Compositions with enhanced bioavailability and fast acting inhibitor of gastric acid secretion

Abstract

The present invention relates to the use of pharmaceutically acceptable zinc salts, preferably water soluble zinc salts alone or optionally, in combination with one or more of a protein pump inhibitor (PPI), H2 blocker, anti- H. pylori antibiotic/antimicrobial, cytoprotective agent or a combination agent as otherwise described herein for providing fast action with optional long duration effect in reducing gastric acid secretion, raising the pH of the stomach during resting phase as well as decreasing the duration of stomach acid release during a secretagogue phase and for treating conditions including gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), Zollinger-Ellison syndrome (ZE disease), ulcer disease, and gastric cancer, as well as preventing or reducing the likelihood of ulcer disease. In addition, the present methods are useful for treating patients who are non-responsive to proton pump inhibitors (PPI) and as an alternative to traditional therapies or conditions which are caused by rapid and complete inhibition of secretagogue induced acid secretion. The present invention also relates to the use of one or more water soluble zinc salts, administered in combination with a therapeutic compound or agent (second therapeutic agent) which may be delivered orally with enhanced bioavailability (compared to compounds which are administered in the absence of water soluble zinc salts) or other favorable benefits. In addition, therapeutic agents which exhibit sensitivity to low pH may be advantageously orally administered in combination with an effective amount of at least one water soluble zinc salt. Compositions according to the present invention exhibit greater bioavailability of the active agent when formulated in combination with a water soluble zinc salt in oral dosage form than when administered with the water soluble zinc salt.

1 . A method of increasing the pH of the gastric juices of the stomach of a patient, said method comprising administering to said patient an effective amount of at least one pharmaceutically acceptable zinc salt. 
     
     
         2 . The method according to  claim 1  wherein a mixture of at least two zinc salts is administered to said patient. 
     
     
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         17 . A method of reducing the likelihood of an ulcer developing in a patient at risk for an ulcer because of elevated acid release in the stomach of said patient comprising administering to said patient at risk an effective amount at least one pharmaceutically acceptable zinc salt. 
     
     
         18 . The method according to  claim 17  wherein a mixture of at least two zinc salts is administered to said patient. 
     
     
         19 . The method according to  claim 17  wherein said zinc salt is selected from the group consisting of zinc acetate, zinc ascorbate, zinc butryate, zinc carbonate, zinc citrate, zinc chloride, zinc iodide, zinc sulfate, zinc gluconate, zinc glycerate, zinc glycolate, zinc formate, zinc lactate, zinc malate, zinc maleate, zinc picolinate, zinc salicylate, zinc stearate, zinc succinate, zinc tartrate, zinc undecylenate, a zinc amino acid chelate and mixtures thereof. 
     
     
         20 . (canceled) 
     
     
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         23 . A method of treating a patient for a disease state or condition selected from the group consisting of gastroesophageal reflux disease, (GERD), non-erosive reflux disease (NERD), Zollinger-Ellison syndrome (ZE syndrome), ulcer disease and gastric cancer comprising administering to said patient an effective amount of at least one pharmaceutically acceptable zinc salt. 
     
     
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         56 . A pharmaceutical composition comprising an effective amount of at least one pharmaceutically acceptable zinc salt in combination with an effective amount of a proton pump inhibitor, an H2 blocker, an anti- H. pylori  agent, a cytoprotective agent, or mixtures thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. 
     
     
         57 . The composition according to  claim 56  wherein said proton pump inhibitor is esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole or mixtures thereof. 
     
     
         58 . The composition according to  claim 56  wherein said H2 blocker is cimetidine, famotidine, nizatidine, ranitidine or mixtures thereof. 
     
     
         59 . The composition according to  claim 56  wherein said anti- H. pylori  agent is selected from the group consisting of amoxicillin, clarithromycin (biaxin), metronidazole (flagyl), tetracycline and mixtures thereof. 
     
     
         60 . The composition according to  claim 56  wherein said cytoprotective agent is bismuth subsalicylate or sucralfate. 
     
     
         61 . (canceled) 
     
     
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         86 . A method of increasing the pH of the gastric juices of the stomach of a patient, said method comprising administering to said patient an effective amount of at least one pharmaceutically acceptable zinc salt selected from the group consisting of zinc acetate, zinc ascorbate, zinc benzoate, zinc bromide, zinc butyrate, zinc caprylate, zinc carbonate, zinc carnosine, zinc citrate, zinc chloride, zinc fluoride, zinc formate, zinc fumarate, zinc gallate, zinc gluconate, zinc glutarate, zinc glycerate, zinc glycerophosphate, zinc glycolate, zinc hydroxide, zinc iodide, zinc lactate, zinc malate, zinc maleate, zinc myristate, zinc nitrate, zinc oxide, zinc phenol sulfonate, zinc phosphate, zinc picolinate, zinc picrate, zinc propionate, zinc salicylate, zinc selenate, zinc succinate, zinc sulfate, zinc tartrate, zinc titanate, zinc undecylenate, zinc valerate, a zinc chelate and mixtures thereof. 
     
     
         87 . The method according to  claim 86  wherein a mixture of at least two zinc salts is administered to said patient. 
     
     
         88 . (canceled) 
     
     
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         92 . A pharmaceutical composition comprising effective amounts of at least one water soluble zinc salt in combination with at least one therapeutic agent which is favorably orally administered in combination with said water soluble zinc salt, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. 
     
     
         93 . The composition according to  claim 92  wherein said water soluble zinc salt is selected from the group consisting of zinc acetate, zinc ascorbate, zinc benzoate, zinc bromide, zinc butyrate, zinc caprylate, zinc carbonate, zinc carnosine, zinc citrate, zinc chloride, zinc fluoride, zinc formate, zinc fumarate, zinc gallate, zinc gluconate, zinc glutarate, zinc glycerate, zinc glycerophosphate, zinc glycolate, zinc hydroxide, zinc iodide, zinc lactate, zinc malate, zinc maleate, zinc myristate, zinc nitrate, zinc oxide, zinc phosphate, zinc picolinate, zinc picrate, zinc propionate, zinc salicylate, zinc selenate, zinc succinate, zinc sulfate, zinc tartrate, zinc titanate, zinc undecylenate, zinc valerate, a zinc chelate and mixtures thereof. 
     
     
         94 . (canceled) 
     
     
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         100 . The composition according to  claim 92  wherein said therapeutic agent is a non-steroidal antiinflammatory drug (NSAID). 
     
     
         101 . The composition according to  claim 92  wherein said therapeutic agent is an immunosuppressive agent. 
     
     
         102 . The composition according to  claim 92  wherein said therapeutic agent is an anti-asthma agent. 
     
     
         103 . The composition according to  claim 92  wherein said therapeutic agent is a statin. 
     
     
         104 . A method of increasing the bioavailability and/or reducing or alleviating the side effects of an orally administered therapeutic compound comprising coadministering with an effective amount of said compound an amount of at least one water soluble zinc salt effective to enhance the bioavailability and/or reduce or alleviate the side effects of said therapeutic compound. 
     
     
         105 . The method according to  claim 104  wherein said water soluble zinc salt is selected from the group consisting of zinc acetate, zinc ascorbate, zinc benzoate, zinc bromide, zinc butyrate, zinc caprylate, zinc carbonate, zinc carnosine, zinc citrate, zinc chloride, zinc fluoride, zinc formate, zinc fumarate, zinc gallate, zinc gluconate, zinc glutarate, zinc glycerate, zinc glycerophosphate, zinc glycolate, zinc hydroxide, zinc iodide, zinc lactate, zinc malate, zinc maleate, zinc myristate, zinc nitrate, zinc oxide, zinc phosphate, zinc picolinate, zinc picrate, zinc propionate, zinc salicylate, zinc selenate, zinc succinate, zinc sulfate, zinc tartrate, zinc titanate, zinc undecylenate, zinc valerate, a zinc chelate and mixtures thereof. 
     
     
         106 . (canceled) 
     
     
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         110 . The method according to  claim 104  wherein said therapeutic agent is selected from the group consisting of 13-cis-Retinoic Acid; 2-Chlorodeoxyadenosine; 5-Azacitidine; 5-Fluorouracil; 6-Mercaptopurine; 6-Thioguanine; Abraxane; Isotretinoin; Actinomycin-D; Doxorubicin Hydrochloride; Anagrelide; Hydrocortisone; Aldesleukin; Alemtuzumab; Pemetrexed; Alitretinoin; Vinblastine; Melphalan; All-transretinoic Acid; AlphaInterferon; Altretamine; Amethopterin; Amifostine; Aminoglutethimide; Aminoglutethimide; Anagrelide; Asparaginase; Hydrocortone Phosphate; Leurocristine; Lenalidomide; Letrozole; Leucovorin; Leukeran; Sargramostim; Leuprolide; Cladribin; Liposomal Ara-C; Deltasone; Lomustine; L-phenylalanine mustard; L-Sarcolysin; Leuprolide Acetate; Procarbazine; Maxidex; Mechlorethamine; Mechlorethamine Hydrochloride; Methylprednisolone; Megestrol Acetate; Melphalan; Mercaptopurine; Mesna; Methotrexate; Nilutamide; Anastrozole; Arabinosylcytosine; Darbepoetin Alpha); Pamidronate; Exemestane); Nelarabine; Arsenic Trioxide; Atragen; Bevacizumab; Azacitidine; BCG ( Bacillus  Calmette Guerin); BCNU (Carmustine); Bexarotene; Tositumomab; Bicalutamide; Bleomycin; Bortezomib; Busulfan; Eribitux; Calcium Leucovorin; Alemtuzumab; Irinotecan hydrochloride; Camptothecin-11; Capecitabine; Carboplatin; Bicalutamide; CC-5013 (Revlimid); CCNU (lomustine); CDDP (Cisplatin); CeeNU; Daunorubicin; Cetuximab; Chlorambucil; Mitomycin; Mitomycin-C; Mitoxantrone; Mustine; Mitomycin; Hydroxyurea; Gemtuzumab Ozogamicin; Vinorelbine Tartrate; Nelarabine; Cyclophosphamide; Pegfilgrastim; Oprelvekin; Filgrastim; Sorafenib; Nilutamide); Pentostatin; Nitrogen Mustard; Genox; Mitoxantrone; Octreotide; Octreotide acetate; Pegylated asparaginase; Vincristine Sulfate); Denileukin Diftitox; Paclitaxel; Oprevelkin; Prednisolone Sodium Phosphate; Prednisone; Oxaliplatin; Paclitaxel; Paclitaxel Protein-bound; Pamidronate; Panitumumab; Paraplatin; Dactinomycin; Topotecan; Cyclophosphamide; Aminoglutethimide; Cytarabine; Cytarabine Liposomal; Dacarbazine; Dacogen; Dactinomycin; Dasatinib; Daunomycin; Daunorubicin; Daunorubicin Hydrochloride; Daunorubicin Liposomal; Decadron; Decitabine; Prednisolone; Prednisone; Denileukin diftitox; Cytarabine liposome; Dexamethasone; Dexamethasone acetate; Dexamethasone Sodium Phosphate; Dexasone; Dexrazoxane; Novantrone; Disseminated intravascular coagulation; Diodex; Docetaxel; Doxorubicin; Hydroxyurea; Dacarbazine; dacarbazine; PEG Interferon; Pegaspargase; Pegfilgrastim; Peginterferon alfa-2b; PEG-L-asparaginase; PEMETREXED; Pentostatin; Phenylalanine Mustard; Procarbazine; Epoetin Alfa; Aldesleukin; Prolifeprospan 20 with Carmustine; Implant; Mercaptopurine; Raloxifene; Lenalidomide; Trexall; Rituximab; (adriamycin); Rubidomycin hydrochloride; Octreotide Acetate; Sargramostim; Hydrocortisone Sodium Succinate; Methylprednisolone sodium succinate; Sorafenib; Dasatinib; Gleevec; Streptozocin; SU11248; Sunitinib; Sunitinib Malate; Tamoxifen; Erlotinib; Bexarotene; Paclitaxel; Epirubicin hydrochloride; Oxaliplatin; Estramustine; Epirubicin; Epoetin alfa; Cetuximab; Erlotinib;  Erwinia  L-asparaginase; Ethyol; Etoposide Phosphate; Etoposide; Flutamide; Raloxifene; Exemestane; Toremifene; Fulvestrant; Letrozole; Filgrastim; Floxuridine; Fludarabine; Fluoxymesterone; Flutamide; Folinic Acid; Floxuridine; Fulvestrant; Neupogen; Gefitinib; Gemcitabine; Gemtuzumab; ozogamicin; Gemcitabine); Carmustine Wafer; Goserelin; Granulocyte Colony Stimulating Factor; Docetaxel; Temozolomide; Teniposide; Thiotepa; Thalidomide; BCG (TheraCys strain); Thioguanine; Thiophosphamide; Thiotepa; Etoposide; Topotecan; Toremifene; Tositumomab; Trastuzumab; Tretinoin; Arsenic; VCR; Panitumumab; Vinblastine Sulfate Bortezomib; Azacitidine; Vinblastine; Vinblastine Sulfate; Vincristine; Vinorelbine; Vinorelbine tartrate; VM-26; Vorinostat; Teniposide; Capecitabine); Streptozocin; Fluoxymesterone; Trastuzumab; Hexadrol; Altretamin; Hexamethylmelamine; Hycamtin; Hydroxyurea; Ibritumomab; Ibritumomab Tiuxetan; Idarubicin; Idarubicin; Ifosfamide; IFN-alpha; IL-11; IL-2; Imatinib mesylate; Imidazole Carboxamide; Interferon alfa; Interferon Alfa-2b (PEG Conjugate); Interleukin-2; Interleukin-11; interferon alfa-2b; Getfitinib; Irinotecan; Isotretinoin; Dexrazoxane; Goserelin; Zoledronic acid; Zolinza and mixtures thereof. 
     
     
         110 . (canceled) 
     
     
         111 . The method according to  claim 104  wherein said therapeutic agent is a non-steroidal antiinflammatory drug (NSAID). 
     
     
         112 . The method according to  claim 104  wherein said therapeutic agent is an immunosuppressive agent. 
     
     
         113 . The method according to  claim 104  wherein said therapeutic agent is an anti-asthma agent. 
     
     
         114 . The method according to  claim 104  wherein said therapeutic agent is a statin. 
     
     
         115 . The method according to  claim 104  wherein said therapeutic agent is a chemotherapeutic agent.