JP2008500365A - Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using the same - Google Patents

Abstract

The present invention comprises at least one acid labile proton pump inhibitor and at least one antacid, and has improved bioavailability, chemical stability, physical stability, dissolution profile, disintegration time , Pharmaceutical preparations having safety and other improved pharmacokinetic, pharmacodynamic, chemical and / or physical properties. The present invention provides a method for treating, preventing or reducing the risk of developing gastrointestinal disorders or diseases, or symptoms associated with or associated with gastrointestinal disorders or diseases in a subject in need thereof, Directed to kits, combinations, and compositions.

Description

FIELD OF THE INVENTION The present invention comprises at least one acid labile proton pump inhibitor and at least one antacid, bioavailability, chemical stability, physical stability, dissolution profile, disintegration time Relates to solid oral dosage form pharmaceutical formulations with improved safety and other pharmacokinetic, pharmacodynamic, chemical and / or physical properties. Similar bioavailability, chemical stability, physics for similar combinations containing at least one proton pump inhibitor and antacids of about 5 mEq to about 11 mEq, and higher than 11 mEq Also described herein are pharmaceutical formulations having mechanical stability, dissolution profile, disintegration time, safety, and other pharmacokinetic, pharmacodynamic, chemical and / or physical properties. .

  The present invention provides a method for treating, preventing or reducing the risk of developing gastrointestinal disorders or diseases, or symptoms associated with or associated with gastrointestinal disorders or diseases in a subject in need thereof, Directed to kits, combinations, and compositions.

  The present invention relates to U.S. Provisional Application No. 60 / 574,646, filed May 25, 2004, and U.S. application filed May 25, 2004, the contents of which are hereby fully incorporated by reference. The benefit of provisional application number 60 / 574,663 is claimed under 35 USC 119 (e).

Background of the Invention Upon digestion, most acid labile pharmaceutical compounds must be protected from contact with gastric acid secretion in order to maintain their pharmacological activity. To achieve this, a composition with an enteric coating is used at a neutral pH to ensure that the drug is released in the proximal region of the small intestine (duodenum), rather than in the acidic environment of the stomach. It has been designed to dissolve. However, due to the pH-dependent attributes and retention time uncertainties of these enteric-coated compositions, in vivo performance as well as variability between and within a subject can control drug control. Are all major failures in using enteric coated systems for release

  In addition, Phillips et al. Describe pharmaceutical compositions that are not non-enteric coated. These compositions that allow for the direct release of the pharmaceutically active ingredient into the stomach include the administration of one or more antacids with an acid labile medical agent such as a proton pump inhibitor. This antacid is believed to interfere with substantial degradation of the acid labile pharmaceutical agent in the acidic environment of the stomach by raising the pH. For example, see US Pat. Nos. 5,840,737 (Patent Document 1) and 6,489,346 (Patent Document 2).

One class of acid labile pharmaceutical compounds that are administered as enteric coated dosage forms are proton pump inhibitors. Exemplary proton pump inhibitors include: omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®) ), Rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole. This class of drugs suppresses gastrointestinal acid secretion by specifically inhibiting the H ⁺ / K ⁺ -ATPase enzyme system (proton pump) on the secretory surface of gastrointestinal parietal cells. Most proton pump inhibitors are sensitive to acid degradation and thus are rapidly degraded when the pH is lowered to acidic levels. Therefore, if the enteric coatings of these formulated products are destroyed (e.g., comminution into compound liquids or chewing capsules or tablets), or antacids sufficiently reduce the gastrointestinal pH. If unsuccessful, the drug is subject to degradation by gastrointestinal acid in the stomach.

  Omeprazole is a substituted bicyclic aryl-imidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, which inhibits gastrointestinal acid secretion Is an example of a proton pump inhibitor. U.S. Pat.No. 4,786,505 to Lovgren et al. Describes a pharmacological oral solid dosage form of omeprazole protected from contact with acidic gastrointestinal fluids by an enteric coating to maintain its pharmacological activity. Teaches what must be and describes enteric-coated omeprazole preparations comprising one or more subcoats between the core material and the enteric coating.

  Proton pump inhibitors are typically active duodenal ulcer, gastrointestinal ulcer, gastroesophageal reflux disease (GERD), severe erosive esophagitis, hyporesponsive symptomatic GERD, and pathological gastrointestinal hypersecretion It is prescribed for short-term treatment of sexually transmitted diseases, such as Zollinger-Ellison syndrome. These above listed conditions are generally elevated in healthy or seriously ill patients of all ages and may be accompanied by upper gastrointestinal bleeding.

Omeprazole, lansoprazole, and other proton pump inhibitors are gastrointestinal acid production by inhibiting mural cell H ⁺ / K ⁺ -ATPase, which is the ultimate general pathway for gastrointestinal acid secretion Is believed to decrease. For example, see: 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) (Non-patent Document 3).

Proton pump inhibitors have the ability to act as weak bases reaching the mural cells from the blood and diffuse into secretory tubules. There the drug is protonated and thereby trapped. The protonated compound can then be rearranged to form sulfenamide, which is a sulfhydryl at a critical site in the extracellular (luminal) domain of transmembrane H ⁺ / K ⁺ -ATPase. Can interact covalently with the group. For example, see Hardman et al., Goodman &Gilman's The Pharmacological Basis of Therapeutics, 907 (9th ed. 1996) (Non-Patent Document 4). Thus, proton pump inhibitors are prodrugs that must be activated in order to be effective. The specificity of the effects of proton pump inhibitors also depends on: (a) the selective distribution of H ⁺ / K ⁺ -ATPase; (b) the need for acidic conditions to catalyze the formation of reactive inhibitors And (c) trapping protonated drug and cationic sulfenamide in acidic tubules and adjacent to the target enzyme. For example, see Hardman et al.

U.S. Pat.No. 5,840,737 U.S. Pat.No. 6,489,346 U.S. Pat.No. 4,786,505 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) Fryklund et al., Function and Structure of Parietal Cells After H + / K + -ATPase Blockade, Am. J Physiol., 254 (1988) Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 907 (9th ed. 1996)

The present invention provides (a) at least one acid labile proton pump inhibitor, and (b) gastric pH to increase to a pH that prevents acid degradation of at least some proton pump inhibitors in gastric juice. Directed to a solid oral dosage form pharmaceutical formulation comprising at least one antacid that is sufficient to deliver a therapeutically effective amount of a proton pump inhibitor upon oral administration to a patient, wherein proton pump inhibition The T _max of the agent is obtained within about 75 minutes after administration. In alternative embodiments, the T _max of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In certain embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

In one embodiment, (a) at least one acid labile proton pump inhibitor; (b) to increase the pH of gastric juice to a pH that interferes with the acid degradation of at least some proton pump inhibitors in the gastric juice. A sufficient amount of sodium bicarbonate; (c) less than about 3% disintegrant, wherein upon oral administration to a patient, a therapeutically effective amount of a proton pump inhibitor is delivered and the proton pump inhibitor T _{The max} describes a solid oral dosage form pharmaceutical formulation obtained within about 75 minutes after administration. In other embodiments, the pharmaceutical formulation comprises less than about 2% or less than about 1% disintegrant. In alternative embodiments, the T _max of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In certain embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

(a) at least one acid labile proton pump inhibitor; and (b) an amount sufficient to increase the pH of gastric juice to a pH that interferes with acid degradation of at least some proton pump inhibitors in the gastric juice. At least one antacid, wherein no binder is included; upon oral administration to a patient: a therapeutically effective amount of a proton pump inhibitor is delivered, and the T _{max of the} proton pump inhibitor is about Also provided herein is a solid oral dosage form of a stable pharmaceutical formulation obtained within 75 minutes. In some embodiments, the antacid is present in an amount greater than about 5 mEq. 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 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 30 mEq or about 35 mEq In certain embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

(a) at least one acid labile proton pump inhibitor; (b) at least about 5 mEq of an antacid that is a combination of at least two different antacids; and (c) from about 3% to about 11%. Where, upon oral administration to a patient: a solid oral dosage form in which a therapeutically effective amount of a proton pump inhibitor is delivered and a T _max of the proton pump inhibitor is obtained within about 75 minutes A stable pharmaceutical formulation of is also provided herein. In certain 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, the T _max of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In certain embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

(a) at least one acid labile proton pump inhibitor; (b) about 5 to about 15 mEq sodium bicarbonate, and (c) less than about 3% disintegrant, wherein the oral administration to the patient Also provided herein is a stable pharmaceutical formulation in a single capsule dosage form in which a therapeutically effective amount of a proton pump inhibitor is delivered and the T _max of the proton pump inhibitor is obtained within about 75 minutes. The In certain 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 sodium bicarbonate. In yet other embodiments, the T _max of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration.

(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) about 3 Containing less than% disintegrant, where no binder is included; and upon oral administration to a patient: a therapeutically effective amount of proton pump inhibitor is delivered, and the T _{max of the} proton pump inhibitor is about 75 minutes after administration Also provided herein are stable pharmaceutical formulations of solid oral dosage forms obtained within. In certain embodiments, the pharmaceutical formulation comprises between about 5 mEq and about 20 mEq, or between about 5 mEq and about 15 mEq, or between about 10 mEq and about 15 mEq. In other embodiments, the pharmaceutical formulation comprises less than about 2% sodium bicarbonate. In yet other embodiments, the T _max of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In certain embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

(a) at least one acid labile proton pump inhibitor; (b) about 5 to about 30 mEq of an antacid selected from magnesium hydroxide, magnesium oxide, sodium carbonate, sodium bicarbonate, and calcium carbonate; Including, upon oral administration to a patient: a stable pharmaceutical formulation in a single capsule dosage form wherein a therapeutically effective amount of a proton pump inhibitor is delivered and a _Tmax of the proton pump inhibitor is obtained within about 75 minutes after administration Are also provided herein. In other embodiments, the T _max 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 is a solid oral dosage form pharmaceutical formulation wherein the weight percent of the disintegrant is at least the same amount as the weight percent of the binder. In certain embodiments, the pharmaceutical formulation is substantially free of binder. In other embodiments, the solid oral dosage form is a tablet (eg, a caplet) and the binder is present in an amount less than about 20%, or less than about 10%, or less than about 5%. In other embodiments, the solid oral dosage form is a capsule and the binder is present in an amount from about 0% to about 5% by weight.

  The present invention provides a pharmaceutical formulation comprising a proton pump inhibitor and an antacid from about 5 mEq to about 11 mRq for oral administration and digestion by a subject.

  comprising (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of antacid, wherein upon oral administration to a subject, the oral organism of the proton pump inhibitor Included are pharmaceutical formulations that have a bioavailability of at least 25% and a maximum serum concentration of 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 yet other embodiments, the oral bioavailability of the proton pump inhibitor is from about 25% to about 60%, or from about 30% to about 50%, or at least about 30%, or at least about 35%, or at least About 40%.

  The pharmaceutical formulation comprises (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of antacid, wherein the pharmaceutical formulation comprises (a) It is bioequivalent to a pharmaceutical formulation comprising at least one acid labile proton pump inhibitor and (b) greater than about 11 mEq of antacid. In certain 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 administered with more than 11 mEq antacids. It is. In other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is about ± 10% of the area under the serum concentration time curve for the proton pump inhibitor when administered with more than 11 mEq of antacid. Is within. In yet other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is about ± 5 of the area under the serum concentration time curve for the proton pump inhibitor when administered with more than 11 mEq of antacid. Within%.

  The pharmaceutical formulation comprises (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of antacid, wherein the pharmaceutical formulation comprises (a) Bioequivalent to a pharmaceutical formulation comprising at least one acid labile proton pump inhibitor and (b) greater than 15 mEq antacid. In certain 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 administered with more than 15 mEq antacids. Or within about ± 10%, or within about ± 5%.

  The pharmaceutical formulation comprises (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of antacid, wherein the pharmaceutical formulation comprises (a) Bioequivalent to a pharmaceutical formulation comprising at least one acid labile proton pump inhibitor, and (b) greater than 20 mEq antacid. In certain 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 administered with more than 20 mEq antacids. Or within about ± 10%, or within about ± 5%.

  The pharmaceutical formulation comprises (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of antacid, wherein the pharmaceutical formulation comprises proton pump inhibition Biologically equivalent to drug product. In certain embodiments, the pharmaceutical formulation is bioequivalent to Priolosec®, Nexium®, Prevacid®, Protonic®, and Aciphex®. . In other embodiments, the maximum concentration of 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 certain embodiments, the maximum concentration of the proton pump inhibitor for a pharmaceutical formulation is the maximum concentration (Cmax) for the proton pump inhibitor product when the pharmaceutical formulation and the proton pump inhibitor product are administered to the same patient. Within about 80% and 120%.

  Provided herein is a pharmaceutical formulation comprising (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of an antacid, wherein the subject is orally administered to a subject. Upon administration, the pharmaceutical composition has an area under the serum concentration time curve (AUC) of the proton pump inhibitor when the enteric proton pump inhibitor is delivered without an antacid. In certain embodiments, the area under the serum concentration time curve for the proton pump inhibitor is the area under the serum concentration time curve for the proton pump inhibitor when the enteric proton pump inhibitor is delivered without an antacid. Is within about ± 20%. In yet other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is the serum concentration time curve for the proton pump inhibitor when the enteric proton pump inhibitor is delivered without an antacid. Within about ± 15% of the area under, or within about ± 10%, or within about ± 5%.

  A therapeutic dose of a proton pump inhibitor is delivered as a single capsule, tablet, or caplet, (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq. Pharmaceutical formulations containing antacids are provided herein.

  Upon oral administration to a patient: a therapeutically effective amount of a proton pump inhibitor is delivered; an antacid is at least about 30 minutes or less by a simulated gastric model, such as the Fuchs kinetic in vitro pH model (A) at least one acid labile proton pump inhibitor, and (b) from about 5 mEq to about 11 mEq, increasing the pH of the stomach to 3.5; and a maximum concentration of proton pump inhibitor is obtained within about 75 minutes; Also provided herein are pharmaceutical formulations comprising between these antacids. In certain embodiments, the antacid increases gastric pH to at least about 3.5 in less than about 30 minutes, or in less than about 25 minutes, or in less than about 20 minutes, or in less than 15 minutes, or in less than 10 minutes. Let In other embodiments, the maximum concentration of proton pump inhibitor is obtained within about 60 minutes.

  A pharmaceutical formulation comprising about 5 mg to about 200 mg of a proton pump inhibitor, comprising (a) at least one acid labile proton pump inhibitor, and (b) between about 5 mEq and about 11 mEq of an antacid. Provided in the specification. In other embodiments, the pharmaceutical formulation comprises about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 80 mg, or about 120 mg of 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.

  The composition is provided such that the initial serum concentration of the proton pump inhibitor is greater than about 100 ng / ml at any time within about 30 minutes of administration of the formulation. The initial serum concentration of the proton pump inhibitor can be greater than about 100 ng / ml at any time within about 15 minutes. The initial serum concentration of the proton pump inhibitor can be greater than about 200 ng / ml at any time within about 1 hour of administration and greater than about 300 ng / ml at any time within about 45 minutes of administration. Can be expensive.

  The composition is provided such that a serum concentration greater than about 100 ng / ml can be maintained for at least about 30 minutes to about 1 hour after administration of the composition. The composition is provided such that a serum concentration of proton pump inhibitor greater than about 100 ng / ml can be maintained for at least about 15 minutes to about 30 minutes after administration. The composition is provided such that a serum concentration greater than about 100 ng / ml can be maintained for at least about 30 minutes to about 45 minutes after administration. The composition is provided such that a serum concentration greater than about 250 ng / ml can be maintained for at least about 30 minutes to about 1 hour after administration. The composition is provided such that a serum concentration greater than about 250 ng / ml can be maintained for at least about 30 minutes to about 45 minutes after administration. The composition is provided such that a serum concentration greater than about 250 ng / ml can be maintained for at least about 15 minutes to about 30 minutes after administration.

  The compositions of the invention can be administered in an amount to maintain a serum concentration of proton pump inhibitor greater than about 150 ng / ml from about 15 minutes to about 1 hour after administration. The compositions of the invention can be administered in an amount to maintain a serum concentration of proton pump inhibitor greater than about 150 ng / ml from about 15 minutes to about 1.5 hours after administration. The compositions of the invention can be administered in an amount to maintain a serum concentration of proton pump inhibitor greater than about 100 ng / ml from about 15 minutes to about 1.5 hours after administration. The compositions of the invention can be administered in an amount to maintain a serum concentration of proton pump inhibitor greater than about 150 ng / ml from about 15 minutes to about 30 minutes after administration.

  The compositions of the invention can be administered in an amount to achieve an initial serum concentration of proton pump inhibitor of greater than about 150 ng / ml at any time from about 5 minutes to about 30 minutes after administration. The compositions of the invention can be administered in an amount to achieve an initial serum concentration of proton pump inhibitor greater than about 150 ng / ml at any time within about 30 minutes after administration.

  Upon oral administration to a subject, at least about 50% of the area under the total serum concentration time curve (AUC) for the proton pump inhibitor is present within about 2 hours after administration of a single dose of the composition to the subject Compositions are provided that provide such a pharmacokinetic profile. Compositions are provided wherein upon oral administration to a subject, the area under the serum concentration time curve (AUC) for the proton pump inhibitor within 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 within the first 2 hours is at least about 70% of the total area.

  Compositions are provided wherein at least about 50% of the area under the total serum concentration time curve (AUC) for the proton pump inhibitor is present 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 the area under the total serum concentration time curve (AUC) for the proton pump inhibitor is present 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 the area under the total serum concentration time curve (AUC) for the proton pump inhibitor is present within about 1 hour after administration of a single dose of the composition to the subject.

  Compositions and methods that provide a pharmacokinetic profile such that upon oral administration to a subject, the proton pump inhibitor reaches a maximum serum concentration within about 75 minutes after administration of a single dose of the pharmaceutical formulation. Provided. In still other embodiments, the maximum serum concentration is reached within about 60 minutes after administration of the pharmaceutical formulation, or within about 45 minutes after administration. In yet other embodiments, the maximum serum concentration is reached within about 30 minutes after administration of the pharmaceutical formulation.

  Duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, hyporesponsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretion disease, Zollinger-Ellison syndrome, heartburn, esophageal disorder, and many Methods are provided for treating gastric acid related disorders, including but not limited to acidic dyspepsia. A method is provided wherein a proton pump inhibitor treats the development of a gastric acid related disorder.

  In certain embodiments, the proton pump inhibitor is a substituted bicyclic arylimidazole. In other embodiments, the proton pump inhibitor is omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole , Ransoprazole, parisoprazole, leminoprazole; or consisting of their free bases, free acids, salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, or prodrugs Selected from the group. In still other embodiments, the proton pump inhibitor is lansoprazole, tenatoprazole, esomeprazole, rabeprazole and pantoprazole, or their free bases, free acids, salts, hydrates, esters, amides, enantiomers, It is selected from the group consisting of isomers, tautomers, polymorphs, or prodrugs.

  The pharmaceutical formulations of the present invention comprise, for example, from about 5 mg to about 200 mg of proton pump inhibitor. In various embodiments, the pharmaceutical formulation may comprise about 10 mg, or about 15 mg, or about 20 mg, or about 40 mg, or about 60 mg, or about 120 mg of proton pump inhibitor.

  In various embodiments of the present invention, the antacid is an alkali metal salt or a Group IA metal selected from Group IA metal bicarbonates, Group IA metal carbonates. In other embodiments, the antacid may be, but is not limited to: amino acids, alkali metal salts of amino acids, aluminum hydroxide, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation, aluminum hydroxide, hydroxide Aluminum / magnesium hydroxide coprecipitation, aluminum hydroxide / sodium bicarbonate coprecipitation, 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, di-succinate Sodium, 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 aluminate metasilicate , Magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, phosphorus Potassium acetate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate Sodium, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, tripolylin Sodium phosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, trisodium pyrophosphate, tripotassium phosphate, trisodium phosphate, trometamol, Effesoda® (mixture of sodium bicarbonate and sodium carbonate) and these Mixture of. In yet other embodiments, the antacid may be sodium bicarbonate, sodium carbonate, Effesoda®, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. In certain embodiments, the composition is substantially free of sucralfate. In other embodiments, the composition does not include an amino acid buffer. In yet other embodiments, the composition is a combination of two or more antacids, wherein the at least two antacids are not amino acids.

  The pharmaceutical formulations of the present invention may contain various amounts of antacid. For example, in certain embodiments, the pharmaceutical formulation comprises about 100-3000 mg of antacid. In other embodiments, the pharmaceutical formulation comprises about 400 to about 1300 mg of antacid. In yet other embodiments, the pharmaceutical formulation comprises from about 5 mEq to about 30 mEq, or from about 8 mEq to about 20 mEq, or from about 10 mEq to about 15 mEq. In a further embodiment, the pharmaceutical formulation comprises about 13 mEq of antacid.

  The pharmaceutical formulations of the present invention include tablets (including suspension tablets, chewable tablets, rapidly dissolving tablets, bite-disintegration tablets, rapidly disintegrating tablets, effervescent tablets, or caplets), pills, powders ( Sterile packaged powders, dispersible powders, or effervescent powders), capsules (both soft and hard capsules, eg capsules made from animal-derived gelatin or plant-derived HPMC), lozenges, sachets, It may be in the form of a troche, pellet, granule, or aerosol. In certain 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 chewable tablets. In addition, the pharmaceutical formulations of the invention may be administered as a single capsule or in multiple capsule dosage forms. In certain embodiments, the pharmaceutical formulation is administered in two, three, or four capsules.

  In various aspects of the invention, the proton pump inhibitor may be microencapsulated with a substance that enhances the shelf life of the pharmaceutical formulation. In certain embodiments, the substance that enhances the shelf life of the pharmaceutical formulation is selected from the group consisting of: cellulose hydroxypropyl ether; low substituted hydroxypropyl ether; cellulose hydroxypropyl methyl ether; methyl cellulose polymer; ethyl cellulose and mixtures thereof; Polyvinyl alcohol; hydroxyethyl cellulose; salts of carboxymethyl cellulose and carboxymethyl cellulose; polyvinyl alcohol and polyethylene glycol copolymer; monoglyceride; triglyceride: polyethylene glycol, modified food starch, acrylic polymer; mixture of acrylic polymer with cellulose ether; cellulose acetate phthalate; Sepifilms, cyclodextrins; and mixtures thereofIn other embodiments, the substance that enhances the shelf life of the pharmaceutical formulation further comprises an antioxidant, sodium bicarbonate, or a plasticizer.

  In various embodiments, the pharmaceutical formulations of the present invention comprise mural cell cell activators, organic solvents, erosion enhancers, flavoring agents, sweeteners, diffusion enhancers, antioxidants, and binders, suspending agents, Further enhancers selected from the group consisting of disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, anti-adhesive agents, and carrier materials selected from antifoam agents. Further includes a dosage form.

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. Methods, kits, combinations, for treating, preventing or reducing the risk of developing gastrointestinal disorders or diseases, or signs associated with or associated with gastrointestinal disorders or diseases in a subject in need thereof And compositions are also provided.

  While the invention may be embodied in many different forms, it should be understood that the specification is intended as an illustration of the principles of the invention and that the invention is limited to the illustrated embodiments. Discussed herein with the understanding that it is not intended. For example, the present invention may include omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, periprazole, lansoprazole, paliprazole, or remino When illustrated with a specific reference to prazole, if desired, any other proton pump inhibitor may be, in whole or in part, in the methods, kits, combinations, and compositions described herein. It will be understood that substitutions may be made for such agents.

  To facilitate an understanding of the present invention and its preferred embodiments, the meaning of the terms used herein will become apparent from the context of the present specification, taking into account the general usage of the various terms. And clear definitions of other terms are provided in the following glossary or the following description.

Glossary As used herein, the terms “including”, “including”, and “such as” are used in their open, non-limiting sense.

  The term “about” is used synonymously with the term “approximately.” As those skilled in the art will appreciate, the exact boundary of “about” depends on the components of the composition. By way of example, use of the term “about” means a value slightly outside the quoted value, ie plus or minus 0.1% to 10%, which is also effective and safe.

  The phrase “acid-labile medical agent” refers to any pharmaceutically active drug subject that is susceptible to acid-catalyzed degradation.

  "Anti-adhesive", "glue" or "anti-adhesion" agents prevent the ingredients of the formulation from clumping or sticking and improve the flow properties of the substance. Such compounds include, for example, colloidal silicon dioxide such as Cab-o-sil®; tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, stear Examples include calcium phosphate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid®).

  “Antifoaming agents” reduce foam formation during processing which can result in solidification of the aqueous dispersion, foam in the finished film, or generally processing failure. Exemplary antifoaming agents include silicon emulsions or sorbitan sesquioleic acid.

  “Antioxidants” include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

  “Binders” impart adhesive properties, including for example: alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (eg Methocel®), hydroxypropyl Methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (eg, Klucel®), ethylcellulose (eg, Ethocel®), and microcrystalline cellulose (eg, Avicel®); microcrystalline dextrose; amylose Magnesium silicate; polysaccharide acid; bentonite; gelatin; polyvinylpolypyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, sugar, eg sucrose (eg D ipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg Xylitab®) and lactose; natural or synthetic gums such as acacia, tragacanth, ghatti gum, isapol Musk of isapol husk, polyvinylpyrrolidone (e.g. Polyvidon® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegum®, polyethylene glycol , Wax, sodium alginate and so on.

  “Bioavailability” refers to the extent to which an active moiety, eg, a drug, prodrug, or metabolite is absorbed into the general circulation and becomes available at the site of drug action in the body. Thus, proton pump inhibitors administered through IV are 100% bioavailable. "Oral bioavailability" means that the pharmaceutical composition is taken orally and the proton pump inhibitor (or other active moiety) is absorbed into the general circulation and available at the site of drug action in the body The degree to become.

“Bioequivalence” or “bioequivalence” means that the area under the serum concentration time curve (AUC) and the peak serum concentration (C _max ) are within 80% and 120%, respectively.

  The “carrier substance” includes any commonly used excipient in pharmaceutics and should be selected based on compatibility with the proton pump inhibitor and the desired dosage form release profile characteristics. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. “Pharmaceutically compatible carrier materials” include, for example, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, phosphorus Tricalcium acid, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch and the like may also be included. For example, 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, Pennsylvania 1975; Liberman, HA and See Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

  A “trait record” includes, for example, aroma, basic taste, and sensory factors. The intensity of the trait record can be graded from 0-none, 1-mild, 2-moderate, and 3-intensity.

  A “derivative” is a compound made from another compound of similar structure by replacement or substitution of an atom, molecule or group by another suitable atom, molecule or group. For example, one or more hydrogen atoms of a compound may be substituted with one or more alkyl groups, acyl groups, amino groups, hydroxyl groups, halo groups, haloalkyl groups, aryl groups, heteroaryl groups, cycloalkyl (cycloaolkyl) groups, Substitution with a heterocycloalkyl group or heteroalkyl group may produce a derivative of the compound.

  “Diffusion enhancers” and “dispersants” include substances that control the diffusion of an aqueous solution through a coating. Exemplary diffusion promoters / dispersants include hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, and the like. Combinations of one or more diffusion enhancers and one or more erosion enhancers can also be used in the present invention.

  A “diluent” increases the bulk of the composition to facilitate compression. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; dibasic calcium phosphate; dicalcium phosphate dihydrate; Calcium; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinized starch; compressible sugars such as Di-Pac® (Amstar); mannitol; hydroxypropylmethylcellulose; sucrose-based diluent; Saccharides; monobasic calcium phosphate monohydrate; calcium sulfate dihydrate; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol;

  The term “disintegrate” includes both dissolution and dispersion of the dosage form when in contact with gastrointestinal fluid.

  A “disintegrant” facilitates the decomposition or disintegration of a substance. Examples of disintegrants include: starch, for example natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijel®, or Promogel® or Sodium starch glycolate such as Explotab®; cellulose such as wood products, microcrystalline cellulose, eg Avicel®, Avicel® PH101, Avicel® PH102, Avicel® ) PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked sodium carboxymethylcellulose ( Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked cellulose such as crosslinked croscarmellose; Cross-linked starch such as sodium pungglycolate; cross-linked polymer such as crospovidone; cross-linked polyvinyl pyrrolidone; alginates such as sodium alginate or alginates such as alginate; Veegum® HV (aluminum magnesium silicate); agar, Guam, locust bean, karaya, pectin, or tragacanth gum; sodium starch glycolate; bentonite; natural sponge; surfactant; resin such as cation exchange resin; citrus pulp; sodium lauryl sulfate; lauryl sulfate combined with starch Sodium etc.

  “Drug absorption” or “absorption” refers to the process of movement from the site of administration of a drug toward the general circulation, eg, into the bloodstream of the subject.

  An “enteric coating” is a substance that remains substantially intact in the stomach but releases the drug once it reaches the small intestine. In general, enteric coatings prevent release in the low pH environment of the stomach, but ionize at slightly higher pH, usually pH 4 or 5, and are therefore well dissolved and active there in the small intestine. Includes polymeric material that gradually releases the agent.

  An “enteric proton pump inhibitor” is used to ensure that at least some of the drug is released to some or most extent in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach. It is intended to mean that the proton pump inhibitor is enteric coated.

  "Erosion promoter" includes substances that control the erosion of certain substances in gastrointestinal fluid. Erosion promoters are generally known to those skilled in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

  “Fillers” include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, 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, for example, the following: acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavaroa, 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, chikuro, siramate (cylamate), dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream , Monoammonium glycyrrhizylate (MagnaSweetTM), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet (registered trademark) ) Powder, Raspberry, Root Beer, Lamb, Saccharin, Safrol, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Saccharin Sodium, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Tallinn, Sylitol, Sucralose, Sorbitol, Swiss cream, tagaroose, tangerine, thaumatin, tutti fruity, vanilla, walnut, watermelon, wild cherry , Winter green, xylitol, or any combination of these flavoring ingredients, for example, anise-menthol, cherry-anis, 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 subject's gastric secretions or subject's saliva fluid after oral administration of the composition of the present invention, or an equivalent thereof. “Gas secretion equivalent” includes in vitro fluids having similar contents and / or pH as gastric secretions, such as, for example, 1% aqueous sodium dodecyl sulfate or 0.1 N aqueous HCl.

  “Half-life” refers to the time required for a plasma drug concentration or amount to decrease by 50% of its maximum concentration in the body.

  A “lubricant” is a compound that interferes with, reduces, or inhibits adhesion or friction of a substance. Exemplary lubricants include, for example: stearic acid; calcium hydroxide; talc; sodium stearyl fumarate; hydrocarbons such as mineral oil, or hydrogenated soybean oil (Sterotex ™). Higher hydrogenated vegetable oils; higher fatty acids and their alkali metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, benzoic acid Sodium, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax (TM), sodium oleate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium, colloid such as Syloid (TM) Jo silica, Car-O-Sil (TM), starch such as corn starch, silicone oil, and surfactants.

  “Measurable serum concentration” or “Measurable plasma concentration” is the mg, μg, or ng of a therapeutic agent that is absorbed into the bloodstream after administration, typically per ml, dl, or l of serum. The serum or plasma concentration measured as a therapeutic agent is described. One skilled in the art can determine the serum concentration or plasma concentration of a proton pump inhibitor or prokinetic agent. See, for example, Gonzalez H. et al., J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci., Vol. 780, pp459-65, (Nov. 25, 2002).

  “Mural cell activators” or “active agents” stimulate mural cells and enhance the pharmacological activation of proton pump inhibitors. Wall cell activators include, for example: chocolate; alkaline substances such as sodium bicarbonate; calcium such as calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate; peppermint oil; Spearmint oil; coffee; tea and cocoa (even decaffeinated); caffeine; theophylline; theobromine; amino acids (especially aromatic amino acids such as phenylalanine and tryptophan); and combinations thereof.

  “Pharmacodynamics” refers to the factors that determine the biological response observed relative to the concentration of drug at the site of action.

  “Pharmacokinetics” refers to the factors that determine the attainment and maintenance of an appropriate concentration of drug at the site of action.

“Plasma concentration” refers to the concentration of a substance in the plasma or serum of a subject. It is understood that the plasma concentration of a therapeutic agent can vary from subject to subject in very large multiples due to variability with respect to the metabolism of the therapeutic agent. In accordance with one aspect of the invention, the plasma concentration of proton pump inhibitor and / or prokinetic agent can vary from subject to subject. Similarly, values such as maximum serum concentration (C _max ) or time to maximum serum concentration (T _max ), or area under the serum concentration time curve (AUC) can vary from subject to subject. Due to this variability, the amount necessary to constitute a “therapeutically effective amount” of a proton pump inhibitor, exercise promoter, or other therapeutic agent can vary from subject to subject. If average plasma concentrations are disclosed for the subject population, it is understood that these average values may include substantial variation.

  A “plasticizer” is a compound used to soften microencapsulated materials or film coatings and make them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, and triacetin.

  “Prevent” or “prevention”, when used in the context of a gastric acid related disorder, if there has been no onset, no onset of gastrointestinal disorder or disease, or already onset of gastrointestinal disorder or disease If there is, it means that there is no further gastrointestinal disorder or disease onset. Its ability to prevent some or all signs associated with gastrointestinal disorders or diseases is also considered.

  “Prodrug” refers to a drug or compound that produces a pharmacological effect from transformation by metabolic processes in the body. Prodrugs are generally drug precursors that are converted to active or more active species through several processes, such as conversion by metabolic pathways, after administration to a subject and subsequent absorption. is there. Some prodrugs have chemical groups present on the prodrug that make it more inert and / or confer solubility or some other property to the drug. Once the chemical group is cleaved and / or modified from the prodrug, the active drug is produced. Prodrugs may be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues. To date, prodrug designs have been designed to increase the effective water solubility of therapeutic compounds to target areas where water is the primary solvent. For example, 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 ACS Symposium Series; and Edward B. Roche , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

  “Proton pump inhibitor product” refers to products that are on the market. Proton pump inhibitors include, for example, Priorocec®, Nexium®, Prevacid®, Protonic®, and Aciphex®.

“Serum concentration” refers to the concentration of a substance such as a therapeutic agent in the plasma or serum of a subject. It is understood that the serum concentration of a therapeutic agent can vary from subject to subject in very large multiples due to variability in the metabolism of the therapeutic agent. According to one aspect of the invention, the serum concentration of proton pump inhibitors and / or prokinetic agents can vary from subject to subject. Similarly, values such as maximum serum concentration (C _max ) or time to maximum serum concentration (T _max ), or area under the serum concentration time curve (AUC) can vary from subject to subject. Due to this variability, the amount necessary to constitute a “therapeutically effective amount” of a proton pump inhibitor, exercise promoter, or other therapeutic agent can vary from subject to subject. It is understood that if mean serum concentrations are disclosed for the subject population, 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.

  “Stabilizer” includes compounds such as any antioxidant, buffer, acid, and the like.

  “Suspending agents” or “thickening agents” include compounds such as: polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol, such as 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; porsorbate-80; hydroxyethylcellulose; sodium alginate Gums such as tragacanth gum and acacia gum; guar gum; gums such as xanthan including xanthan gum; sugars; eg sodium carboxymethylcellulose, methylcellulose, carboxymethyl Polysorbate-80; sodium alginate; sodium cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, cellulose derivatives such as hydroxyethyl cellulose polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone like.

  `` Surfactants '' include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaroxomer, bile salts, glyceryl monooleate, copolymers of ethylene oxide and propylene oxide such as Pluronic ( (Registered trademark) (BASF) and the like.

  A “therapeutically effective amount” or “effective amount” is the amount of a pharmaceutical agent that achieves 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 pharmacological effect or therapeutic improvement without undue adverse side effects. For example, an effective amount of a proton pump inhibitor can reduce acid secretion, increase the pH of gastrointestinal fluid, reduce gastrointestinal bleeding, or reduce the need for blood transfusions, Or refers to the amount of proton pump inhibitor that improves survival or provides a more rapid recovery from gastric acid related disorders. An effective amount of the pharmaceutical agent is selected by one skilled in the art depending on the particular patient and the level of the disease. “Effective amount” or “therapeutically effective amount” is the metabolic variation, age, weight, general condition of the subject, condition being treated, condition treated, such as proton pump inhibitors and / or prokinetic agents It is understood that it can vary from subject to subject due to the severity of the condition and the judgment of the prescribing physician.

  “Total fragrance intensity” is an overall immediate representation of fragrance intensity and includes both aromatic compounds and nasal sensory stimulation.

  “Total intensity of flavor” is an overall immediate representation of the intensity of the flavor, including aromatics, basic taste and sensory stimulation of the mouth.

  “Treat” or “treatment”, when used in the context of a gastric acid related disorder, may be predisposed to any treatment of a disorder or disease associated with a gastrointestinal disorder, eg, a disorder or disease. However, preventing the onset of the disorder or disease in a subject not yet diagnosed as having the disorder or disease; inhibiting the disease or disorder, eg, stopping the onset of the disorder or disease, or It refers to alleviating a disease, causing a disorder or regression of the disease, alleviating a condition caused by the disease or disorder, or stopping signs of the disease or disorder. Thus, as used herein, the term “treating” is used synonymously with the term “preventing”.

  "Wetting agents" include oleic acid, glyceryl monooleate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxylene sorbitan monooleate, polyoxyethylene monolaurate, sodium oleate, lauryl Sodium sulfate and the like are included.

Proton Pump Inhibitors "Proton Pump Inhibitors", "PPIs" and "Proton Pump Inhibitors" to describe any acid labile pharmaceutical agent that has pharmacological activity as an inhibitor of H + / K + -ATPase Can be used interchangeably. Proton pump inhibitors can be treated with free bases, salts, esters, hydrates, amides, enantiomers, isomers, tautomers, prodrugs or any other pharmacologically appropriate derivative, if desired. In the form of free base, free acid, salt, ester, hydrate, anhydride, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, etc. May be.

  In various embodiments, the proton pump inhibitor can be a substituted bicyclic arylimidazole, wherein the aryl group can be, for example, a pyridine group, a phenyl group, or a pyrimidine group, and the 4-position and 5 of the imidazole ring. Combined with the position. Proton pump inhibitors including substituted bicyclic aryl-imidazoles include omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, tenatoprazole, lansoprazole , Parisprazole, leminoprazole or its free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug or derivative . See, for example, The Merck Index, Merck & Co. Rahway, N.J. (2001).

  Other proton pump inhibitors include but are not limited to: soraprazan (Altana); ilaprazole (US 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-fluoro (Phenyl) -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, stopped) WO 95/27714; Pharmaprojects No. 4891 (EP 700899) (Aventis); Pharmaproject s 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 published WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT published WO 97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); 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); Uffipra Ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or the free bases, free acids, salts, hydrates, esters, amides, enantiomers, isomers, Mutants, polymorphs, prodrugs or derivatives.

  Still other proton pump inhibitors contemplated by the present invention include those described in the following US patent numbers: 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; 5,855,914; 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; 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;

  Other substituted bicyclic aryl imidazole compounds, as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs or derivatives, are known to those skilled in the art of synthetic chemistry. May be prepared using standard techniques known in the art. For example, 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 salt” or “salt” includes, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, Maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid , Ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, β-hydroxybutyric acid, galactaric acid and galacturonic acid And proton pump inhibitor salts.

  In one embodiment, acid addition salts are prepared from the free base using conventional methodology, including the reaction of the free base with the appropriate acid. Suitable acids for preparing acid addition salts include organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, Citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Both are included.

  In other embodiments, the acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the acid addition salt of the proton pump inhibitor is a halide salt prepared using hydrochloric acid or hydrobromic acid. In yet other embodiments, the basic salt is an alkali metal salt, such as a sodium salt.

  Salt form proton pump inhibitors include but are not limited to: sodium salt forms such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or as described in US Pat. No. 5,900,424 A magnesium salt form such as esomeprazole magnesium or omeprazole; a calcium salt form; or a potassium salt such as the potassium salt of esomeprazole described in US Patent Application No. 02/0198239 and US Pat. No. 6,511,996 Type. Other salts of esomeprazole are described in US Pat. No. 4,738,974 and US Pat. No. 6,369,085. The salt forms of pantoprazole and lansoprazole are discussed in US Pat. Nos. 4,758,579 and 4,628,098, respectively.

In one embodiment, the preparation of the ester involves functionalization of hydroxyl and / or carboxyl groups that may be present in the molecular structure of the drug. In one embodiment, the ester is an acyl-substituted derivative of a free alcohol group, eg, a moiety derivatized from a carboxylic acid of formula RCOOR ₁ where R ₁ is a lower alkyl group. Esters can be reconverted to the free acids, if desired, by using conventional techniques such as hydrogenolysis or hydrolysis.

  “Amides” are known to those skilled in the art or may be prepared using techniques described in the relevant literature. For example, amides may be prepared using suitable amine reactants, or they may be prepared from anhydrides or acid chlorides by reaction with amine groups such as ammonia or lower alkyl amines. .

  “Tautomers” of substituted bicyclic aryl-imidazoles include, for example, the following US Patents: 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087 And omeprazole tautomers such as those described in US Patent Application No. 02/0156103; and 6,444,689;

  Exemplary “isomers” of substituted bicyclic aryl-imidazoles are Oishi et al., Acta Cryst. (1989), C45, 1921-1923; US Pat. No. 6,150,380; US Patent Application No. 02/0156284; And isomers of omeprazole, including but not limited to the isomers described in PCT Publication WO 02/085889.

  Exemplary “polymorphs” include PCT Publication WO 92/08716, as well as the following US Patents: 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 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; No. 5,536,735; No. 5,576,025; No. 5,599,794; No. 5,629,305; No. 5,639,478; No. 5,690,960; No. 5,703,110; No. 5,705,517; No. 5,714,504; No. 5,731,006; No. 5,879,708; No. 5,948,773; No. 5,997,903; No. 6,017,560; No. 6,123,962; No. 6,147,103; No. 6,150,380; No. 6,166,213; No. 6,191,148; No. 5,187,340; No. 6,268,385; No. 6,316,020; No. 6,328,994; No. 6,326,384; No. 6,369,085; No. 6,369,087; No. 6,38 No. 0,234; No. 6,428,810; No. 6,444,689; and No. 6,462,0577.

Micronized Proton Pump Inhibitor The particle size of the proton pump inhibitor can affect the solid dosage form in many ways. The decrease in particle size increases the surface area (S), and this decrease in particle size provides an increase in the rate of dissolution (dM / dt) expressed in the following Noyes-Whitney equation:
dM / dt = dS / h (Cs-C)
M = mass of dissolved drug; t = time; D = diffusion coefficient of drug; S = effective surface area of drug particles; H = static layer thickness; Cs = solution concentration at saturation; and C = solution at time t Concentration.

  Since omeprazole, like other proton pump inhibitors, has poor water solubility, various aspects of the present invention are used in drug product formulations to assist in rapid absorption of drug products. Used proton pump inhibitors.

  In various embodiments of the invention, the proton pump inhibitor is micronized. In certain embodiments, the average particle size of at least about 90% of 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 about 15 μm. Or less than about 10 μm. In other embodiments, at least 80% of 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 about Have an average particle size of less than 10 μm. In yet other embodiments, at least 70% of 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 Having an average particle size of less than about 10 μm;

  The micronized proton pump inhibitor is within about 1 hour of dissolution test, 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 about Compositions are provided that are sized to allow more than 75% of the proton pump inhibitor to be released within 5 minutes. In another embodiment of the invention, the micronized proton pump inhibitor is within about 1 hour of dissolution test, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, Or a size that allows more than 90% of the proton pump inhibitor to be released within about 10 minutes, or within about 5 minutes. See U.S. Patent Application No. 10 / 893,092, filed July 16, 2004, claiming priority to U.S. Provisional Patent Application No. 60 / 488,324, filed July 18, 2003 . Both of these are hereby incorporated by reference in their entirety.

Particle size of insoluble materials The particle size of proton pump inhibitors, antacids and excipients is an important factor that can affect bioavailability, blend uniformity, separation, and flow properties. In general, the smaller the drug in the particle, the faster the biodegradation rate of the drug with substantially poor water solubility by increasing the surface area. The particle size of the drug and particles 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 powder 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 agglomerates is between about 25 microns in diameter and about 300 microns in diameter. In yet other embodiments, the average particle size of the agglomerates is between about 25 microns in diameter and about 150 microns in diameter. And in still further embodiments, the average particle size of the agglomerates is between about 25 microns in diameter and about 100 microns in diameter. The term “average particle size” is intended to describe the average diameter of the particles and / or aggregates used in the pharmaceutical formulation.

  In another embodiment, the average particle size of the insoluble excipient is between about 5 μm and 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 about Less than 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 about Less than 10 μm, or less than about 5 μm.

  In other embodiments of the 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 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. Have 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 the other excipient is selected to be approximately the same as the particle size of the antacid. In yet another embodiment, the particle size of the insoluble excipient is selected to be approximately the same as the particle size of the proton pump inhibitor.

  Several factors can be considered in selecting an appropriate excipient and its amount. For example, the excipient should be pharmaceutically acceptable. Similarly, in some instances, rapid dissolution and gastric acid neutralization to maintain gastric pH at about 6.5 for at least one hour. Excipients contacted with the proton pump inhibitor should also be chemically compatible with the proton pump inhibitor, if any. “Chemically compatible” is intended to mean that the material does not cause more than 10% degradation of the proton pump inhibitor when stored at room temperature for at least about 1 year.

  The mural cell activator is administered in an amount sufficient to produce the desired stimulating effect without causing adverse side effects for the patient. In one embodiment, the mural cell activator is administered in an amount of about 5 mg to about 2.5 grams per 20 mg dose of proton pump inhibitor.

Antacids The pharmaceutical compositions of the present invention comprise one or more antacids. A class of antacids useful in the present invention includes, but is not limited to, antacids having pharmacological activity as a base. In one embodiment, the antacid is formulated or delivered with a proton pump inhibitor for a period of time, for example, to preserve the bioavailability of the administered proton pump inhibitor. For a sufficient amount of time, it functions to substantially prevent or inhibit acid degradation of the proton pump inhibitor by the gastrointestinal fluid. 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 is, for example, a group IA metal hydrogen carbonate, a group IA metal (alkali metal) salt including a group IA metal carbonate; an antacid alkaline earth metal (IIA). Group metal); antacid aluminum; antacid calcium; or antacid magnesium.

  Other antacids that are suitable for the present invention include, for example, carbonic acid, phosphoric acid, hydrogen carbonate, citric acid, such as phosphoric acid, citric acid, boronic acid, acetic acid, hydrogen carbonate, and sodium or potassium carbonate. Alkaline metals (Group IA metals including but not limited to lithium, sodium, potassium, rubidium, cesium, and francium) or alkaline earth metals (such as, but not limited to) acid, boronic acid, acetic acid, phthalic acid, tartaric acid, succinic acid, etc. Group IIA metals including but not limited to beryllium, magnesium, calcium, strontium, barium, radium).

  In various embodiments, the antacid comprises: amino acids, alkali metal salts of amino acids, aluminum hydroxide, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation, aluminum hydroxide, aluminum hydroxide / magnesium hydroxide Coprecipitation, aluminum hydroxide / sodium bicarbonate coprecipitation, 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 water Aluminum oxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium aluminate metasilicate, magnesium oxide, Magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, polyphosphorus Potassium acid, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate Sodium, 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, Effersoda (Registered trademark) (a mixture of sodium bicarbonate and sodium carbonate), synthetic hydrotalcite, tetrapotassium pyrophosphate, trisodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometamol (e.g., The Merck Index, Merck & See the list provided by Co. Rahway, NJ (2001)). Certain proteins or protein hydrolysates that rapidly neutralize acids can serve as antacids in the present invention. Combinations of the antacids mentioned above may also be used in the pharmaceutical compositions described herein.

  Antacids that are useful in the present invention are also antacids or antacids that interact with the same acid faster than proton pump inhibitors interact with HCl (or other acids in the environment of interest). Contains a combination of agents. 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.

  The particle size of the buffer, especially that of an insoluble buffer, can affect the occurrence of in vivo neutralization of gastric acid. Since particle size reduction increases surface area, particle size reduction provides an increase in the rate of acid neutralization, which provides excellent protection of PPI from gastric acid degradation. On the other hand, the extremely small particle size of the buffering agents results in powder mixtures that are difficult to manufacture on a commercial scale due to their poor flowability and processing (ie, compression and encapsulation) difficulties.

In various embodiments of the present invention, the antacid is micronized. In some embodiments, the particle size (D ₉₀ ) of at least 90% of the antacid 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 (D ₇₅ ) has 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. In yet other embodiments, at least 50% of the antacid (D ₅₀ ) has 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.

  Spray dried antacids can also accelerate the rate of neutralization by reacting quickly with the acid upon contact. Spray dried antacids typically have a spherical particle shape, which helps to achieve a homogeneous blend during the manufacturing process. In one embodiment, the antacid is spray dried with at least 15% of a coating material such as maltodextrin or starch. In still other embodiments, the antacid is spray dried with at least 10% of a coating material such as maltodextrin or starch. In yet another embodiment, the antacid is spray dried with at least 15% of a coating material such as maltodextrin or starch.

Kinetic gastric model The acid neutralization ability and pH profile of various antacid combinations can be assessed using an in vitro gastric model. Some of such simulated dynamic models are known in the art. For example, see: 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. Beekman, Preparation and Properties of New Gastric Antacids I, Aluminum Hydroxide-Magne sium Carbonate Dried Gels, J. Am. Pharm. Assoc., 49, 191 (1960). For example, a modified Fuch model that adds a continuous infusion of 0.5 mEq of acid to the initial 5.0 mEq of acid can be used with the present invention to simulate a fasted state of the stomach.

  In various embodiments of the present invention, the antacids can increase the gastric pH to at least about 3.5 within about 90 minutes, as measured by a simulated gastric model, such as Fuch's kinetic in vitro pH model. To increase. In other embodiments, the antacid increases the pH to at least about 3.5 within about 60 minutes. In yet other embodiments, the antacid increases the pH to about 3.5 within 45 minutes. Depending on the buffer system used (i.e., antacid type and amount), in certain embodiments of the invention, as measured by a simulated gastric model, such as Fuch's kinetic in vitro pH model. In addition, antacids increase gastric pH to at least about 3.5 within about 30 minutes. In other embodiments, the antacid increases the gastric pH to at least about 3.5 in less than about 25 minutes, as measured by a simulated gastric model, such as Fuch's kinetic in vitro pH model. In yet other embodiments, the antacids have a gastric pH of less than about 20 minutes, or less than about 15 minutes, as measured by a simulated stomach model, such as Fuch's kinetic in vitro pH model. Or increase to at least about 3.5 in less than about 10 minutes. In each of these embodiments, the antacid protects at least some 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 proton pump inhibitor and a therapeutically effective amount of the proton pump inhibitor is delivered to the subject.

Disintegrants Many PPIs are slightly insoluble in water and therefore show a strong correlation of disintegration time to bioavailability. Therefore, it is important to optimize the disintegration time in order to enhance the in vivo dissolution of the drug. In order to release the active ingredient from the solid dosage matrix as much as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. Disintegrants help the dosage form matrix rupture by swelling or capillary action when moisture is absorbed into the dosage form. Starch is the oldest disintegrant, suggesting 5-15% levels (Remington, 20th Ed, p862). Superdisintegrants 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 granules, generally the same percentage is used as for direct compression formulations. This is often added to both wet masses and dry granules before compression. As with direct compression, its use level is typically in the range of 1-3 percent, with half of the material added to the wet mass and half to the flowing powder. This promotes the disintegration of both granules and tablets.

  The amount of Ac-Di-Sol used in capsule formulations is generally in the range of 4-6 percent. Reduced contact between particles in the capsule facilitates the need for increased levels of disintegrant. Contrary to semi-automatic or manual filling machines, capsules filled with an automatic dosater device are due to the greater compressive force required to form a stopper and to transfer it successfully to a gelatin shell. , Have a denser and harder structure. Larger plug firmness results in greater effectiveness of Ac-Di-Sol.

Solid Oral Dosage Form In certain embodiments of the present invention, the pharmaceutical formulation has greater than about 1% by weight of disintegrant. In various embodiments of the invention, the pharmaceutical formulation has between about 1% and about 11% by weight of a disintegrant. In certain embodiments, the disintegrant is Ac-Di-Sol. In other embodiments, the disintegrant is a glycolated starch, such as Promogel® or Explotab®. In yet other embodiments, the pharmaceutical formulation has between about 2 wt% and about 8 wt% disintegrant. In yet other embodiments, the pharmaceutical formulation has greater than about 2% disintegrant.

  Because sodium bicarbonate has effervescent properties when mixed with an acid such as gastric juice, in certain embodiments, a pharmaceutical formulation of the present invention comprises at least about 400 mg sodium bicarbonate and greater than about 1% by weight. Disintegrants can be included. In certain embodiments, the pharmaceutical formulation comprises about 2% by weight disintegrant, or about 3% by weight disintegrant, or about 4% by weight disintegrant. In yet other embodiments, the pharmaceutical formulation comprises less than 8% disintegrant. In other embodiments, the pharmaceutical formulation comprises less than about 5% disintegrant, or less than about 4% disintegrant, or less than about 3% disintegrant, or less than about 2% disintegrant, or Contains less than about 1% by weight of disintegrant. In other embodiments, the sodium bicarbonate helps to promote the disintegration of the capsule product.

  In certain embodiments of the invention, the weight percent of disintegrant can be reduced and the amount of sodium bicarbonate can be increased to achieve the desired bioavailability of the proton pump inhibitor. In other embodiments, the weight percent of disintegrant can be increased and the amount of sodium bicarbonate can be decreased.

Binders Binders provide adhesion to solid oral dosage forms: for capsule formulations filled with powder, they aid plug formation that can be filled into hard shells and for tablet formulations These ensure that the tablets remain intact after compression. Materials commonly used as binders include starch, gelatin, and sugars such as sucrose, glucose, dextrose, molasses, and lactose. The quality of the binder used affects the dosage form and / or the manufacturing process. For example, dosator-type encapsulation devices (e.g., Zanasi machines) typically require the filling material to be a mechanically powerful stopper, whereas dosing disk-type encapsulation devices (e.g., HK machines) It does not require the same high level of plug breaking force. In general, a binder level of 1-10% is used in powder filled hard gel capsule formulations. The level of binder usage in the tablet formulation will vary regardless of other excipients such as direct compression, wet granulation, or fillers which themselves can act as a moderate binder. Formulators in the art can determine the binder level for a formulation, but binder usage levels of 2-25% are common in tablet formulations.

Solid oral dosage form In certain embodiments of the invention, the weight percent of the disintegrant is at least equivalent to the weight percent of the binder. For example, the formulations of the present invention may comprise about 5% by weight disintegrant and about 2% by weight binder, or about 3% by weight disintegrant and about 3% by weight binder. In other embodiments, the solid oral dosage form does not include a binder. In certain embodiments, the solid oral dosage form comprises significantly more disintegrant than the binder. For example, the binder may be present in an amount less than 2% by weight, while the disintegrant is present in an amount greater than 5% by weight. 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% by weight and the disintegrant may be present in an amount of about 3% by weight.

Microencapsulation According to one aspect of the present invention, the composition can be used to enhance the shelf life of the composition and / or to enhance the taste of the pharmaceutical composition with a micropump of a proton pump inhibitor or antacid. Encapsulation may be included. See US Patent Application No. 10 / 893,203, filed July 16, 2004, which claims priority to US Provisional Patent Application No. 60 / 488,321, filed July 18, 2003 . Both of these are hereby incorporated by reference in their entirety.

  Materials useful for enhancing the shelf life of the pharmaceutical composition of the present invention and / or hiding its taste are compatible with the proton pump inhibitor of the pharmaceutical composition, Fully isolate the proton pump inhibitor from incompatible excipients. Materials that are compatible with the proton pump inhibitors of the present invention are those that enhance the lifetime of the proton pump inhibitor by slowing or stopping the degradation of the proton pump inhibitor.

  Exemplary microencapsulated materials useful for enhancing the shelf life of pharmaceutical compositions comprising proton pump inhibitors include, but are not limited to, such as: Klucel® or Nisso HPC Hydroxypropyl cellulose ether (HPC); low substituted hydroxypropyl cellulose ether (L-HPC); Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Hydroxymethylpropylcellulose ether (HPMC) such as Benecel MP843; Methylcellulose polymers such as Methocel®-A and Metolose®; E461, Ethocel®, Aqualon®-EC, Surelease Ethylcellulose (EC) such as (registered trademark) and mixtures thereof; Polyvinyl alcohol such as Opadry AMB; Hydroxyethyl cell such as Natrosol (registered trademark) Carboxymethylcellulose and salts of carboxymethylcellulose (CMC) such as Aqualon®-CMC; copolymers of polyvinyl alcohol and polyethylene glycol such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX) A mixture of acrylic polymers and acrylic polymers with cellulose ethers, such as polyethylene glycol, modified food starch, Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; HPMC And sepifilms such as mixtures of stearic acid, cyclodextrins; and mixtures of these materials.

  In various embodiments, an antacid such as sodium bicarbonate or sodium carbonate is incorporated into the microcapsule material. In other embodiments, an antioxidant such as BHT is incorporated into the microcapsule material. In yet other embodiments, plasticizers such as polyethylene glycol, eg, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are microencapsulated materials. Is taken in. In other embodiments, microcapsule materials useful for enhancing the half-life of a pharmaceutical composition are from USP or National Formulary (NF). In yet other embodiments, the encapsulating material is Klucel. In yet another embodiment, the microcapsule material is methocel.

  In further embodiments, one or more other compatible materials are present in the microcapsule material. Exemplary materials include, but are not limited to: pH adjusters, wall cell activators, erosion enhancers, diffusion enhancers, anti-adhesive agents, antifoam agents, antioxidants, flavoring agents, And carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents and diluents.

  In accordance with one aspect of the invention, several proton pump inhibitors are coated. This coating can be, for example, a gastric resistant coating such as an enteric coating (see, e.g., WO 91/16895 and WO 91/16886), controlled release coating, enzyme controlled coating, film coating, sustained release coating, It may be an immediate release coating or a delayed release coating. In accordance with another aspect of the present invention, the coating may be useful for enhancing the stability of the pharmaceutical composition of the present invention.

  In addition to microencapsulating the proton pump inhibitor using materials as described herein, the pharmaceutical compositions of the present invention may also include one or more flavoring agents. In some embodiments, one or more flavoring agents are mixed with a taste masking agent prior to encapsulating the proton pump inhibitor and / or antacid. In other embodiments, the flavoring agent is mixed with incompatible excipients during the formulation process, and thus is not contacted with proton pump inhibitors and / or antacids, and is one of the microcapsule materials. Not a part.

  Examples of “flavoring agents” or “sweeteners” that are useful in the pharmaceutical compositions of the present invention include, for example: Acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavaloa, berry, Blackcurrant, 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, chiclo, siramate, Dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetic acid, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, glycy Monoammonium lysinate (MagnaSweetTM), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet (R) Powder, raspberry, root beer, lamb, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, saccharin sodium, saccharin, aspartame, acesulfame potassium, mannitol, tallinn, sucralose, sorbitol, swiss cream, Tagarose, tangerine, thaumatin, tutti fruity, vanilla, walnut, watermelon, wild cherry, winter green , Xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anis, 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 proton pump inhibitors, antacids, and excipients, and the amount of each one, one of ordinary skill in the art is best to provide an optimally scented product for consumer demand and compliance. See, for example, Roy et al., Modifying Bitterness: Mechanism, Ingredients, and Applications (1997).

Method of microencapsulation The proton pump inhibitor and / or antacid may be microencapsulated by methods known to those skilled in the art. Such methods include, for example, spray drying processes, rotating disc-solvent processes, thermal dissolution processes, spray cooling methods, liquefaction beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, liquid-gas or solid- Polymerization on the gas underside, pressure extrusion, or spray solvent extraction tanks are included. In addition to these, several chemical techniques such as complex coacervation, solvent vaporization, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, drying in liquid, and in liquid media Desolvation with can also be used.

  The rotating disk method allows: 1) increased production rate due to higher feed rates and higher solids filling in the feed solution, 2) production of more spherical particles, 3) Production of even more coatings, and 4) limited clogging of the spray nozzle during the process.

  Spray drying is often readily available for scale up. In various embodiments, the material used in the spray-drying encapsulation process is emulsified or dispersed in a concentrated form, eg, 10-60% solid core material. The microcapsule material, in one embodiment, is emulsified until about 1-3 μm droplets are obtained. Once the dispersion and encapsulating material of the proton pump inhibitor is obtained, the emulsion is supplied as droplets to the heating chamber of the spray dryer. In some embodiments, these droplets are sprayed into the chamber or shaken down on a rotating disk. The microparticles are then dried in a heating chamber and dropped to the bottom of the spray drying chamber where they are collected.

  In certain embodiments, the microparticles have an irregular geometry. In other embodiments, the microparticles are aggregates of smaller particles.

  In various embodiments, the proton pump inhibitor and / or antacid is greater than 1% relative to the microcapsule material used to enhance the stability of the pharmaceutical composition or the material that masks taste. , More than 2.5%, more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45% , More than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95% Present in the microparticles in a proton pump inhibitor in an amount of weight percent greater than 98%.

Stability The pharmaceutical formulations of the present invention, for example, have a proton pump inhibitor that degrades less than about 0.5% after 1 month storage at room temperature, or less than about 1% degradation after 1 month storage at room temperature, or room temperature. Less than about 1.5% degradation after 1 month storage, or less than about 2% degradation after 1 month storage at room temperature, or less than 2.5% degradation after 1 month storage at room temperature, or 1 month storage at room temperature It is stable if it is later decomposed to less than about 3%.

  In other embodiments, the pharmaceutical formulation of the invention is a pharmaceutical formulation that is stored after about 3 years of storage, or after about 2.5 years of storage, or after about 2 years of storage, or after about 1.5 years of storage, Or after about 1 year storage, or after 11 months storage, after 10 months storage, after 9 months storage, after 8 months storage, after 7 months storage, or after 6 months 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 and contain less than about 5% total impurities. Can have.

  In a further embodiment, the pharmaceutical formulation of the invention may comprise microencapsulated omeprazole, and the pharmaceutical formulation is more than a proton pump inhibitor in the same formulation that is not microencapsulated or “naked”. However, lifetime stability is enhanced if it includes less degradation of the proton pump inhibitor. For example, a naked proton pump inhibitor in a pharmaceutical formulation degrades more than about 2% after 1 month of storage at room temperature, and the microencapsulated material is stored for 1 month at room temperature. If less than about 2% later degrades, the proton pump inhibitor was microencapsulated with a compatible material that enhances the shelf life of the pharmaceutical formulation.

Dosing Proton pump inhibitors are administered and dosed according to good medical practice, taking into account the individual patient's clinical condition, site and method of administration, schedule of administration, and other factors known to the physician. In human therapy, it is important to provide a dosage form that delivers the required therapeutic amount of the therapeutic agent in vivo and that makes the 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. Patent Nos. 5,840,737, 6,489,346, 6,699,885, and 6,645,988 are incorporated herein by reference. Be incorporated.

  As long as a therapeutically effective amount, such as a gastrointestinal disorder effective amount of a proton pump inhibitor, is absorbed after administration of the pharmaceutical composition to a subject, the percentage of intact drug absorbed into the bloodstream is less critical. Absent. An effective amount for gastrointestinal disorders can be found in US Pat. No. 5,622,719. It will be appreciated that the amount of proton pump inhibitor and / or antacid administered to a subject will depend on a number of factors, such as the subject's gender, general health, diet, and / or body weight.

  By way of example, administration of substituted bicyclic aryl-imidazoles to infants or small animals, such as dogs, relatively small amounts of proton pump inhibitors, such as about 1 mg to about 30 mg, are often serum consistent with therapeutic efficacy Give the concentration. If the subject is an adult human or a large animal, such as a horse, achieving a therapeutically effective serum concentration will result in more dosage units, such as about 10 mg, or about 15 mg for an adult human, or A dose of about 20 mg, or about 30 mg, or about 40 mg, or about 80 mg, or about 120 mg, or for adult horses, a dose of about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mg, or An 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 is required.

  In various other embodiments of the invention, the amount of proton pump inhibitor administered to the subject is, for example, about 0.5-2 mg / kg body weight, or about 0.5 mg / kg body weight, or about 1 mg / kg body weight, or about 1.5 mg / kg body weight, or about 2 mg / kg body weight.

  Treatment dosages may generally be titrated to optimize safety and efficacy. Typically, a dose-effect relationship from in vitro and / or in vivo studies may initially provide a useful indicator for the exact dose for subject administration. It should be appreciated that depending on the treatment protocol, the dosage administered will depend on a number of factors, including the particular drug being administered, the route selected for administration, and the condition of the particular subject.

  In various embodiments, the unit dosage form for humans is from 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 proton pump inhibitor.

  In a further embodiment of the invention, the pharmaceutical composition achieves a measurable serum concentration greater than about 100 ng / ml of non-acid degrading proton pump inhibitor within about 30 minutes after administration of the pharmaceutical composition. To be administered. In another embodiment of the invention, the pharmaceutical composition comprises more than about 100 ng / ml of non-acidolytic or non-acidic proton pump inhibitor within about 15 minutes after administration of the pharmaceutical composition. It is administered in an amount that achieves a high measurable serum concentration. In yet another embodiment, the pharmaceutical composition has a measurement greater than about 100 ng / ml of proton pump inhibitor that is not acid decomposed or acid-reacted within about 10 minutes after administration of the pharmaceutical composition. It is administered in an amount that achieves a possible serum concentration.

  In another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 150 ng / ml within 15 minutes, and from about 15 minutes to about 1 after administration of the composition. Administered to the subject in an amount that maintains a serum concentration of proton pump inhibitor greater than about 150 ng / ml over time. In yet another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 250 ng / ml within about 15 minutes, and about 15 minutes after administration of the composition. The subject is administered in an amount that maintains a serum concentration of proton pump inhibitor greater than about 250 ng / ml for about 1 hour. In another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 350 ng / ml within about 15 minutes, and from about 15 minutes to about 15 minutes after administration of the composition The subject is administered in an amount that maintains a serum concentration of proton pump inhibitor greater than about 350 ng / ml for 1 hour. In another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 450 ng / ml within about 15 minutes, and from about 15 minutes to about about 15 minutes after administration of the composition Administered to the subject in an amount that maintains a serum concentration of proton pump inhibitor greater than about 450 ng / ml for 1 hour.

  In another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 150 ng / ml within about 30 minutes, and from about 30 minutes to about 30 minutes after administration of the composition Administered to the subject in an amount that maintains a serum concentration of proton pump inhibitor greater than about 150 ng / ml for 1 hour. In yet another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 250 ng / ml within about 30 minutes, and from about 30 minutes after administration of the composition The subject is administered in an amount that maintains a serum concentration of proton pump inhibitor greater than about 250 ng / ml for about 1 hour. In another embodiment of the invention, the composition achieves a measurable serum concentration of proton pump inhibitor greater than about 350 ng / ml within about 30 minutes, and from about 30 minutes to about 30 minutes after administration of the composition Administered to the subject in an amount that maintains a serum concentration of proton pump inhibitor greater than about 350 ng / ml for 1 hour. In another embodiment of the invention, the composition achieves a measurable serum concentration of the proton pump inhibitor greater than about 450 ng / ml within about 30 minutes, and from about 30 minutes to about after administration of the composition Administered to the subject in an amount that maintains a serum concentration of proton pump inhibitor greater than about 450 ng / ml for 1 hour.

  In yet another embodiment of the invention, the composition comprises a measurable serum of non-acid-degraded or non-acid-reacting proton pump inhibitor greater than about 500 ng / ml within about 1 hour after administration. The dose is administered to the subject in an amount that achieves the concentration. In yet another embodiment of the invention, the composition comprises a measurable serum of non-acidolytic or non-acidic proton pump inhibitor greater than about 300 ng / ml within about 45 minutes after administration. The dose is administered to the subject in an amount that achieves the concentration.

  In one embodiment of the invention, the composition is administered to the subject in an effective amount for gastrointestinal disorders, i.e., the composition is of a proton pump inhibitor for a period of time to elicit the desired therapeutic effect. Administered in the subject's serum in an amount to achieve a therapeutically effective dose. As an example, in fasting adult humans (generally fasting for at least 10 hours), the composition can be treated with a proton pump inhibitor in the subject's serum within about 45 minutes after administration of the composition. It is administered in the serum of the subject to achieve a dose. In another embodiment of the invention, the therapeutically effective dose of the proton pump inhibitor is achieved in the serum of the subject within about 30 minutes from the time of administration of the composition to the subject. In yet another embodiment, the therapeutically effective dose of the proton pump inhibitor is achieved in the subject's serum within about 20 minutes from the time of administration to the subject. In yet another embodiment of the invention, a therapeutically effective dose of the proton pump inhibitor is achieved in the serum of the subject within about 15 minutes from the time of administration of the composition to the subject.

  In a further embodiment, 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 yet another embodiment, 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% bioavailability, or at least 60 %.

In alternative embodiments, the pharmaceutical composition comprises at least about 5 mEq of an antacid, Prilocec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. Biologically equivalent to proton pump inhibitor products such as In other embodiments, the pharmaceutical composition comprises between about 5 mEq and about 30 mEq of an antacid, Prilocec®, Nexium®, Prevacid®, Protonic®, or It is bioequivalent to proton pump inhibitor products such as Aciphex®. In yet other embodiments, the pharmaceutical composition is between about 5 mEq and 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 20 mEq, or about Contains 22mEq, or about 25mEq, or about 27mEq, or about 30mEq of antacid, Priorocec®, Nexium®, Prevacid®, Protonic®, or Aciphex® Is bioequivalent to proton pump inhibitor products such as “Biologically equivalent” is intended to mean that the area under the serum concentration time curve (AUC) and the peak serum concentration (C _max ) are within 80% and 120%, respectively.

  In alternative embodiments, the pharmaceutical composition comprises at least about 5 mEq of an antacid, Priorocec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. Biologically equivalent to proton pump inhibitor products such as In other embodiments, the pharmaceutical composition comprises between about 5 mEq and about 11 mEq of an antacid, Priorocec®, Nexium®, Prevacid®, Protonic®, or It is bioequivalent to proton pump inhibitor products such as Aciphex®. In still other embodiments, the pharmaceutical composition comprises between about 5 mEq and 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, or about 11 mEq. And bioequivalent to proton pump inhibitor products such as Priorocec®, Nexium®, Prevacid®, Protonic®, or Aciphex® It is.

  In other embodiments, when administered to a subject, the pharmaceutical composition of the invention provides a serum concentration time curve for the proton pump inhibitor when the enteric proton pump inhibitor is delivered without an antacid. It has the area under the serum concentration time curve (AUC) for the proton pump inhibitor, which is equivalent to the lower area (AUC). “Equivalent” means that the area under the serum concentration time curve (AUC) for proton pump inhibitors is enteric coated with the same dose of proton pump inhibitor and delivered to the subject with an antacid less than 1 mEq. It is intended to mean within ± 30% of the area under the serum concentration time curve (AUC). An “enteric proton pump inhibitor” is used to ensure that at least some of the drug is released to some or most extent in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach. It is intended to mean that the proton pump inhibitor is enteric coated.

  In yet other embodiments, the pharmaceutical composition uses a USP dissolution method to provide a release profile of the proton pump inhibitor, so that more than about 50% of the proton pump after exposure to gastrointestinal fluid Inhibitor is released from the composition within about 2 hours; or more than about 50% proton pump inhibitor is released from the composition within about 1.5 hours; or more than about 50% proton pump The inhibitor is released from the composition within about 1 hour. In another embodiment, after exposure to gastrointestinal fluid, more than about 60% of the proton pump inhibitor is released from the composition within about 2 hours; or more than about 60% of the proton pump inhibitor is about 1.5%. Released from the composition within hours; or more than about 50% of the proton pump inhibitor is released from the composition within about 1 hour. In yet another embodiment, more than about 70% of the proton pump inhibitor is released from the composition within about 2 hours after exposure to gastrointestinal fluid; or more than about 70% of the proton pump inhibitor is about Released from the composition within 1.5 hours; or more than about 70% of the proton pump inhibitor is released from the composition within about 1 hour.

  The compositions contemplated by the present invention provide a therapeutic effect as a proton pump inhibitor drug over an interval of about 5 minutes to about 24 hours after administration, if desired, for example, once a day, 1 Allows administration twice a day or three times a day. Generally speaking, a compound that is effective to achieve a serum level commensurate with the concentration found to be effective in vivo for a time effective to elicit a therapeutic effect. It is desirable to administer an amount. The determination of these parameters is within the skill of the art.

Dosage Form The pharmaceutical composition of the present invention comprises the desired amount of proton pump inhibitor and antacid and can be of the following types: tablets (suspension tablets, chewable tablets, fast dissolving tablets, occlusal disintegrating tablets) , Including rapidly disintegrating tablets, effervescent tablets, or caplets), pills, powders (sterile packaged powders, dispensable powders, or effervescent powders), capsules (both soft and hard capsules, eg animal origin) Capsules made from gelatin or plant-derived HPMC), lozenges, sachets, troches, pellets, granules, or aerosols. The pharmaceutical compositions of the invention can be manufactured by conventional pharmacological techniques.

  In certain embodiments, the pharmaceutical compositions of the invention are in a solid dosage form containing the desired amount of proton pump inhibitor and antacid. In other embodiments, the pharmaceutical compositions of the invention comprise a desired amount of proton pump inhibitor and antacid, and capsules (both soft or hard capsules, such as animal-derived gelatin or plant-derived HPMC Administered in the form of capsules made from The pharmaceutical compositions of the invention can be manufactured by conventional pharmacological techniques.

  Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granules. (5) wet granulation or (6) fusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include spheronization, spray drying, pan coating, melt granulation, granulation, Wurster coating, tangential coating, top spray, extrusion, coacervation and the like.

  In one embodiment, the proton pump inhibitor is microencapsulated prior to being formulated into one of the above types. In another embodiment, some proton pump inhibitor is microencapsulated prior to being formulated. In another embodiment, some or most of the antacid is microencapsulated before being formulated. In yet another embodiment, standard coating techniques such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000) are used before some or most of the proton pump inhibitor is further formulated. Coated by. In yet other embodiments contemplated by the present invention, a film coating is provided around the pharmaceutical composition.

  In other embodiments, the pharmaceutical composition comprises one or more additional materials, e.g., pharmaceutically compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, Surfactant, preservative, lubricant, colorant, diluent, solubilizer, wetting agent, stabilizer, humidifier, anti-adhesive agent, wall cell activator, antifoaming agent, antioxidant, chelating agent, It further comprises an antifungal agent, an antibacterial agent, or one or more combinations thereof.

  In other embodiments, one or more layers of the pharmaceutical composition are plasticized. By way of example, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added from about 0.01% to about 50% of the coating composition by weight (w / w). Plasticizers include, for example, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate and casters Contains oil.

Exemplary solid oral dosage compositions Solid oral dosage compositions such as tablets, chewable tablets, effervescent tablets, caplets, and capsules include, for example, proton pump inhibitors, one or more antacids, and pharmaceuticals It can be prepared by mixing excipients to form a bulk blend composition. When these bulk blend compositions are homogeneous, proton pump inhibitors and antacids are evenly distributed throughout the composition so that the composition is an equally effective unit dosage form, e.g., It means that it can be easily subdivided into tablets, pills and capsules. Individual unit dosages may also include a film coating that disintegrates upon oral digestion or upon contact with a diluent.

  Compressed tablets are solid dosage forms prepared by condensing the bulk blend composition described above. In various embodiments, the compressed tablets of the present invention include one or more functional excipients such as binders and / or disintegrants. In other embodiments, the compressed tablet includes a film surrounding the final compressed tablet. In other embodiments, the compressed tablet includes one or more excipients and / or flavoring agents.

  Chewable tablets may be prepared by condensing the bulk blend composition described above. In one embodiment, the chewable tablet comprises a material effective to enhance the shelf life of the pharmaceutical composition. In another embodiment, the microencapsulation material has the property of hiding taste. 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 comprises both a material that is useful to enhance the shelf life of the pharmaceutical formulation and one or more flavoring agents.

  In various embodiments, the proton pump inhibitor, the antacid, and any one or more excipients are dry blended and compressed into a mass, such as an oral tablet or caplet, which, after administration, 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, less than about 60 minutes And thus release antacids and proton pump inhibitors into the gastrointestinal fluid. When at least 50% of the pharmaceutical composition is disintegrated, the compressed mass is substantially disintegrated.

  Capsules can be prepared by placing any of the above bulk blend compositions in a capsule. In certain embodiments of the invention, the therapeutic dose is divided into multiple (eg, two, three, or four) capsules. In certain embodiments, the entire dose of proton pump inhibitor and antacid is delivered in capsule form. For example, the capsule may contain between about 10 mg to about 120 mg of proton pump inhibitor, and about 5 mEq to about 30 mEq of antacid. In certain embodiments, the antacid may be selected from sodium bicarbonate, magnesium hydroxide, calcium carbonate, magnesium oxide, and mixtures thereof. In an alternative embodiment, the capsule comprises 5 mEq to about 30 mEq sodium bicarbonate.

Exemplary Powder Composition A powder for suspension may be prepared by combining at least one acid labile proton pump inhibitor and between about 5 mEq and about 11 mEq of antacid. In various embodiments, the powder may include one or more pharmaceutical excipients and flavors. A powder for suspension may be prepared, for example, by mixing a proton pump inhibitor, one or more antacids, and any pharmaceutical excipients to form a bulk blend composition. Good. This bulk blend is subdivided evenly into single dose packaging or multiple dose packaging units. The term “homogeneously” means that the homogeneity of the bulk blend is substantially maintained during the packaging process.

  In certain embodiments, some or all of the proton pump inhibitor is micronized. Further embodiments of the invention also include suspending and / or wetting agents.

  Expandable powders are also prepared according to the present invention. Effervescent salts have been used to disperse medicines in water for oral administration. The effervescent salt is a granule or coarse powder containing the pharmaceutical agent in a dry mixture usually composed of sodium bicarbonate, citric acid and / or tartaric acid. When the salt of the present invention is added to water, the acid and base react to liberate carbon dioxide gas, thereby producing “foaming”. Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. As long as the ingredients are suitable for pharmaceutical use and produce a pH of about 6.0 or higher, any acid-base combination that results in the release of carbon dioxide can be substituted for sodium bicarbonate and citric acid and tartaric acid. Can be used.

  The method of preparation of expandable granules of the present invention utilizes three basic processes: wet granulation, dry granulation and fusion. The fusion method is used for the preparation of most commercial foamable powders. Although these methods are intended for the preparation of granules, it should be noted that the effervescent salt formulations of the present invention can also be prepared as tablets according to known techniques for tablet preparation.

Powder for Suspension In certain embodiments, a pharmaceutical for oral administration to a subject comprising at least one proton pump inhibitor, from about 5 mEq to about 11 mEq of antacid, and at least one suspension. A composition is provided. The composition can be a powder for suspension, and a substantially uniform suspension is obtained upon mixing with water. See U.S. Patent Application No. 10 / 893,092, filed July 16, 2004, claiming priority to U.S. Provisional Patent Application No. 60 / 488,324, filed July 18, 2003 . Both of these are hereby incorporated by reference in their entirety.

  A suspension is "substantially" when it is mostly homogeneous, i.e., when it is composed of approximately the same concentration of proton pump inhibitor at any point throughout the suspension. Is uniform. " Suspensions may vary in concentration by 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%. When present between samples taken from various points from the suspension, the entire suspension is judged to consist of approximately the same concentration of proton pump inhibitor.

  The concentration at various points throughout the suspension can be determined by any suitable means known in the art. For example, one suitable method for determining concentrations at various points involves dividing the suspension into three substantially equal sections: top, middle, and bottom. These layers start from the top of the suspension. Split to end at the bottom of the suspension. Any number of sections suitable to determine the homogeneity of the suspension may be used, for example, 2 sections, 3 sections, 4 sections, 5 sections, or 6 or more sections it can.

  In one embodiment, the composition of the present invention comprises at least one proton pump inhibitor, between about 5 mq and about 11 mEq of antacid, and a gum suspension, wherein the average particle size of the insoluble material Is less than about 200 μm. In certain 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. This composition is a powder for suspension, and upon mixing with water, a first suspension is obtained, which includes a proton pump inhibitor, an antacid, and a suspension. It is substantially more homogeneous when compared to the suspension of 2, where the suspension is not xanthan gum.

  In another embodiment, the composition of the present invention comprises omeprazole, sodium bicarbonate and xanthan gum. This composition is a powder for suspension, and upon mixing with water, a substantially uniform suspension is obtained. In yet another embodiment, the composition is a powder for suspension and comprises omeprazole, between about 5 mq and about 11 mEq of sodium bicarbonate, xanthan gum, and at least one sweetener or flavoring.

Combination Therapy The compositions and methods described herein may also be used with other well known therapeutic agents that are selected for their particular usefulness against the condition being treated. In general, in the compositions described herein and in embodiments in which combination therapy is utilized, no other agent need be administered in the same pharmaceutical composition, and different physical and chemical properties. For this reason, it must be administered by different routes. Determination of the mode of administration and determination of suitability of administration is within the knowledge of skilled clinicians, where possible, in the same pharmaceutical composition. If initial administration can be made according to established protocols known in the art, then the dosage, mode of administration and number of administrations can be modified by skilled clinicians based on the observed effects.

  The particular choice of compound used will depend on the diagnosis of the attending physician and the physician's judgment of the patient's condition and the appropriate treatment protocol. The compounds are administered together (e.g., simultaneously, essentially simultaneously, or in the same treatment protocol) or sequentially, depending on the nature of the proliferative disease, the condition of the patient, and the actual choice of compound used. May be. Determination of the order of administration and the number of repetitions of administration of each therapeutic agent during the treatment protocol is well within the knowledge of a skilled physician after assessment of the disease being treated and the condition of the patient.

  It will be appreciated that the dosage regimen for treating, preventing, or ameliorating a condition in need of alleviation may be modified according to various factors. These factors include the type of gastric acid disorder that the subject suffers from, the proton pump inhibitor that is administered, and the age, weight, sex, diet, and medical status of the subject, and therefore the actual regimen utilized. Can vary widely and, therefore, can deviate from the dosage regimes presented herein. For example, proton pump inhibitors can be formulated to deliver rapid relief of gastric acid related disorders as well as sustained relief.

  The pharmaceutical agents that make up the combination therapy disclosed herein may be in combination or separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially with any compound being administered by a regime that requires two-step administration. A two-stage regimen may require sequential administration of the active agents or administrations separated by separate active agents. The length of time between multiple administration steps depends on the properties of each medical drug, such as potency, solubility, bioavailability, plasma half-life, and the kinetic profile of the medical drug, It can range from a few minutes to a few hours. Circadian variation of the target molecule concentration can also determine the optimal dosing interval.

In certain embodiments, the methods, kits, and compositions of the invention are associated with another medical agent indicated for treating or preventing a gastrointestinal disorder, such as an antibacterial agent, alginic acid, a prokinetic agent, or this disorder. It can be used in combination with commonly administered H ₂ antagonists and the like to minimize pain and / or complications. These drugs have certain disadvantages associated with their use. Some of these drugs are not fully effective in the treatment of the above-mentioned conditions and / or produce adverse side effects such as confusion, constipation, diarrhea, and thrombocytopenia.

  In other embodiments, the methods, kits, and compositions of the present invention can be used in combination with other medical agents including, but not limited to: enfenamic acid, etofe Etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, teloflumate NSAIDs including but not limited to terofenamate, and aminoarylcarboxylic acid derivatives such as tolfenamic acid; aceclofenac, acemetacin, alclofenac, amfenac , Amtolmetin guacil, bromfenac, bufexamac (bufexamac), cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenbinac acid, fenclozic acid, fentiazac, glucametacin, glucametacin (ibufenac), indomethacin, isofezolac, isoxepac, lonazolac, methiazinic acid, mofezolac, oxametacine, pirazolac, progouracins arylacetic acid derivatives such as proglumetacin, sulindac, tiaramide, tolmetin, tropesin, and zomepirac; bumadizon, butibufen, fenbufen, xenbufen arylbutyric acid derivatives such as (xenbucin); Arylcarboxylic acids such as dandan (clidanac), ketorolac, and tinoridine; aluminoprofen, benoxaprofin, bermoprofen, bucloxic acid, carprofen (carprofen), fenoprofen, frunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen , Naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, prof ), And zaltoprofen (zal arylpropionic acid derivatives such as toprofen; pyrazoles such as difenamizole and epirozole; apazone, benzpiperylon, feprazone, mofebutazone, morabutazone, morazone, oxyfenbuta Pyrazolones such as oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, prostaglandin, ramifenazone, suxibuzone, and thiazolinobutazone; Acetaminosalol, aspirin, benolylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentricic acid (gent isic acid), glycol salicylate, imidazolic salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthylsalicylic acid, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide Amido o-acetic acid, salicyl sulfate, salsalate, sulfasalazine and other salicylic acid derivatives; ampiroxicam, droxicam, isoxicam, lomoxicam, piroxicam And thiazinecarboxamides such as tenoxicam; cyclooxygenase II inhibitors ("COX-II") such as Celebrex (Celecoxib), Vioxx, Relafen, Lodine, and Voltaren, and others such as ε- Aceto Amidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, α-bisabolol, bucololome, difenpyramide (difenpiramide), ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, isoxalper , Proquazone, tenidap and dilenton; benzodiazepine hypnotics, non-benzodiazepine hypnotics, antihistamine hypnotics, antidepressant hypnotics, herbal extracts, barbiturates, peptide hypnotics, triazolam, brotizolam, loprazolam Lormetzepam etazepam), flumitrazepam (flunitrazepam), flurazepam (flurazepam), nitrazepam, quazepam (quazepam), estazolam, temazepam, lorazepam, oxazepam, diazepam, halazepam, prazepam, alprazolam, chlordiazepoxide, chlordiazepoxide, chlordiazepoxide (zolpidem) or zolpidem tartrate, zopiclone, eszopiclone, zaleplon, indiplone, diphenhydramine, doxylamine, phenyltoloxamine, pyrilamine, doxepin, amtriptyline, trimipramine zo , Nefazodone, bupropion, bupramityiptyline, valerian extract or amentoflavone Sleep aids including but not limited to hormones such as natural products, melatonin or gabapeptin; motility drugs including but not limited to 5-HT inhibitors such as cisapride, domperidone, and metoclopramide, and irritable bowel Drugs useful for treating the syndrome.

  For the sake of brevity, all cited patents and other references are incorporated herein by reference in their entirety.

EXAMPLES The invention is further illustrated by the following examples, which should not be construed as limiting in any way. Experimental procedures for generating the data shown are discussed in more detail below. For all formulations in this example, multiple doses may use the compound proportionately as is known in the art. Coatings, layers and encapsulations were applied in a conventional manner using conventional equipment for these purposes.

  Although the present invention has been described in an exemplary manner, the terminology used is intended to be in the nature of description rather than limitation.

Example 1: Modified Fuch Model for Antacid Selection Samples were prepared and analyzed using a method that is a variation of the Fuch procedure described in the literature. The described procedure simulates a gastric environment with continuous acid influx. A description of the experimental setup and sample analysis is provided below. Changes to these instructions may be made after initial sample evaluation for sample analysis and collection of related information.

Setting:
1. A glass sample container (˜150 mL capacity) containing 50 mL of standardized 0.1N HCl solution was placed in a water bath set at 37 ° C. (± 2 ° C.).
2. A second glass container containing> 70 mL of standardized 1.0 N HCl solution was placed in the same water bath.
3. The stir bar was then placed in the same sample container and set to the appropriate speed. The speed of the stir bar was recorded and used for all samples analyzed. The speed of the stir bar should be appropriate to dissolve the sample and added acid without causing pH measurement interference or splashing the solution.
4. Prior to the start of each sample analysis, a tube system was prepared and confirmed 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 transfer of 1.0N HCl acid to the sample container.
5. The pH meter is calibrated to accurately measure pH between 1 and 10, and the electronic storage device is ready to collect pH and / or temperature data at a predetermined rate It was confirmed.
6. If necessary, the sample was ground to a fine powder using a mortar and pestle, then transferred to a suitable container and weighed.
7. The pH probe was placed in a glass sample container 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 to a container and the exact time that the sample was introduced into the acid was recorded. The sample container was then weighed again to determine the exact weight added.
9. The sample was then stirred for approximately 6 minutes and a 1.0N HCl flow at a rate of 0.5 mL / min was initiated. The exact starting point of the acid flow was recorded.
10. For samples with ANC below 30 mEq (≦ 30 mEq), the sample was continuously stirred and the pH was monitored for 1 hour at 15 second intervals.
11. The duration of the test was recorded and the total volume of 0.1N HCl added was calculated based on the flow rate.

  Various buffer combinations were screened using this modified Fuchs in vitro kinetic gastric model as described above, and the theoretical ANC correlation of a given buffer to the actual neutralizing capacity and its rate is It has been found that it depends on several factors such as sex, particle size, presence and level of binders and / or disintegrants. For example, it has been determined that the smaller the buffer particle size, the closer the theoretical value for a given buffer to the actual ANC. This particle size effect was particularly noticeable for insoluble or slightly soluble antacids such as calcium carbonate or magnesium hydroxide. In contrast, the larger the antacid particle size, the smaller the actual ANC (eg, magnesium hydroxide below 100 US mesh size, below 80 US mesh size, and below 60 US mesh size).

  Spray-dried magnesium hydroxide with 5% starch, such as MS-90® from SPI Pharma, is produced by precipitation at a set rate of neutralization (USP grade magnesium hydroxide) It was also determined that the performance was better. In a similar pattern, spray-dried calcium carbonate with 5% starch, such as Destab® calcium carbonate-95S from Particle Dynamics, is actually measured by the area under the curve (AUC) of the dynamic pH profile. It was also determined that the performance was better than the USP grade calcium carbonate produced by precipitation, at the set rate of neutralization, as well as the neutralization power of.

Example 2: Disintegrant Optimization Test: Mixed Buffer System Most proton pump inhibitors are slightly soluble in water. These somewhat poorly soluble drugs have a strong correlation of degradation time to bioavailability, which is important for optimizing disintegration times that enhance the in vivo dissolution of the drug. This test uses a formulation based on magnesium hydroxide of 80 mesh US mesh size or less, as shown in Table 2A, and for capsule dosage form performance, a level of disintegrant between 3 and 11% (cross Carmellose sodium, Ac-di-Sol) was tested. The disintegration test outlined by the USP (United States Pharmacopeia) was chosen as the test method to determine the optimal level of disintegrant. All capsule products containing between 5% and 11% Ac-Di-Sol performed similarly in terms of their physical characteristics, flow properties, and encapsulation characteristics. Sample disintegration tests using a mixed buffer system showed that the capsule disintegration time decreased when the disintegrant level was increased from 3% to 5%. Increasing the level of disintegrant above 5% did not significantly reduce the disintegration time.

(Table 2.A.1) Disintegrant optimization test

(Table 2.A.2) Disintegrant optimization test

Example 2B. Disintegrant Optimization Test-Sodium Bicarbonate Buffer Sodium bicarbonate has effervescent properties when mixed with acids such as gastric juice. This promotes the disintegration time of the capsule product and the disintegration requirements are less than the mixed buffer system when sodium bicarbonate buffer is used as the single buffer. This test uses a USP # 2 grade sodium bicarbonate based formulation as shown in Table 2.B.1., With a level of disintegrant between 1% and 5% for capsule dosage form performance. (Croscarmellose sodium, Ac-di-Sol) was tested. The disintegration test outlined by the USP (United States Pharmacopeia) was chosen as the test method to determine the optimal level of disintegrant. All capsule products containing between 1% and 5% Ac-Di-Sol performed similarly in terms of their physical characteristics, flow properties, and encapsulation characteristics. However, disintegration testing of the sample showed that the capsule degradation time decreased when the level of disintegrant was increased from 1% to 2%. Increasing the level of disintegrant above 3% did not significantly reduce the disintegration time.

(Table 2.B.1) Disintegrant optimization test

(Table 2.B.2) Disintegrant optimization test: sodium bicarbonate buffer

Example 3: Binder optimization test
A low level of 3-8% binder is commonly used in capsule product manufacture to make a stopper prior to encapsulation. The use of binders such as Klucel®-EXP (hydroxypropylcellulose) or microcrystalline cellulose (Avicel® PH-102, PH-200) can be used for dynamic gastric models (modified Fuchs models). Used to evaluate performance in the presence of 0-5% disintegrant in the powder. In general, the use of binders had a negative effect on the rate of neutralization in actual ANC and pH profile tests unless used in combination with disintegrants.

(Table 3.A.1) Binder optimization test

(Table 3.A.2) Binder optimization test

  The results of the pH test (Table 3.A.1. and Table 3.A.2.) show that capsules containing 5-10% level of binder have a very slow rate of binding. It shows that the capsule with the agent and disintegrant had a moderately fast neutralization. Capsules without binder and without disintegrant had moderate neutralization rates. Table 3BB showed similar findings that the presence of the binder slows the rate of neutralization while the use of a disintegrant reduces the negative effects of the binder in the formulation.

Table 3.B.1 Neutralization rate of capsules using various levels of binders and disintegrants

Table 3.B.2 Capsule neutralization rates using various levels of binders and disintegrants

Example 4: Capsule Formulation The following formulation was prepared by the following process: Sodium bicarbonate and omeprazole were combined in a mixer and blended for 5 minutes. To this mixture, magnesium hydroxide and croscarmellose sodium were added and blended for 5 minutes. It was then passed through a # 20 mesh s / s sieve and then mixed for 10 minutes. Magnesium stearate was then added to the mixture and blended for 3 minutes. The material was then encapsulated in a hard gelatin capsule shell.

Example 5: Capsules with sodium bicarbonate and less than 3% disintegrant The following specific formulations are provided for reference only and are not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI and sufficient buffer to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of buffer is expressed in terms of weight as well as molar equivalent weight (mEq). Capsules were prepared by blending PPI with one or more buffers and intimately blending with excipients. An appropriate weight of the bulk blend composition is filled into hard gelatin capsules (eg, size 00) using an automatic encapsulation device. PPI can be micronized.

Example 6 Capsules with Mixed Buffer System and 3-11% Disintegrant The following specific formulations are provided for reference only and are not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI and sufficient buffer to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of buffer is expressed in terms of weight as well as molar equivalent weight (mEq). Capsules were prepared by blending PPI with one or more buffers and intimately blending with excipients. An appropriate weight of the bulk blend composition is filled into hard gelatin capsules (eg, size 00) using an automatic encapsulation device. PPI can be micronized.

Example 7 Capsule Formulation Without Binder The following specific formulation is provided for reference only and is not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI and sufficient buffer to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of buffer is expressed in terms of weight as well as molar equivalent weight (mEq). Capsules were prepared by blending PPI with one or more buffers and intimately blending with excipients. An appropriate weight of the bulk blend composition is filled into hard gelatin capsules (eg, size 00) using an automatic encapsulation device. PPI can be micronized.

Example 8: Capsule Formulation The following specific formulation is provided for reference only and is not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI, as well as sufficient antacid to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of antacid is expressed in terms of weight as well as molar equivalent weight (mEq). Capsules were prepared by blending antacids and PPI and intimately blending with excipients as shown in Tables 8.A.-8.H. below. The appropriate weight of the bulk blend composition is filled into hard gelatin capsules (eg size 00) using an automatic encapsulation device (H & K 1500 or MG2 G60). PPI can be micronized.

(Table 8. A.) Omeprazole (20 mg) capsules

(Table 8.B.) Omeprazole (40 mg) capsules

Table 8. C. Lansoprazole (15 mg) capsules

Table 8. D. Lansoprazole (30 mg) capsules

(Table 8.E.) Omeprazole (60 mg) capsules

(Table 8.F.) Omeprazole (60 mg) capsules

(Table 8. G.) Omeprazole (10 mg) capsules

(Table 8. H.) Omeprazole (40 mg) capsules

Example 9: Tablet formulation The following specific formulation is provided for reference only and is not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI, as well as sufficient antacid to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of antacid is expressed in terms of weight as well as molar equivalent weight (mEq). Tablets were prepared by blending antacids and PPI and intimately blending with excipients as shown in Tables 9.A.-9.H. below. An appropriate weight of the bulk blend composition is compressed using an oval shape process in a rotary press (Manesty Express) to achieve a hardness of 15-20 kPa. PPI can be micronized.

(Table 9. A.) Omeprazole (20 mg) tablets

(Table 9.B.) Omeprazole (40 mg) tablets

Table 9. C. Lansoprazole (15 mg) tablets

Table 9. D. Lansoprazole (30 mg) tablets

Table 9. E. Omeprazole (60 mg) tablets

Table 9. F. Omeprazole (20 mg) tablets

Table 9. G. Omeprazole (10 mg) tablets

Table 9. H. Omeprazole (40 mg) tablets

Example 10: Chewable tablet formulations The following specific formulations are provided for reference only and are not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI, as well as sufficient antacid to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of antacid is expressed in terms of weight as well as molar equivalent weight (mEq). Tablets were prepared by blending antacids and PPI and intimately blending with excipients as shown in Tables 10.A. to 10.H. below. An appropriate weight of the bulk blend composition is compressed using a 17 mm FFBE process on a rotary press (Manesty Express) to achieve a hardness of 10-14 kPa. PPI can be micronized.

(Table 10.A.) Omeprazole (20 mg) chewable tablets

(Table 10.B.) Omeprazole (40 mg) chewable tablets

Table 10. C. Lansoprazole (15 mg) chewable tablets

Table 10. D. Lansoprazole (30 mg) chewable tablets

(Table 10.E.) Omeprazole (60 mg) chewable tablets

(Table 10.F.) Omeprazole (60 mg) chewable tablets

(Table 10. G.) Omeprazole (10 mg) chewable tablets

(Table 10. H.) Omeprazole (40 mg) chewable tablets

Example 11: Occlusal Disintegrating Chewable Tablet Formulation The following specific formulations are provided for reference only and are not intended to limit the scope of the present invention. Each formulation contains a therapeutically effective dose of PPI, as well as sufficient antacid to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. The amount of antacid is expressed in terms of weight as well as molar equivalent weight (mEq). Tablets were prepared by blending antacids and PPI and intimately blending with excipients as shown in Tables 11.A.-11.H. below. An appropriate weight of the bulk blend composition is compressed using a 10 mm FFBE process on a rotary press (Manesty Express) to achieve a hardness of 5-9 kPa. PPI can be micronized.

(Table 11. A.) Omeprazole (20 mg) occlusal disintegrable chewable tablets

(Table 11. B.) Omeprazole (40 mg) occlusal disintegrable chewable tablets

Table 11. C. Lansoprazole (15 mg) occlusal disintegrable chewable tablets

Table 11. D. Lansoprazole (30 mg) occlusal disintegrable chewable tablets

(Table 11. E.) Omeprazole (60 mg) occlusal disintegrable chewable tablets

(Table 11. F.) Omeprazole (60 mg) occlusal disintegrable chewable tablets

Table 11. G. Omeprazole (10 mg) occlusal disintegrable chewable tablets

(Table 11. H.) Omeprazole (40 mg) occlusal disintegrable chewable tablets

Example 12: Powder for Suspension Formulation The following specific formulation is provided for reference only and is not intended to limit the scope of the invention. Each formulation contains a therapeutically effective dose of PPI, as well as sufficient antacid to prevent at least some acid degradation of PPI by raising the pH of the gastric juice. PPI can be micronized.

Table 12. A. Microencapsulated omeprazole (20/40/60/120 mg) powder for suspension

Table 12. B. Omeprazole (20 mg) powder for suspension

Table 12. C. Omeprazole (40 mg) powder for suspension

Table 12. D. Omeprazole (60 mg) powder for suspension

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

A comparison of buffer systems containing various mixtures of NaHCO ₃ and Mg (OH) ₂ is shown. A comparison of buffer systems containing various mixtures of NaHCO ₃ and Mg (OH) ₂ is shown. Figure 3 shows the effect of magnesium hydroxide particle size on in vitro / in vivo neutralization. Figure 3 shows the effect of magnesium hydroxide particle size on the pharmacokinetics of various formulations. Figure 2 shows the effect of binders on various pharmaceutical formulations. Figure 6 shows the capsule dissolution effect using a 5% binder when compared to a powder for suspension. Results of pH studies of high / low Ac-Di-Sol (disintegrant) are shown. The results of a pharmacokinetic study of high / low Ac-Di-Sol (disintegrant) compared to Prilosec are shown. The pharmacokinetic profiles for 6 different pharmaceutical formulations are shown. A summary of all CTM lots with ANC present in individual pharmaceutical formulations. 1 is an overview of the pharmacokinetics of various formulations. Shows capsule stability of SAN-10E, SAN-10BB, and SAN-10B. A comparison of the concentration / time curve for Prilosec® to that of SAN-10K (10.5 mEq sodium bicarbonate and 40 mg omeprazole) is shown.

Claims (46)

Capsule or caplet oral dosage form pharmaceutical formulation comprising:
(a) about 5 mg to about 200 mg of at least one acid labile proton pump inhibitor;
(b) an amount of at least one antacid that is sufficient to increase the pH of the gastric fluid to a pH that interferes with acid degradation of the proton pump inhibitor in at least some of the gastric fluid; An antacid containing about 400 mg of NaHCO ₃ ; and
(c) greater than about 2% by weight of disintegrant.   2. The pharmaceutical preparation according to claim 1, wherein the proton pump inhibitor is omeprazole, or its free base, free acid, salt, hydrate, or prodrug.   2. The pharmaceutical formulation according to claim 1, wherein the proton pump inhibitor is esomeprazole, or its free base, free acid, salt, hydrate, or prodrug.   2. The pharmaceutical formulation according to claim 1, wherein the proton pump inhibitor is lansoprazole, or its free base, free acid, salt, hydrate, or prodrug.   2. The pharmaceutical formulation of claim 1, comprising about 20 mg proton pump inhibitor.   2. The pharmaceutical formulation of claim 1, comprising about 40 mg proton pump inhibitor.   The pharmaceutical formulation according to claim 1, wherein the antacid is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. .   2. The pharmaceutical formulation of claim 1, wherein the sodium bicarbonate is present in an amount of at least about 800 mg.   2. The pharmaceutical formulation according to claim 1, wherein the antacid is sodium bicarbonate.   2. The pharmaceutical formulation of claim 1, wherein the antacid is present in an amount of about 400 mg to about 1600 mg.   2. The pharmaceutical formulation of claim 1, wherein the antacid is present in an amount of about 5 mEq to about 20 mEq.   2. The pharmaceutical formulation of claim 1, wherein the antacid is present in an amount of about 8 mEq to about 12 mEq.   2. The pharmaceutical formulation according to claim 1, wherein the oral dosage form is a capsule.   14. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation is administered as a single capsule.   2. The pharmaceutical preparation according to claim 1, wherein the disintegrant is Ac-Di-Sol.   2. The pharmaceutical formulation of claim 1, wherein the disintegrant is present in an amount of about 2% to about 8% by weight.   2. The pharmaceutical formulation of claim 1, wherein the formulation does not comprise a binder.   The pharmaceutical formulation of claim 1, further comprising a binder, wherein the disintegrant is present in at least the same weight percent as the binder.   19. The pharmaceutical formulation of claim 18, wherein the binder is present in an amount less than about 10% by weight.   2. The pharmaceutical preparation according to claim 1, wherein the preparation does not contain a flavoring agent.   2. The pharmaceutical formulation of claim 1, wherein the initial serum concentration of the proton pump inhibitor is greater than about 0.1 [mu] g / ml at any time within about 30 minutes after administration of the pharmaceutical formulation. (a) at least one acid labile proton pump inhibitor:
(b) sodium bicarbonate between about 5 mEq and about 20 mEq; and
(c) between about 2% and about 5% by weight of a disintegrant;
Wherein a therapeutically effective amount of a proton pump inhibitor is delivered upon oral administration to a subject, and a T _{max of the} proton pump inhibitor is obtained within about 60 minutes. A pharmaceutical preparation.   23. The pharmaceutical formulation of claim 22, wherein the proton pump inhibitor is omeprazole, or its free base, free acid, salt, hydrate, or prodrug.   24. The pharmaceutical formulation of claim 23, wherein omeprazole is present in an amount of about 20 mg.   24. The pharmaceutical formulation of claim 23, wherein omeprazole is present in an amount of about 40 mg.   24. The pharmaceutical formulation of claim 22, wherein the sodium bicarbonate is present in an amount from about 800 mg to about 1300 mg.   23. The pharmaceutical formulation of claim 22, wherein sodium bicarbonate is present in an amount of about 1100 mg.   23. A pharmaceutical formulation according to claim 22 administered as a single capsule.   23. A pharmaceutical formulation according to claim 22, wherein the disintegrant is Ac-Di-Sol.   23. A pharmaceutical formulation according to claim 22, wherein the formulation does not comprise a binder.   23. The pharmaceutical formulation of claim 22, wherein the initial serum concentration of the proton pump inhibitor is greater than about 0.1 [mu] g / ml at any time within about 30 minutes after administration of the pharmaceutical formulation.   2. A method of administering a compound according to claim 1 for the treatment of a gastric acid related disorder.   Gastroacid-related disorders include duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, hyporeactive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretion disease, Zollinger-Ellison syndrome, heartburn, 35. The method of claim 32, wherein the method is esophageal disorder, upper gastrointestinal bleeding, or polyacidic dyspepsia. 14. The pharmaceutical formulation of claim 13, wherein the T _{max of the} proton pump inhibitor is obtained within about 75 minutes after oral administration of the pharmaceutical formulation to the subject. 14. The pharmaceutical formulation of claim 13, wherein the T _{max of the} proton pump inhibitor is obtained within about 60 minutes after oral administration of the pharmaceutical formulation to the subject. 14. The pharmaceutical formulation of claim 13, wherein the _{Tmax of the} proton pump inhibitor is obtained within about 45 minutes after oral administration of the pharmaceutical formulation to the subject.   14. The pharmaceutical formulation of claim 13, wherein the serum concentration of the proton pump inhibitor is greater than about 0.3 μg / ml within about 1 hour after oral administration of the pharmaceutical formulation to the subject.   14. The pharmaceutical formulation of claim 13, wherein the serum concentration of the proton pump inhibitor is greater than about 0.3 μg / ml within about 45 minutes after oral administration of the pharmaceutical formulation to the subject.   14. The pharmaceutical formulation of claim 13, wherein the mean Cmax of proton pump inhibitor is less than about 1250 ng / ml after oral administration of the pharmaceutical formulation to the subject.   14. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation disintegrates substantially within about 45 minutes after oral administration of the pharmaceutical formulation to the subject. 23. The pharmaceutical formulation of claim 22, wherein the proton pump inhibitor T _max is obtained within about 45 minutes after oral administration of the pharmaceutical formulation to the subject.   23. The pharmaceutical formulation of claim 22, wherein the serum concentration of the proton pump inhibitor is greater than about 0.3 [mu] g / ml within about 1 hour after oral administration of the pharmaceutical formulation to the subject.   23. The pharmaceutical formulation of claim 22, wherein the serum concentration of the proton pump inhibitor is greater than about 0.3 [mu] g / ml within about 45 minutes after oral administration of the pharmaceutical formulation to the subject.   23. The pharmaceutical formulation of claim 22, wherein the mean Cmax of proton pump inhibitor is less than about 1250 ng / ml after oral administration of the pharmaceutical formulation to the subject. Is administered to the subject prior to a meal, T _max of the proton pump inhibitor is obtained within about 60 minutes after oral administration of the pharmaceutical formulation to a subject, a pharmaceutical preparation according to claim 1, wherein the.   24. The pharmaceutical formulation of claim 22, wherein the pharmaceutical formulation is administered to a subject prior to a meal.

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