WO2007070164A1 - Pharmaceutical composition comprising a proton pump inhibitor, a buffering agent and an anti-h. pylori active substance and methods of using same - Google Patents

Pharmaceutical composition comprising a proton pump inhibitor, a buffering agent and an anti-h. pylori active substance and methods of using same Download PDF

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Publication number
WO2007070164A1
WO2007070164A1 PCT/US2006/040756 US2006040756W WO2007070164A1 WO 2007070164 A1 WO2007070164 A1 WO 2007070164A1 US 2006040756 W US2006040756 W US 2006040756W WO 2007070164 A1 WO2007070164 A1 WO 2007070164A1
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composition
proton pump
active substance
pump inhibitor
buffering agent
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PCT/US2006/040756
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French (fr)
Inventor
Jeffrey O. Phillips
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The Curators Of The University Of Missouri
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Publication of WO2007070164A1 publication Critical patent/WO2007070164A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical compositions comprising a proton pump inhibitor, a buffering agent, and an anti-H. pylori active substance such as an antibiotic. Methods of using such compositions are also provided.
  • H. pylori is a spiral-shaped bacterium that is found in the gastric mucous layer or adherent to the epithelial lining of the stomach.
  • H. pylori infection to gastrointestinal disease in humans.
  • H. pylori is the most common cause of gastritis in humans, and greater than 90% of duodenal ulcer patients are infected with H. pylori.
  • PPIs used in H. pylori treatment includes substituted benzimidazole compounds that contain a sulfinyl group bridging substituted benzimidazole and pyridine rings. At neutral pH, these PPIs are chemically stable, lipid-soluble compounds that have little or no inhibitory activity. Unfortunately, most commercially available PPIs are unstable at neutral or acidic pH and undergo decomposition in gastrointestinal fluid upon oral administration, thereby resulting in loss of therapeutic activity. To overcome this acid instability, such compounds are typically formulated for oral delivery as enteric coated solid dosage forms, for example enteric coated tablets in which the enteric coating protects the drug from contact with acidic stomach secretions.
  • enteric coated PPIs provide no immediate benefit in terms of increased gastric pH. In fact, it often it takes 4 or 5 days for enteric coated PPIs to exert their maximal effect on gastric pH.
  • the pH of the stomach is typically about 2 to about 4
  • antibiotics are inefficient when administered together with an enteric coated proton pump inhibitors because the gastrointestinal fluid is well below the ideal pH for bacterial growth; again the enteric coated proton pump inhibitors do not have an effect on gastric pH until several hours after ingestion and this effect is not maximal until approximately 4 or 5 days after continued dosing of the PPI.
  • any antibiotic taken simultaneously with the enteric coated PPI will be absorbed (into the bloodstream) from the duodenum or lower gastrointestinal tract well after the antibiotic has passed through the stomach.
  • high initial concentrations of antibiotics in the stomach will not coincide with ideal gastric pH conditions (pH of about 5.5. to about 7.5) for optimal susceptibility to antibiotics.
  • the PPI will only begin to increase gastric pH after the antibiotic has been absorbed into the bloodstream and is secreted back into the gastric fluid at concentrations that are 10- to 100-fold lower than the initial high stomach concentrations prior to absorption.
  • the present invention provides pharmaceutical compositions comprising a proton pump inhibitor, a buffering agent, and an anti- Helicobacter pylori active substance (also referred to as an anti-H. pylori active substance), for example an antibiotic.
  • an anti-H. pylori active substance also referred to as an anti-H. pylori active substance
  • at least a therapeutically effective amount or portion of the proton pump inhibitor is not enteric coated.
  • the present invention provides a method for treating a subject in need of H. pylori treatment and/or treatment of an acid related gastrointestinal disease or disorder such as ulcer, comprising administering to the subject a composition comprising an an ⁇ -Helicobacter pylori active substance, a buffering agent, and a PPI.
  • a composition comprising an an ⁇ -Helicobacter pylori active substance, a buffering agent, and a PPI.
  • at least a therapeutically effective portion of the proton pump inhibitor is not enteric coated.
  • upon administration of the composition to the subject at least a therapeutically effective amount of the proton pump inhibitor and/or anti-H. pylori active substance is available for absorption in the subject's stomach.
  • the invention provides a method of treating a human subject in need of H.
  • compositions comprising at least one of (or all three of): an anti-H. pylori active substance, a buffering agent, and a PPI, wherein a portion of the PPI is optionally enteric coated or the entire amount of PPI is free of enteric coating.
  • the composition is designed such that a therapeutically effective amount of the anti-H. pylon active substance is available in the subject's stomach at a time when the subject's stomach secretions are at a p ⁇ of about 5 to about 8 or about 5.5 to about 7.5.
  • Such a result can be accomplished in any suitable manner, for example by coordinating the timing of administration of the one or more compositions, or by providing a single composition that provides controlled release of the anti-H. pylori active substance, buffering agent and proton pump inhibitor such that a therapeutically effective amount of the anti-H. pylori active substance is available for absorption in the subject's stomach when the subject's stomach secretions are at the desired p ⁇ .
  • compositions of the invention comprise at least one pharmaceutically acceptable acid labile, substituted benzimidazole H + ,K + -ATPase proton pump inhibitor (PPI).
  • PPI proton pump inhibitor
  • the term proton pump inhibitor or PPI means any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase.
  • a PPI may, if desired, be in the form of free base, free acid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active or undergoes conversion within or outside of the body to a therapeutically active form.
  • illustrative PPIs are those compounds of Formula (I):
  • R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
  • R 2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
  • R and R are the same or different and each is hydrogen, alkyl, C 1-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy;
  • R 4 is hydrogen, alkyl, Cj -4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
  • Q is nitrogen, CH, or CR 1 ;
  • W is nitrogen, CH, or CR 1 ;
  • y is an integer of 0 through 4.
  • Z is nitrogen, CH, or CR ' ;
  • PPIs include esomeprazole (also referred to as S-omeprazole), dontoprazole, ilaprazole, lansoprazole, s-lansoprazole, omeprazole, hydroxyomeprazole, pantoprazole, pariprazole, rabeprazole, lansoprazole, tenatoprazole, leminoprazole and nepaprazole or a free base, a free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
  • esomeprazole also referred to as S-omeprazole
  • dontoprazole also referred to as S-omeprazole
  • ilaprazole lansoprazole
  • s-lansoprazole omeprazole
  • hydroxyomeprazole pantoprazole
  • pariprazole
  • proton pump inhibitors include but are not limited to: soraprazan (Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB -641257) (2-pyrimidinamine, 4-(3 ,4-dihydro- 1 -methyl-2( lH)-isoquinolinyl)-N- (4-fluo- rophenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447 (Imidazo(l,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3- thieny- 1) (Shinnippon); 3-hydroxymethyl-2rnethyl-9-phenyl-7H-8,9-dihydro- pyrano(2,- 3-c)-imidazo(l,2-a)pyridine (PCT Publication WO
  • Still other suitable proton pump inhibitors include those described in the following U.S. Pat. Nos.: 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281; 6,136,
  • Proton pump inhibitors as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley- Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et at, Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
  • “Pharmaceutically acceptable salts,” or “salts,” include the salt of a proton pump inhibitor prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta- hydroxybutyric, galactaric and galacturonic acids.
  • acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid.
  • suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • an acid addition salt is reconverted to the free base by treatment with a suitable base.
  • the acid addition salts of the proton pump inhibitors are halide salts, which are prepared using hydrochloric or hydrobromic acids.
  • the basic salts are alkali metal salts, e.g., sodium salt.
  • Salt forms of proton pump inhibitors include, but are not limited to: a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or omeprazole magnesium, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole, described in U.S. Pat. No. 6,511,996.
  • Other salts of esomeprazole are described in U.S. Pat. Nos.: 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
  • esters involves functionalizing hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug.
  • the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOORi where R 1 is a lower alkyl group.
  • Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
  • amides may be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group such as ammonia or a lower alkyl amine.
  • Tautomers of substituted bicyclic aryl-imidazoles include, e.g., tautomers of omeprazole such as those described in U.S. Pat. Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689.
  • An exemplary "isomer" of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et al, Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.
  • Exemplary "polymorphs” include, but are not limited to, those described in PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903;
  • no portion of the PPI is enteric coated.
  • at least some amount or portion of the proton pump inhibitor is free of enteric coating.
  • at least a therapeutically effective amount or portion of the PPI is not enteric coated.
  • at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or about 60%, or about 70% or about 80%, or about 90%, by weight, of the PPI is not enteric coated.
  • some amount or portion of the PPI comprises a "thin enteric coat".
  • thin enteric coat refers to a pH sensitive coating that is applied in a manner or amount such that it delays release of the coated substance in gastrointestinal fluid for a period of time, but ultimately allows release of some of the coated substance in the gastrointestinal tract prior to passage of the substance into the duodenum.
  • a first amount or portion of the PPI is enteric coated and a second amount or portion of the PPI is not enteric coated.
  • at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%, by weight, of the PPI is not enteric coated and the balance of PPI is enteric coated.
  • the PPI is enteric coated and the balance of PPI is not enteric coated.
  • the PPI, or a portion thereof, is micronized.
  • the PPI has a D 90 , Dgo, D 7 o or D 5 o particle size, by weight or by number, of less than about 500 ⁇ m, less than about 400 ⁇ m, less than about 300 ⁇ m, less than about 200 ⁇ m, less than about 150 ⁇ m, less than about 100 ⁇ m, less than about 80 ⁇ m, less than about 60 ⁇ m, less than about 40 ⁇ m, less than about 35 ⁇ m, less than about 30 ⁇ m, less than about 25 ⁇ m, less than about 20 ⁇ m, less than about 15 ⁇ m, or less than about 10 ⁇ m, for example about 10 to about 500 ⁇ m, about 10 to about 400 ⁇ m, about 10 to about 300 ⁇ m, about 10 to about 200 ⁇ m, about 10 to about 100 ⁇ m, about 10 to about 80 ⁇ m, or about 10 to about 60 ⁇ m.
  • compositions are provided wherein the micronized proton pump inhibitor is of a particle size which allows greater than about 90% or greater than about 75% of the proton pump inhibitor to be released from the dosage unit within about 1 hour, within about 50 minutes, within about 40 minutes, within about 30 minutes, within about 20 minutes, within about 10 minutes, or within about 5 minutes after placement in a standard USP dissolution test.
  • compositions of the invention comprise one or more PPIs in a total amount of about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 5 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 250 mg, about 5 mg to about 100 mg, about 5 mg to about 75 mg, or about 5 mg to about 50 mg, for example about 7.5 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg, about 40 mg or about 45 mg.
  • compositions of the invention comprise one or more pharmaceutically acceptable buffering agents.
  • Buffering agents useful in the present invention include agents possessing pharmacological activity as a weak or strong base.
  • the buffering agent when formulated with or administered substantially simultaneously with a PPI, functions to raise the pH of gastrointestinal fluid and thereby to substantially prevent or inhibit acid degradation of the PPI by gastrointestinal fluid for a period of time.
  • the period of time is a period sufficient to preserve bioavailability of at least a therapeutically effective amount of the PPI administered.
  • buffering agents useful in accordance with the present invention comprise a salt of a alkali (Group IA) earth metal or an akaline (Group HA; e.g. beryllium, magnesium, calcium, strontium, barium, radium) earth metal.
  • Illustrative salts include bicarbonates, carbonates, phosphates, citrates, borates, acetates, phthalates, tartrate, succinates, etc.
  • Additional classes of buffering agents useful in accordance with the present invention include amino acids, an alkaline salt of an amino acid, an aluminum buffering agent, a bismuth buffering agent, a calcium buffering agent, a sodium buffering agent, or a magnesium buffering agent.
  • Non-limiting examples of suitable buffering agents include aluminum, magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate co-precipitate, aluminum glycinate, bismuth subcitrate, bismuth subcarbonate, bismuth subsalicylate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminat
  • Buffering agents useful in the present invention also include buffering agents or combinations of buffering agents that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase such as water, these buffering agents produce and maintain a pH greater than the pKa of the proton pump inhibitor.
  • the buffering agent is present in a composition of the invention in a total amount of about 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibitor, about 0.5 mEq/mg to about 3 mEq/mg of the proton pump inhibitor, about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pump inhibitor, about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor, or about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor.
  • the buffering agent is present in an amount of at least about 0.5 mEq/mg of the proton pump inhibitor, at least about 0.75 mEq/mg of the proton pump inhibitor, or at least about 1 mEq/mg of the proton pump inhibitor on a dry weight basis.
  • one or more buffering agents are present in a composition of the invention in a total amount of about 0.5 mEq to about 160 mEq, about 1 mEq to about 150 mEq, about 10 mEq to about 150 mEq, about 10 mEq to about 75 mEq, about 10 mEq to about 60 mEq, or about 10 mEq to about 50 mEq.
  • a composition of the invention can comprise about 1 mEq, or about 5 mEq, or about 10 mEq, or about 15 mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq, or about 80 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 niEq, or about 140 mEq, or about 150 mEq, or about 160 mEq of buffering agent.
  • one or more buffering agents are present in a composition of the invention in a total amount of at least about 10 mEq, at least about 11 mEq, at least about 12 mEq, at least about 13 mEq, at least about 14 mEq, at least about 15 mEq, at least about 16 mEq, at least about 17 mEq, at least about 18 mEq, at least about 19 mEq, at least about 20 mEq or at least about 21 mEq.
  • one or more buffering agents and the PPI are present in a composition of the invention in a weight ratio of at least about 5:1, at least about 7:1, at least about 10:1, at least about 20:1, greater than 20:1, at least about 21:1, at least about 22:1, at least about 23:1, at least about 24:1, at least about 25:1, at least about 30:1, at least about 35:1, at least about 40:1, greater than 40:1, or at least about 45:1.
  • the amount of buffering agent present in a composition of the invention ranges from about 200 to about 3500 mg, about 300 to about 3000 mg, about 400 to about 2500 mg, or about 500 to about 2200 mg, about 600 to about 2000, or about 700 to about 1800 mg.
  • the amount of buffering agent present in a composition of the invention is about 200 mgs, or about 300 mgs, or about 400 mgs, or about 500 mgs, or about 600 mgs, or about 700 mgs, or about 800 mgs, or about 900 mgs, or about 1000 mgs, or about 1100 mgs, or about 1200 mgs, or about 1300 mgs, or about 1400 mgs, or about 1500 mgs, or about 1600 mgs, or about 1700 mgs, or about 1800 mgs, or about 1900 mgs, or about 2000 mgs, or about 2100 mgs, or about 2200 mgs, or about 2300 mgs, or about 2400 mgs, or about 2500 mgs, or about 2600 mgs, or about 2700 mgs, or about 2800 mgs, or about 2900 mgs, or about 3000 mgs, or about 3200 mgs, or about 3500 mgs.
  • one or more buffering agents are present in a composition of the invention in a total amount that is greater than 800 mg, for example at least about 920 mg or at least about 1000 mg.
  • the buffering agent and PPI are present in a weight ratio greater than 20:1, not less than about 21:1, not less than about 22:1, not less than about 23:1, not less than about 24:1, not less than about 25:1, not less than about 26:1, not less than about 27:1, not less than about 28:1, not less than about 29:1, not less than about 30:1, not less than about 31:1, not less than about 32:1, not less than about 33:1, not less than about 34:1, not less than about 35:1, not less than about 36:1, not less than about 37:1, not less than about 38:1, not less than about 39:1, not less than about 40:1, not less than about 41:1, not less than about 42:1, not less than about 43:1, not less than about 44:1, not less than
  • a composition that comprises a combination of at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate.
  • the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).
  • the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg. In another embodiment, the composition contains no poly[phosphoryl/sulfon]-ated carbohydrate.
  • the total amount of amino acid buffering agent present in the pharmaceutical composition is less than about 5 mEq, less than about 4 mEq, or less than about 3 mEq.
  • amino acid buffering agent includes amino acids, amino acid salts, and amino acid alkali salts including: glycine, alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum glycinate and/or lysine glutamic acid salt, glycine hydrochloride, L-alanine, DL-alanine, L-threonine, DL-threonine, L-isoleucine, L-valine, L- phenylalanine, L-glutamic acid, L-glutamic acid hydrochloride, L-glutamic acid sodium salt, L-asparaginic acid, L-asparaginic acid sodium salt, L-lysine and L- lysine-L-glutamic acid salt.
  • non-amino acid buffering agent herein includes buffering agents as defined
  • a composition of the invention comprises at least one non-amino acid buffering agent wherein the non-amino acid buffering agent is present in the composition in a total amount greater than 800 mg.
  • the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).
  • the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg.
  • a composition that comprises at least one buffering agent in a total amount of at least about 10 mEq.
  • an amino acid buffering agent is present in the composition, at least one of the following conditions is met: (1) the weight ratio of amino acid buffering agent:proton pump inhibitor is greater than 20:1; (2) the composition comprises at least two non-amino acid buffering agents; (3) the composition comprises at least one non-amino acid buffering agent wherein the weight ratio of the at least one non-amino acid buffering agentproton pump inhibitor is greater than 20:1; and/or (4) the weight ratio of total buffering agentproton pump inhibitor is greater than 40:1.
  • the two or more buffering agents comprise at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate.
  • the buffering agent comprises a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in an amount of about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump inhibitor.
  • compositions comprising at least one soluble buffering agent.
  • soluble buffering agent refers to a buffering agent that has a solubility of at least about 500 mg/mL, at least about 300 mg/mL, at least about 200 mg/mL, or at least about 100 mg/mL in gastrointestinal fluid or simulated gastrointestinal fluid.
  • the buffering agent is micronized.
  • the buffering agent has a defined particle size distribution.
  • the D 5 o, D 7 o, D 8 o, or D 90 particle size of the buffering agent, by weight or by number is no greater than about 20 ⁇ m, no greater than about 30 ⁇ m, no greater than about 40 ⁇ m, no greater than about 50 ⁇ m, no greater than about 60 ⁇ m, no greater than about 70 ⁇ m, no greater than about 80 ⁇ m, no greater than about 90 ⁇ m, no greater than about 100 ⁇ m in diameter, no greater than about 200 ⁇ m in diameter, no greater than about 300 ⁇ m in diameter, no greater than about 400 ⁇ m in diameter, or no greater than about 100 ⁇ m in diameter.
  • compositions of the invention comprise one or more an ⁇ -Helicobacter pylori active substances.
  • anti-Helicobacter pylori active substance or "anti-H. pylori active substance” refers to any pharmaceutically acceptable substance that kills, reduces and/or inhibits or disrupts the growth of H. pylori, whether directly or indirectly.
  • the anti-H. pylori active substance is an antibiotic.
  • antibiotic herein refers to any drug or agent, whether naturally occurring, synthetically or semi- synthetically derived, that kills or reduces the growth of bacterial infection, hi another embodiment, the anti-H. pylori active substance is effective against gram negative bacteria.
  • the anti-H. pylori active substance is not an antibiotic
  • the anti-H. pylori active substance is a mucolytic agent or an essential oil.
  • compositions of the invention comprise one or more various anti-H. pylori active substances, for example one or more of an antibiotic, an essential oil and/or a mucolytic agent.
  • antibiotics include, but are not limited to, antibiotic penicillins ⁇ e.g. amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), antibiotic cefems or cephalosporins ⁇ e.g. cefixime, cefuroxime, cefuroxime axetil, cefaclor, ceftizoxime, cefotaxime, ceftazidime, etc.) antibiotic macrolides ⁇ e.g. erythromycin, clarithromycin, azithromycin, telithromycin, roxithromycin, etc.) antibiotic tetracylines ⁇ e.g.
  • antibiotic aminoglycosides ⁇ e.g. gentamicin, kanamycin, netilmicin, amikacin, tobramycin, etc.
  • antibiotic carbapenems ⁇ e.g. imipenem, meropenem, doripenem, etc.
  • carbapenem ester type prodrug ⁇ e.g. tebipenem pivoxil, faropenem daloxate, other oral carbapenem prodrugs include GV-118819, CS-834, L-084, DZ-2649, CL-191121, etc., See below), antibiotic quinolones ⁇ e.g.
  • norfloxacin ofloxacin, levofloxacin, ciprofloxacin, sitafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, pazufloxacin, prulifloxacin, olamufloxacin, ganefloxacin, gemifloxacin, and trovafloxacin, etc.
  • antibiotic nitroimidazoles ⁇ e.g. metronidazole, tinidazole), antibiotic rifamycin or ansamycin analogues ⁇ e.g.
  • rifabutin rifampicin, rifampin, rifaximin, rifalazil, and ryfamycin derivatives such as 3'-hydroxy-5'-(4- propylpiperazinyl)benzoxazinorifamycin- (shown as structure I below), which are illustratively disclosed in ⁇ . Saito et ah, In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins, Antimicrob. Agents Chemother., 1991 March; 35(3): 542-547, the entire disclosure of which is hereby incorporated by reference herein, and other antibiotics such as mupirocin.
  • compositions of the invention can comprise a full daily dose of anti-H. pylori active substance ⁇ e.g. 250 mg to about 5 g), or a fraction of the daily dose ⁇ e.g.
  • Typical daily doses of antibiotics are as follows: furazolidone: about 400 mg (about 200 mg twice daily); tetracycline: about 250 - about 2000 mg (typically about 500 mg one to four times daily); amoxicillin: about 2000 mg (about 1000 mg twice daily); clarithromycin: about 1000 mg (about 500 mg twice daily); metronidazole: 800 mg (400 mg twice daily).
  • Aminoglycosides such as gentamicin, tobramycin, amikacin, kanamycin, netilmicin, etc., are typically administered in doses of about 25 mg to about 1 g one to four times per day.
  • Quinolones such as norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, gatifloxacin, moxifloxacin, trovafloxacin are typically administered in doses of about 50 mg to about 1 g one to four times per day.
  • Essential oils can also be used as an anti-H. pylori active substance according to various embodiments of the invention.
  • Essential oils contain one or more compounds that make up the essential oil and can be synthesized or derived from any suitable naturally occurring substance such as carrot seed, cinnamon bark, clove, eucalyptus, white grapefruit, lemongrass, etc.
  • clove oil contains: alpha-cubeben, alpha-pinene, beta-caryophyllene, eugenol, and isoeugenol.
  • Illustrative pure compounds present in various essential oils can, individually or in combination, comprise an anti-H.
  • pylori active substance according to various embodiments of the invention and include alpha-copaen, alpha-cubeben, alpha-pinene, alpha-selinen, beta-caryophyllene, beta-pinene, beta- selinen, camphor, carotol, carvacrol, cinnamaldehyde, citral, citronellal, decanal, eucalyptol, eugenol, gamma-terpinene, geraniol, geranyl acetate, isoeugenol, limonene, linalool, myrcene, nerol, nootkatone, octanal, para-cymene, sabinene, thymol, etc.
  • one or more essential oils, if present, are present in a composition of the invention in an amount of about 0.0025% to about 5%, about 0.005% to about 4%, or about
  • Pronase is an illustrative mucolytic agent that can be used as an anti-H. pylori active substance.
  • a mucolytic agent is present in a composition of the invention in an amount of about 2000 tyrosine units to about 100,000 tyrosine units, about 5,000 tyrosine units to about 90,000 tyrosine units, or about 10,000 tyrosine units to about 80,000 tyrosine units.
  • Cholestyramine can also be used as an anti-H. pylori active substance in compositions of the invention. If present, cholestyramine is present in an amount of about 50 mg to about 2 g, about 75 mg to about 1.75 g, about 100 mg to about 1.5 g or about 125 mg to about 1 g.
  • Bile salts can also be used as an anti-H. pylori active substance in compositions of the invention.
  • Bile salts are polar derivatives of cholesterol. These compounds are detergents because they contain both polar and nonpolar regions.
  • the anti-H. pylori active substance if present, is present in a total amount of about 0.1% to about 90%, 0.2% to about 85%about 0.5% to about 75%, or about 1% to about 60%, by total weight of the composition.
  • the anti-H. pylori active substance if present, is present in a total amount of about 0.1% to about 90%, 0.2% to about 85%about 0.5% to about 75%, or about 1% to about 60%, by total weight of the composition.
  • pylori active substance can be present in an amount of about 1%, about 2% about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 46%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about
  • an anti-H. pylori active substance if present, is present in a total amount of about 1 mg to about 5000 mg, about 100 mg to about 4000 mg, about 150 mg to about 3000 mg, about 200 mg to about 2000 mg, about 200 mg to about 1500 mg or about 200 mg to about 1000 mg.
  • an anti-H. pylori active substance is present in a composition of the invention in an amount of about 50 mg, about 100 mg about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg,
  • no portion of the anti-H. pylori active substance is enteric coated. In another embodiment, at least a portion of the anti-H. pylori active substance is not enteric coated. In another embodiment, at least a therapeutically effective portion of the anti-H. pylori active substance is not enteric coated.
  • At least about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or about 60%, by weight, of the anti-H. pylori active substance is not enteric coated.
  • a portion of the antibiotic comprises a "thin enteric coat" as is defined herein above.
  • compositions of the invention can, if desired, include one or more pharmaceutically acceptable excipients.
  • excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition.
  • Excipients include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, lubricants, glidants, surface modifying agents, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Any such excipients can be used in any dosage forms according to the present invention, including liquid, solid or semi-solid dosage forms.
  • Excipients optionally employed in compositions of the invention can be solids, semi-solids, liquids or combinations thereof.
  • Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with a drug or therapeutic agent.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients.
  • suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches ⁇ e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose ⁇ e.g., CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of ⁇ - and amorphous cellulose (
  • Such diluents if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition.
  • the diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
  • extragranular microcrystalline cellulose that is, microcrystalline cellulose added to a wet granulated composition after a drying step
  • hardness for tablets
  • disintegration time for disintegration time
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations.
  • Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g., NationalTM 1551, NationalTM 1550, and ColocornTM 1500), clays (e.g., VeegumTM HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums.
  • starches including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g
  • Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to a granulation step or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.
  • Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, typically constitutes about 0.2% to about 10%, about 0.2% to about 7%, or about 0.2% to about 5%, of the total weight of the composition.
  • Compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations. Such binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
  • Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., KlucelTM); and ethylcellulose (e.g., EthocelTM).
  • Such binding agents and/or adhesives if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients.
  • surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetosteary
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients.
  • suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • Such lubricants if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25%
  • Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend. Talc, if present, constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the composition.
  • Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate.
  • compositions of the present invention can comprise one or more anti- foaming agents.
  • Simethicone is an illustrative anti-foaming agent.
  • compositions of the present invention can comprise one or more flavoring agents, sweetening agents, and/or colorants.
  • Flavoring agents useful in the present invention include, without limitation, acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butter, butter pecan, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut,
  • Sweetening agents that can be used in the present invention include, for example, acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol, neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.
  • acesulfame potassium acesulfame K
  • alitame alitame
  • aspartame cyclamate
  • cylamate dextrose
  • dextrose isomalt
  • MagnaSweet® maltitol
  • mannitol mannitol
  • neohesperidine DC neotame
  • excipients can have multiple roles as is known in the ait.
  • starch can serve as a filler as well as a disintegrant.
  • the classification of excipients above is not to be construed as limiting in any manner.
  • compositions of the invention are in the form of an orally deliverable dosage unit.
  • oral administration or “orally deliverable” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed.
  • oral administration includes buccal and sublingual as well as esophageal administration.
  • compositions of the present invention can be formulated as solid, liquid or semi-solid dosage forms.
  • such compositions are in the form of discrete dose units or dosage units.
  • dose unit and/or “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect.
  • dosage units may be administered one to a small plurality (i.e. 1 to about 4) times per day, or as many times as needed to elicit a therapeutic response.
  • a particular dosage form can be selected to accommodate any desired frequency of administration to achieve a specified daily dose.
  • one dose unit, or a small plurality (i.e. up to about 4) of dose units provides a sufficient amount of the active drug to result in the desired response or effect.
  • compositions of the invention can also be formulated for rectal, topical, or parenteral (e.g. subcutaneous, intramuscular, intravenous and intradermal or infusion) delivery.
  • parenteral e.g. subcutaneous, intramuscular, intravenous and intradermal or infusion
  • compositions of the invention are suitable for rapid onset of therapeutic effect, particularly with respect to the PPI, buffer and/or anti- H. pylori active substance.
  • upon oral administration of a composition of the invention to a subject at least a therapeutically effective amount of the PPI and/or anti-H. pylori active substance is available for absorption in the stomach of the subject.
  • enteric coating to prevent exposure of the PPI to gastrointestinal fluids (and consequent drug degradation) by way of p ⁇ dependent coatings. Such coating, in turn, prevents rapid PPI absorption and therapeutic onset of action.
  • compositions of the present invention do not require enteric coating to maintain drug stability in gastrointestinal fluids and thereby provide for rapid absorption and onset of therapeutic effect.
  • a composition comprises at least a therapeutically effective amount of PPI that is not enteric coated.
  • a single dosage unit comprises a therapeutically and/or prophylactically effective amount of PPI and/or an anti-H. pylori active substance.
  • therapeutically effective amount or “therapeutically and/or prophylactically effective amount” as used herein refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
  • a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject.
  • a "subject" herein to which a therapeutic agent or composition thereof can be administered includes a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or a horse.
  • compositions of the invention are in the form of solid dosage forms or dosage units.
  • suitable solid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hard gelatin capsule), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably adapted for oral administration.
  • Tablets can be prepared according to any of the many relevant, well known pharmacy techniques.
  • tablets or other solid dosage forms can be prepared by processes that employ one or a combination of methods including, without limitation, (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion.
  • the individual steps in the wet granulation process of tablet preparation typically include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation and final grinding.
  • Dry granulation involves compressing a powder mixture into a rough tablet or "slug" on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator.
  • the individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). Typically, no wet binder or moisture is involved in any of the steps.
  • solid dosage forms such as tablets can be prepared by mixing a PPI with at least one buffering agent as described herein above and, if desired, with one or more optional pharmaceutical excipients to form a substantially homogeneous preformulation blend.
  • the preformulation blend can then be subdivided and optionally further processed (e.g. compressed, encapsulated, packaged, dispersed, etc.) into any desired dosage forms.
  • Compressed tablets can be prepared by compacting a powder or granulation composition of the invention.
  • the term “compressed tablet” generally refers to a plain, uncoated tablet suitable for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression. Tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. In one embodiment, any such coating will be selected so as to not substantially delay onset of therapeutic effect of a composition of the invention upon administration to a subject.
  • sustained tablet refers to a compressed tablet that rapidly disintegrates after placement in water.
  • a composition of the invention comprises a multilayer tablet having a core comprising a proton pump inhibitor; the core is substantially or completely surrounded by a buffering agent and/or anti-H. pylori active substance.
  • the buffering agent layer can be surrounded by an anti-H. pylori active substance layer, which can optionally be coated with one or more coating materials.
  • the optional coating is not an enteric coating.
  • the buffering agent layer completely surrounds the core.
  • the buffering agent layer partially surrounds the core.
  • the buffering agent layer is in contact with a portion of or with all of the surface area of the core.
  • one or more intermediate layers exists in between the core and the buffering agent.
  • the intermediate layers can comprise any pharmaceutically acceptable material, preferably inert and non-p ⁇ sensitive coating materials such as polymer based coatings.
  • a composition of the invention comprises . a multi-layer tablet having a core comprising an anti-H. pylori active substance; the core is substantially or completely surrounded by the PPI and the buffering agent.
  • an intermediate layer can exist between the anti-H. pylori active substance core and the PPI/buffering agent surrounding the core.
  • the optional intermediate layer is a coating layer.
  • the coating layer is not an enteric coating.
  • the buffering agent/PPI layer completely surrounds the core. In another embodiment, the buffering agent/PPI layer partially surrounds the core. In yet another embodiment, the buffering agent/PPI layer is in contact with a portion of or with all of the surface area of the core.
  • compositions of the invention can be microencapsulated wherein the PPI, buffering agent and/or anti-H. pylori active substance are microencapsulated together, for example as modified from the description in U.S. Patent Publication No. 2005/0037070, hereby incorporated by reference herein in its entirety.
  • a composition of the invention comprises a proton pump inhibitor, an anti-H. pylori active substance and a buffering agent mixed together in powder form and optionally filled into a capsule, for example a hard or soft gelatin or ⁇ PMC capsule.
  • compositions of the invention can be in the form of liquid dosage forms or units.
  • suitable liquid dosage forms include solutions, suspension, elixirs, syrups, liquid aerosol formulations, etc.
  • compositions of the invention are in the form of a powder for suspension that can be suspended in a liquid vehicle prior to administration to a subject. While the powder for suspension itself, can be a solid dosage form of the present invention, the powder dispersed in liquid also comprises a liquid embodiment of the invention.
  • Suspension compositions of the invention comprise at least one PPI, a buffering agent, an anti-H. pylori active substance, a liquid medium (e.g. water, de- ionized water, etc.) and one or more optional pharmaceutical excipients.
  • compositions upon storage in a closed container maintained at either room temperature, refrigerated (e.g. about 5 -10 °C) temperature, or freezing temperature for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%, at least about 92.5%, at least about 95%, or at least about 97.5% of the original PPI and/or anti-H. pylori active substance present therein.
  • compositions of the invention are useful in the treatment of H. pylori infection and other gastrointestinal diseases and disorders including but not limited to duodenal ulcer, gastric ulcer, acid dyspepsia, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, (acid reflux), heartburn, nighttime heartburn symptoms, nocturnal acid breakthrough (NAB), acid dyspepsia, heartburn, and/or NSAID induced ulcer and gastrointestinal pathological hypersecretory conditions such as Zollinger Ellison Syndrome.
  • GSD gastroesophageal reflux disease
  • NAB nocturnal acid breakthrough
  • NSAID induced ulcer and gastrointestinal pathological hypersecretory conditions such as Zollinger Ellison Syndrome.
  • a composition of the invention is effective at reducing or eradicating H. pylori infection and/ or ulcer upon administration about 1 to about 4 times per day for a period of about 1 to about 10 days, about 1 to about 5 days, or about 1 to about 3 days, for example about 1 day or about 2 days.
  • a single dose of a composition of the invention is sufficient to reduce or eradicate H. pylori infection.
  • 1 to 3 doses of a composition of the invention is sufficient to reduce or eradicate H. pylori infection.
  • the invention provides method for reducing duration (and/or the number of doses required) of H. pylori or ulcer therapy by comparison with conventional therapies.
  • the method comprises the steps of administering to a subject in need of H. pylori treatment a therapeutically effective amount of an anti- H. pylori active substance, a buffering agent, and a non-enteric coated PPI in one or more doses (as described above) over a period of about 1 to about 7 days, about 1 to about 5 days, about 1 to about 4 days, about 1 to about 3 days or about 1 to about 2 days.
  • compositions of the invention are suitable for rapid onset of therapeutic effect, particularly with respect to the PPI and/or anti-H. pylori active substance.
  • at least a therapeutically effective amount of the PPI and/or anti-H. pylori active substance are available for absorption in the stomach of the subject.
  • available for absorption in the stomach in reference to an active ingredient such as a PPI means that the ingredient remains intact and in active form in the stomach for a sufficient amount of time to allow for absorption into the blood.
  • compositions of the invention do not require enteric coating to maintain drug stability in gastrointestinal fluids and thereby allow for rapid absorption and onset of therapeutic effect.
  • a composition comprises at least a therapeutically effective amount of PPI that is not enteric coated.
  • the invention provides compositions having PPI which is substantially completely not enteric coated.
  • the subjects upon oral administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit a gastric p ⁇ not less than about 5, about 5.1 about 5.2 about 5.3, about 5.4, about 5.5, about 5.6 about 5.7, about 5.7 about 5.9 or about 6 within about 0.5 minutes, 1 minutes, 2 minutes, 3 minutes, 4 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, or 30 minutes after administration.
  • the subjects upon oral administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit a gastric p ⁇ not less than about 5, about 5.1 about 5.2 about 5.3, about 5.4, about 5.5, about 5.6 about 5.7, about 5.7 about 5.9 or about 6 for a period beginning within about 0.5 minute, 1 minute, 2 minutes, 3 minutes, 4 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, or 30 minutes after said administration and the pH is maintained at not less than about 5, about 5.1 about 5.2 about 5.3, about 5.4, about 5.5, about 5.6 about 5.7, about 5.7 about 5.9 or about 6 for a period of at least about 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes after administration.
  • the maximum concentration of anti-H. pylori active substance in the stomach fluid is achieved when the p ⁇ of the stomach fluid is not less than about 5, not less than about 5.1, not less than about 5.2, not less than about 5.3, not less than about 5.4, not less than about 5.5, not less than about 5.6, not less than about 5.7, not less than about 5.8, not less than about 5.9 or not less than about 6.
  • the anti-H. pylori active substance is absorbed into the bloodstream and upon subsequently being secreted from the bloodstream into the stomach, the stomach secretions are at a p ⁇ not less than about 5, not less than about 5.1, not less than about 5.2, not less than about 5.3, not less than about 5.4, not less than about 5.5, not less than about 5.6, not less than about 5.7, not less than about 5.8, not less than about 5.9 or not less than about 6.
  • composition of the invention upon oral administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit an average T max of PPI and/or anti-H. pylori active substance within about 30 seconds to about 90 minutes, within about 1 minute to about 80 minutes, within about 5 minutes to about 60 minutes, within about 10 minutes to about 50 minutes, or within about 10 minutes to about 45 minutes.
  • the subjects upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit an average plasma concentration of the PPI and/or anti-H.
  • pylori active substance of at least about 0.1 ⁇ g/ml, at least about 0.15 ⁇ g/ml, at least about 0.2 ⁇ g/ml, at least about 0.3 ⁇ g/ml, at least about 0.4 ⁇ g/ml, at least about 0.5 ⁇ g/ml, at least about 0.6 ⁇ g/ml, at least about 0.7 ⁇ g/ml, at least about 0.8 ⁇ g/ml, at least about 0.9 ⁇ g/ml, at least about 1 ⁇ g/ml, at least about 1.5 ⁇ g/ml, or at least about 2.0 ⁇ g/ml at any time within about 90 minutes, within about 75 minutes, within about 60 minutes, within about 55 minutes, within about 50 minutes, within about 45 minutes, within about 40 minutes, within about 35 minutes, within about
  • pylori active substance of at least about 0.1 ⁇ g/ml, at least about 0.15 ⁇ g/ml, at least about 0.2 ⁇ g/ml, at least about 0.3 ⁇ g/ml, at least about 0.4 ⁇ g/ml, at least about 0.5 ⁇ g/ml, at least about 0.6 ⁇ g/ml, at least about 0.7 ⁇ g/ml, at least about 0.8 ⁇ g/ml, at least about 0.9 ⁇ g/ml, at least about 1.0 ⁇ g/ml, at least about 1.5 ⁇ g/ml or at least about 2.0 ⁇ g/ml, maintained from at latest about 15 minutes to at earliest about 60 minutes after administration, preferably at latest about 15 minutes after administration to at earliest about 90 minutes after administration, more preferably at latest about 15 minutes to
  • the subjects upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit at least one of: a mean C max of PPI and/or anti-H.
  • pylori active substance of about 500 ⁇ g/ml to about 2000 ⁇ g/ml, about 600 ⁇ g/ml to about 1900 ⁇ g/ml, or about 700 ng/ml to about 1800 ⁇ g/ml; a mean T max of PPI and/or anti-H.
  • pylori active substance of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and/or a mean AUQo-i nf ) of PPI and/or anti-H.
  • pylori active substance of about 1000 to about 3000 ⁇ g-Jir/ml, about 1500 to about 2700 ⁇ g * hr/ml, or about 1700 to about 2500 ⁇ g * hr/ml.
  • the subjects upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit: a mean C max of PPI and/or anti-H.
  • pylori active substance of about 500 ⁇ g/ml to about 2000 ⁇ g/ml, about 600 ⁇ g/ml to about 1900 ⁇ g/ml, or about 700 ⁇ g/ml to about 1800 ⁇ g/ml; a mean T max of PPI and/or anti-H.
  • pylori active substance of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and a mean AUC(o-i nf ) of PPI and/or anti-H.
  • pylori active substance of about 1000 to about 3000 ng * hr/ml, about 1500 to about 2700 ng * hr/ml, or about 1700 to about 2500 ng * hr/ml.
  • a composition of the invention is formulated such that upon administration of the composition to a subject, maximum concentration of the anti-H. pylori active substance in the stomach is achieved while the stomach secretions have a p ⁇ of about 5 to about 8.5, about 5.2 to about 8.3, or about 5.5 to about 8.
  • the PPI, buffering agent and antibiotic can be separately formulated.
  • the administration of such compositions is sequenced such that maximum concentration (T ma ⁇ ) of the anti-H. pylori active substance in the stomach is achieved while the stomach secretions have a p ⁇ of about 5 to about 8.5, about 5.2 to about 8.3, or about 5.5 to about 8.
  • a composition of the present invention can further include one or more parietal cell activators.
  • Parietal cell activators such as chocolate, calcium and sodium bicarbonate and other alkaline substances stimulate the parietal cells and enhance the pharmacologic activity of the PPI administered.
  • “parietal cell activator” or “activator” shall mean any compound or mixture of compounds possessing such stimulatory effect including, but not limited to, chocolate, sodium bicarbonate, calcium (for example, calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate), peppermint oil, spearmint oil, coffee, tea and colas (even if decaffeinated), caffeine, theophylline, theobromine, and amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan) and combinations thereof.
  • Parietal cell activators are typically present in a composition of the invention in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients.
  • chocolate as raw cocoa, is administered in an amount of about 5 mg to 2.5 g per 20 mg dose of omeprazole (or equivalent pharmacologic dose of another proton pump inhibiting agent).
  • the dose of activator administered to a subject, for example, a human, in the context of the present invention should be sufficient to result in enhanced effect of a PPI over a desired time frame.
  • the approximate effective ranges for various parietal cell activators per 20 mg dose of omeprazole include, Chocolate (raw cocoa) - 5 mg to 2.5 g; Sodium bicarbonate - 7 mEq to 25 niEq; Calcium carbonate - 1 mg to 1.5 g; Calcium gluconate - 1 mg to 1.5 g; Calcium lactate - 1 mg to 1.5 g; Calcium hydroxide - 1 mg to 1.5 g; Calcium acetate - 0.5 mg to 1.5 g; Calcium glycerophosphate - 0.5 mg to 1.5 g; Peppermint oil - (powdered form) 1 mg to 1 g; Spearmint oil - (powdered form) 1 mg to 1 g; Coffee - 20 ml to 240 ml; Tea - 20 ml to 240 ml; Cola - 20 ml to 240 ml; Caffeine - 0.5 mg to
  • compositions Cl - ClO are prepared as shown in Table 1. Such compositions can, if desired, be tableted or encapsulated or prepared as other dosage forms as described hereinabove. Furthermore, the PPIs, anti-H. pylori active substance and buffering agents are interchangeable with on another. Table 1. Compositions Cl - ClO.
  • compositions may optionally comprise a bismuth compound, for example colloidal bismuth subcitrate, in an amount of about 100 mg to about 800 mg.
  • a bismuth compound for example colloidal bismuth subcitrate

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Abstract

The present invention relates to pharmaceutical compositions comprising a proton pump inhibitor or related compound, a buffering agent, and an anti-H, pylori active substance. Methods of using such compositions in treatment of H. pylori and other disorders and methods of manufacture of such compositions are also provided.

Description

TITLE
PHARMACEUTICAL COMPOSITION COMPRISING A PROTON PUMP
INHIBITOR, A BUFFERING AGENT AND AN ANTI-H. PYLORI ACTIVE
SUBSTANCE AND METHODS OF USING SAME
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions comprising a proton pump inhibitor, a buffering agent, and an anti-H. pylori active substance such as an antibiotic. Methods of using such compositions are also provided.
BACKGROUND OF THE INVENTION
[0002] Helicobacter pylori (H. pylori) is a spiral-shaped bacterium that is found in the gastric mucous layer or adherent to the epithelial lining of the stomach. Several studies have linked H. pylori infection to gastrointestinal disease in humans. Specifically, H. pylori is the most common cause of gastritis in humans, and greater than 90% of duodenal ulcer patients are infected with H. pylori.
[0003] Traditional therapy for H. pylori infection consists of 10 days to 2 weeks of one or two effective antibiotics, such as amoxicillin, tetracycline (not to be used for children <12 yrs.), metronidazole, or clarithromycin, plus ranitidine bismuth citrate, bismuth subsalicylate, or an enteric coated proton pump inhibitor (PPI). Because these regimens often require multiple dosing per day over a period of many days, patient compliance is a significant barrier to effective treatment. Furthermore, the treatments, even when complied with, are unsuccessful in many patients.
[0004] One particular class of PPIs used in H. pylori treatment includes substituted benzimidazole compounds that contain a sulfinyl group bridging substituted benzimidazole and pyridine rings. At neutral pH, these PPIs are chemically stable, lipid-soluble compounds that have little or no inhibitory activity. Unfortunately, most commercially available PPIs are unstable at neutral or acidic pH and undergo decomposition in gastrointestinal fluid upon oral administration, thereby resulting in loss of therapeutic activity. To overcome this acid instability, such compounds are typically formulated for oral delivery as enteric coated solid dosage forms, for example enteric coated tablets in which the enteric coating protects the drug from contact with acidic stomach secretions. An undesirable consequence of such enteric coating is that therapeutic onset time is significantly delayed. Enteric coated PPIs provide no immediate benefit in terms of increased gastric pH. In fact, it often it takes 4 or 5 days for enteric coated PPIs to exert their maximal effect on gastric pH.
[0005] Unfortunately, the above described slow onset characteristics of enteric coated PPIs, when used as part of a combination therapy for treatment of H. pylori, are undesirable. In order for most antibiotics to effectively kill bacteria such as H. pylori, the bacteria must be in a growth phase. In Acid Related Disease-Biology and Treatment (1998) eds. Modlin, IM; Sachs, G. Schnetzto-Verlag GmbH D- Konstanz, page 331. Ideal pH conditions for H. pylori growth are about 5.5 to about 7.5; H. pylori are thus sensitive to antibiotics in this pH range but unresponsive to them below a pH of about 5.5. Further, H. pylori chemotactic activities are increased at pH 3 to 5.5 and reduced at pH values greater than 6. O. Tadjrobehkar, H. Abdollahi. Survival and Chemotactic Behavior of H pylori at Different Media pH. Iran J Med Sci 2004; 29(2):81-84.
[0006] Since the pH of the stomach is typically about 2 to about 4, antibiotics are inefficient when administered together with an enteric coated proton pump inhibitors because the gastrointestinal fluid is well below the ideal pH for bacterial growth; again the enteric coated proton pump inhibitors do not have an effect on gastric pH until several hours after ingestion and this effect is not maximal until approximately 4 or 5 days after continued dosing of the PPI. Thus, any antibiotic taken simultaneously with the enteric coated PPI will be absorbed (into the bloodstream) from the duodenum or lower gastrointestinal tract well after the antibiotic has passed through the stomach. As a result, high initial concentrations of antibiotics in the stomach will not coincide with ideal gastric pH conditions (pH of about 5.5. to about 7.5) for optimal susceptibility to antibiotics. Instead, the PPI will only begin to increase gastric pH after the antibiotic has been absorbed into the bloodstream and is secreted back into the gastric fluid at concentrations that are 10- to 100-fold lower than the initial high stomach concentrations prior to absorption.
[0007] Further, even after 4 or 5 days of repeated dosing of PPIs when the maximal effect of the PPI is exerted to inhibit gastric acid secretion, the gastric pH is rarely above 5; again, this is a disadvantage as the pH for maximal bactericidal effect is in the range of about 5.5 to about 7.5. Grayson et ah, Effect of varying pH on the susceptibility of Campylobacter pylori to antimicrobial agents, Eur. J. Clin. Micr. Infect. Dis. 1989; 8:888-889. (Note: Campylobacter was the prior Genus name for Helicobacter).
[0008] If one or more of the above problems could be overcome, a significant advance in the treatment of H. pylori and other gastrointestinal disorders would result.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the present invention provides pharmaceutical compositions comprising a proton pump inhibitor, a buffering agent, and an anti- Helicobacter pylori active substance (also referred to as an anti-H. pylori active substance), for example an antibiotic. Optionally, at least a therapeutically effective amount or portion of the proton pump inhibitor is not enteric coated. Methods of using such compositions to treat various diseases and disorders are also provided as well as methods for manufacturing such compositions.
[0010] In another embodiment, the present invention provides a method for treating a subject in need of H. pylori treatment and/or treatment of an acid related gastrointestinal disease or disorder such as ulcer, comprising administering to the subject a composition comprising an anύ-Helicobacter pylori active substance, a buffering agent, and a PPI. Optionally, at least a therapeutically effective portion of the proton pump inhibitor is not enteric coated. In a related embodiment, upon administration of the composition to the subject, at least a therapeutically effective amount of the proton pump inhibitor and/or anti-H. pylori active substance is available for absorption in the subject's stomach. [0011] In still another embodiment, the invention provides a method of treating a human subject in need of H. pylori treatment and/or treatment of an acid related gastrointestinal disease or disorder, comprising administering to the subject one or more compositions comprising at least one of (or all three of): an anti-H. pylori active substance, a buffering agent, and a PPI, wherein a portion of the PPI is optionally enteric coated or the entire amount of PPI is free of enteric coating. In this embodiment, the composition is designed such that a therapeutically effective amount of the anti-H. pylon active substance is available in the subject's stomach at a time when the subject's stomach secretions are at a pΗ of about 5 to about 8 or about 5.5 to about 7.5. Such a result can be accomplished in any suitable manner, for example by coordinating the timing of administration of the one or more compositions, or by providing a single composition that provides controlled release of the anti-H. pylori active substance, buffering agent and proton pump inhibitor such that a therapeutically effective amount of the anti-H. pylori active substance is available for absorption in the subject's stomach when the subject's stomach secretions are at the desired pΗ.
[0012] Various other embodiments and aspects of the present invention are described herein below.
DETAILED DESCRIPTION OF THE INVENTION
[0013] While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
[0014] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about." In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. As used herein, the terms "about" and "approximately" when referring to a numerical value shall have their plain and ordinary meanings to one skilled in the art of pharmaceutical sciences or the art relevant to the range or element at issue. The amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors to be considered may include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. Thus, as a general matter, "about" or "approximately" broaden the numerical value. For example, in some cases, "about" or "approximately" may mean ± 5%, or ±10%, or ±20%, or ±30% depending on the relevant technology. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values.
Proton Pump Inhibitors
[0015] Compositions of the invention comprise at least one pharmaceutically acceptable acid labile, substituted benzimidazole H+,K+-ATPase proton pump inhibitor (PPI). The term proton pump inhibitor or PPI means any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase. A PPI may, if desired, be in the form of free base, free acid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active or undergoes conversion within or outside of the body to a therapeutically active form.
[0016] In one embodiment, illustrative PPIs are those compounds of Formula (I):
Figure imgf000007_0001
wherein
[0017] R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
[0018] R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
[0019] R and R are the same or different and each is hydrogen, alkyl, C1-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy;
[0020] R4 is hydrogen, alkyl, Cj-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
[0021] Q is nitrogen, CH, or CR1 ;
[0022] W is nitrogen, CH, or CR1 ;
[0023] y is an integer of 0 through 4; and
[0024] Z is nitrogen, CH, or CR ' ;
[0025] or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.
[0026] Specific examples of suitable PPIs include esomeprazole (also referred to as S-omeprazole), dontoprazole, ilaprazole, lansoprazole, s-lansoprazole, omeprazole, hydroxyomeprazole, pantoprazole, pariprazole, rabeprazole, lansoprazole, tenatoprazole, leminoprazole and nepaprazole or a free base, a free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
[0027] Other proton pump inhibitors include but are not limited to: soraprazan (Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB -641257) (2-pyrimidinamine, 4-(3 ,4-dihydro- 1 -methyl-2( lH)-isoquinolinyl)-N- (4-fluo- rophenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447 (Imidazo(l,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3- thieny- 1) (Shinnippon); 3-hydroxymethyl-2rnethyl-9-phenyl-7H-8,9-dihydro- pyrano(2,- 3-c)-imidazo(l,2-a)pyridine (PCT Publication WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950 (3-hydroxymethyl-2-meth.yl-9-pb.enyl-- 7H-8,9-dihydro- -pyrano(2,3-c)-imidazo(l,2-a)pyridine) (AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis); WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); nepaprazole (To a Eiyo); HN-11203 (Nycomed Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SKand F-95601 (GSK, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); SKand F- 96067 (EP 259174) (Altana); SUN 8176 (Daiichi Phama); Ro-18-5362 (Roche); ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds.
[0028] Still other suitable proton pump inhibitors include those described in the following U.S. Pat. Nos.: 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281; 6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167, each of which are hereby individually incorporated herein by reference in their respective entireties.
[0029] Proton pump inhibitors as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley- Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et at, Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
[0030] "Pharmaceutically acceptable salts," or "salts," include the salt of a proton pump inhibitor prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta- hydroxybutyric, galactaric and galacturonic acids.
[0031] In one embodiment, acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. [0032] In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the acid addition salts of the proton pump inhibitors are halide salts, which are prepared using hydrochloric or hydrobromic acids. In still other embodiments, the basic salts are alkali metal salts, e.g., sodium salt.
[0033] Salt forms of proton pump inhibitors include, but are not limited to: a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or omeprazole magnesium, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole, described in U.S. Pat. No. 6,511,996. Other salts of esomeprazole are described in U.S. Pat. Nos.: 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
[0034] In one embodiment, preparation of esters involves functionalizing hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug. In another embodiment, the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOORi where R1 is a lower alkyl group. Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
[0035] "Amides" may be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group such as ammonia or a lower alkyl amine.
[0036] "Tautomers" of substituted bicyclic aryl-imidazoles include, e.g., tautomers of omeprazole such as those described in U.S. Pat. Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689.
[0037] An exemplary "isomer" of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et al, Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.
[0038] Exemplary "polymorphs" include, but are not limited to, those described in PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 6,147,103; 6,150,380; 6,166,213; 6,191,148; 5,187,340; 6,268,385; 6,262,086; 6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085; 6,369,087; 6,380,234; 6,428,810; 6,444,689; and 6,462,0577.
[0039] In one embodiment, no portion of the PPI is enteric coated. In another embodiment, at least some amount or portion of the proton pump inhibitor is free of enteric coating. In another embodiment, at least a therapeutically effective amount or portion of the PPI is not enteric coated. In another embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or about 60%, or about 70% or about 80%, or about 90%, by weight, of the PPI is not enteric coated. In another embodiment, some amount or portion of the PPI comprises a "thin enteric coat". The term "thin enteric coat" herein refers to a pH sensitive coating that is applied in a manner or amount such that it delays release of the coated substance in gastrointestinal fluid for a period of time, but ultimately allows release of some of the coated substance in the gastrointestinal tract prior to passage of the substance into the duodenum. In another related embodiment, a first amount or portion of the PPI is enteric coated and a second amount or portion of the PPI is not enteric coated. For example, in one embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%, by weight, of the PPI is not enteric coated and the balance of PPI is enteric coated. In another embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%, by weight, of the PPI is enteric coated and the balance of PPI is not enteric coated. [0040] In one embodiment, the PPI, or a portion thereof, is micronized. In another embodiment, the PPI, or a portion thereof, has a D90, Dgo, D7o or D5o particle size, by weight or by number, of less than about 500 μm, less than about 400 μm, less than about 300 μm, less than about 200 μm, less than about 150 μm, less than about 100 μm, less than about 80 μm, less than about 60 μm, less than about 40 μm, less than about 35 μm, less than about 30 μm, less than about 25 μm, less than about 20 μm, less than about 15 μm, or less than about 10 μm, for example about 10 to about 500 μm, about 10 to about 400 μm, about 10 to about 300 μm, about 10 to about 200 μm, about 10 to about 100 μm, about 10 to about 80 μm, or about 10 to about 60 μm.
[0041] In another embodiment, compositions are provided wherein the micronized proton pump inhibitor is of a particle size which allows greater than about 90% or greater than about 75% of the proton pump inhibitor to be released from the dosage unit within about 1 hour, within about 50 minutes, within about 40 minutes, within about 30 minutes, within about 20 minutes, within about 10 minutes, or within about 5 minutes after placement in a standard USP dissolution test.
[0042] In another embodiment, compositions of the invention comprise one or more PPIs in a total amount of about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 5 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 250 mg, about 5 mg to about 100 mg, about 5 mg to about 75 mg, or about 5 mg to about 50 mg, for example about 7.5 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg, about 40 mg or about 45 mg.
Buffering Agent
[0043] Compositions of the invention comprise one or more pharmaceutically acceptable buffering agents. Buffering agents useful in the present invention include agents possessing pharmacological activity as a weak or strong base. In one embodiment, the buffering agent, when formulated with or administered substantially simultaneously with a PPI, functions to raise the pH of gastrointestinal fluid and thereby to substantially prevent or inhibit acid degradation of the PPI by gastrointestinal fluid for a period of time. Illustratively, the period of time is a period sufficient to preserve bioavailability of at least a therapeutically effective amount of the PPI administered.
[0044] In another embodiment, buffering agents useful in accordance with the present invention comprise a salt of a alkali (Group IA) earth metal or an akaline (Group HA; e.g. beryllium, magnesium, calcium, strontium, barium, radium) earth metal. Illustrative salts include bicarbonates, carbonates, phosphates, citrates, borates, acetates, phthalates, tartrate, succinates, etc. Additional classes of buffering agents useful in accordance with the present invention include amino acids, an alkaline salt of an amino acid, an aluminum buffering agent, a bismuth buffering agent, a calcium buffering agent, a sodium buffering agent, or a magnesium buffering agent.
[0045] Non-limiting examples of suitable buffering agents include aluminum, magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate co-precipitate, aluminum glycinate, bismuth subcitrate, bismuth subcarbonate, bismuth subsalicylate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometarnol. (Based in part upon the list provided in The Merck Index, Merck & Co. Rahway, NJ. (2001)). In addition, due to the ability of proteins or protein hydrolysates to react with stomach acids, they too can serve as buffering agents in the present invention. Furthermore, combinations or mixtures of the above mentioned buffering agents can be used in the pharmaceutical formulations described herein.
[0046] Buffering agents useful in the present invention also include buffering agents or combinations of buffering agents that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase such as water, these buffering agents produce and maintain a pH greater than the pKa of the proton pump inhibitor.
[0047] In various other embodiments of the present invention, the buffering agent is present in a composition of the invention in a total amount of about 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibitor, about 0.5 mEq/mg to about 3 mEq/mg of the proton pump inhibitor, about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pump inhibitor, about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor, or about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor. In another embodiment, the buffering agent is present in an amount of at least about 0.5 mEq/mg of the proton pump inhibitor, at least about 0.75 mEq/mg of the proton pump inhibitor, or at least about 1 mEq/mg of the proton pump inhibitor on a dry weight basis.
[0048] In another embodiment, one or more buffering agents are present in a composition of the invention in a total amount of about 0.5 mEq to about 160 mEq, about 1 mEq to about 150 mEq, about 10 mEq to about 150 mEq, about 10 mEq to about 75 mEq, about 10 mEq to about 60 mEq, or about 10 mEq to about 50 mEq. Illustratively, a composition of the invention can comprise about 1 mEq, or about 5 mEq, or about 10 mEq, or about 15 mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq, or about 80 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 niEq, or about 140 mEq, or about 150 mEq, or about 160 mEq of buffering agent.
[0049] In yet another embodiment, one or more buffering agents are present in a composition of the invention in a total amount of at least about 10 mEq, at least about 11 mEq, at least about 12 mEq, at least about 13 mEq, at least about 14 mEq, at least about 15 mEq, at least about 16 mEq, at least about 17 mEq, at least about 18 mEq, at least about 19 mEq, at least about 20 mEq or at least about 21 mEq.
[0050] In still another embodiment, one or more buffering agents and the PPI are present in a composition of the invention in a weight ratio of at least about 5:1, at least about 7:1, at least about 10:1, at least about 20:1, greater than 20:1, at least about 21:1, at least about 22:1, at least about 23:1, at least about 24:1, at least about 25:1, at least about 30:1, at least about 35:1, at least about 40:1, greater than 40:1, or at least about 45:1.
[0051] In another embodiment, the amount of buffering agent present in a composition of the invention ranges from about 200 to about 3500 mg, about 300 to about 3000 mg, about 400 to about 2500 mg, or about 500 to about 2200 mg, about 600 to about 2000, or about 700 to about 1800 mg. In other embodiments, the amount of buffering agent present in a composition of the invention is about 200 mgs, or about 300 mgs, or about 400 mgs, or about 500 mgs, or about 600 mgs, or about 700 mgs, or about 800 mgs, or about 900 mgs, or about 1000 mgs, or about 1100 mgs, or about 1200 mgs, or about 1300 mgs, or about 1400 mgs, or about 1500 mgs, or about 1600 mgs, or about 1700 mgs, or about 1800 mgs, or about 1900 mgs, or about 2000 mgs, or about 2100 mgs, or about 2200 mgs, or about 2300 mgs, or about 2400 mgs, or about 2500 mgs, or about 2600 mgs, or about 2700 mgs, or about 2800 mgs, or about 2900 mgs, or about 3000 mgs, or about 3200 mgs, or about 3500 mgs.
[0052] In another embodiment, one or more buffering agents are present in a composition of the invention in a total amount that is greater than 800 mg, for example at least about 920 mg or at least about 1000 mg.
[0053] In still another embodiment, particularly where the composition is other than a dosage form selected from the group consisting of a suspension tablet, a chewable tablet, an effervescent powder, an effervescent tablet, lozenge and/or a troche, the buffering agent and PPI are present in a weight ratio greater than 20:1, not less than about 21:1, not less than about 22:1, not less than about 23:1, not less than about 24:1, not less than about 25:1, not less than about 26:1, not less than about 27:1, not less than about 28:1, not less than about 29:1, not less than about 30:1, not less than about 31:1, not less than about 32:1, not less than about 33:1, not less than about 34:1, not less than about 35:1, not less than about 36:1, not less than about 37:1, not less than about 38:1, not less than about 39:1, not less than about 40:1, not less than about 41:1, not less than about 42:1, not less than about 43:1, not less than about 44:1, not less than about 45:1, not less than about 46:1, not less than about 47:1, not less than about 48:1, not less than about 49:1, or not less than about 50:1.
[0054] In another embodiment, a composition is provided that comprises a combination of at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate. In a related embodiment, if such a composition comprises a poly[phosphoryl/sulfon]- ated carbohydrate, the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05). Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg. In another embodiment, the composition contains no poly[phosphoryl/sulfon]-ated carbohydrate.
[0055] In other embodiments, if the pharmaceutical composition comprises an amino acid buffering agent, the total amount of amino acid buffering agent present in the pharmaceutical composition is less than about 5 mEq, less than about 4 mEq, or less than about 3 mEq.
[0056] The phrase "amino acid buffering agent" as used herein includes amino acids, amino acid salts, and amino acid alkali salts including: glycine, alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum glycinate and/or lysine glutamic acid salt, glycine hydrochloride, L-alanine, DL-alanine, L-threonine, DL-threonine, L-isoleucine, L-valine, L- phenylalanine, L-glutamic acid, L-glutamic acid hydrochloride, L-glutamic acid sodium salt, L-asparaginic acid, L-asparaginic acid sodium salt, L-lysine and L- lysine-L-glutamic acid salt. The term "non-amino acid buffering agent" herein includes buffering agents as defined hereinabove but does not include amino acid buffering agents.
[0057] In another embodiment, a composition of the invention comprises at least one non-amino acid buffering agent wherein the non-amino acid buffering agent is present in the composition in a total amount greater than 800 mg. In a related embodiment, if such a composition comprises a poly[phosphoryl/sulfon]- ated carbohydrate, the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05). Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg.
[0058] In still another embodiment, a composition is provided that comprises at least one buffering agent in a total amount of at least about 10 mEq. In a related embodiment, if an amino acid buffering agent is present in the composition, at least one of the following conditions is met: (1) the weight ratio of amino acid buffering agent:proton pump inhibitor is greater than 20:1; (2) the composition comprises at least two non-amino acid buffering agents; (3) the composition comprises at least one non-amino acid buffering agent wherein the weight ratio of the at least one non-amino acid buffering agentproton pump inhibitor is greater than 20:1; and/or (4) the weight ratio of total buffering agentproton pump inhibitor is greater than 40:1.
[0059] In other embodiments, where two or more buffering agents are present, the two or more buffering agents comprise at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate.
[0060] In still another embodiment, the buffering agent comprises a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in an amount of about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump inhibitor.
[0061] Also provided herein are pharmaceutical compositions comprising at least one soluble buffering agent. The term "soluble buffering agent" as used herein refers to a buffering agent that has a solubility of at least about 500 mg/mL, at least about 300 mg/mL, at least about 200 mg/mL, or at least about 100 mg/mL in gastrointestinal fluid or simulated gastrointestinal fluid.
[0062] In some embodiments of the present invention, the buffering agent is micronized. hi another embodiment, the buffering agent has a defined particle size distribution. For example, in one embodiment, the D5o, D7o, D8o, or D90 particle size of the buffering agent, by weight or by number, is no greater than about 20 μm, no greater than about 30 μm, no greater than about 40 μm, no greater than about 50 μm, no greater than about 60 μm, no greater than about 70 μm, no greater than about 80 μm, no greater than about 90 μm, no greater than about 100 μm in diameter, no greater than about 200 μm in diameter, no greater than about 300 μm in diameter, no greater than about 400 μm in diameter, or no greater than about 100 μm in diameter.
Anti-Helicobacter pylori active substance
[0063] In one embodiment, compositions of the invention comprise one or more anύ-Helicobacter pylori active substances. The term "anti-Helicobacter pylori active substance" or "anti-H. pylori active substance" refers to any pharmaceutically acceptable substance that kills, reduces and/or inhibits or disrupts the growth of H. pylori, whether directly or indirectly. In one embodiment, the anti-H. pylori active substance is an antibiotic. The term "antibiotic" herein refers to any drug or agent, whether naturally occurring, synthetically or semi- synthetically derived, that kills or reduces the growth of bacterial infection, hi another embodiment, the anti-H. pylori active substance is effective against gram negative bacteria. In yet another embodiment, the anti-H. pylori active substance is not an antibiotic, hi another embodiment, the anti-H. pylori active substance is a mucolytic agent or an essential oil. hi one embodiment, compositions of the invention comprise one or more various anti-H. pylori active substances, for example one or more of an antibiotic, an essential oil and/or a mucolytic agent.
[0064] Exemplary antibiotics include, but are not limited to, antibiotic penicillins {e.g. amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), antibiotic cefems or cephalosporins {e.g. cefixime, cefuroxime, cefuroxime axetil, cefaclor, ceftizoxime, cefotaxime, ceftazidime, etc.) antibiotic macrolides {e.g. erythromycin, clarithromycin, azithromycin, telithromycin, roxithromycin, etc.) antibiotic tetracylines {e.g. tetracyline, minocycline, doxycycline, tigecycline, etc.) antibiotic aminoglycosides {e.g. gentamicin, kanamycin, netilmicin, amikacin, tobramycin, etc.) antibiotic carbapenems {e.g. imipenem, meropenem, doripenem, etc.), carbapenem ester type prodrug {e.g. tebipenem pivoxil, faropenem daloxate, other oral carbapenem prodrugs include GV-118819, CS-834, L-084, DZ-2649, CL-191121, etc., See below), antibiotic quinolones {e.g. norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, sitafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, pazufloxacin, prulifloxacin, olamufloxacin, ganefloxacin, gemifloxacin, and trovafloxacin, etc.), antibiotic nitroimidazoles {e.g. metronidazole, tinidazole), antibiotic rifamycin or ansamycin analogues {e.g. rifabutin, rifampicin, rifampin, rifaximin, rifalazil, and ryfamycin derivatives such as 3'-hydroxy-5'-(4- propylpiperazinyl)benzoxazinorifamycin- (shown as structure I below), which are illustratively disclosed in Η. Saito et ah, In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins, Antimicrob. Agents Chemother., 1991 March; 35(3): 542-547, the entire disclosure of which is hereby incorporated by reference herein, and other antibiotics such as mupirocin.
Figure imgf000019_0001
[0065] GV-118819
Figure imgf000020_0001
[0066] CL 191,121 or
[0067]
Figure imgf000020_0002
CCH3 wherein R is:
Figure imgf000020_0003
[0071] The compound 3'-hydroxy-5'-(4-propylpiperazinyl) benzoxazinorifamycin- has a chemical structure (II) shown below.
Figure imgf000021_0001
[0073] The above antibiotics are typically administered in daily amounts of about 250 mg to about 5 g. Compositions of the invention can comprise a full daily dose of anti-H. pylori active substance {e.g. 250 mg to about 5 g), or a fraction of the daily dose {e.g. 1/8*, 1/6Λ, 1/4*, l/3rd, V2, etc.) Typical daily doses of antibiotics are as follows: furazolidone: about 400 mg (about 200 mg twice daily); tetracycline: about 250 - about 2000 mg (typically about 500 mg one to four times daily); amoxicillin: about 2000 mg (about 1000 mg twice daily); clarithromycin: about 1000 mg (about 500 mg twice daily); metronidazole: 800 mg (400 mg twice daily). Aminoglycosides such as gentamicin, tobramycin, amikacin, kanamycin, netilmicin, etc., are typically administered in doses of about 25 mg to about 1 g one to four times per day. Quinolones such as norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, gatifloxacin, moxifloxacin, trovafloxacin are typically administered in doses of about 50 mg to about 1 g one to four times per day.
[0074] Essential oils can also be used as an anti-H. pylori active substance according to various embodiments of the invention. Essential oils contain one or more compounds that make up the essential oil and can be synthesized or derived from any suitable naturally occurring substance such as carrot seed, cinnamon bark, clove, eucalyptus, white grapefruit, lemongrass, etc. For example, clove oil, contains: alpha-cubeben, alpha-pinene, beta-caryophyllene, eugenol, and isoeugenol. Illustrative pure compounds present in various essential oils can, individually or in combination, comprise an anti-H. pylori active substance according to various embodiments of the invention and include alpha-copaen, alpha-cubeben, alpha-pinene, alpha-selinen, beta-caryophyllene, beta-pinene, beta- selinen, camphor, carotol, carvacrol, cinnamaldehyde, citral, citronellal, decanal, eucalyptol, eugenol, gamma-terpinene, geraniol, geranyl acetate, isoeugenol, limonene, linalool, myrcene, nerol, nootkatone, octanal, para-cymene, sabinene, thymol, etc. In one embodiment, one or more essential oils, if present, are present in a composition of the invention in an amount of about 0.0025% to about 5%, about 0.005% to about 4%, or about 0.01% to about 3%, by weight of the composition.
[0075] Pronase is an illustrative mucolytic agent that can be used as an anti-H. pylori active substance. In one embodiment, if present, a mucolytic agent is present in a composition of the invention in an amount of about 2000 tyrosine units to about 100,000 tyrosine units, about 5,000 tyrosine units to about 90,000 tyrosine units, or about 10,000 tyrosine units to about 80,000 tyrosine units.
[0076] Cholestyramine can also be used as an anti-H. pylori active substance in compositions of the invention. If present, cholestyramine is present in an amount of about 50 mg to about 2 g, about 75 mg to about 1.75 g, about 100 mg to about 1.5 g or about 125 mg to about 1 g.
[0077] Bile salts can also be used as an anti-H. pylori active substance in compositions of the invention. Bile salts are polar derivatives of cholesterol. These compounds are detergents because they contain both polar and nonpolar regions.
[0078] In other embodiments, the anti-H. pylori active substance, if present, is present in a total amount of about 0.1% to about 90%, 0.2% to about 85%about 0.5% to about 75%, or about 1% to about 60%, by total weight of the composition. Illustratively, the anti-H. pylori active substance can be present in an amount of about 1%, about 2% about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 46%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83% about 84%, or about 85%, by weight of the total composition.
[0079] In another embodiment, an anti-H. pylori active substance, if present, is present in a total amount of about 1 mg to about 5000 mg, about 100 mg to about 4000 mg, about 150 mg to about 3000 mg, about 200 mg to about 2000 mg, about 200 mg to about 1500 mg or about 200 mg to about 1000 mg.
[0080] In other embodiments, an anti-H. pylori active substance is present in a composition of the invention in an amount of about 50 mg, about 100 mg about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg or about 5000 mg.
[0081] In one embodiment, no portion of the anti-H. pylori active substance is enteric coated. In another embodiment, at least a portion of the anti-H. pylori active substance is not enteric coated. In another embodiment, at least a therapeutically effective portion of the anti-H. pylori active substance is not enteric coated.
[0082] In another embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or about 60%, by weight, of the anti-H. pylori active substance is not enteric coated. In another embodiment, a portion of the antibiotic comprises a "thin enteric coat" as is defined herein above.
Pharmaceutical Excipients
[0083] Compositions of the invention can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, lubricants, glidants, surface modifying agents, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Any such excipients can be used in any dosage forms according to the present invention, including liquid, solid or semi-solid dosage forms.
[0084] Excipients optionally employed in compositions of the invention can be solids, semi-solids, liquids or combinations thereof. Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with a drug or therapeutic agent.
[0085] Compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches {e.g., Celutab™ and Emdex™); mannitol; sorbitol; xylitol; dextrose {e.g., Cerelose™ 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of α- and amorphous cellulose (e.g., Rexcel™) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition. The diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
[0086] The use of extragranular microcrystalline cellulose (that is, microcrystalline cellulose added to a wet granulated composition after a drying step) can be used to improve hardness (for tablets) and/or disintegration time.
[0087] Compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations. Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., Explotab™ of PenWest) and pregelatinized corn starches (e.g., National™ 1551, National™ 1550, and Colocorn™ 1500), clays (e.g., Veegum™ HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™ of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums.
[0088] Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to a granulation step or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.
[0089] Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, typically constitutes about 0.2% to about 10%, about 0.2% to about 7%, or about 0.2% to about 5%, of the total weight of the composition. [0090] Compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations. Such binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., National™ 1511 and National™ 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., Tylose™); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., Klucel™); and ethylcellulose (e.g., Ethocel™). Such binding agents and/or adhesives, if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.
[0091] Compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, for example propylene glycol laurate (e.g., Lauroglycol™ of Gattefosse), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition.
[0092] Compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients. Suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., Compritol™ 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the total weight of the composition.
[0093] Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates. Talc is a anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend. Talc, if present, constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the composition.
[0094] Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate.
[0095] Compositions of the present invention can comprise one or more anti- foaming agents. Simethicone is an illustrative anti-foaming agent.
[0096] Compositions of the present invention can comprise one or more flavoring agents, sweetening agents, and/or colorants. Flavoring agents useful in the present invention include, without limitation, acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butter, butter pecan, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut, orange, peanut butter, pear, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and combinations thereof, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, etc.
[0097] Sweetening agents that can be used in the present invention include, for example, acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol, neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.
[0098] The foregoing excipients can have multiple roles as is known in the ait. For example, starch can serve as a filler as well as a disintegrant. The classification of excipients above is not to be construed as limiting in any manner.
Pharmaceutical Dosage Forms
[0099] In one embodiment, compositions of the invention are in the form of an orally deliverable dosage unit. The terms "oral administration" or "orally deliverable" herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed. Thus "oral administration" includes buccal and sublingual as well as esophageal administration.
[0100] Compositions of the present invention can be formulated as solid, liquid or semi-solid dosage forms. In one embodiment, such compositions are in the form of discrete dose units or dosage units. The terms "dose unit" and/or "dosage unit" herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a small plurality (i.e. 1 to about 4) times per day, or as many times as needed to elicit a therapeutic response. A particular dosage form can be selected to accommodate any desired frequency of administration to achieve a specified daily dose. Typically one dose unit, or a small plurality (i.e. up to about 4) of dose units, provides a sufficient amount of the active drug to result in the desired response or effect.
[0101] Alternatively, compositions of the invention can also be formulated for rectal, topical, or parenteral (e.g. subcutaneous, intramuscular, intravenous and intradermal or infusion) delivery.
[0102] In one embodiment, compositions of the invention are suitable for rapid onset of therapeutic effect, particularly with respect to the PPI, buffer and/or anti- H. pylori active substance. In another embodiment, upon oral administration of a composition of the invention to a subject, at least a therapeutically effective amount of the PPI and/or anti-H. pylori active substance is available for absorption in the stomach of the subject. As discussed above, most commercially available PPIs require enteric coating to prevent exposure of the PPI to gastrointestinal fluids (and consequent drug degradation) by way of pΗ dependent coatings. Such coating, in turn, prevents rapid PPI absorption and therapeutic onset of action. Compositions of the present invention, by contrast, do not require enteric coating to maintain drug stability in gastrointestinal fluids and thereby provide for rapid absorption and onset of therapeutic effect. In one embodiment, a composition comprises at least a therapeutically effective amount of PPI that is not enteric coated.
[0103] In another embodiment, a single dosage unit, be it solid or liquid, comprises a therapeutically and/or prophylactically effective amount of PPI and/or an anti-H. pylori active substance. The term "therapeutically effective amount" or "therapeutically and/or prophylactically effective amount" as used herein refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
[0104] It will be understood that a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject. A "subject" herein to which a therapeutic agent or composition thereof can be administered includes a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or a horse.
Solid and Liquid Dosage Forms
[0105] In various embodiments, compositions of the invention are in the form of solid dosage forms or dosage units. Non-limiting examples of suitable solid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hard gelatin capsule), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably adapted for oral administration.
[0106] Tablets can be prepared according to any of the many relevant, well known pharmacy techniques. In one embodiment, tablets or other solid dosage forms can be prepared by processes that employ one or a combination of methods including, without limitation, (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion.
[0107] The individual steps in the wet granulation process of tablet preparation typically include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation and final grinding. Dry granulation involves compressing a powder mixture into a rough tablet or "slug" on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator. The individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). Typically, no wet binder or moisture is involved in any of the steps. [0108] In another embodiment, solid dosage forms such as tablets can be prepared by mixing a PPI with at least one buffering agent as described herein above and, if desired, with one or more optional pharmaceutical excipients to form a substantially homogeneous preformulation blend. The preformulation blend can then be subdivided and optionally further processed (e.g. compressed, encapsulated, packaged, dispersed, etc.) into any desired dosage forms.
[0109] Compressed tablets can be prepared by compacting a powder or granulation composition of the invention. The term "compressed tablet" generally refers to a plain, uncoated tablet suitable for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression. Tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. In one embodiment, any such coating will be selected so as to not substantially delay onset of therapeutic effect of a composition of the invention upon administration to a subject. The term "suspension tablet" as used herein refers to a compressed tablet that rapidly disintegrates after placement in water.
[0110] In one embodiment, a composition of the invention comprises a multilayer tablet having a core comprising a proton pump inhibitor; the core is substantially or completely surrounded by a buffering agent and/or anti-H. pylori active substance. Optionally, the buffering agent layer can be surrounded by an anti-H. pylori active substance layer, which can optionally be coated with one or more coating materials. In one embodiment, the optional coating is not an enteric coating. In a related embodiment, the buffering agent layer completely surrounds the core. In another embodiment, the buffering agent layer partially surrounds the core. In yet another embodiment, the buffering agent layer is in contact with a portion of or with all of the surface area of the core.
[0111] In another embodiment, one or more intermediate layers exists in between the core and the buffering agent. The intermediate layers can comprise any pharmaceutically acceptable material, preferably inert and non-pΗ sensitive coating materials such as polymer based coatings. [0112] In another embodiment, a composition of the invention comprises. a multi-layer tablet having a core comprising an anti-H. pylori active substance; the core is substantially or completely surrounded by the PPI and the buffering agent. Optionally, an intermediate layer can exist between the anti-H. pylori active substance core and the PPI/buffering agent surrounding the core. In one embodiment, the optional intermediate layer is a coating layer. In another embodiment, the coating layer is not an enteric coating.
[0113] In one such embodiment, the buffering agent/PPI layer completely surrounds the core. In another embodiment, the buffering agent/PPI layer partially surrounds the core. In yet another embodiment, the buffering agent/PPI layer is in contact with a portion of or with all of the surface area of the core.
[0114] In still another embodiment, compositions of the invention can be microencapsulated wherein the PPI, buffering agent and/or anti-H. pylori active substance are microencapsulated together, for example as modified from the description in U.S. Patent Publication No. 2005/0037070, hereby incorporated by reference herein in its entirety.
[0115] In another embodiment, a composition of the invention comprises a proton pump inhibitor, an anti-H. pylori active substance and a buffering agent mixed together in powder form and optionally filled into a capsule, for example a hard or soft gelatin or ΗPMC capsule.
[0116] hi another embodiment, compositions of the invention can be in the form of liquid dosage forms or units. Non-limiting examples of suitable liquid dosage forms include solutions, suspension, elixirs, syrups, liquid aerosol formulations, etc.
[0117] hi one embodiment, a liquid composition comprising water or other solvent, PPI, a buffering agent and an anti-H. pylori active substance can be prepared. In another embodiment, compositions of the invention are in the form of a powder for suspension that can be suspended in a liquid vehicle prior to administration to a subject. While the powder for suspension itself, can be a solid dosage form of the present invention, the powder dispersed in liquid also comprises a liquid embodiment of the invention. [0118] Suspension compositions of the invention comprise at least one PPI, a buffering agent, an anti-H. pylori active substance, a liquid medium (e.g. water, de- ionized water, etc.) and one or more optional pharmaceutical excipients. Such compositions, upon storage in a closed container maintained at either room temperature, refrigerated (e.g. about 5 -10 °C) temperature, or freezing temperature for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%, at least about 92.5%, at least about 95%, or at least about 97.5% of the original PPI and/or anti-H. pylori active substance present therein.
Administration and Bioavailability
[0119] Compositions of the invention are useful in the treatment of H. pylori infection and other gastrointestinal diseases and disorders including but not limited to duodenal ulcer, gastric ulcer, acid dyspepsia, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, (acid reflux), heartburn, nighttime heartburn symptoms, nocturnal acid breakthrough (NAB), acid dyspepsia, heartburn, and/or NSAID induced ulcer and gastrointestinal pathological hypersecretory conditions such as Zollinger Ellison Syndrome.
[0120] In one embodiment, a composition of the invention is effective at reducing or eradicating H. pylori infection and/ or ulcer upon administration about 1 to about 4 times per day for a period of about 1 to about 10 days, about 1 to about 5 days, or about 1 to about 3 days, for example about 1 day or about 2 days. In one embodiment, a single dose of a composition of the invention is sufficient to reduce or eradicate H. pylori infection. In another embodiment, 1 to 3 doses of a composition of the invention is sufficient to reduce or eradicate H. pylori infection.
[0121] In one embodiment, the invention provides method for reducing duration (and/or the number of doses required) of H. pylori or ulcer therapy by comparison with conventional therapies. The method comprises the steps of administering to a subject in need of H. pylori treatment a therapeutically effective amount of an anti- H. pylori active substance, a buffering agent, and a non-enteric coated PPI in one or more doses (as described above) over a period of about 1 to about 7 days, about 1 to about 5 days, about 1 to about 4 days, about 1 to about 3 days or about 1 to about 2 days.
[0122] In one embodiment, compositions of the invention are suitable for rapid onset of therapeutic effect, particularly with respect to the PPI and/or anti-H. pylori active substance. In another embodiment, upon oral administration of a composition of the invention to a subject, at least a therapeutically effective amount of the PPI and/or anti-H. pylori active substance are available for absorption in the stomach of the subject. The phrase "available for absorption in the stomach" in reference to an active ingredient such as a PPI means that the ingredient remains intact and in active form in the stomach for a sufficient amount of time to allow for absorption into the blood. As discussed above, most commercially available PPIs require enteric coating to prevent exposure of the PPI to gastrointestinal fluids (and consequent drug degradation) by way of pΗ dependent coatings. Such coating, in turn, prevents rapid PPI absorption and therapeutic onset of action. In one embodiment, compositions of the invention do not require enteric coating to maintain drug stability in gastrointestinal fluids and thereby allow for rapid absorption and onset of therapeutic effect. In one embodiment, a composition comprises at least a therapeutically effective amount of PPI that is not enteric coated. In another embodiment, the invention provides compositions having PPI which is substantially completely not enteric coated.
[0123] In another embodiment, upon oral administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit a gastric pΗ not less than about 5, about 5.1 about 5.2 about 5.3, about 5.4, about 5.5, about 5.6 about 5.7, about 5.7 about 5.9 or about 6 within about 0.5 minutes, 1 minutes, 2 minutes, 3 minutes, 4 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, or 30 minutes after administration. In another embodiment, upon oral administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit a gastric pΗ not less than about 5, about 5.1 about 5.2 about 5.3, about 5.4, about 5.5, about 5.6 about 5.7, about 5.7 about 5.9 or about 6 for a period beginning within about 0.5 minute, 1 minute, 2 minutes, 3 minutes, 4 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, or 30 minutes after said administration and the pH is maintained at not less than about 5, about 5.1 about 5.2 about 5.3, about 5.4, about 5.5, about 5.6 about 5.7, about 5.7 about 5.9 or about 6 for a period of at least about 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes after administration.
[0124] In another embodiment, upon oral administration of a composition of the invention to a fasted adult human subject, the maximum concentration of anti-H. pylori active substance in the stomach fluid is achieved when the pΗ of the stomach fluid is not less than about 5, not less than about 5.1, not less than about 5.2, not less than about 5.3, not less than about 5.4, not less than about 5.5, not less than about 5.6, not less than about 5.7, not less than about 5.8, not less than about 5.9 or not less than about 6.
[0125] In another embodiment, upon oral administration of a composition of the invention to a fasted adult human subject, the anti-H. pylori active substance is absorbed into the bloodstream and upon subsequently being secreted from the bloodstream into the stomach, the stomach secretions are at a pΗ not less than about 5, not less than about 5.1, not less than about 5.2, not less than about 5.3, not less than about 5.4, not less than about 5.5, not less than about 5.6, not less than about 5.7, not less than about 5.8, not less than about 5.9 or not less than about 6.
[0126] In another embodiment, upon oral administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit an average Tmax of PPI and/or anti-H. pylori active substance within about 30 seconds to about 90 minutes, within about 1 minute to about 80 minutes, within about 5 minutes to about 60 minutes, within about 10 minutes to about 50 minutes, or within about 10 minutes to about 45 minutes.
[0127] In still another embodiment, upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit an average plasma concentration of the PPI and/or anti-H. pylori active substance of at least about 0.1 μg/ml, at least about 0.15 μg/ml, at least about 0.2 μg/ml, at least about 0.3 μg/ml, at least about 0.4 μg/ml, at least about 0.5 μg/ml, at least about 0.6 μg/ml, at least about 0.7 μg/ml, at least about 0.8 μg/ml, at least about 0.9 μg/ml, at least about 1 μg/ml, at least about 1.5 μg/ml, or at least about 2.0 μg/ml at any time within about 90 minutes, within about 75 minutes, within about 60 minutes, within about 55 minutes, within about 50 minutes, within about 45 minutes, within about 40 minutes, within about 35 minutes, within about 30 minutes, within about 25 minutes, within about 20 minutes, within about 17 minutes, within about 15 minutes, within about 12 minutes, or within about 10 minutes after administration.
[0128] In yet another embodiment, upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit a plasma concentration of PPI and/or anti-H. pylori active substance of at least about 0.1 μg/ml, at least about 0.15 μg/ml, at least about 0.2 μg/ml, at least about 0.3 μg/ml, at least about 0.4 μg/ml, at least about 0.5 μg/ml, at least about 0.6 μg/ml, at least about 0.7 μg/ml, at least about 0.8 μg/ml, at least about 0.9 μg/ml, at least about 1.0 μg/ml, at least about 1.5 μg/ml or at least about 2.0 μg/ml, maintained from at latest about 15 minutes to at earliest about 60 minutes after administration, preferably at latest about 15 minutes after administration to at earliest about 90 minutes after administration, more preferably at latest about 15 minutes to at earliest about 120 minutes after administration, and still more preferably at latest about 15 minutes to at earliest about 180 minutes after administration.
[0129] In another embodiment, upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit at least one of: a mean Cmax of PPI and/or anti-H. pylori active substance of about 500 μg/ml to about 2000 μg/ml, about 600 μg/ml to about 1900 μg/ml, or about 700 ng/ml to about 1800 μg/ml; a mean Tmax of PPI and/or anti-H. pylori active substance of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and/or a mean AUQo-inf) of PPI and/or anti-H. pylori active substance of about 1000 to about 3000 μg-Jir/ml, about 1500 to about 2700 μg*hr/ml, or about 1700 to about 2500 μg*hr/ml. [0130] In another embodiment, upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit: a mean Cmax of PPI and/or anti-H. pylori active substance of about 500 μg/ml to about 2000 μg/ml, about 600 μg/ml to about 1900 μg/ml, or about 700 μg/ml to about 1800 μg/ml; a mean Tmax of PPI and/or anti-H. pylori active substance of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and a mean AUC(o-inf) of PPI and/or anti-H. pylori active substance of about 1000 to about 3000 ng*hr/ml, about 1500 to about 2700 ng*hr/ml, or about 1700 to about 2500 ng*hr/ml.
[0131] In another embodiment, a composition of the invention is formulated such that upon administration of the composition to a subject, maximum concentration of the anti-H. pylori active substance in the stomach is achieved while the stomach secretions have a pΗ of about 5 to about 8.5, about 5.2 to about 8.3, or about 5.5 to about 8.
[0132] In another embodiment, the PPI, buffering agent and antibiotic can be separately formulated. Illustratively, where two or more compositions are to be administered to a subject, the administration of such compositions is sequenced such that maximum concentration (Tmaχ) of the anti-H. pylori active substance in the stomach is achieved while the stomach secretions have a pΗ of about 5 to about 8.5, about 5.2 to about 8.3, or about 5.5 to about 8.
Parietal Cell Activators
[0133] In one embodiment, a composition of the present invention can further include one or more parietal cell activators. Parietal cell activators such as chocolate, calcium and sodium bicarbonate and other alkaline substances stimulate the parietal cells and enhance the pharmacologic activity of the PPI administered. For the purposes of this application, "parietal cell activator" or "activator" shall mean any compound or mixture of compounds possessing such stimulatory effect including, but not limited to, chocolate, sodium bicarbonate, calcium (for example, calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate), peppermint oil, spearmint oil, coffee, tea and colas (even if decaffeinated), caffeine, theophylline, theobromine, and amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan) and combinations thereof.
[0134] Parietal cell activators, if desired, are typically present in a composition of the invention in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients. For example, chocolate, as raw cocoa, is administered in an amount of about 5 mg to 2.5 g per 20 mg dose of omeprazole (or equivalent pharmacologic dose of another proton pump inhibiting agent). The dose of activator administered to a subject, for example, a human, in the context of the present invention should be sufficient to result in enhanced effect of a PPI over a desired time frame.
[0135] Illustratively, the approximate effective ranges for various parietal cell activators per 20 mg dose of omeprazole (or equivalent dose of other PPI) include, Chocolate (raw cocoa) - 5 mg to 2.5 g; Sodium bicarbonate - 7 mEq to 25 niEq; Calcium carbonate - 1 mg to 1.5 g; Calcium gluconate - 1 mg to 1.5 g; Calcium lactate - 1 mg to 1.5 g; Calcium hydroxide - 1 mg to 1.5 g; Calcium acetate - 0.5 mg to 1.5 g; Calcium glycerophosphate - 0.5 mg to 1.5 g; Peppermint oil - (powdered form) 1 mg to 1 g; Spearmint oil - (powdered form) 1 mg to 1 g; Coffee - 20 ml to 240 ml; Tea - 20 ml to 240 ml; Cola - 20 ml to 240 ml; Caffeine - 0.5 mg to 1.5 g; Theophylline - 0.5 mg to 1.5 g; Theobromine - 0.5 mg to 1.5g; Phenylalanine - 0.5 mg to 1.5 g; and Tryptophan - 0.5 mg to 1.5 g.
[0136] All U.S. Patents and U.S. Patent Publications disclosed herein are hereby individually incorporated herein by reference in their entirety.
EXAMPLES
[0137] The examples below are for illustrative purposes only and are not to be construed as limiting the invention in any manner.
Example 1
[0138] The following compositions, Cl - ClO, are prepared as shown in Table 1. Such compositions can, if desired, be tableted or encapsulated or prepared as other dosage forms as described hereinabove. Furthermore, the PPIs, anti-H. pylori active substance and buffering agents are interchangeable with on another. Table 1. Compositions Cl - ClO.
Figure imgf000039_0001
The above compositions may optionally comprise a bismuth compound, for example colloidal bismuth subcitrate, in an amount of about 100 mg to about 800 mg.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising a proton pump inhibitor, at least a therapeutically effective portion of which is not enteric coated, at least one buffering agent in a total amount of about 5 mEq to about 100 niEq, and a therapeutically effective amount of an anti-H. pylon active substance.
2. The composition of claim 1 wherein the proton pump inhibitor is of Formula (I):
Figure imgf000040_0001
wherein
R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
R is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
R and R5 are the same or different and each is hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;
R4 is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
Q is nitrogen, CH, or CR1;
W is nitrogen, CH, or CR1; y is an integer of 0 through 4; and
Z is nitrogen, CH, or CR1; or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.
3. The composition of claim 1 wherein the proton pump inhibitor is selected from the group consisting of omeprazole, tenatoprazole, lansoprazole, s- lanzoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug, of such compounds.
4. The composition of claim 3 wherein the proton pump inhibitor is selected from omeprazole, lansoprazole, s-lanzoprazole, rabeprazole, pantoprazole or esomeprazole.
5. The composition of claim 1 wherein the proton pump inhibitor is omeprazole, esomeprazole or lansoprazole.
6. The composition of claim 1 wherein the proton pump inhibitor is present in an amount of about 8 mg to about 45 mg.
7. The composition of claim 6 wherein the buffering agent is present in an amount of about 400 mg to about 3000 mg.
8. The composition of claim 7 wherein the buffering agent is present in an amount of about 500 mg to about 2500 mg.
9. The composition of claim 8 wherein the anti-H. pylori active substance is an antibiotic selected from the group consisting of amoxicillin, benzylpenicillin, piperacillin, mecillinam, cefixime, cefaclor, fefotaxime, cefotaxime, ceftazidime, erythromycin, clarithromycin, azithromycin, telithromycin, roxithromycin, tetracyline, minocycline, doxycycline, gentamicin, kanamycin, netilmicin, amikacin, tobramycin, imipenem, meropenem, doripenem, tebipenem pivoxil, faropenem daloxate, norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, sitafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, pazufloxacin, prulifloxacin, olamufloxacin, ganefloxacin, gemifloxacin, and trovafloxacin, and mupirocin.
10. The composition of claim 8 wherein the antibiotic is present in the composition in an amount of about 0.1% to about 85%, by weight.
11. The composition of either of claims 10 wherein the antibiotic is present in an amount of about 1% to about 60%, by weight.
12. The composition of claim.1 further comprising at least one pharmaceutically acceptable excipient.
13. The composition of claim 1 wherein the composition is a solid dosage form.
14. The composition of claim 13 wherein the solid dosage form is selected from a tablet, a suspension tablet, a bite suspension tablet, a rapid dispersion tablet, a chewable tablet, an effervescent tablet, a bilayer tablet, a caplet, a capsule, a powder, a lozenge, a sachet, a cachet, a troche, a pellet, a granule and a microgranule.
15. A method of treating a human H. pylori infected subject, comprising orally administering to the subject a composition comprising an anti-H. pylori active substance, a buffering agent, and a proton pump inhibitor, wherein upon administration of the composition to the subject, at least a therapeutically effective amount of the proton pump inhibitor is available for absorption in the subject's stomach.
16. A method for reducing duration of H. pylori therapy, the method comprising the steps of administering to a subject in need of H. pylori treatment a therapeutically effective amount of an anti-H. pylori active substance, a buffering agent, and a non-enteric coated proton pump inhibitor over a period of about 1 to about 5 days.
17. The method of claim 16 wherein the anti-H. pylori active substance, buffering agent, and non-enteric coated proton pump inhibitor are administered substantially simultaneously.
18. The method of claim 16 wherein the anti-H. pylori active substance, buffering agent, and non-enteric coated proton pump inhibitor are administered substantially simultaneously.
19. The method of claim 16 wherein the anti-H. pylori active substance, buffering agent, and non-enteric coated proton pump inhibitor are administered within 30 minutes of each other.
20. The method of claim 16 wherein the anti-H. pylori active substance, buffering agent, and non-enteric coated proton pump inhibitor are comprised in a single composition.
PCT/US2006/040756 2005-10-19 2006-10-18 Pharmaceutical composition comprising a proton pump inhibitor, a buffering agent and an anti-h. pylori active substance and methods of using same WO2007070164A1 (en)

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US9101160B2 (en) 2005-11-23 2015-08-11 The Coca-Cola Company Condiments with high-potency sweetener
US20100041688A1 (en) * 2006-12-22 2010-02-18 Yuhan Corporation Revaprazan-containing solid dispersion and process for the preparation thereof
US8663658B2 (en) * 2006-12-22 2014-03-04 Yuhan Corporation Revaprazan-containing solid dispersion and process for the preparation thereof
WO2010006904A3 (en) * 2008-06-23 2010-04-01 Krka, Tovarna Zdravil, D.D., Novo Mesto Crystalline forms of rabeprazole sodium
WO2010006904A2 (en) * 2008-06-23 2010-01-21 Krka, Tovarna Zdravil, D.D., Novo Mesto New crystalline forms of rabeprazole sodium
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US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
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US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US20200016126A1 (en) * 2016-12-15 2020-01-16 Spero Therapeutics, Inc. Novel tebipenem pivoxil immediate and modified release oral dosage forms
EP3886884A4 (en) * 2018-11-28 2023-03-01 Locus IP Company, LLC Compositions and methods for treating and preventing helicobacter pylori infections
CN110169956A (en) * 2019-05-08 2019-08-27 成都药云科技有限公司 A kind of sitafloxacin microcapsule formulation and preparation method thereof

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