprise, for example, about 5 mgs to about 200 mgs of a proton pump inhibitor. In various embodiments, the pharmaceutical formulation may comprise about 10 mgs, or about 15 mgs, or about 20 mgs, or about 40 mgs, or about 60 mgs, or about 120 mgs of the proton pump inhibitor.
In various embodiments of the present invention, the antacid is an alkaline metal salt or a Group IA metal selected from a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal. In other embodiments, the antacid can be, but is not limited to, an amino acid, an alkali metal salt of an amino acid, aluminum hydroxide, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminum magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate, 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, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, 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, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, trometamol, Effersoda® (a mixture of sodium bicarbonate and sodium carbonate) and mixtures thereof. In yet other embodiments, the antacid can be sodium bicarbonate, sodium carbonate, Effersoda®, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. In some embodiments, the composition is substantially free of sucralfate. In other embodiments, the composition does not contain an amino acid buffer. In still other embodiments, the composition is a combination of two or more antacids, wherein at least two of the antacids are not amino acids.
Pharmaceutical formulations of the present invention may comprise varying amounts of antacid. For example, in some embodiments, the pharmaceutical formulation comprises about 100 to 3000 mg of antacid. In other embodiments, the pharmaceutical formulation comprises about 400 to about 1300 mg of antacid. In still other embodiments the pharmaceutical formulation comprises about 5 mEq to about 30 mEq, or about 8 mEq to about 20 mEq, or about 10 mEq to about 15 mEq of antacid. In further embodiments, the pharmaceutical formulations comprise about 13 mEq of antacid.
Pharmaceutical formulations of the present invention may be in the form of a tablet, (including a suspension tablet, a chewable tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC) a lozenge, a sachet, a troche, pellets, granules, or an aerosol. In some embodiments, the pharmaceutical formulation is in the form of a powder for suspension. In other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a chewable tablet. Additionally, pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules.
In various embodiments of the present invention, the proton pump inhibitor may be microencapsulated with a material that enhances the shelf life of the pharmaceutical formulation. In some embodiments, the material that enhances the shelf life of the pharmaceutical formulation is selected from the group consisting of cellulose hydroxypropyl ethers; low-substituted hydroxypropyl ethers; cellulose hydroxypropyl methyl ethers; methylcellulose polymers; ethylcelluloses and mixtures thereof; polyvinyl alcohol; hydroxyethylcelluloses; carboxymethylcelluloses and salts of carboxymethylcelluloses; polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides; triglycerides; polyethylene glycols, modified food starch, acrylic polymers; mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms, cyclodextrins; and mixtures thereof. In other embodiments, the material that enhances the shelf life of the pharmaceutical formulation further comprise an antioxidant, sodium bicarbonate, or a plasticizer.
In various embodiments, the pharmaceutical formulations of the present invention further comprise or more excipients selected from the group consisting of parietal cell activators, organic solvents, erosion facilitators, flavoring agents, sweetening agents, diffusion facilitators, antioxidants and carrier materials selected from binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, anti-adherents, and antifoaming agents.



DESCRIPTION OF THE FIGURES
FIG. 1 shows a comparison of buffer systems comprising various mixtures of NaHCO3 and Mg(OH)2.
FIG. 2 shows a comparison of buffer systems comprising various mixtures of NaHCO3 and Mg(OH)2.
FIG. 3 shows the particle size effect of magnesium hydroxide on in-vitro/in-vivo neutralization.
FIG. 4 shows the particle size effect of magnesium hydroxide on the pharmacokinetics of various formulations.
FIG. 5 shows the binder effect on various pharmaceutical formulations.
FIG. 6 shows the capsule dissolution effect with 5% binder as compared to a powder for suspension.
FIG. 7 shows the pH study results of high/low Ac-Di-Sol (disintegrant).
FIG. 8 shows the pharmacokinetic study results of high/low Ac-Di-Sol (disintegrant) as compared to Prilosec.
FIG. 9 shows the pharmacokinetic profiles for six different pharmaceutical formulations.
FIG. 10 is a summary of all the CTM lots with the ANC present in the individual pharmaceutical formulations.
FIG. 11 is a summary of the pharmacokinetics of various formulations.
FIG. 12 shows the capsule stability of SAN-10E, SAN-10BB, and SAN-10B.
FIG. 13 compares the concentration/time curve for Prilosec® to the concentration/time curve of SAN-10K (10.5 mEq of Sodium Bicarbonate and 40 mg omeprazole).



DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to methods, kits, combinations, and compositions for treating a condition or disorder where treatment with an acid labile proton pump inhibitor is indicated. Also provided are 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.
While the present invention may be embodied in many different forms, several specific embodiments are discussed herein with the understanding that the present disclosure is to be considered only as an exemplification of the principles of the invention, and it is not intended to limit the invention to the embodiments illustrated. For example, where the present invention is illustrated herein with particular reference to omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, periprazole, ransoprazole, pariprazole, or leminoprazole, it will be understood that any other proton pump inhibiting agent, if desired, can be substituted in whole or in part for such agents in the methods, kits, combinations, and compositions herein described.
To more readily facilitate an understanding of the invention and its preferred embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description.
Glossary
As used herein, the terms “comprising,” “including,” and “such as” are used in their open, non-limiting sense.
The term “about” is used synonymously with the term “approximately.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the composition. Illustratively, the use of the term “about” indicates that values slightly ouside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe.
The phrase “acid-labile pharmaceutical agent” refers to any pharmacologically active drug subject to acid catalyzed degradation.
“Anti-adherents,” “glidants,” or “anti-adhesion” agents prevent components of the formulation from aggregating or sticking and improve flow characteristics of a material. Such compounds include, e.g., colloidal silicon dioxide such as Cab-o-sil®; tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid®)and the like.
“Antifoaming agents” reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.
“Antioxidants” include, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
“Binders” impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.
“Bioavailability” refers to the extent to which an active moiety, e.g., drug, prodrug, or metabolite, is absorbed into the general circulation and becomes available at the site of drug action in the body. Thus, a proton pump inhibitor administered through IV is 100% bioavailable. “Oral bioavailability” refers to the extent to which the proton pump inhibitor (or other active moiety) is absorbed into the general circulation and becomes available at the site of drug action in the body when the pharmaceutical composition is taken orally.
“Bioequivalence” or “bioequivalent” means that the area under the serum concentration time curve (AUC) and the peak serum concentration (Cmax) are each within 80% and 120%.
“Carrier materials” include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with the proton pump inhibitor and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. “Pharmaceutically compatible carrier materials” may comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 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 & Wilkins1999).
“Character notes” include, e.g., aromatics, basis tastes, and feeling factors. The intensity of the character note can be scaled from 0-none, 1-slight, 2-moderate, or 3-strong.
A “derivative” is a compound that is produced from another compound of similar structure by the replacement of substitution of an atom, molecule or group by another suitable atom, molecule or group. For example, one or more hydrogen atom of a compound may be substituted by one or more alkyl, acyl, amino, hydroxyl, halo, haloalkyl, aryl, heteroaryl, cycloaolkyl, heterocycloalkyl, or heteroalkyl group to produce a derivative of that compound.
“Diffusion facilitators” and “dispersing agents” include materials that control the diffusion of an aqueous fluid through a coating. Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG and the like. Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present invention.
“Diluents” increase bulk of the composition to facilitate compression. Such compounds include e.g., lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; dibasic calcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinzed starch; compressible sugar, such as Di-Pac® (Amstar); mannitol; hydroxypropylmethylcellulose; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite; and the like.
The term “disintegrate” includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
“Disintegration agents” facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, 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 starch; and the like.
“Drug absorption” or “absorption” refers to the process of movement from the site of administration of a drug toward the systemic circulation, e.g., into the bloodstream of a subject.
An “enteric coating” is a substance that remains substantially intact in the stomach but dissolves and releases the drug once the small intestine is reached. Generally, the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a slightly higher pH, typically a pH of 4 or 5, and thus dissolves sufficiently in the small intestines to gradually release the active agent therein.
The “enteric form of the proton pump inhibitor” is intended to mean that some or most of the proton pump inhibitor has been enterically coated to ensure that at least some of the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach.
“Erosion facilitators” include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.
“Filling agents” include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose; dextrates; dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
“Flavoring agents” or “sweeteners” useful in the pharmaceutical compositions of the present invention include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.
“Gastrointestinal fluid” is the fluid of stomach secretions of a subject or the saliva of a subject after oral administration of a composition of the present invention, or the equivalent thereof. An “equivalent of stomach secretion” includes, e.g., an in vitro fluid having similar content and/or pH as stomach secretions such as a 1% sodium dodecyl sulfate solution or 0.1N HCl solution in water.
“Half-life” refers to the time required for the plasma drug concentration or the amount in the body to decrease by 50% from its maximum concentration.,
“Lubricants” are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid; calcium hydroxide; talc; sodium stearyl fumerate; a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®); higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes; Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, sodium oleate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as SyloidTM, Carb-O-Sil®, a starch such as corn starch, silicone oil, a surfactant, and the like.
A “measurable serum concentration” or “measurable plasma concentration” describes the blood serum or blood plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of blood serum, of a therapeutic agent that is absorbed into the bloodstream after administration. One of ordinary skill in the art would be able to measure the serum concentration or plasma concentration of a proton pump inhibitor or a prokinetic agent. See, e.g., Gonzalez H. et al., J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci., vol. 780, pp 459-65, (Nov. 25, 2002).
“Parietal cell activators” or “activators” stimulate the parietal cells and enhance the pharmaceutical activity of the proton pump inhibitor. Parietal cell activators include, e.g., chocolate; alkaline substances such as sodium bicarbonate; calcium such as calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate; peppermint oil; spearmint oil; coffee; tea and colas (even if decaffeinated); caffeine; theophylline; theobromine; amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan); and combinations thereof.
“Pharmacodynamics” refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.
“Pharmacokinetics” refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
“Plasma concentration” refers to the concentration of a substance in blood plasma or blood serum of a subject. It is understood that the plasma concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents. In accordance with one aspect of the present invention, the plasma concentration of a proton pump inhibitors and/or prokinetic agent may 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 serum concentration time curve (AUC) may vary from subject to subject. Due to this variability, the amount necessary to constitute “a therapeutically effective amount” of proton pump inhibitor, prokinetic agent, or other therapeutic agent, may vary from subject to subject. It is understood that when mean plasma concentrations are disclosed for a population of subjects, these mean values may include substantial variation.
“Plasticizers” are compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin.
“Prevent” or “prevention” when used in the context of a gastric acid related disorder means no gastrointestinal disorder or disease development if none had occurred, or no further gastrointestinal disorder or disease development if there had already been development of the gastrointestinal disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the gastrointestinal disorder or disease.
A “prodrug” refers to a drug or compound in which the pharmacological action results from conversion by metabolic processes within the body. Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug which renders it 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 may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. The design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J. Physiology, 269:G210-218 (1995); McLoed et al., Gastroenterol., 106:405-413 (1994); Hochhaus et al., 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.
“Proton pump inhibitor product” refers to a product sold on the market. Proton pump inhibitor products include, for example, Priolosec®, Nexium®, Prevacid®, Protonic®, and Aciphex®.
“Serum concentration” refers to the concentration of a substance such as a therapeutic agent, in blood plasma or blood serum of a subject. It is understood that the serum concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents. In accordance with one aspect of the present invention, the serum concentration of a proton pump inhibitors and/or prokinetic agent may vary from subject to subject. Likewise, values such as maximum serum concentration (Cmax) or time to reach maximum serum concentration (Tmax), or total area under the serum concentration time curve (AUC) may vary from subject to subject. Due to this variability, the amount necessary to constitute “a therapeutically effective amount” of proton pump inhibitor, prokinetic agent, or other therapeutic agent, may vary from subject to subject. It is understood that when mean serum concentrations are disclosed for a population of subjects, these mean values may include substantial variation.
“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 antioxidation agents, buffers, acids, and the like.
“Suspending agents” or “thickening agents” include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; sodium carboxymethylcellulose; methylcellulose; hydroxy-propylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gums, such as, e.g., gum tragacanth and gum acacia; guar gum; xanthans, including xanthan gum; sugars; cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose; polysorbate-80; sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone and the like.
“Surfactants” include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF); and the like.
A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a proton pump inhibitor is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. For example, an effective amount of a proton pump inhibitor refers to an amount of proton pump inhibitor that reduces acid secretion, or raises gastrointestinal fluid pH, or reduces gastrointestinal bleeding, or reduces the need for blood transfusion, or improves survival rate, or provides for a more rapid recovery from a gastric acid related disorder. The effective amount of a pharmaceutical agent will be selected by those skilled in the art depending on the particular-patient and the disease level. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of therapeutic agents such as proton pump inhibitors and/or prokinetic agents, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
“Total intensity of aroma” is the overall immediate impression of the strength of the aroma and includes both aromatics and nose feel sensations.
“Total intensity of flavor” is the overall immediate impression of the strength of the flavor including aromatics, basic tastes and mouth feel sensations.
“Treat” or “treatment” as used in the context of a gastric acid related disorder refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, such as preventing the disorder or disease from occurring in a subject which may be predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. Thus, as used herein, the term “treat” is used synonymously with the term “prevent.”
“Wetting agents” include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, and the like.
Proton Pump Inhibitors
The terms “proton pump inhibitor,” “PPI,” and “proton pump inhibiting agent” can be used interchangeably to describe any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase. A proton pump inhibitor may, if desired, be in the form of free base, free acid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active.
In various embodiments, the proton pump inhibitor can be a substituted bicyclic aryl-imidazole, wherein the aryl group can be, e.g., a pyridine, a phenyl, or a pyrimidine group and is attached to the 4- and 5-positions of the imidazole ring. Proton pump inhibitors comprising a substituted bicyclic aryl-imidazoles include, but are not limited to, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, tenatoprazole, ransoprazole, pariprazole, leminoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative thereof. See, e.g., The Merck Index, Merck & Co. Rahway, N.J. (2001).
Other proton pump inhibitors include but are not limited to: soraprazan (Altana); ilaprazole (U.S. Pat. No. 5,703,097) (Il-Yang); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidinamine, 4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447 (Imidazo(1,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3-thienyl) (Shinnippon); 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imidazo(1,2-a)pyridine (PCT Publication WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imidazo(1,2-a)pyridine) (AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis); WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yananouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); nepaprazole (Toa Eiyo); HN-11203 (Nycomed Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SKandF-95601 (GSK, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); SKandF-96067 (EP 259174) (Altana); SUN 8176 (Daiichi Phama); Ro-18-5362 (Roche); ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds.
Still other proton pump inhibitors contemplated by the present invention include those described in the following U.S. Pat. Nos: 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281; 6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167.
Other substituted bicyclic aryl-imidazole compounds as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
“Pharmaceutically acceptable salts,” or “salts,” include, e.g., the salt of a proton pump inhibitor 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, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids.
In one embodiment, acid addition salts are prepared from the free base using conventional methodology involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the acid addition salts of the proton pump inhibitors are halide salts, which are prepared using hydrochloric or hydrobromic acids. In still other embodiments, the basic salts are alkali metal salts, e.g., sodium salt.
Salt forms of proton pump inhibiting agents include, but are not limited to: 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, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole, described in U.S. patent application Ser. No. 02/0198239 and U.S. Pat. No. 6,511,996. Other salts of esomeprazole are described in U.S. Pat. Nos. 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
In one embodiment, preparation of esters involves fictionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug. In one embodiment, the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOOR1 where R1 is a lower alkyl group. Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
“Amides” may be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group such as ammonia or a lower alkyl amine.
“Tautomers” of substituted bicyclic aryl-imidazoles include, e.g., tautomers of omeprazole such as those 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 U.S. Patent Publication No. 02/0156103.
An exemplary “isomer” of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.
Exemplary “polymorphs” include, but are not limited to, those described in PCT Publication No. WO 92/08716, and U.S. Pat. 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; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 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; 6,444,689; and 6,462,0577.
Micronized Proton Pump Inhibitor
Particle size of the proton pump inhibitor can affect the solid dosage form in numerous ways. Since decreased particle size increases in surface area (S), the particle size reduction provides an increase in the rate of dissolution (dM/dt) as expressed in the Noyes-Whitney equation below:

dM/dt=dS/h(Cs−C)

M=mass of drug dissolved; t=time; D=diffusion coefficient of drug; S=effective surface area of drug particles; H=stationary layer thickness; Cs=concentration of solution at saturation; and C=concentration of solution at time t.

Because omeprazole, as well as other proton pump inhibitors, has poor water solubility, to aid the rapid absorption of the drug product, various embodiments of the present invention use micronized proton pump inhibitor is used in the drug product formulation.
In various embodiments of the present invention, the proton pump inhibitor is micronized. In some embodiments, the average particle size of at least about 90% the micronized proton pump inhibitor is less than about 40 μm, or less than about 35 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm. In other embodiments, at least 80% of the micronized proton pump inhibitor has an average particle size of less than about 40 μm, or less than about 35 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm. In still other embodiments, at least 70% of the micronized proton pump inhibitor has an average particle size of less than about 40 μm, or less than about 35 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm.
Compositions are provided wherein the micronized proton pump inhibitor is of a size which allows greater than 75% of the proton pump inhibitor to be released within about 1 hour, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes of dissolution testing. In another embodiment of the invention, the micronized proton pump inhibitor is of a size which allows greater than 90% of the proton pump inhibitor to be released within about 1 hour, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes of dissolution testing. See U.S. patent application Ser. No. 10/893,092, filed Jul. 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,324 filed Jul. 18, 2003, both of which are incorporated by reference in their entirety.
Particle Size of Insoluble Materials
The particle size of the proton pump inhibitor, antacid and excipients is an important factor which can effect bioavailability, blend uniformity, segregation, and flow properties. In general, smaller particle sizes of a drug increases the bioabsorption rate of the drug with substantially poor water solubility by increasing the surface area. The particle size of the drug and excipients can also affect the suspension properties of the pharmaceutical formulation. For example, smaller particles are less likely to settle and therefore form better suspensions.
In various embodiments, the average particle size of the dry powder (which can be administered directly, as a poweder for suspension, or used in a solid dosage form) is less than about 500 microns in diameter, or less than about 450 microns in diameter, or less than about 400 microns in diameter, or less than about 350 microns in diameter, or less than about 300 microns in diameter, or less than about 250 microns in diameter, or less than about 200 microns in diameter, or less than about 150 microns in diameter, or less than about 100 microns in diameter, or less than about 75 microns in diameter, or less than about 50 microns in diameter, or less than about 25 microns in diameter, or less than about 15 microns in diameter. In other embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 300 microns in diameter. In still other embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 150 microns in diameter. And, in still further embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 100 microns in diameter. The term “average particle size” is intended to describe the average diameter of the particles and/or agglomerates used in the pharmaceutical formulation.
In another embodiment, the average particle size of the insoluble excipients is between about 5 μm to about 500 μm, or less than about 400 μm, or less than about 300 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 90 μm, or less than about 80 μm, or less than about 70 μm, or less than about 60 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm, or less than about 5 μm.
In other embodiments of the present invention, at least about 80% of the particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 500 μm. In another embodiment, at least about 85% of the dry powder particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm. In still other embodiments of the present invention, at least about 90% of the dry powder particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm. In yet another embodiment, at least about 95% of the dry powder particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm.
In another embodiment, the particle size of other excipients is chosen to be about the same as the particle size of the antacid. In yet another embodiment, the particle size of the insoluable excipients is chosen to be about the same as the particle size of the proton pump inhibitor.
Several factors can be considered in choosing both the proper excipient and its quantity. For example, the excipient should be pharmaceutically acceptable. Also, in some examples, rapid dissolution and neutralization of gastric acid to maintain the gastric pH at about 6.5 for at least one hour. The excipients which will be in contact with the proton pump inhibitor, if any, should also be chemically compatible with the proton pump inhibitor. “Chemically compatible” is intended to mean that the material does not lead to more than 10% degradation of the proton pump inhibitor when stored at room temperature for at least about 1 year.
Parietal cell activators are administered in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients. In one embodiment, the parietal cell activator is administered in an amount of about 5 mg to about 2.5 grams per 20 mg dose of the proton pump inhibitor.
Antacids
The pharmaceutical composition of the invention comprises one or more antacids. A class of antacids useful in the present invention include, but are not limited to, antacids possessing pharmacological activity as a base. In one embodiment, the antacid, when formulated or delivered with an proton pump inhibiting agent, functions to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastrointestinal fluid for a period of time, e.g., for a period of time sufficient to preserve the bioavailability of the proton pump inhibitor administered. The antacid can be delivered before, during and/or after delivery of the proton pump inhibitor. In one aspect of the present invention, the antacid includes a salt of a Group IA metal (alkali metal), including, e.g., a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal; an alkaline earth metal antacid (Group IIA metal); an aluminum antacid; a calcium antacid; or a magnesium antacid.
Other antacids suitable for the present invention include, e.g., alkali metal (a 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, radium) 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 antacid includes an amino acid, an alkali metal salt of an amino acid, aluminum hydroxide, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminum magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate, 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, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, 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, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, Effersod® (mixture of sodium bicarbonate and sodium carbonate), synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometamol. (See, e.g., lists provided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Certain proteins or protein hydrolysates that rapidly neutralize acids can serve as antacids in the present invention. Combinations of the above mentioned antacids may also be used in the pharmaceutical compositions described herein.
The antacids useful in the present invention also include antacids or combinations of antacids that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase, such as water, these antacids produce and maintain a pH greater than the pKa of the proton pump inhibitor.
In various embodiments, the antacid is selected from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, and mixtures thereof.
Particle size of the buffer, especially that an insoluble buffer can affect the onset of in-vivo neutralization of the stomach acid. Since decreased particle size increases in surface area, the particle size reduction provides an increase in the rate of acid neutralization, leading to superior protection of PPI from gastric acid degradation. On the other hand, extremely fine particle size of buffer will result in the powder mixture that is difficult to manufacture in commercial scale due to their poor flow and difficulties in processing (i.e., compression and encapsulation).
In various embodiments of the present invention, the antacid is micronized. In some embodiments, particle size of at least 90% of antacid (D90) is less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm. In other embodiments, at least 75% of the antacid (D75) has particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm. In still other embodiments, at least 50% of the antacid (D50) has particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm.
Spray dried antacid can also facilitate the speed of neutralization by fast reacting with acid upon contact. Sprayed dried antacid typically has spherical particle shape which aids with achieving homogeneous blend during manufacturing process. In one embodiment the antacid is spray dried with at least 15% of coating material such as maltodextrin or starch. In still other embodiment the antacid is spray dried with at least 10% of coating material such as maltodextrin or starch. Yet another embodiment the antacid is spray dried with at least 15% of coating material such as maltodextrin or starch.
Kinetic Stomach Model
The acid neutralizing capacity and pH profile of various antacid combinations can be evaluated by using an in-vitro stomach model. Several of these simulated dynamic models are known in the art. See, e.g., Smyth et al., Correlation of In-Vivo Methodology for Evaluation of Antacids, J. Pharm. Sci. Vol. 65, 1045 (1976); Hobert, Fordham et al., In-Vivo Evaluation of Liquid Antacids, New England Journal of Med. 288, 923 (1973); Johnson et al., The Chemical Testing of Antacids, Gut 5, 585 (1964); Clain et al., In-Vitro Neutralizing Capacity of Commercially Available Antacid Mixtures and Their Role in the Treatment of Peptic Ulcer, S. Afr. Med. J., 57, 158 (1980); Rossett et al., In-Vitro Evaluation of Efficacy of More Frequently Used Antacids with Particular Attention to Tablets, Gastroentrology, 26, 490; Decktor et al., Comparative Effects of Liquid Antacids on Esophageal and Gastric pH in Patients with Heartburn, Am. J. of Therapeutics, 2, 481 (1995); Charles Fuchs, Antacids: Their Function, Formulation and Evaluation, Drug and Cosmetic Industry, 49, 692; Stewart M. Beckman, Preparation and Properties of New Gastric Antacids I, Aluminium Hydroxide-Magnesium Carbonate Dried Gels, J. Am. Pharm. Assoc., 49, 191 (1960). For example, a modified Fuch's model where the continuous influx of 0.5 mEq of acid is added to initial 5.0 mEq of acid to simulate a fasting state of stomach can be used with the present invention.
In various embodiments of the present invention, the antacid increases the gastric pH to at least about 3.5 for no more than about 90 minutes as measured by a simulated stomach model such as Fuch's kinetic in-vitro pH model. In other embodiments, the antacid increases the pH to at least about 3.5 for no more than about 60 minutes. In still other embodiments, the antacid increases the pH to at least about 3.5 for no more than 45 minutes. Depending on the buffer system used (i.e., type of antacid and amount) some embodiments of the present invention, the antacid increases the gastric pH to at least about 3.5 for no more than about 30 minutes as measured by a simulated stomach model such as Fuchs' kinetic in-vitro pH model. In other embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 25 minutes as measured by a simulated stomach model such as Fuch's kinetic in-vitro pH model. In yet other embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes as measured by a stimulated stomach model such as Fuch's kinetic in-vitro pH model. In each of these embodiments, the antacid protects at least some of the proton pump inhibitor and a therapeutically effective amount of the proton pump inhibitor is delivered to the subject.
In each of these embodiments, the antacid protects at least some of the proton pump inhibitor and a therapeutically effective amount of the proton pump inhibitor is delivered to the subject.
Disintegrants
Most PPIs are sparingly soluble in water and therefore exhibit a strong correlation of disintegration time to bioavailability. Thus, it is important to optimize the disintegration time in order to enhance in vivo dissolution of the drug. In order to release the active ingredient from a solid dosage form matrix as efficiently as possible, disintegrant is often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Starch is the oldest disintegrants and 5-15% level is suggested (Remington, 20th Ed, p862). Super disintegrants such as Ac-di-Sol or Crospovidones are effective at lower levels (2-4%).
Ac-Di-Sol is effective in both direct compression and wet granulation formulations. The amount of Ac-Di-Sol used in direct compression tableting may vary with typical usage levels between 1 and 3 percent. When added to granulations, generally the same percent is used as with a direct compression formulation. It is often added to both the wet mass and the dried granulations before compression. As with direct compression, the use level typically ranges from 1 to 3 percent with half of the material added to the wet mass and half added to the running powder. This promotes disintegration of both the granules and the tablet.
The amount of Ac-Di-Sol used in capsule formulations generally ranges from 4-6 percent. Reduced interparticle contact within a capsule facilitates the need for elevated levels of disintegrant. Capsules filled on automatic dosater types of equipment, as opposed to semi-automatic or hand-filled machines, are more dense and have a harder structure due to the greater compressional forces needed to form the plug and successfully transfer it into the gelatin shell. Greater plug hardness results in greater effectiveness of Ac-Di-Sol.
Solid Oral Dosage Forms
In some embodiments of the present invention, the phamaceutical formulation has greater than about 1 wt-% of a disintegrant. In various embodiments of the present invention, the pharmaceutical formulations have between about 1 wt-% to about 11 wt-% of a disintegrant. In some embodiments the disintegrant is Ac-Di-Sol. In other embodiments the disintegrant is sodium starch glycolated such as Promogel® or Explotab®. In still other embodiments, the pharmaceutical formulations have between about 2 wt-% to about 8 wt-% disintegrant. In yet other embodiments, the pharmaceutical formualtions have greater than about 2 wt-% disintegrant.
Because sodium bicarbonate has effervescent characteristic when mixed with acid such as gastric fluid, in some embodiments the pharmaceutical formulations of the present invention can comprise at least about 400 mgs of sodium bicarbonate and greater than about 1 wt-% of a disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2 wt-% disintegrant, or about 3 wt-% disintegrant, or about 4 wt-% disintegrant. In yet other embodiments, the pharmaceutical formulation comprises less than 8 wt-% disintegrant. In other embodiments, the pharmaceutical formulations have less than about 5 wt-% disintegrant, or less than about 4 wt-% disintegrant, or less than about 3 wt-% disintegrant, or less than about 2 wt-% disintegrant, or less than about 1 wt-% disintegrant. In other embodiments, the sodium bicarbonate helps facilitate the disintegration of the capsule product.
In some embodiments of the present invention, the wt-% of disintegrant can be decreased and the amount of sodium bicarbonate increased to achieve the desired bioavailability of the proton pump inhibitor. In other embodiments, the wt-% of disintegrant can be increased and the amount of sodium bicarbonate decreased.
Binders
Binders impart a cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into a hard sell capsules and for tablet formulation, they ensure the tablet remaining intact after compression. Materials commonly used as binders include starch gelatin, and sugars such as sucrose, glucose, dextrose, molasses, and lactose. The quantity of binder used influences the characteristics of the dosage form and/or manufacturing processes. For example, dosator type encapsulators (e.g. Zanasi machine) normally requires the filling material to be mechanically strong plugs whereas dosing disc type encapsulators (e.g., HK machine) do not require the same degree of high plug breaking force. In. general, binder level of 1-10% are used in powder-filled hard gel capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of 2-25% in tablet formulations is common.
Solid Oral Dosage Forms
In some embodiments of the present invention, the wt-% of the disintegrant is at least equivalent to the wt-% of the binder. For example, formulations of the present invention may comprise about 5 wt-% of disintegrant and about 2 wt-% of a binder or about 3 wt-% of a disintegrant and about 3 wt-% of a binder. In other embodiments, the solid oral dosage form does not comprise a binder. In some embodiments, the solid oral dosage form comprises significantly more disintegrant than binder. For example, the binder may be present in an amount of less than 2 wt-% while the disintegrant is present in an amount of greater than 5 wt-%. In other embodiments, the binder and disintegrant are present in the formulation in substantially the same amount. For example, the binder may be present in an amount of about 2 wt-% and the disintegrant may be present in an amout of about 3 wt-%.
Microencapsulation
In accordance with one aspect of the present invention, compositions may include microencapsulation of the proton pump inhibitor or the antacid, in order to enhance the shelf life of the composition and/or enhance the taste of the pharmaceutical composition. See U.S. application Ser. No. 10/893,203, filed Jul. 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,321 filed Jul. 18, 2003, both of which are incorporated by reference in their entirety.
Materials useful for enhancing the shelf life and/or masking the taste of the pharmaceutical compositions of the present invention include materials compatible with the proton pump inhibitor of the pharmaceutical compositions which sufficiently isolate the proton pump inhibitor from other non-compatible excipients. Materials compatible with the proton pump inhibitors of the present invention are those that enhance the shelf life of the proton pump inhibitor, i.e., by slowing or stopping degradation of the proton pump inhibitor.
Exemplary microencapsulation materials useful for enhancing the shelf life of pharmaceutical compositions comprising a proton pump inhibitor include, but are not limited to: hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel®-A and Metolose®; Ethylcelluloses (EC) and mixtures thereof 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 co-polymers such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD 100, and Eudragit® E100; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins; and mixtures of these materials.
In various embodiments, an antacid such as sodium bicarbonate or sodium carbonate is incorporated into the microencapsulation material. In other embodiments, an antioxidant such as BHT is incorporated into the microencapsulation material. In still other embodiments, plasticizers such as polyethylene glycols, e.g., 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 microencapsulating material useful for enhancing the shelf life of the pharmaceutical compositions is from the USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.
In further embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, parietal cell activators, erosion facilitators, diffusion facilitators, anti-adherents, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
According to one aspect of the invention, some of the proton pump inhibitor is coated. The coating may be, for example, a gastric resistant coating such as an enteric coating (See, e.g, WO 91/16895 and WO 91/16886), a controlled-release coating, an enzymatic-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 may be useful for enhancing the stability of the pharmaceutical compositions of the present invention.
In addition to microencapsulating the proton pump inhibitors with a material as described herein, the pharmaceutical compositions of the present invention may also comprise one or more flavoring agents. In some embodiments, one or more flavoring agents are mixed with the taste-masking material prior to microencapsulating the proton pump inhibitor and/or antacid. In other embodiments, the flavoring agent is mixed with non-compatible excipients during the formulation process and is therefore not in contact with the proton pump inhibitor and/or antacid, and not part of the microencapsulation material.
“Flavoring agents” or “sweeteners” useful in the pharmaceutical compositions of the present invention include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In other embodiments, sodium chloride is incorporated into the pharmaceutical composition. Based on the proton pump inhibitor, antacid, and excipients, as well as the amounts of each one, one of skill in the art would be able to determine the best combination of flavors to provide the optimally flavored product for consumer demand and compliance. See, e.g., Roy et al., Modifying Bitterness: Mechanism, Ingredients, and Applications (1997).
Methods of Microencapsulation
The proton pump inhibitor and/or antacid may be microencapsulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used.
The spinning disk method allows for: 1) an increased production rate due to higher feed rates and use of higher solids loading in feed solution, 2) the production of more spherical particles, 3) the production of a more even coating, and 4) limited clogging of the spray nozzle during the process.
Spray drying is often more readily available for scale-up. In various embodiments, the material used in the spray-dry encapsulation process is emulsified or dispersed into the core material in a concentrated form, e.g., 10-60% solids. The microencapsulation material is, in one embodiment, emulsified until about 1 to 3 μm droplets are obtained. Once a dispersion of proton pump inhibitor and encapsulation material are obtained, the emulsion is fed as droplets into the heated chamber of the spray drier. In some embodiments, the droplets are sprayed into the chamber or spun off a rotating disk. The microspheres are then dried in the heated chamber and fall to the bottom of the spray drying chamber where they are harvested.
In some embodiments of the present invention, the microspheres have irregular geometries. In other embodiments, the microspheres are aggregates of smaller particles.
In various embodiments, the proton pump inhibitor and/or antacid are present in the microspheres in an amount greater than 1%, greater than 2.5%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90% greater than 95% or greater than 98% weight percent of the proton pump inhibitor to the microencapsulation material used to enhance the stability of the pharmaceutical composition or the taste-masking material.
Stability
A pharmaceutical formulation of the present invention is stable if, e.g., the proton pump inhibitor has less than about 0.5% degradation after one month of storage at room temperature, or less than about 1% degradation after one month at room temperature, or less than about 1.5% degradation after one month of storage at room temperature, or less than about 2% degradation after one month storage at room temperature, or less than about 2.5% degradation after one month of storage at room temperature, or less than about 3% degradation after one month of storage at room temperature.
In other embodiments, a pharmaceutical formulation of the present invention may have stable if the pharmaceutical formulation contains less than about 5% total impurities after about 3 years of storage, or after about 2.5 years of storage, or about 2 years of storage, or about 1.5 years of storage, or about 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.
In further embodiments, pharmaceutical formulations of the present invention may contain microencapsulated omeprazole and have enhanced shelf life stability if the pharmaceutical formulation contains less degradation of the proton pump inhibitor than proton pump inhibitor in the same formulation which is not microencapsulated, or “bare”. For example, if bare proton pump inhibitor in the pharmaceutical formulation degrades at room temperature by more than about 2% after one month of storage and the microencapsulated material degrades at room temperature by less than about 2% after one month of storage, then the proton pump inhibitor has been microencapsulated with a compatible material that enhances the shelf life of the pharmaceutical formulation.
Dosage
The proton pump inhibiting agent is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, 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 therapeutic agent in vivo, and renders therapeutic agent bioavailable in a rapid manner. In addition to the dosage forms described herein, the dosage forms described by Phillips et al. in U.S. Pat. Nos. 5,840,737, 6,489,346, 6,699,885 and 6,645,988 are incorporated herein by reference.
The percent of intact drug that is absorbed into the bloodstream is not narrowly critical, as long as a therapeutically effective amount, e.g., a gastrointestinal-disorder-effective amount of a proton pump inhibiting agent, is absorbed following administration of the pharmaceutical composition to a subject. Gastrointestinal-disorder-effective amounts may be found in U.S. Pat. No. 5,622,719. It is understood that the amount of proton pump inhibiting agent and/or antacid that is administered to a subject is dependent on a number of factors, e.g., the sex, general health, diet, and/or body weight of the subject.
Illustratively, administration of a substituted bicyclic aryl-imidazole to a young child or a small animal, such as a dog, a relatively low amount of the proton pump inhibitor, e.g., about 1 mg to about 30 mg, will often provide blood serum concentrations consistent with therapeutic effectiveness. Where the subject is an adult human or a large animal, such as a horse, achievement of a therapeutically effective blood serum concentration will require larger dosage units, e.g., about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 80 mg, or about 120 mg dose for an adult human, or about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mg dose, or about 1500 mg dose, or about 2000 mg dose, or about 2500 mg dose, or about 3000 mg dose or about 3200 mg dose or about 3500 mg dose for an adult horse.
In various other embodiments of the present invention, the amount of proton pump inhibitor administered to a subject is, e.g., about 0.5-2 mg/Kg of body weight, or about 0.5 mg/Kg of body weight, or about 1 mg/Kg of body weight, or about 1.5 mg/Kg of body weight, or about 2 mg/Kg of body weight.
Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for subject administration. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route chosen for administration, and the condition of the particular subject.
In various embodiments, unit dosage forms for humans contain about 1 mg to about 120 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg of a proton pump inhibitor.
In a further embodiment of the present invention, the pharmaceutical composition is administered in an amount to achieve a measurable serum concentration of a non-acid degraded proton pump inhibiting agent greater than about 100 ng/ml within about 30 minutes after administration of the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition is administered to the subject in an amount to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 100 ng/ml within about 15 minutes after administration of the pharmaceutical composition. In yet another embodiment, the pharmaceutical composition is administered to the subject in an amount to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 100 ng/ml within about 10 minutes after administration of the pharmaceutical 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 inhibiting agent greater than about 150 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml from about 15 minutes to about 1 hour 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 inhibiting agent greater than about 250 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 250 ng/ml from about 15 minutes to about 1 hour 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 inhibiting agent greater than about 350 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 350 ng/ml from about 15 minutes to about 1 hour 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 inhibiting agent greater than about 450 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 450 ng/ml from about 15 minutes to about 1 hour 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 inhibiting agent greater than about 150 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml from about 30 minutes to about 1 hour 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 inhibiting agent greater than about 250 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 250 ng/ml from about 30 minutes to about 1 hour 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 inhibiting agent greater than about 350 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 350 ng/ml from about 30 minutes to about 1 hour 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 inhibiting agent greater than about 450 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 450 ng/ml from about 30 minutes to about 1 hour 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 a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 500 ng/ml within about 1 hour 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 a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 300 ng/ml within about 45 minutes after administration of the composition.
In one embodiment of the present invention, the composition is administered to a subject in a gastrointestinal-disorder-effective amount, that is, the composition is administered in an amount that achieves a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject for a period of time to elicit a desired therapeutic effect. Illustratively, in a fasting adult human (fasting for generally at least 10 hours) the composition is administered to achieve a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject within about 45 minutes after administration of the composition. In another embodiment of the present invention, a therapeutically-effective dose of the proton pump inhibiting 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 yet another embodiment, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject within about 20 minutes from the time of administration to the subject. In still another embodiment of the present invention, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject at about 15 minutes from the time of administration of the composition to the subject.
In further embodiments, the oral bioavailability of the proton pump inhibitor is at least about 25%. In other embodiments, the oral bioavailability of the proton pump inhibitor is at least about 30%. In still other embodiments, the oral bioavailability of the proton pump inhibitor is at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55% bioavailable, or at least 60%.
In alternative embodiments, the pharmaceutical composition comprises at least about 5 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 30 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In still other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 30 mEq, or about 5 mEq, or about 7 mEq, or about 10 mEq, or about 13 mEq, or about 15 mEq, or about 17 mEq, or about 20 mEq, or about 22 mEq, or about 25 mEq, or about 27 mEq, or about 30 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. “Bioequivalent” is intended to mean that the area under the serum concentration time curve (AUC) and the peak serum concentration (Cmax) are each within 80% and 120%.
In alternative embodiments, the pharmaceutical composition comprises at least about 5 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 11 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In still other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 11 mEq, or about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®.
In other embodiments, when administered to a subject, the pharmaceutical composition has an area under the serum concentration time curve (AUC) for the proton pump inhibitor that is equivalent to the area under the serum concentration time curve (AUC) for the proton pump inhibitor when the enteric form of the proton pump inhibitor is delivered without antacid. “Equivalent” is intended to mean that the area under the serum concentration time curve (AUC) for the proton pump inhibitor is within ±30% of the area under the serum concentration time curve (AUC) when the same dosage amount of the proton pump inhibitor is enterically coated and delivered to the subject with less than 1 mEq of antacid. The “enteric form of the proton pump inhibitor” is intended to mean that some or most of the proton pump inhibitor has been enterically coated to ensure that at least some of the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach.
In yet other embodiments, the pharmaceutical compositions provide a release profile of the proton pump inhibitor, using USP dissolution methods, whereby greater than about 50% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 50% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 50% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid. In another embodiment, greater than about 60% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 60% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 60% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid. In yet another embodiment, greater than about 70% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 70% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 70% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid.
Compositions contemplated by the present invention provide a therapeutic effect as proton pump inhibiting agent medications over an interval of about 5 minutes to about 24 hours after administration, enabling, for example, once-a-day, twice-a-day, or three times a day administration if desired. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a therapeutic effect. Determination of these parameters is well within the skill of the art.
Dosage Forms
The pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibitor and antacid and can be in the form of: a tablet, (including a suspension tablet, a chewable tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC) a lozenge, a sachet, a troche, pellets, granules, or an aerosol. The pharmaceutical compositions of the present invention can be manufactured by conventional pharmacological techniques.
In some embodiments, the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibiting inhibitor and antacid and are in a solid dosage form. In other embodiments, the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibitor and antacid and are administered in the form of a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatineor plant-derived HPMC). The pharmaceutical compositions of the present invention can be manufactured by conventional pharmacological techniques.
Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of industrial Pharmacy (1986). Other methods include, e.g., prilling, spray drying, pan coating, melt granulation, granulation, wurster coating, tangential coating, top spraying, extruding, coacervation and the like.
In one embodiment, the proton pump inhibitor is microencapsulated prior to being formulated into one of the above forms. In another embodiment, some of the proton pump inhibitor is microencapsulated prior to being formulated. In another embodiment, some or all of the antacid is microencapsulated prior to being formulated. In still another embodiment, some or most of the proton pump inhibitor is coatedprior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In yet other embodiments contemplated by the present invention, a film coating is provided around the pharmaceutical composition.
In other embodiments, the pharmaceutical compositions further comprise one or more additional materials such as a pharmaceutically compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, surfactant, preservative, lubricant, colorant, diluent, solubilizer, moistening agent, stabilizer, wetting agent, anti-adherent, parietal cell activator, anti-foaming agent, antioxidant, chelating agent, antifungal agent, antibacterial agent, or one or more combination thereof.
In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, e.g., diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
Exemplary Solid Oral Dosage Compositions
Solid oral dosage compositions, e.g., tablets, chewable tablets, effervescent tablets, caplets, and capsules, can be prepared, for example, by mixing the proton pump inhibitor, one or more antacid, and pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the proton pump inhibitor and antacid are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also comprise film coatings, which disintegrate upon oral ingestion or upon contact with diluent.
Compressed tablets are solid dosage forms prepared by compacting the bulk blend compositions described above. In various embodiments, compressed tablets of the present invention will comprise one or more functional excipients such as binding agents and/or disintegrants. In other embodiments, the compressed tablets will comprise a film surrounding the final compressed tablet. In other embodiments, the compressed tablets comprise one or more excipients and/or flavoring agents.
A chewable tablet may be prepared by compacting bulk blend compositions, described above. In one embodiment, the chewable tablet comprises a material useful for enhancing the shelf life of the pharmaceutical composition. In another embodiment, the microencapsulated material has taste-masking properties. In various other embodiments, the chewable tablet comprises one or more flavoring agents and one or more taste-masking materials. In yet other embodiments the chewable tablet comprised both a material useful for enhancing the shelf life of the pharmaceutical formulation and one or more flavoring agents.
In various embodiments, the proton pump inhibitor, antacid, and optionally one or more excipients, are dry blended and compressed into a mass, such as a tablet or caplet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the antacid and the proton pump inhibitor into the gastrointestinal fluid. When at least 50% of the pharmaceutical composition has disintegrated, the compressed mass has substantially disintegrated.
A capsule may be prepared by placing any of the bulk blend compositions described above, into a capsule. In some embodiments of the present invention, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the proton pump inhibitor and antacid are delivered in a capsule form. For example, the capsule may comprise between about 10 mg to about 120 mg of a proton pump inhibitor and between about 5 mEq to about 30 mEq of antacid. In some embodiments, the antacid may be selected from sodium bicarbonate, magnesium hydroxide, calcium carbonate, magnesium oxide, and mixtures thereof. In alternative embodiments the capsule comprises 5 mEq to about 30 mEq of sodium bicarbonate.
Exemplary Powder Compositions
A powder for suspension may be prepared by combining at least one acid labile proton pump inhibitor and between about 5 mEq to about 11 mEq of antacid. In various embodiments, the powder may comprise one or more pharmaceutical excipients and flavors. A powder for suspension may be prepared, for example, by mixing the proton pump inhibitor, one or more antacids, and optional pharmaceutical excipients to form a bulk blend composition. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units. The term “uniform” means the homogeneity of the bulk blend is substantially maintained during the packaging process.
In some embodiments, some or all of the proton pump inhibitor is micronized. Additional embodiments of the present invention also comprise a suspending agent and/or a wetting agent.
Effervescent powders are also prepared in accordance with the present invention. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid. When salts of the present invention are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing “effervescence.” Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.
The method of preparation of the effervescent granules of the present invention employs three basic processes: wet granulation, dry granulation and fusion. The fusion method is used for the preparation of most commercial effervescent powders. It should be noted that, although these methods are intended for the preparation of granules, the formulations of effervescent salts of the present invention could also be prepared as tablets, according to known technology for tablet preparation.
Powder for Suspension
In some embodiments, compositions are provided comprising a pharmaceutical at least one proton pump inhibitor, about 5 mEq to about 11 mEq of an antacid, and at least one suspending agent for oral administration to a subject. The composition may be a powder for suspension, and upon admixture with water, a substantially uniform suspension is obtained. See U.S. patent application Ser. No. 10/893,092, filed Jul. 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,324 filed Jul. 18, 2003, both of which are herein incorporated by reference in their entirety.
A suspension is “substantially uniform” when it is mostly homogenous, that is, when the suspension is composed of approximately the same concentration of proton pump inhibitor at any point throughout the suspension. A suspension is determined to be composed of approximately the same concentration of proton pump inhibitor throughout the suspension when there is less than about 20%, less than about 15%, less than about 13%, less than about 11%, less than about 10%, less than about 8%, less than about 5%, or less than about 3% variation in concentration among samples taken from various points in the suspension.
The concentration at various points throughout the suspension can be determined by any suitable means known in the art. For example, one suitable method of determining concentration at various points involves dividing the suspension into three substantially equal sections: top, middle and bottom. The layers are divided starting at the top of the suspension and ending at the bottom of the suspension. Any number of sections suitable for determining the uniformity of the suspension can be used, such as for example, two sections, three sections, four sections, five sections, or six or more sections.
In one embodiment, the composition comprises at least one proton pump inhibitor, between about 5 mEq to about 11 mEq of antacid, and a gum suspending agent, wherein the average particle size of the insoluble material is less than about 200 μm. In some embodiments, the average particle size of the insoluble material is less than about 100 μm. In other embodiments, the average particle size of the insoluble material is less than about 50 μm. The composition is a powder for suspension, and upon admixture with water, a first suspension is obtained that is substantially more uniform when compared to a second suspension comprising the proton pump inhibitor, the antacid, and suspending agent, wherein the suspending agent is not xanthan gum.
In another embodiment, the composition comprises omeprazole, sodium bicarbonate and xanthan gum. The composition is a powder for suspension, and upon admixture with water, a substantially uniform suspension is obtained. In yet another embodiment, the composition is a powder for suspension and comprises omeprazole, about 5 mEq to about 11 mEq sodium bicarbonate, xanthan gum, and at least one sweetener or flavoring agent.
Combination Therapy
The compositions and methods described herein may also be used in conjunction with other well known therapeutic reagents that are selected for their particular usefulness against the condition that is being treated. In general, the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
The particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol. The compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of compounds used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, can be modified in accordance with a variety of factors. These factors include the type of gastric acid disorder from which the subject suffers, the proton pump inhibitor being administered, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein. For example, proton pump inhibitors can be formulated to deliver rapid relief as well as sustained relief of a gastric acid related disorder.
The pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentration may also determine the optimal dose interval.
In some embodiments, the present methods, kits, and compositions can be used in combination with another pharmaceutical agent that is indicated for treating or preventing a gastrointestinal disorder, such as, for example, an anti-bacterial agent, an alginate, a prokinetic agent, or an H2-antagonist which are commonly administered to minimize the 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 aforementioned conditions and/or produce adverse side effects, such as mental confusion, constipation, diarrhea, and thrombocytopenia.
In other embodiments, the present methods, kits, and compositions can be used in combination with other pharmaceutical agents, including but not limited to: NSAIDs including but not limited to aminoarylcarboxylic acid derivatives such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, and zomepirac; arylbutyric acid derivatives such as bumadizon, butibufen, fenbufen, xenbucin; arylcarboxylic acids such as clidanac, ketorolac, tinoridine; arylpropionic acid derivatives such as alminoprofen, benoxaprofin, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen; pyrazoles such as difenamizole, and epirozole; pyrazolones such as apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, prostaglandins, ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives such as acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphtyl 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, Lodine, and Voltaren and others, such as epsilon-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutytic acid, amixetrine, bendazac, benzydamine, α-bisabolol, bucololome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, tenidap and zilenton; sleep aids including but not limited to a benzodiazepine hypnotic, non-benzodiazepine hypnotic, antihistamine hypnotic, antidepressant hypnotic, herbal extract, barbiturate, peptide hypnotic, triazolam, brotizolam, loprazolam, lormetazepam, flunitrazepam, flurazepam, nitrazepam, quazepam, estazolam, temazepam, lorazepam, oxazepam, diazepam, halazepam, prazepam, alprazolam, chlordiazepoxide, clorazepate, an imidazopyridine or pyrazolopyrimidine hypnotic, zolpidem or zolpidem tartarate, zopiclone, eszopiclone, zaleplon, indiplone, diphenhydramine, doxylamine, phenyltoloxamine, pyrilamine, doxepin, amtriptyline, trimipramine, trazodon, nefazodone, buproprion, bupramityiptyline, an herbal extract such as valerian extract or amentoflavone, a hormone such as melatonin,or gabapeptin; motility agents, including but not limited to 5-HT inhibitors such as cisapride, domperidone, and metoclopramide, and agents usefuil for treating irritable bowel syndrome.
For the sake of 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 should not be construed as limiting in any way. The experimental procedures to generate the data shown are discussed in more detail below. For all formulations herein, multiple doses may be proportionally compounded as is known in the art. The coatings, layers and encapsulations are applied in conventional ways using equipment customary for these purposes.
The invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation.
Example 1
Modified Fuchs Model for Antacid Selection
Samples were prepared and analyzed using a method that is a variation of the Fuchs' procedure described in the literature. The procedure described simulates a gastric environment with continuous acid influx. A description of experimental set-up and sample analysis is provided below. Changes may be made to these instructions after initial sample evaluation to optimize sample analysis and collection of relevant information.
Set-up:


    
    
        1. A glass sample vessel ( ̃150 mL capacity) containing 50 mL of a standardized solution of 0.1 N HCl was placed into a water bath set at 37° C. (±2° C.).
        2. A second glass vessel containing >70 mL of a standardized solution of 1.0 N HCl was placed into the same water bath.
        3. The stir paddle was then placed into the sample vessel and set at an appropriate speed. The speed of the stir paddle was recorded and used for all samples analyzed. The speed of the paddle should be adequate to dissolve the sample and added acid without causing interference with the pH measurement or splashing of the solution.
        4. Prior to the start of each sample analysis, the tubing was primed and it was verified that the flow rate with 1.0 N HCl was 0.5 mL/min and the temperature was 37° C. (±2 ° C.). The pump and tubing were then set-up to allow the transfer of 1.0 N HCl acid into the sample vessel.
        5. The pH meter was calibrated to accurately measure pH between 1 and 10 and it was verified that the electronic storage device was ready to collect pH and/or temperature data at a pre-defined rate.
        6. When necessary, the sample was crushed into a fine powder using a mortar and pestle and then transferred to a suitable container and weighed.
        7. The pH probe was placed into the glass sample vessel containing 50 mL of 0.1 N HCl at 37° C. (±2° C.).
        8. The timer and pH data collection was then started. The sample was then transferred into the vessel and the exact time that the sample was introduced into the acid was recorded. The sample container was then re-weighed to determine the exact weight added.
        9. The sample was then stirred for approximately 6 minutes and the flow of the 1.0 N HCl at a rate of 0.5 mL/min was started. The exact start time of the acid flow was recorded.
        10. For samples with not more than (≦) 30 mEq ANC the sample continued to stir and the pH was monitored for 1 hour in 15 second intervals.
        11. The duration of the test was recorded and the total volume of 0.1 N HCl added was calculated based on the flow rate.
    
    


Various buffer combinations were screened using this modified Fuchs in-vitro dynamic stomach model, described above, and it was discovered that the correlation of the theoretical ANC of a given buffer to the actual neutralization capacity and the speed depended on several factors such as solubility, particle size, presence and level of binders and/or disintegrants. For example, it was determined that the smaller the particle size of the buffer the closer the theoretical value was to the actual ANC of a given buffer. This particle size effect was especially noticeable for the insoluble or sparingly soluble antacids such as calcium carbonate or magnesium hydroxide. Contrastingly, the larger the particles size of the antacids, the lower the actual ANC was (e.g., sub-100 US mesh size, sub-80 US mesh size, and sub-60 mesh size of Magnesium Hydroxide).
It was also determined that spray dried magnesium hydroxide with 5% starch such as MS-90® from SPI Pharma performed better than the USP grade manufactured by precipitation (USP grade Magnesium Hydroxide) in the on set speed of neutralization. In similar pattern, It spray dried calcium carbonate with 5% starch such as Destab® Calcium carbonate-95S from Particle Dynamics performed better than the USP grade calcium carbonate manufactured by precipitation in the on set speed of neutralization as well as the actual neutralization capacity measured by the area under curve (AUC) of the dynamic pH profile.
Example 2
Disintegrant Optimization Trials: Mixed Buffer System
Most proton pump inhibitors are sparingly soluble in water. These sparingly soluble drugs have a strong correlation of disintegration time to bioavailability, and it is important to optimize the disintegration time, which enhances in vivo dissolution of the drug. This trial used a sub-80 mesh US mesh size magnesium hydroxide based formulation as shown in table 2A and tested levels between 3% and 11% levels of disintegrant (Croscarmellose Sodium, Ac-di-Sol) for the capsule dosage form performance. Disintegration test outlined by USP (United State Pharmacopia) was chosen as the test method to determine the optimal level of disintegrant. All capsule products containing between 5% to 11% Ac-Di-Sol performed similarly in terms of their physical characteristic, flow properties, and encapsulation characteristics. Disintegration testing of samples with mixed buffer systems indicated that capsule disintegration time is reduced when the level of disintegrant is increased from 3% to 5%. Increasing the level of disintegrant beyond 5% did not lower the disintegration time significantly.







TABLE 2.A.1







Disintegrant Optimization Trials












SAN-10D1
SAN-10D2
SAN-10D3
SAN-10D4



3%
5%
8%
11%



Disintegrant
Disintegrant
Disintegrant
Disintegrant















Ingredients
Mg/cap
%
Mg/cap
%
Mg/cap
%
Mg/cap
%


















OMEPRAZOLE USP
40.8
4.1
40.8
4.1
40.8
3.9
40.8
3.8


Sodium Bicarbonate #2 USP
420
43.4
420
42.6
420
41.2
420
39.9


Magnesium Hydroxide
470
48.6
470
47.7
470
46.2
470
44.6


(sieved) sub 80 mesh










Croscarmellose Sodium NF
30
3.1
49
5.0
81
8.0
116
11.0


Magnesium Stearate NF
7
0.7
7
0.7
7
0.7
7
0.7


Totals:
967
100.0
986
100.0
1018
100.0
1053
100.0
















TABLE 2.A.2







Disintegrant Optimization Trials










Disintegration



Trial Number/
Times










Description
First
Last
Comments/Observations





SAN-10D1 (3% Ac-Di-Sol)
9′10′′
11′20′′
Virtually all disintegrated





at 9 mins.


SAN-10D2 (5% Ac-Di-Sol)
7′30′′
12′
Virtually all disintegrated





at 7 mins 30 secs.


SAN-10D3 (8% Ac-Di-Sol)
8′
11′
Virtually all disintegrated





at 7 mins.


SAN-10D4 (11% Ac-Di-Sol)
7′30′′
10′30′′
Virtually all disintegrated





at 7 mins.









Example 2B
Disintegrant Optimization Trials—Sodium Bicarbonate Buffer
Sodium bicarbonate has effervescent characteristic when mixed with acid such as gastric fluid. This facilitates the disintegration time of a capsule product, and the disintegration requirement would be less than that of the mixed buffer system when sodium bicarbonate is used as a single buffer. This trial used a USP#2 grade sodium bicarbonate based formulation as shown in table 2.B.1. and tested levels between 1% and 5% levels of disintegrant (Croscarmerllose Sodium, Ac-di-Sol) for the capsule dosage form performance. Disintegration test outlined by USP (United State Pharmacopia) was chosen as the test method to determine the optimal level of disintegrant. All capsule products containing between 1% to 5% Ac-Di-Sol performed similarly in terms of their physical characteristic, flow properties, and encapsulation characteristics. However, disintegration testing of samples indicated that capsule disintegration time is reduced when the level of disintegrant is increased from 1% to 2%. Increasing the level of disintegrant beyond 3% did not lower the disintegration time significantly.







TABLE 2.B.1







Disintegrant Optimization Trials












SAN-10BB1
SAN-10BB2
SAN-10BB3
SAN-10BB4



1%
2%
3%
5%



Disintegrant
Disintegrant
Disintegrant
Disintegrant















Ingredients
Mg/cap
%
Mg/cap
%
Mg/cap
%
Mg/cap
%


















OMEPRAZOLE USP
40
3.5
40
3.4
40
3.4
40
3.3


Sodium Bicarbonate #2 USP
1100
94.9
1100
94.0
1100
93.1
1100
91.1


Croscarmellose Sodium NF
12
1.0
23
20.
35
3.0
60
5.0


Magnesium Stearate NF
7
0.6
7
0.6
7
0.6
7
0.6


Totals:
967
100.0
986
100.0
1018
100.0
1053
100.0
















TABLE 2.B.2







Disintegrant Optimization Trials: Sodium Bicarbonate Buffer










Disintegration



Trial Number/
Times










Description
First
Last
Comments/Observations





SAN-10BB1 (1% Ac-Di-Sol)
6′40′′
8′20′′
Virtually all disintegrated





at 7 mins.


SAN-10BB2 (2% Ac-Di-Sol)
4′30′′
6′
Virtually all disintegrated





at 5 mins 30 secs.


SAN-10BB3 (3% Ac-Di-Sol)
4′
5′30′′
Virtually all disintegrated





at 5 mins.


SAN-10BB4 (5% Ac-Di-Sol)
4′
5′30′′
Virtually all disintegrated





at 5 mins.









Example 3
Binder Optimization Trials
A low level of binder 3-8% is commonly-used in capsule product manufacturing to make a plug before encapsulation. The use of the binder such as Klucel®-EXP (hydroxypropyl cellulose) or microcrystalline cellulose (Avicel® PH-102, PH-200) was evaluated with the presence of 0-5% of disintegrant in the powder for the performance using the dynamic stomach model (modified Fuchs model). In general use of the binder had a negative impact on the actual ANC and the speed of neutralization in the pH profiling tests, unless used in combination with a disintegrant.







TABLE 3.A.1







Binder Optimization Trials













SAN-10F1
SAN-10F2
SAN-10F3
SAN-10F4
SAN-10F5

















Ingredients
Mg/cap
%
Mg/cap
%
Mg/cap
%
Mg/cap
%
Mg/cap
%




















Omeprazole USP
40.0
4.5
40.0
4.0
40.0
3.8
40.0
3.6
40.0
3.6


Sodium Bicarbonate #2
250
27.9
250
25.1
350
33.4
350
31.9
350
31.9


USP












Magnesium Hydroxide
600.0
66.9
600.0
60.2
600.0
57.3
600.0
54.7
600.0
54.7


Klucel-EXP
0
0.0
100
10.0
50
4.8
100
9.1
50
4.6


Croscarmellose Sodium
0
0.0
0
0.0
0
0.0
0
0.0
50
4.6


NF












Magnesium Stearate
7
0.8
7
0.7
7
0.7
7
0.6
7
0.6


NF












Totals:
897.0
100.0
997.0
100.0
997.0
100.0
1,097.0
100.0
1,097.0
100.0
















TABLE 3.A.2







Binder Optimization Trials













TR2001
TR2002
TR2003
TR2004
TR2005

















Ingredients
Mg/cap
%
Mg/cap
%
Mg/cap
%
Mg/cap
%
Mg/cap
%




















Omeprazole USP
40
4.5
40
4.0
40
4.0
40
3.6
40
3.6


Sodium
450
50.2
450
45.1
450
45.1
450
41.0
450
41.0


Bicarbonate #2












USP












Magnesium
500
55.7
500
50.2
500
50.2
500
45.6
500
45.6


Hydroxide












Klucel-EXP
20
2.2
20
2.0
50
5.0
50
4.6
0
0.0


Croscarmellose
20
2.2
50
5.0
50
5.0
20
1.8
20
1.8


Sodium NF












Magnesium
7
0.8
7
0.7
7
0.7
7
0.6
7
0.6


Stearate NF












Totals:
897
100.0
997
100.0
997
100.0
1067.0
100.0
1017.0
100.0









The pH test results (table 3.A.1. and table 3.A.2.) shows that the capsules with the binders at 5-10% level had a very slow neutralization speed while the capsule with binder and disintegrant had an adequate speed of neutralization. The capsules with no binder and no disintegrant showed a medium neutralization speed. Table 3BB showed the similar findings that the presence of binder slows down the neutralization speed while use of disintegrant mitigate the negative impact of binder in the formulation.







TABLE 3.B.1







Neutralization Speed of Capsules with Various Level of Binder and


Disintegrant












Binder

Total
Total Time



Level
Disintegrant
ANC
Above pH (min)














Sample
(%)
Level (%)
(mEq)
3.5
5.0
6.0
6.5

















SAN-10F1
0
0
23.6
14.75
11.25
5.75
1.50


SAN-10F2
10
0
23.6
0
0
0
0


SAN-10F3
0
0
24.7
12.5
11.25
5.25
0


SAN-10F4
9.1
0
24.7
0
0
0
0


SAN-10F5
4.6
4.6
24.7
34.25
30.00
22.50
15.25
















TABLE 3.B.2







Neutralization Speed of Capsules with Various Level of Binder and


Disintegrant












Binder

Total




Level
Disintegrant
ANC
Total Time Above pH (min)














Sample
(%)
Level (%)
(mEq)
3.5
5.0
6.0
6.5

















TR2001
2.2
2.2
22.5
0
0
0
0


TR2002
2.0
5.0
22.5
7.25
6
0.25
0


TR2003
5.0
5.0
22.5
8.5
7
0.25
0


TR2004
4.6
1.8
22.5
0
0
0
0


TR2005
0.0
1.8
22.5
0
0
0
0









Example 4
Capsule Formulations
The following formulations were prepared by the following process: The sodium bicarbonate and omeprazole were combined in a mixer and blended for 5 minutes. To that mixture, the magnesium hydroxide and croscarmellose sodium were added and mixed for 5 minutes. The blend was then passes through a #20 mesh s/s screen and then mixed for 10 minutes. Magnesium stearate was then added to the mixture and blended for 3 minutes. The material was then encapsulated into hard gelatinecapsule shells.















SAN-10A
SAN-10B
SAN-10BB
SAN-10C


Ingredients
Mg/caps
Mg/caps
Mg/caps
Mg/caps



















OMEPRAZOLE USP
40
40
40
20


Sodium Bicarbonate
420
420
1100
800


#2 USP


Magnesium Hydroxide
470
0
0
0


(sieved) 100 mesh


Magnesium Hydroxide
0
470
0
0


(sieved) 60 mesh


Croscarmellose
30
30
20
20


Sodium NF


Magnesium Stearate
10
10
10
8


NF






Totals:
970
970
1170
848

























SAN-10D
SAN-10E
SAN-10F
SAN-10G
SAN-10H


Ingredients
Mg/caps
Mg/caps
Mg/caps
Mg/caps
Mg/caps




















OMEPRAZOLE USP
40
40
40
40
40


Sodium Bicarbonate #2
420
378
335
378
420


USP







Magnesium Hydroxide
470
0
0
0
0


(sieved) 80 mesh







Magnesium Hydroxide
0
0
375
0
375


(sieved) 60 mesh







Magnesium Hydroxide 95-
0
447.4
0
447.4
0


MS







Croscarmellose Sodium NF
30
27
24
56
82


Magnesium Stearate NF
7
6
5
6
5


Totals:
967
898.4
779.8
928
922





















PPI
Buffering Agent
Excipient







40 mg micronized
13.1 mEq or 1100 mg
30 mg croscarmellose sodium


omeprazole
USP #2 NaHCO3
10 mg magnesium stearate


per capsule

Size 00 capsule


20 mg micronized
13.1 mEq or 1100 mg
30 mg croscarmellose sodium


omeprazole
USP #2 NaHCO3
10 mg magnesium stearate


per capsule

Size 00 capsule









Example 5
Capsule Formulations with Sodium Bicarbonate and Less than 3% Disintegrant
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with one or more buffering agents, and homogeneously blending with excipients. The appropriate weight of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsulator. The PPI can be in a micronized form.












PPI
Buffering Agent
Excipient







40 mg omeprazole
11.3 mEq or 950 mg
50 mg Klucel



NaHCO3
30 mg Ac-di-Sol




10 mg magnesium stearate




2.8% disintegrant





















PPI
Buffering Agent
Excipient







40 mg omeprazole
10.5 mEq or 880 mg
30 mg Klucel



NaHCO3
20 mg Crospovidone




10 mg magnesium stearate




2.0% disintegrant





















PPI
Buffering Agent
Excipient







60 mg omeprazole
11.4 mEq or 960 mg
20 mg MCC


per capsule
NaHCO3
25 mg Ac-Di-Sol




10 mg magnesium stearate




1.9% disintegrant









Example 6
Capsule Formulations with Mixed Buffer Systems and 3-11% Disintegrant
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with one or more buffering agents, and homogeneously blending with excipients. The appropriate weight of bulk blend composition is filled into a hard gelatinecapsule (e.g., size 00) using an automatic encapsulator. The PPI can be in a micronized form.












PPI
Buffering Agent
Excipient







40 mg
20.6 mEq or 600 mg Mg(OH)2
20 mg MCC


omeprazole
  3 mEq or 250 mg NaHCO3
50 mg Ac-di-Sol



23.6 mEq or 950 mgs total
10 mg magnesium



buffer
stearate




5.2% disintegrant





















PPI
Buffering Agent
Excipient







40 mg
20.6 mEq or 600 mg Mg(OH)2
100 mg MCC


omeprazole
  3 mEq or 250 mg NaHCO3
 50 mg Ac-di-Sol



23.6 mEq or 950 mgs total
 10 mg magnesium



buffer
stearate




4.8% disintegrant





















PPI
Buffering Agent
Excipient







40 mg
20.6 mEq or 600 mg Mg(OH)2
 30 mg MCC


omeprazole
  3 mEq or 250 mg NaHCO3
100 mg sodium starch



23.6 mEq or 950 mgs total
glycolate (Primojel ®)



buffer
 10 mg magnesium




stearate




9.7% disintegrant





















PPI
Buffering Agent
Excipient







40 mg
20.6 mEq or 600 mg Mg(OH)2
50 mg Klucel


omeprazole
  3 mEq or 250 mg NaHCO3
50 mg Ac-di-Sol



23.6 mEq or 850 mgs total
10 mg magnesium



buffer
stearate




5.0% disintegrant





















PPI
Buffering Agent
Excipient







40 mg
20.6 mEq or 600 mg Mg(OH)2
30 mg Klucel


omeprazole
  3 mEq or 250 mg NaHCO3
30 mg Ac-di-Sol



23.6 mEq or 850 mgs total
10 mg magnesium



buffer
stearate




3.1% disintegrant





















PPI
Buffering Agent
Excipient







20 mg
20.6 mEq or 600 mg Mg(OH)2
100 mg Klucel


omeprazole
  3 mEq or 250 mg NaHCO3
 30 mg Ac-di-Sol



23.6 mEq or 850 mgs total
 10 mg magnesium



buffer
stearate




3.0% disintegrant





















PPI
Buffering Agent
Excipient







20 mg
20.6 mEq or 600 mg Mg(OH)2
30 mg Klucel


omeprazole
 3.0 mEq or 250 mg NaHCO3
70 mg Crospovidone



23.6 mEq or 850 mgs total
10 mg magnesium



buffer
stearate




7.1% disintegrant





















PPI
Buffering Agent
Excipient







20 mg
20.6 mEq or 600 mg Mg(OH)2
50 mg Ac-Di-Sol


omeprazole
 3.0 mEq or 250 mg NaHCO3
30 mg Klucel


per capsule
23.6 mEq or 850 mgs total
10 mg magnesium



buffer
stearate




5.2% disintegrant





















PPI
Buffering Agent
Excipient







20 mg
20.6 mEq or 600 mg Mg(OH)2
40 mg Ac-Di-Sol


omeprazole
 4.2 mEq or 350 mg NaHCO3
35 mg Klucel


per capsule
24.7 mEq or 950 mg total
10 mg magnesium



buffer
stearate




4.1% disintegrant





















PPI
Buffering Agent
Excipient







15 mg
17.1 mEq or 500 mg Mg(OH)2
50 mg Ac-Di-Sol


microencapsulated
 3.0 mEq or 250 mg NaHCO3
15 mg Klucel


lansoprazole
20.7 1 mEq or 750 mg total
 7 mg


per capsule
buffer
magnesium




stearate




6.0% disintegrant





















PPI
Buffering Agent
Excipient







30 mg
17.1 mEq or 500 mg Mg(OH)2
40 mg Ac-Di-Sol


lansoprazole per
 4.2 mEq or 350 mg NaHCO3
30 mg Klucel


capsule
21.3 mEq or 850 mg total
10 mg magnesium



buffer
stearate




4.2% disintegrant





















PPI
Buffering Agent
Excipient







60 mg
17.1 mEq or 500 mg Mg(OH)2
30 mg Crospovidone


ompeprazole
 3.0 mEq or 250 mg NaHCO3
15 mg Klucel


per capsule
20.1 mEq or 750 mg total
 7 mg magnesium



buffer
stearate




3.5% disintegrant





















PPI
Buffering Agent
Excipient







10 mg ompeprazole per
17.1 mEq or 500 mg
30 mg sodium starch


capsule
Mg(OH)2
glycolate (Explotab ®)



3.0 mEq or 250 mg
15 mg Klucel



NaHCO3
7 mg magnesium stearate



20.1 mEq or 750 mg
3.7% disintegrant



total buffer





















PPI
Buffering Agent
Excipient







20 mg microencapsulated
20.6 mEq or 600
50 mg Ac-Di-Sol


omeprazole per capsule
mg Mg(OH)2
50 mg Klucel



3.0 mEq or 250
10 mg magnesium stearate



mg NaHCO3
5.1% disintegrant



23.6 mEq or 850



mg total



buffer






















Buffering



PPI
Agent
Excipient







40 mg omeprazole per
17.1 mEq or
40 mg Ac-Di-Sol


capsule
500 mg Mg(OH)2
45 mg Klucel



4.2 mEq or
10 mg magnesium stearate



350 mg NaHCO3
4.1% disintegrant



21.3 mEq or



850 mg total



buffer





















PPI
Buffering Agent
Excipient







15 mg
17.1 mEq or 500 mg Mg(OH)2
30 mg Crospovidone


lansoprazole
 3.0 mEq or 250 mg NaHCO3
15 mg Klucel


per capsule
20.1 mEq or 750 mg total
 7 mg magnesium



buffer
stearate




3.7% disintegrant





















PPI
Buffering Agent
Excipient







20 mg
17.1 mEq or 500 mg Mg(OH)2
50 mg Ac-Di-Sol


omeprazole per
 3.0 mEq or 250 mg NaHCO3
30 mg Klucel


capsule
20.1 mEq or 750 mg total
10 mg magnesium



buffer
stearate




5.8% disintegrant





















PPI
Buffering Agent
Excipient







40 mg omeprazole per
20.6 mEq or
40 mg Ac-Di-Sol


capsule
600 mg Mg(OH)2
35 mg Klucel



4.2 mEq or
10 mg magnesium stearate



350 mg NaHCO3
3.7% disintegrant



24.8 mEq or



950 mg total



buffer





















PPI
Buffering Agent
Excipient







15 mg microencapsulated
17.1 mEq or
60 mg Ac-Di-Sol


lansoprazole
500 mg Mg(OH)2
15 mg Klucel


per capsule
3.0 mEq or
7 mg magnesium stearate



250 mg NaHCO3
7.1% disintegrant



20.1 mEq or



750 mg total



buffer





















PPI
Buffering Agent
Excipient







60 mg ompeprazole per
17.1 mEq or
30 mg Ac-Di-Sol


capsule
500 mg Mg(OH)2
15 mg Klucel



3.0 mEq or
7 mg magnesium stearate



250 mg NaHCO3
3.5% disintegrant



20.1 mEq or



750 mg total



buffer





















PPI
Buffering Agent
Excipient







20 mg omeprazole per
6.9 mEq or
30 mg Ac-Di-Sol


capsule
200 mg Mg(OH)2
35 mg Klucel


Size 0 capsule
3.9 mEq or
6 mg magnesium stearate



330 mg NaHCO3
4.8% disintegrant



10.8 mEq or



530 mg total



buffer





















PPI
Buffering Agent
Excipient







15 mg microencapsulated
6.9 mEq or
35 mg Ac-Di-Sol


lansoprazole per capsule
200 mg Mg(OH)2
20 mg Klucel


Size 1 capsule
2.6 mEq or
6 mg magnesium stearate



220 mg NaHCO3
7.1% disintegrant



8.5 mEq or



420 mg total



buffer





















PPI
Buffering Agent
Excipient







30 mg
3.4 mEq or 100 mg Mg(OH)2
20 mg Ac-Di-Sol


lansoprazole
3.8 mEq or 315 mg NaHCO3
30 mg Klucel


per capsule

 5 mg magnesium




stearate


Size 1 capsule
7.2 mEq or 415 mg total
4.0% disintegrant



buffer





















PPI
Buffering Agent
Excipient







60 mg ompeprazole per
5.1 mEq or
20 mg Ac-Di-Sol


capsule
150 mg Mg(OH)2
10 mg Klucel


Size 2 capsule
3.0 mEq or
4 mg magnesium stearate



250 mg NaHCO3
4.1% disintegrant



8.1 mEq or



400 mg total



buffer





















PPI
Buffering Agent
Excipient







120 mg ompeprazole per
8.6 mEq or
30 mg Ac-Di-Sol


capsule
250 mg Mg(OH)2
30 mg Klucel


Size 1 capsule
2.4 mEq or
8 mg magnesium stearate



200 mg NaHCO3
4.7% disintegrant



11.0 mEq or



450 mg total



buffer





















PPI
Buffering Agent
Excipient







10 mg ompeprazole
3.4 mEq or 100 mg Mg(OH)2
18 mg Ac-Di-Sol


per capsule
3.0 mEq or 250 mg NaHCO3
15 mg Klucel


Size 2 capsule
6.4 mEq or 350 mg total
 7 mg magnesium



buffer
stearate




4.5% disintegrant









Example 7
Capsule Formulations without Binder
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with one or more buffering agents, and homogeneously blending with excipients. The appropriate weight of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsualtor. The PPI can be in a micronized form.












PPI
Buffering Agent
Excipient







40 mg
20.6 mEq or 600 mg Mg(OH)2
50 mg Ac-di-Sol


omeprazole
 3.0 mEq or 250 mg NaHCO3
10 mg magnesium



23.6 mEq or 950 mgs total
stearate



buffer





















PPI
Buffering Agent
Excipient







40 mg
15.4 mEq or 450 mg Mg(OH)2
30 mg Ac-Di-Sol


micro-
 2.4 mEq or 200 mg NaHCO3
 7 mg magnesium


encapsulated
17.8 mEq or 650 mg total
stearate


ompeprazole
buffer


per capsule





















PPI
Buffering Agent
Excipient







40 mg
10.5 mEq or 880 mg NaHCO3
20 mg Ac-Di-Sol


omeprazole
10.5 mEq or 880 mg total
 9 mg magnesium stearate


per capsule
buffer
Size 0 Elongated capsule





















PPI
Buffering Agent
Excipient







40 mg
3.4 mEq or 100 mg Mg(OH)2
20 mg Ac-Di-Sol


microencapsulated
2.4 mEq or 200 mg NaHCO3
 5 mg magnesium


ompeprazole
5.8 mEq or 300 mg total
stearate


per capsule
buffer
Size 2 capsule









Example 8
Capsule Formulations
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with antacids, and homogeneously blending with excipients as shown in Tables 8.A. to 8.H. below. The appropriate weight of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsualtor (H & K 1500 or MG2 G60). The PPI can be in a micronized form.







TABLE 8.A







Omeprazole (20 mg) Capsule









PPI
Antacid
Excipient





20 mg
 6.9 mEq or 200 mg Mg(OH)2
30 mg Ac-Di-Sol


omeprazole
 3.9 mEq or 330 mg NaHCO3
35 mg Klucel


per capsule
10.8 mEq or 530 mg total
 6 mg magnesium



antacid
stearate




Size 0 capsule
















TABLE 8.B







Omeprazole (40 mg) Capsule









PPI
Antacid
Excipient





40 mg
10.5 mEq or 880 mg NaHCO3
40 mg Ac-Di-Sol


omeprazole
10.5 mEq or 880 mg total
 9 mg magnesium stearate


per capsule
antacid
Size 0 Elongated capsule
















TABLE 8.C







Lansoprazole (15 mg) Capsule









PPI
Antacid
Excipient





15 mg
6.9 mEq or 200 mg Mg(OH)2
35 mg Ac-Di-Sol


microencapsulated
2.6 mEq or 220 mg NaHCO3
20 mg Klucel


lansoprazole
9.5 mEq or 420 mg total
 6 mg magnesium


per capsule
antacid
stearate




Size 1 capsule
















TABLE 8.D







Lansoprazole (30 mg) Capsule









PPI
Antacid
Excipient





30 mg lansoprazole
3.4 mEq or 100 mg Mg(OH)2
20 mg Ac-Di-Sol


per capsule
3.8 mEq or 315 mg NaHCO3
30 mg Klucel



7.2 mEq or 415 mg total
 5 mg magnesium



antacid
stearate




Size 1 capsule
















TABLE 8.E







Omeprazole (60 mg) Capsule









PPI
Antacid
Excipient





60 mg omeprazole
5.1 mEq or 150 mg Mg(OH)2
20 mg Ac-Di-Sol


per capsule
3.0 mEq or 250 mg NaHCO3
10 mg Klucel



8.1 mEq or 400 mg total
 4 mg magnesium



antacid
stearate




Size 2 capsule
















TABLE 8.F







Omeprazole (60 mg) Capsule









PPI
Antacid
Excipient





120 mg
 8.6 mEq or 250 mg Mg(OH)2
30 mg Ac-Di-Sol


omeprazole per
 2.4 mEq or 200 mg NaHCO3
30 mg Klucel


capsule
11.0 mEq or 450 mg total
 8 mg magnesium



antacid
stearate




Size 1 capsule
















TABLE 8.G







Omeprazole (10 mg) Capsule









PPI
Antacid
Excipient





10 mg
3.4 mEq or 100 mg Mg(OH)2
18 mg Ac-Di-Sol


microencapsulated
3.0 mEq or 250 mg NaHCO3
15 mg


omeprazole
6.4 mEq or 350 mg total
Microcrystalline


per capsule
antacid
Cellulose




(MCC, PH102)




 7 mg magnesium




stearate




Size 2 capsule
















TABLE 8.H







Omeprazole (40 mg) Capsule









PPI
Antacid
Excipient





40 mg
3.4 mEq or 100 mg Mg(OH)2
20 mg Ac-Di-Sol


microencapsulated
2.4 mEq or 200 mg NaHCO3
 5 mg magnesium


omeprazole
5.8 mEq or 300 mg total
stearate


per capsule
antacid
Size 2 capsule









Example 9
Tablet Formulations
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The tablets are prepared by blending the PPI and antacids, and homogeneously blending with excipients as shown in Tables 9.A. to 9.H. below. The appropriate weight of bulk blended composition is compressed using oval shaped toolings in a rotary press (Manesty Express) to achieve a hardness of 15-20 kPa. The PPI can be in a micronized form.







TABLE 9.A







Omeprazole (20 mg) Tablet









PPI
Antacid
Excipient





20 mg omeprazole
5.1 mEq or 150 mg Mg(OH)2
30 mg Ac-Di-Sol


per tablet
4.8 mEq or 400 mg NaHCO3
65 mg Klucel



9.9 mEq or 550 mg total
10 mg magnesium



antacid
stearate
















TABLE 9.B







Omeprazole (40 mg) Tablet









PPI
Antacid
Excipient





40 mg
5.1 mEq or 150 mg Mg(OH)2
20 mg Ac-Di-Sol


microencapsulated
3.0 mEq or 250 mg NaHCO3
40 mg


omeprazole
8.1 mEq or 350 mg total
Microcrystalline


per tablet
antacid
cellulose




(MCC, PH102)




 7 mg magnesium




stearate
















TABLE 9.C







Lansoprazole (15 mg) Tablet









PPI
Antacid
Excipient





15 mg
 8.6 mEq or 250 mg Mg(OH)2
30 mg Ac-Di-Sol


microencapsulated
 2.4 mEq or 200 mg NaHCO3
55 mg Plasdone


lansoprazole
11.0 mEq or 450 mg total
 8 mg


per tablet
antacid
magnesium




stearate
















TABLE 9.D







Lansoprazole (30 mg) Tablet









PPI
Antacid
Excipient





30 mg
 6.2 mEq or 180 mg Mg(OH)2
25 mg Ac-Di-Sol


lansoprazole per
 4.2 mEq or 350 mg NaHCO3
55 mg Klucel


tablet
10.4 mEq or 430 mg total
 8 mg magnesium



antacid
stearate
















TABLE 9.E







Omeprazole (60 mg) Tablet









PPI
Antacid
Excipient





60 mg
 7.5 mEq or 220 mg Mg(OH)2
20 mg Ac-Di-Sol


omeprazole per
 3.0 mEq or 250 mg NaHCO3
60 mg Klucel


tablet
10.5 mEq or 470 mg total
10 mg magnesium



antacid
stearate
















TABLE 9.F







Omeprazole (20 mg) Tablet









PPI
Antacid
Excipient





20 mg
7.5 mEq or 220 mg Mg(OH)2
20 mg Ac-Di-Sol


omeprazole
2.4 mEq or 200 mg NaHCO3
60 mg Klucel


per tablet
9.9 mEq or 420 mg total
 8 mg magnesium stearate



antacid
















TABLE 9.G







Omeprazole (10 mg) Tablet









PPI
Antacid
Excipient





10 mg
3.4 mEq or 100 mg Mg(OH)2
15 mg Ac-Di-Sol


microencapsulated
3.0 mEq or 250 mg NaHCO3
40 mg Klucel


omeprazole
6.4 mEq or 350 mg total
 6 mg magnesium


per tablet
antacid
stearate
















TABLE 9.H







Omeprazole (40 mg) Tablet









PPI
Antacid
Excipient





40 mg
5.1 mEq or 150 mg Mg(OH)2
20 mg Ac-Di-Sol


micro-
3.8 mEq or 315 mg NaHCO3
50 mg Microcrystalline


encapsulated
8.9 mEq or 465 mg total
Cellulose (MCC, PH102)


omeprazole
antacid
10 mg magnesium stearate


per tablet









Example 10
Chewable Tablet Formulations
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The tablets are prepared by blending the PPI and antacids, and homogeneously blending with excipients as shown in Tables 10.A to 10.H. below. The appropriate weight of bulk blended composition is compressed using 17mm FFBE toolings in a rotary press (Manesty Express) to achieve a hardness of 10-14 kPa. The PPI can be in a micronized form.







TABLE 10.A







Omeprazole (20 mg) Chewable Tablet









PPI
Antacid
Excipient





20 mg
5.1 mEq or 150 mg Mg(OH)2
100 mg Xylitab


micro-
3.8 mEq or 315 mg NaHCO3
 30 mg Ac-Di-Sol


encapsulated
8.9 mEq or 465 mg total
 80 mg Klucel


omeprazole
antacid
 20 mg Sucralose


per tablet

 10 mg cherry flavor




 10 mg magnesium stearate




 1 mg Red #40 Lake
















TABLE 10.B







Omeprazole (40 mg) Chewable Tablet









PPI
Antacid
Excipient





40 mg
7.5 mEq or 220 mg Mg(OH)2
100 mg Dipac sugar


micro-
2.4 mEq or 200 mg NaHCO3
 20 mg Ac-Di-Sol


encapsulated
9.9 mEq or 420 mg total
 80 mg Klucel


omeprazole
antacid
 17 mg grape flavor


per tablet

 11 mg magnesium stearate




 1 mg Red #40 Lake




 1 mg Blue #2 Lake
















TABLE 10.C







Lansoprazole (15 mg) Chewable Tablet









PPI
Antacid
Excipient





15 mg
5.1 mEq or 150 mg Mg(OH)2
80 mg Xylitab


lansoprazole
2.4 mEq or 200 mg NaHCO3
25 mg Ac-Di-Sol


per tablet
7.5 mEq or 350 mg total
70 mg Microcrystalline



antacid
Cellulose




50 mg Asulfame-K




15 mg grape flavor




10 mg magnesium stearate




 1 mg red #40 lake




 1 mg blue #2 lake
















TABLE 10.D







Lansoprazole (30 mg) Chewable Tablet









PPI
Antacid
Excipient





30 mg
5.1 mEq or 150 mg Mg(OH)2
 70 mg Destab Sugar


micro-
3.8 mEq or 315 mg NaHCO3
 30 mg Ac-Di-Sol


encapsulated
8.9 mEq or 465 mg total
100 mg Klucel


lansoprazole
antacid
 20 mg Asulfame-K


per tablet

 15 mg cherry flavor




 9 mg magnesium stearate




 1 mg Red #40 Lake
















TABLE 10.E







Omeprazole (60 mg) Chewable Tablet









PPI
Antacid
Excipient





60 mg
4.4 mEq or 220 mg Ca(OH)2
 80 mg Xylitab


micro-
3.6 mEq or 300 mg NaHCO3
 30 mg Ac-Di-Sol


encapsulated
8.0 mEq or 520 mg total
100 mg Klucel


omeprazole
antacid
 35 mg Sucralose


per tablet

 10 mg cherry flavor




 9 mg magnesium stearate




 2 mg Red #40 Lake
















TABLE 10.F







Omeprazole (60 mg) Chewable Tablet









PPI
Antacid
Excipient





60 mg
3.0 mEq or 150 mg Ca(OH)2
70 mg Xylitab


omeprazole
3.0 mEq or 250 mg NaHCO3
25 mg Ac-Di-Sol


per tablet
6.0 mEq or 400 mg total
90 mg Microcrystalline



antacid
Cellulose (PH 102)




 8 mg mint flavor




10 mg magnesium stearate
















TABLE 10.G







Omeprazole (10 mg) Chewable Tablet









PPI
Antacid
Excipient





10 mg
 8.0 mEq or 400 mg Ca(OH)2
110 mg Ditab Sugar


omeprazole
 3.6 mEq or 300 mg NaHCO3
 30 mg Ac-Di-Sol


per tablet
11.6 mEq or 700 mg total
 20 mg Sucralose



antacid
100 mg Klucel




 15 mg mint flavor




 15 mg magnesium stearate
















TABLE 10.H







Omeprazole (40 mg) Chewable Tablet









PPI
Antacid
Excipient





40 mg
 7.5 mEq or 350 mg Ca(OH)2
70 mg Xylitab


microencapsulated
 3.0 mEq or 250 mg NaHCO3
30 mg Ac-Di-Sol


omeprazole
10.5 mEq or 600 mg total
10 mg Sucralose


per tablet
antacid
80 mg Klucel




10 mg mint flavor




 8 mg magnesium




stearate









Example 11
Bite-Disintegration Chewable Tablet Formulations
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The tablets are prepared by blending the PPI with antacids, and homogeneously blending with excipients as shown in Tables 11.A to 11.H. below. The appropriate weight of bulk blended composition is compressed using 10 mm FFBE toolings in a rotary press (Manesty Express) to achieve a hardness of 5-9 kPa. The PPI can be in a micronized form.







TABLE 11.A







Omeprazole (20 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





20 mg per
 7.5 mEq or 350 mg Ca(OH)2
20 mg sucralose


tablet
 3.0 mEq or 250 mg NaHCO3
40 mg Ac-Di-Sol



10.5 mEq or 600 mg total
30 mg pregelatinized starch



antacid
30 mg Klucel




15 mg cherry flavor




 8 mg magnesium stearate




 1 mg Red #40 Lake
















TABLE 11.B







Omeprazole (40 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





40 mg
 8.0 mEq or 400 mg Ca(OH)2
20 mg sucralose


microencapsulated
 3.6 mEq or 300 mg NaHCO3
40 mg Ac-Di-Sol


omeprazole
11.6 mEq or 700 mg total
35 mg


per tablet

pregelatinized




starch




25 mg Klucel




15 mg cherry flavor




 8 mg magnesium




stearate




 1 mg Red #40




Lake
















TABLE 11.C







Lansoprazole (15 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





15 mg
 7.9 mEq or 230 mg Mg(OH)2
20 mg sucralose


lansoprazole
 3.6 mEq or 300 mg NaHCO3
35 mg Ac-Di-Sol


per tablet
11.5 mEq or 530 mg total
35 mg pregelatinized




starch




25 mg Klucel




17 mg grape flavor




 8 mg magnesium




stearate




 1 mg Red #40 Lake




 1 mg Blue #2 lake
















TABLE 11.D







Lansoprazole (30 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





30 mg
5.1 mEq or 150 mg Mg(OH)2
27 mg sucralose


microencapsulated
3.8 mEq or 315 mg NaHCO3
40 mg Ac-Di-Sol


lansoprazole
8.9 mEq or 465 mg total
35 mg


per tablet
antacid
pregelatinized starch




30 mg




Microcrystalline




Cellulose (PH101)




20 mg cherry flavor




10 mg magnesium




stearate




 2 mg Red #40




Lake
















TABLE 11.E







Omeprazole (60 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





60 mg
 7.9 mEq or 230 mg Mg(OH)2
34 mg sucralose


microencapsulated
 3.0 mEq or 250 mg NaHCO3
30 mg Ac-Di-Sol


omeprazole
10.9 mEq or 480 mg total
35 mg


per tablet
antacid
pregelatinized




starch




30 mg Klucel




25 mg cherry




flavor




10 mg




magnesium




stearate




 2 mg Red #40




Lake
















TABLE 11.F







Omeprazole (60 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





60 mg
 7.0 mEq or 350 mg Ca(OH)2
30 mg sucralose


omeprazole
 3.0 mEq or 250 mg NaHCO3
40 mg Ac-Di-Sol


per tablet
10.0 mEq or 600 mg total
30 mg pregelatinized starch



antacid
30 mg Klucel




40 mg Xylitab




 7 mg mint flavor




10 mg magnesium




stearate
















TABLE 11.G







Omeprazole (10 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





10 mg
5.0 mEq or 250 mg Ca(OH)2
20 mg sucralose


omeprazole
2.9 mEq or 240 mg NaHCO3
40 mg Ac-Di-Sol


per tablet
7.9 mEq or 490 mg total
30 mg pregelatinized starch



antacid
30 mg Klucel




15 mg cherry flavor




 8 mg magnesium stearate




 1 mg Red #40 Lake
















TABLE 11.H







Omeprazole (40 mg) Bite-Disintegration Chewable Tablet









PPI
Antacid
Excipient





40 mg
 8.0 mEq or 400 mg Ca(OH)2
30 mg sucralose


microencapsulated
 2.9 mEq or 240 mg NaHCO3
40 mg Ac-Di-Sol


omeprazole
10.9 mEq or 1590 mg total
30 mg


per tablet
antacid
pregelatinized




starch




30 mg Klucel




40 mg Xylitab




 7 mg mint flavor




10 mg magnesium




stearate









Example 12
Powder for Suspension Formulations
The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. The PPI can be in a micronized form.







TABLE 12.A







Microencapsulated Omeprazole (20/40/60/120 mg) Powder for Suspension


















1
2
3
4
5
6
7
8
9
10




















Microencapsulated
20
20
20
40
40
40
60
60
120
120


Omeprazole












Sodium Bicarbonate
200
220
300
140
160
200
300
280
150
200


Magnesium Hydroxide
250
170
150
250
170
150
170
150
100
150


Calcium Carbonate
0
0
0
0
100
150
0
100
0
150


Xylitol 300 (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucrose-powder
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


(sweetener)












Sucralose (sweetener)
60
100
150
75
100
70
80
130
125
80


Xanthan Gum
10
55
31
80
39
48
72
25
64
68


Peach Flavor
33
15
75
32
60
50
77
38
35
62


Peppermint
13
10
29
28
36
42
56
17
16
50


Total Weight
2586
2590
2755
2645
2705
2750
2815
2800
2610
2880


Total ANC
11.0
8.4
8.7
10.2
9.7
10.5
9.4
10.5
5.2
10.5
















TABLE 12.B







Omeprazole (20 mg) Powder for Suspension


















1
2
3
4
5
6
7
8
9
10




















Omeprazole
20
20
20
20
20
20
20
20
20
20


Sodium Bicarbonate
200
220
300
140
160
200
300
280
150
200


Magnesium Hydroxide
250
170
150
250
170
150
170
150
100
150


Calcium Carbonate
0
0
0
0
100
150
0
100
0
150


Xylitol 300 (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucrose-powder (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucralose (sweetener)
60
100
150
75
100
70
80
130
125
80


Xanthan Gum
10
55
31
80
39
48
72
25
64
68


Peach Flavor
33
15
75
32
60
50
77
38
35
62


Peppermint
13
10
29
28
36
42
56
17
16
50


Total Weight
2586
2590
2755
2625
2685
2730
2775
2760
2510
2780


Total ANC
11.0
8.4
8.7
10.2
9.7
10.5
9.4
10.5
5.2
10.5
















TABLE 12.C







Omeprazole (40 mg) Powder for Suspension


















1
2
3
4
5
6
7
8
9
10





















Omeprazole
40
40
40
40
40
40
40
40
40
40


Sodium Bicarbonate
200
220
300
140
160
200
300
280
150
200


Magnesium Hydroxide
250
170
150
250
170
150
170
150
100
150


Calcium Carbonate
0
0
0
0
100
150
0
100
0
150


Xylitol 300 (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucrose-powder (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucralose (sweetener)
60
100
150
75
100
70
80
130
125
80


Xanthan Gum 75
10
55
31
80
39
48
72
25
64
68


Peach Flavor
33
15
75
32
60
50
77
38
35
62


Peppermint
13
10
29
28
36
42
56
17
16
50


Total Weight
2606
2610
2775
2645
2705
2750
2795
2780
2530
2800


Total ANC
11.0
8.4
8.7
10.2
9.7
10.5
9.4
10.5
5.2
10.5
















TABLE 12.D







Omeprazole (60 mg) Powder for Suspension


















1
2
3
4
5
6
7
8
9
10





















Omeprazole
60
60
60
60
60
60
60
60
60
60


Sodium Bicarbonate
200
220
300
140
160
200
300
280
150
200


Magnesium Hydroxide
250
170
150
250
170
150
170
150
100
150


Calcium Carbonate
0
0
0
0
100
150
0
100
0
150


Xylitol 300 (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucrose-powder (sweetener)
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000


Sucralose (sweetener)
60
100
150
75
100
70
80
130
125
80


Xanthan Gum 75
10
55
31
80
39
48
72
25
64
68


Peach Flavor
33
15
75
32
60
50
77
38
35
62


Peppermint
13
10
29
28
36
42
56
17
16
50


Total Weight
2626
2630
2795
2665
2725
2770
2815
2800
2550
2820


Total ANC
11.0
8.4
8.7
10.2
9.7
10.5
9.4
10.5
5.2
10.5









Many modifications, equivalents, and variations of the present invention are possible in light of the above teachings, therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described.

## Claims

1. A pharmaceutical formulation in a compressed tablet oral dosage form consisting essentially of:
(a) about 10 mgs to about 100 mgs of a proton pump inhibitor, wherein the proton pump inhibitor is omeprazole;
(b) at least one antacid, wherein the antacid comprises about 400 mgs to about 1400 mgs of NaHCO3;
(c) about 2 wt-% to about 8 wt-% of a disintegrant;
(d) about 3 wt-% to about 8 wt-% of a binder; and
(e) about 0.5 wt-% to about 3 wt-% of a lubricant;
wherein the antacid further comprises magnesium hydroxide and the total amount of antacid present in the tablet is about 10 mEg to about 30 mEg;
wherein the tablet is a homogeneous blend of omeprazole, antacids, disintegrant, binder, and lubricant; and
wherein upon oral administration of the compressed tablet to a fasted human subject, a Tmax of the proton pump inhibitor is obtained within about 45 minutes after administration on day I, and an initial serum concentration of the proton pump inhibitor is greater than 300 ng/ml within 45 minutes after administration; and wherein the compressed tablet has a hardness of between is kPa and 20 kPa.

2. The pharmaceutical formulation according to claim 1, wherein the sodium bicarbonate is present in an amount of at least 700 mgs.

3. The pharmaceutical formulation according to claim 1, wherein the disintegrant is croscarmellose sodium and is present in an amount of about 3 wt-%.

4. The pharmaceutical formulation according to claim 1, wherein the disintegrant is present in an amount of about 3 wt-% to about 5 wt-%.

5. The pharmaceutical composition according to claim 1, wherein the binder is hydroxypropyl cellulose and is present in an amount of about 6 wt-%.

6. The pharmaceutical formulation according to claim 1, wherein the binder is present in an amount of about 5 wt-% to about 8 wt-%.

7. A pharmaceutical formulation in a compressed tablet oral dosage form consisting essentially of:
(a) a proton pump inhibitor, wherein the proton pump inhibitor is omeprazole or a salt thereof in an amount of about 20 mgs or about 40 mgs;
(b) at least one antacid comprising about 700 mgs to about 1400 mgs of NaHCO3;
(c) about 2 wt-% to about 8 wt-% of a disintegrant;
(d) about 3 wt-% to about 8 wt-% of a binder; and
(e) about 0.5 wt-% to about 3 wt-% of a lubricant
wherein the antacid further comprises magnesium hydroxide and the total amount of antacid present in the tablet is about 10 mEq to about 30 mEq; and
wherein the tablet is a homogeneous blend of omeprazole, antacids, disintegrant, binder, and lubricant.

8. The pharmaceutical composition of claim 7 wherein:
(a) the NaHCO3 is present in an amount of about 1100 mgs to about 1400 mgs;
(b) the disintegrant is croscarmellose sodium and is present in an amount of about 3 wt-% to about 5 wt-%; and
(c) the binder is hydroxypropyl cellulose and is present in an amount of about 5 wt-% to about 8 wt-%;
wherein upon oral administration of the tablet to a fasted human subject, a Tmax of the proton pump inhibitor is obtained within about 45 minutes after administration on day 1.

9. A pharmaceutical formulation in a compressed tablet oral dosage form comprising:
(a) about 10 mgs to about 100 mgs of a proton pump inhibitor, wherein the proton pump inhibitor is omeprazole or an enantiomer or salt thereof;
(b) about 10-30 mEg of antacid comprising about 400 mgs to about 1400 mgs of NaHCO3;
(c) about 2 wt-% to about 8 wt-% of a disintegrant; and
(d) about 3 wt-% to about 8 wt-% of a binder,
wherein the antacid further comprises magnesium hydroxide;
wherein the tablet is a homogeneous blend of omeprazole, antacids, disintegrant, and binder; and
wherein the compressed tablet has a hardness of between 15 kPa and 20 kPa.

10. The pharmaceutical formulation according to claim 9, wherein the proton pump inhibitor is omeprazole or a salt thereof.

11. The pharmaceutical formulation according to claim 9, wherein the sodium bicarbonate is present in an amount of about 700 mgs to about 1400 mgs.

12. The pharmaceutical formulation according to claim 9, wherein the disintegrant is croscarmellose sodium and is present in an amount of about 3 wt-%.

13. The pharmaceutical formulation according to claim 9, wherein the disintegrant is present in an amount of about 3 wt-% to about 5 wt-%.

14. The pharmaceutical formulation according to claim 9, wherein the binder is hydroxypropyl cellulose and is present in an amount of about 6 wt-%.

15. The pharmaceutical formulation according to claim 9, wherein the binder is present in an amount of about 5 wt-% to about 8 wt-%.

16. The pharmaceutical formulation of claim 9, wherein the NaHCO3 is present in an amount of about 1100 mgs to about 1400 mgs.

17. The pharmaceutical formulation of claim 16, wherein the disintegrant comprises croscarmellose sodium.

18. The pharmaceutical formulation of claim 17, wherein the croscarmellose sodium is present in an amount of about 3 wt-% to about 5 wt-%.

19. The pharmaceutical composition of claim 18, wherein the binder comprises hydroxypropyl cellulose.

20. The pharmaceutical formulation of claim 19, wherein the hydroxypropyl cellulose is present in an amount of about 5 wt-% to about 8 wt-%.

21. The pharmaceutical formulation of claim 1, wherein the tablet provides greater than 50% release of the proton pump inhibitor in gastrointestinal fluid within about 2 hours.

22. The pharmaceutical formulation of claim 9, wherein the tablet provides greater than 50% release of the proton pump inhibitor in gastrointestinal fluid within about 2 hours.