WO2005074930A1 - Pharmaceutical combinations of (s) -pantoprazole with nsaid or corticosteroids - Google Patents

Pharmaceutical combinations of (s) -pantoprazole with nsaid or corticosteroids Download PDF

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Publication number
WO2005074930A1
WO2005074930A1 PCT/EP2005/050335 EP2005050335W WO2005074930A1 WO 2005074930 A1 WO2005074930 A1 WO 2005074930A1 EP 2005050335 W EP2005050335 W EP 2005050335W WO 2005074930 A1 WO2005074930 A1 WO 2005074930A1
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Prior art keywords
inn
acid
methyl
phenyl
alpha
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PCT/EP2005/050335
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French (fr)
Inventor
Reinhard Huber
Bernhard Kohl
Wolfgang Kromer
Wolfgang-Alexander Simon
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Altana Pharma Ag
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Publication of WO2005074930A1 publication Critical patent/WO2005074930A1/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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention relates to the new use of (S)-pantoprazole and its salts in the prevention or treatment of medicament caused gastrointestinal diseases and/or medicament associated gastrointestinal disorders and to new use of (S)-pantoprazole and its salts in combination therapy, and to new combinations comprising (S)-pantoprazole and its salts.
  • effervescent composition comprising a bisphosphonate, an acidic compound, an alkaline effervescing component, and optionally an anti-ulcer agent, such as a proton pump inhibitor, and methods of treating osteoporosis in a mammal using the effervescent compositions.
  • an anti-ulcer agent such as a proton pump inhibitor
  • (S)-pantoprazole and its salts which are described in greater detail below, have, as a first aspect (aspect 1) of the present invention, advantageous gastro-protective action against certain medicaments (such as, for example, those medicaments mentioned below in the description of this invention, especially antiinflammabilees and antirheumatics, and/or, in particular, those medicaments which cause erosive changes and/or lesions in the gastrointestinal system) and/or are well useful and effective in prevention or treatment of gastrointestinal disorders associated with certain medicaments indicated below and/or are particularly useful and effective in prevention or treatment of gastrointestinal diseases caused by certain medicaments selected from the group consisting of NSAIDs (non-steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO- NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids, and/or can be used, as a second aspect (aspect 2) of the present invention, in combination therapy of diseases and/or disorders which
  • the gastrointestinal safety and tolerability of a combination comprising (a) (S)-pantoprazole and/or its salts as defined herein, and (b) an agent selected from the group consisting from NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids is greater than that, which can be achieved with said agent (b) alone, i.e. greater than the gastrointestinal safety and tolerability of a mono therapy using only said agent (b) unpartnered with (S)- pantoprazole and/or its salts.
  • (S)-pantoprazole and/or its salts is understood to include:
  • Salts in the context of the invention means all pharmaceutically acceptable salts prepared by reacting (S)-pantoprazole [(-)-pantoprazole] with a suitable inorganic or organic base.
  • suitable inorganic or organic base examples of salts with bases which may be mentioned are aluminium, sodium, potassium, lithium, magnesium, zinc or calcium salts. Particularly preferred is the magnesium salt.
  • (S)-pantoprazole and/or its salts are isolated in crystalline form, the crystals may contain variable amounts of solvent Accordingly, according to the invention, the term "(S)-pantoprazole and/or its salts” also includes all solvates, in particular all hydrates, of (S)-pantoprazole and/or its salts.
  • a particularly preferred hydrate of (S)-pantoprazole and/or its salts is the (S)- pantoprazole-magnesium dihydrate.
  • substantially free in the context of the invention means that (S) -pantoprazole and/or its salts contains less than 10 % by weight of (R)-pantoprazole.
  • substantially free means that (S)- pantoprazole and/or its salts contains less than 5 % by weight of (R)-pantoprazole.
  • substantially free means that (S)-pantoprazole and/or its salts contains less than 1 % by weight of (R)-pantoprazole.
  • gastrointestinal diseases refer to gastrointestinal diseases which are induced and/or caused by certain medicaments selected from the group consisting of NSAIDs (non- steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO-NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids, whereby NSAIDs, COX-2 inhibitors, NO- NSAIDs and bisphosphonates are particularly worthy to be mentioned; NSAIDs, COX-2 inhibitors and NO-NSAIDs are to be emphasized, NSAIDs and COX-2 inhibitors are more to be emphasized, and NSAIDs are particularly to be emphasized.
  • NSAIDs non- steroidal antiinflammatory drugs
  • COX-2 cyclooxygenase 2
  • NO-NSAIDs nitric oxide releasing NSAID
  • bisphosphonates corticosteroids
  • NSAIDs within the meaning of the present invention are, in an embodiment (embodiment 1) according to the present invention, glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-methoxyphenyl- alpha-methyl-4-(isobutyl)phenylacetate [Research Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN: ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN: ALMINOPROFEN], 2- amino-3-benzoylphenylacetic acid [INN: AMFENAC
  • NSAIDs according to embodiment 1 which are to be emphasized are: ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, ME- FENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.
  • exemplary NSAIDs according to embodiment 1 which are to be emphasized are: DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.
  • Preferred exemplary NSAIDs according to embodiment 1, which are selected from the above-defined group of exemplary NSAIDs, are 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineaceticacid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], as well as the pharmaceutically acceptable derivatives of these compounds.
  • preferred exemplary NSAIDs according to embodiment 1, which are selected from the above-defined group of exemplary NSAIDs, are 2-[(2,6-dichlorophenyl)amino]- benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1- (4-chlorabenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6- methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2- pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], as well as the pharmaceutically acceptable derivatives of these compounds.
  • DICLOFENAC alpha-p-isobutylphenylpropionic acid
  • exemplary NSAIDs according to embodiment 1 are 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], as well as the pharmaceutically acceptable derivatives of these compounds.
  • a selected, particular preferred exemplary NSAID according to embodiment 1 is 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable derivative thereof.
  • NO-NSAIDs examples include, but are not limited to, those disclosed, particularly those individualized or disclosed as examples, in WO 96/32946, WO 96/35416, WO 96/38136, WO 96/39409, WO 00/50037, US 6,057,347, WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641, WO 97/31654, WO 99/44595, WO 99/45004 and WO 01/45703, as well as the pharmaceutically acceptable derivatives of these compounds.
  • COX-2 inhibitors within the scope of this invention can be mentioned in one embodiment (embodiment 2) according to the present invention, without being restricted to: 5-chloro-6'- methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine [INN: ETORICOXIB], 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide [INN: CELECOXIB], 4-[p- (methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone [INN: ROFECOXIB], N-[[p-(5-methyl-3-phenyl-4- isoxazolyl)phenyl]sulfonyl]propion-amide [INN: PARECOXIB], p-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulf
  • COX-2 inhibitors according to embodiment 2 of this invention which are to be emphasized include, but are not limited to, 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine [INN: ETORICOXIB], 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide [INN: CELECOXIB], 4- [p-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone [INN: ROFECOXIB], N-[[p-(5-methyl-3-phenyl-4- isoxazolyl)phenyl]sulfonyl]propion-amide [INN: PARECOXIB], p-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulfonamide [INN: VALDECOXI
  • COX-2 inhibitors within the scope of this invention can be also mentioned in another embodiment (embodiment 2') according to the present invention, without being restricted to: CELECOXIB ROFECOXIB, as well as the pharmaceutically acceptable derivatives of these compounds.
  • bisphosphonates within the meaning of this invention can be mentioned in one embodiment (embodiment 3) according to the present invention, without being restricted to, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLEDRONIC ACID, CLODRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, PAMIDRONIC ACID and ETIDRONIC ACID, as well as the pharmaceutically acceptable derivatives of these compounds.
  • bisphosphonates to be used in the present invention include also in another embodiment (embodiment 3') according to the present invention, but are not limited to, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLEDRONIC ACID and ETIDRONIC ACID, as well as the pharmaceutically acceptable derivatives of these compounds.
  • corticosteroids within the meaning of this invention can be mentioned in one embodiment (embodiment 4) according to the present invention, without being restricted to, HYDROCORTISONE, PREDNISONE, PREDNISOLONE, METHYLPREDNISOLONE,
  • Examples of preferred corticosteroids to be used in the present invention include also in another embodiment (embodiment 4') according to the present invention, but are not limited to, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE, as well as the pharmaceutically acceptable derivatives of these compounds.
  • a particularly preferred corticosteroid to be used in the present invention is BETAMETHASONE, DEXAMETHASONE, FLUOCORTOLONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, HYDROCORTISONE, BUDESONIDE, TRIAMCINOLONE ACETONIDE, as well as the pharmaceutically acceptable derivatives of these compounds.
  • pharmaceutically acceptable derivative means a pharmaceutically acceptable salt, ester or solvate (e.g. hydrate) or a pharmaceutically acceptable solvate of such salt or ester.
  • gastrointestinal diseases in the context of “medicament caused gastrointestinal diseases” or “gastrointestinal diseases caused by certain medicaments” refers to those gastrointestinal diseases, which are known to the art-skilled person on the base of his/her expert knowledge, to be caused by certain medicaments such as, for example, art-known gastrointestinal inflammatory diseases and lesions, particularly gastric ulcer (e.g. stomach ulcer or duodenal ulcer), heartburn, bleeding or medicament related functional gastropathy, whereby gastric ulcer is particularly to be emphasized.
  • gastric ulcer e.g. stomach ulcer or duodenal ulcer
  • heartburn e.g. heartburn
  • bleeding or medicament related functional gastropathy e.g., bleeding or medicament related functional gastropathy
  • the terms "medicament associated gastrointestinal disorders” and "gastrointestinal disorders associated with certain medicaments” refer to gastrointestinal disorders known to the person skilled in the art (such as e.g. indigestion, mild forms of heartburn, stomach irritation or pain) which are associated with certain medicaments such as, for example, those mentioned above, particularly NSAIDs, as well as e.g. chloroquine, theophylline, dihydralazine, salazosulfapyri- dine, thiazides, iodine-containing contrast media, gold preparations or antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol).
  • indigestion e.g. indigestion, mild forms of heartburn, stomach irritation or pain
  • certain medicaments such as, for example, those mentioned above, particularly NSAIDs, as well as e.g. chloroquine, theophylline, dihydralazine, salazosulfapyri- dine, thia
  • this invention relates to the use of (S)-pantoprazole and/or its salts in the prevention or treatment of medicament caused gastrointestinal diseases and/or medicament associated disorders.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the prevention and/or treatment of medicament induced gastric ulcer.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for the prevention and/or treatment of medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for the prevention of medicament associated gastrointestinal disorders.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for the well-tolerated treatment and/or prevention of inflammatory diseases and/or inflammation associated disorders.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for treating and/or preventing of gastrointestinal or, particularly, non-gastrointestinal inflammatory diseases and/or inflammation associated disorders, and for reducing the risk of medicament associated gastrointestinal disorders or, particularly, for reducing medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions comprising an antiinflammatory or antirheumatic ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids for use in combination therapy, e.g. for use in the treatment and/or prevention of diseases or disorders conventionally treated, ameliorated or prevented monotherapeutically with said antiinflammatory or antirheumatic ingredient, particulariy those diseases or disorders mentioned in the specification of this invention.
  • an antiinflammatory or antirheumatic ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids for use in combination therapy, e.g. for use in the treatment and/or prevention of diseases or disorders conventionally treated, ameliorated or prevented monotherapeutically with said antiinflammatory or antirheumatic ingredient, particulariy those diseases or disorders mentioned in the specification of this invention
  • a further aspect of the present invention is the use of said selected tricyclic imidazo[1,2-a]pyridine compounds in the manufacture of pharmaceutical compositions comprising an active ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids for treating and/or preventing of diseases or disorders which can be treated, ameliorated or prevented by said active ingredient, particularly those diseases or disorders mentioned in the specification of this invention, and for reducing the risk of medicament associated gastrointestinal disorders or, particularly, for reducing medicament caused gastrointestinal diseases, particularly those mentioned in this invention.
  • an active ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids
  • a further aspect of the present invention is the simultaneous, separate or sequential co-administration of a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, preferably a NSAID, with (S)-pantoprazole and/or its salts to prevent medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer.
  • a further aspect of the present invention is the simultaneous, separate or sequential co-administration of a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid with (S)- pantoprazole and/or its salts to treat, ameliorate or prevent diseases or disorders which can be treated, ameliorated or prevented by this NSAID, COX-2 inhibitor, NO-NSAID or bisphosphonate.
  • a further aspect of the present invention is a method for prevention and/or treatment of medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer, comprising administering a therapeutically effective amount of one or more of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid to a mammal.
  • a further aspect of the present invention is a method for prevention and/or treatment of medicament associated gastrointestinal disorders comprising administering a therapeutically effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with said medicament to a human in need thereof.
  • a further aspect of the present invention is a method for treatment or prevention of inflammatory diseases and/or inflammation assodated disorders comprising administering a therapeutically effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid to a mammal.
  • a further aspect of the present invention is a method for amelioration the gastrointestinal tolerance of the therapy of inflammatory diseases and/or inflammation associated disorders comprising administering a therapeutically effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid to a mammal.
  • a further aspect of the present invention is a method for treating, ameliorating or preventing of di s- eases or disorders, which can be treated, ameliorated or prevented by an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and reducing the risk of gastrointestinal diseases caused by said agent or reducing the risk of gastrointestinal disorders associated with said agent, in a human patient in need of such treatment, amelioration or prevention and at risk of gastrointestinal diseases caused by said agent or gastrointestinal disorders associated with said agent comprising administering to said patient an;agent selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids in an amount effective to treat, to ameliorate or to prevent diseases or disorders, which can be treated, ameliorated or prevented by said agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, simultaneously, separately or sequentially
  • a further aspect of the present invention is a method for treating, ameliorating or preventing of diseases or disorders, which can be treated, ameliorated or prevented by an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and reducing the risk of gastrointestinal diseases or disorders caused by or assodated with said agent in a patient in need thereof comprising administering to said patient a combination or a composition according to this invention.
  • an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids
  • a further aspect of the present invention is a preferably orally applicable pharmaceutical composition for simultaneous administration comprising, in admixture, a first active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticoster- oids, and a second active ingredient, which is (S)-pantoprazole and/or its salts, to prevent medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer, in a mammal.
  • a first active ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticoster- oids
  • a second active ingredient which is (S)-pantoprazole and/or its salts
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates or corticosteroids, and a second active ingredient which is (S)-pantoprazole and/or its salts, to prevent and/or treat medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer, in a mammal.
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient, which is selected from a group consisting of chloroquine, theophylline, dihydralazine, sala- zosulfapyridine, thiazides, iodine-containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol), and a second active ingredient, which is (S)- pantoprazole and/or its salts, to prevent medicament associated gastrointestinal disorders in a human.
  • a first active ingredient which is selected from a group consisting of chloroquine, theophylline, dihydralazine, sala- zosulfapyridine, thiazides, iodine-containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol)
  • a further aspect of the present invention is a pharmaceutical composition for simultaneous administration comprising a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salts.
  • a further aspect of the present invention is a composition
  • a composition comprising a first active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, and a second active ingredient which is (S)-pantoprazole and/or its salts, for simultaneous, sequential or separate use in therapy in any order.
  • a further aspect of the present invention is a preferably orally applicable pharmaceutical composition in unit dosage comprising a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salts for use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salts, wherein the NSAID, the COX-2 inhibitor, the NO-NSAID, the bisphosphonate or the corticosteroid and (S)-pantoprazole and/or its salts are administered in a single dosage form, such that the NSAID, the COX-2 inhibitor, the NO-NSAID, the bisphosphonate or the corticosteroid and (S)- pantoprazole and/or its salts are physically separated from each other.
  • a further aspect of the present invention is a composition
  • a composition comprising a first active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and a second adive ingredient which is (S)-panto ⁇ razole and/or its salts, together with a pharmaceutically acceptable carrier.
  • a further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts; and (b) a pharmaceutically effective amount of at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid.
  • a further aspect of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts; and (b) a pharmaceutically effective amount of at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid; wherein component (a) and component (b) are maintained in the same delivery vehicle.
  • a further aspect of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts; and (b) a pharmaceutically effective amount of at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid; wherein component (a) and component (b) are maintained in different delivery vehicles.
  • a further aspect of the present invention is a preferably orally applicable pharmaceutical formulation
  • a first active ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids
  • a second active ingredient which is (S)- pantoprazole and/or its salts
  • a pharmaceutically acceptable carrier diluent, adjuvant, auxiliary or excipient for use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a further aspect of the present invention is a first pharmaceutical formulation comprising (S)- pantoprazole and/or its salts and a pharmaceutically acceptable carrier or diluent; and a second pharmaceutical formulation comprising a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid and a pharmaceutically acceptable carrier or diluent.
  • a further aspect of the present invention is a combination comprising a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid and (S)-pantoprazole and/or its salts for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a further aspect of the present invention is a combination comprising a medicament selected from a group consisting of chloroquine, theophylline, dihydralazine, salazosulfapyridine, thiazides, iodine- containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotri- moxazol), and (S)-pantoprazole and/or its salts, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament associated gastrointestinal disorders in a human.
  • a further aspect of the present invention is a combination, particularly a pharmaceutical combination, such as, for example, a combined preparation, e.g.
  • kits of parts or a composition, particulariy a pharmaceutical composition, comprising a first active ingredient which is an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and a second active ingredient which is (S)-pantoprazole and/or its salts as mentioned in the present invention and, optionally, at least one pharmaceutically acceptable carrier for simultaneous, sequential, separate or chronologically staggered use in therapy, and/or for use as combined unit dosage form or as separate unit dosage forms in therapy, and/or for use as fixed combination in therapy, and/or for use as admixture in therapy, e.g.
  • a further aspect of the present invention relates to combining separate pharmaceutical compositions in kit form.
  • a further aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazoIe and/or its salts, and a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a further aspect of the present invention is a commercial package comprising as active ingredients a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid as well as (S)- pantoprazole and/or its salts together with instructions for simultaneous, sequential or separate use in therapy.
  • a further aspect of the present invention is a commercial package comprising (S)-pantoprazole and/or its salts as adive ingredient together with instructions for simultaneous, sequential or separate use with a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid.
  • a further aspect of the present invention is a commercial package comprising a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid as active ingredient together with instructions for simultaneous, sequential or separate use with (S)-pantoprazole and/or its salts.
  • a further aspect of the present invention is a commercial package comprising a medicament selected from the group consisting of chloroquine, theophylline, dihydralazine, salazosulfapyridine, thiazides, iodine-containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol) together with instructions for simultaneous, sequential or separate use with (S)- pantoprazole and/or its salts.
  • a medicament selected from the group consisting of chloroquine, theophylline, dihydralazine, salazosulfapyridine, thiazides, iodine-containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol) together with instructions for simultaneous, sequential or separate use with (S)- pantoprazole and/or its salts.
  • a further aspect of the present invention is a pharmaceutical product, such as, for example, a commercial package, comprising a combination, such as, for example, a combined preparation, e.g. a kit of parts, or a pharmaceutical composition, comprising a first active ingredient which is an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and a second active ingredient which is (S)-pantoprazole and/or its salts as mentioned in the present invention and, optionally, at least one pharmaceutically acceptable carrier for simultaneous, sequential, separate or chronologically staggered use in therapy, and/or for use as combined unit dosage form or for use as separate unit dosage forms in therapy, and/or for use as fixed combination in therapy, and/or for use as admixture in therapy; together with standard packaging material, and together with instructions for simultaneous, sequential, separate or chronologically staggered use in therapy, e.g.
  • a further aspect of the present invention is a kit comprising at least one dosage unit of a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid as well as at least one dosage unit of (S)-pantoprazole and/or its salts for simultaneous, sequential or separate use in therapy.
  • kit can be provided with instructions for use: «?
  • a further aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a further aspect of the present invention is the use of a pharmaceutical composition, pharmaceutical product, formulation, preparation, combination, commercial package or kit according to the invention in the manufacture of a medicament for the treatment of an inflammatory disease and/or inflammation assodated disorder.
  • a further aspect of the present invention is the use of the pharmaceutical compositions, formulations, preparations, combined preparations, combinations or kits according to this invention in the manufacture of a pharmaceutical product, such as e.g. a commercial package, for the treatment or prevention of diseases or disorders which can be conventionally treated by NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates or corticosteroids.
  • a pharmaceutical produd such as e.g. a commercial package, for the treatment or prevention of gastrointestinal diseases or disorders caused by or associated with NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates or corticosteroids.
  • a further aspect of the present invention is the use of the pharmaceutical compositions, formulations, preparations, combined preparations, combinations or kits, particularly pharmaceutical compositions and kits, according to this invention in the manufacture of a medicament for treating or preventing of diseases or disorders which can be treated by agents selected from NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates and corticosteroids, and for treating or preventing of gastrointestinal diseases or disorders caused by or associated with the therapeutic use of said agents.
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
  • a further aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a first active ingredient which is (S)-pantoprazole and/or its salts
  • a preparation of a second adive ingredient which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid
  • a further aspect of the present invention is a k ' rt comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
  • a further preferred aspect of the present invention is a pharmaceutical product (such as, for example, a commercial package) comprising a first active ingredient which is (S)-pantoprazole magnesium, and a second active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates and corticosteroids; together with instructions for simultaneous, sequential or separate use, e.g. to treat or prevent gastrointestinal diseases caused by said second active ingre- trans and/or to treat or prevent diseases which can be treated or prevented by said second active ingredient.
  • a further preferred aspect of the present invention is a kit comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids; together with instructions for simultaneous, sequential or separate use in therapy, e.g. to treat or prevent gastrointestinal diseases caused by said second active ingredient and/or to treat or prevent diseases which can be treated or prevented by said second active ingredient.
  • a more preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazoIe magnesium dihydrate, and a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
  • a further more preferred aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of (S)-pantoprazole magnesium dihydrate, and a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a second active ingredient which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid
  • a further more preferred aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a preparation of a first active ingredient which is (S)-pantoprazole magnesium dihydrate
  • a preparation of a second active ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids
  • Another preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-aspect, a NSAID, such as e.g. one of those NSAIDs mentioned exemplarily above, or, in a second sub-asped, a COX-2 inhibitor, such as e.g.
  • a bisphosphonate such as e.g. one of those bisphosphonates mentioned exemplarily above, or, in a fourth sub-asped a corticosteroid, such as e.g.
  • a more preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first adive ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a NSAID, such as e.g. one of those NSAIDs mentioned exemplarily above, or, in a more detailed sub- aspect a NSAID selected from the group consisting of
  • ACETYLSALICYLIC ACID DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID AND TOLMETIN, or a pharmaceutically acceptable derivative thereof.
  • a further more preferred asped of embodiment a of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a COX-2 inhibitor, such as e.g. one of those COX-2 inhibitors mentioned exemplarily above, or, in a more detailed sub-asped, a COX-2 inhibitor selected from the group consisting of
  • ETORICOXIB CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB and CIMICOXIB, or a pharmaceutically acceptable derivative thereof.
  • a further more preferred asped of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first adive ingredient which is (S)-pantoprazole and/or its salts; and a second adive ingredient which is a bisphosphonate, such as e.g. one of those bisphosphonates mentioned exemplarily above, or, in a more detailed sub-aspect a bisphosphonate selected from the group consisting of
  • CLODRONIC ACID PAMIDRONIC ACID and ETIDRONIC ACID, or a pharmaceutically acceptable derivative thereof.
  • a further more preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first adive ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a corticosteroid, such as e.g. one of those corticosteroids mentioned exemplarily above, or, in a more detailed sub-aspect a corticosteroid seleded from the group consisting of
  • a particulariy preferred aspect of embodiment a of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-asped, a NSAID, such as e.g. one of those NSAIDs mentioned above, or, in a second sub-asped, a COX-2 inhibitor, such as e.g.
  • a bisphosphonate such as e.g. one of those bisphosphonates mentioned above
  • a corticosteroid such as e.g. one of those corticosteroids mentioned above, or, in a more detailed sub- aspect, an agent selected from the group consisting of
  • ACETYLSALICYLIC ACID DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPAD
  • a yet further particularly preferred asped of embodiment a of the present invention is a pharmaceutical produd (such as, for example, a commercial package) comprising a first adive ingredient which is (S)-pantoprazole magnesium; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-asped, a NSAID, such as e.g.
  • a COX-2 inhibitor such as e.g. one of those COX-2 inhibitors mentioned above, or, in a third sub- asped, a bisphosphonate, such as e.g. one of those bisphosphonates mentioned above, or, in a fourth sub- aspect, a corticosteroid, such as e.g. one of those corticosteroids mentioned above, or, in a more detailed sub- aspect, an agent selected from the group consisting of
  • ACETYLSALICYLIC ACID DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPAD
  • a still further particularly preferred aspect of embodiment a of the present invention is a kit comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-asped, a NSAID, such as e.g.
  • a COX-2 inhibitor such as e.g. one of those COX-2 inhibitors mentioned above, or, in a third sub- asped, a bisphosphonate, such as e.g. one of those bisphosphonates mentioned above, or, in a fourth sub- asped, a corticosteroid, such as e.g. one of those corticosteroids mentioned above, or, in a more detailed sub- asped, an agent selected from the group consisting of
  • ACETYLSALICYLIC ACID DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPAD
  • a particulariy preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium, and a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CEL
  • a further particularly preferred asped of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from t ie group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXA.PROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID,
  • a further particularly preferred asped of the present invention is a kit comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium, a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, R OF
  • a particulariy preferred aspect of the present invention to be especially emphasized is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium, and a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable
  • a further particularly preferred aspect of the present invention to be especially emphasized is a pharmaceutical produd comprising, in combination, a preparation of a first adive ingredient, which is (S)- pantoprazole magnesium, and a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID seleded from the group consisting of ACETYLSALICYLIC AC ID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXI
  • kits comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium, a preparation of a second adive ingredient which is a NSAID or a COX-2 inhibitor or a NO-NSAID selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these
  • a selected particularly preferred aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB,
  • a further selected particularly preferred aspect of the present invention is a pharmaceutical produd comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN
  • a further selected particulariy preferred asped of the present invention is a kit comprisingxa preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOX
  • a selected particulariy preferred aspect of the present invention to be especially emphasized is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO- NSAID selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and
  • a further selected particularly preferred aspect of the present invention to be especially emphasized is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOX
  • kits comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO- NSAID seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and
  • a seleded particulariy preferred asped of the present invention to be especially emphasized is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first adive ingredient, which is (S)-pantoprazole magnesium, and a second adive ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound.
  • a further selected particularly preferred asped of the present invention to be especially emphasized is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole magnesium, and a preparation of a second adive ingredient which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • kits comprising a preparation of a first active ingredient, which is (S)-pantoprazole magnesium, a preparation of a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, and instrudions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a preparation of a first active ingredient which is (S)-pantoprazole magnesium
  • a preparation of a second active ingredient which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound
  • a selected particularly preferred asped of the present invention to be especially emphasized is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound.
  • a further selected particularly preferred asped of the present invention to be especially emphasized is a pharmaceutical produd comprising, in combination, a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium dihydrate, and a preparation of a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
  • a further selected particularly preferred asped of the present invention to be especially emphasized is a kit comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, and instrudions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a first adive ingredient which is (S)-pantoprazole magnesium dihydrate
  • a preparation of a second active ingredient which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound
  • inflammatory diseases which may be mentioned are gastrointestinal inflammatory diseases such as, for example, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, gastroesophageal reflux disease (GERD) and ulcerative colitis, or non- gastrointestinal inflammatory diseases, in particular arthritis, including but not limited to rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis; or asthma, bronchitis and skin related disorders such as psoriasis, eczema, bums and dermatitis.
  • gastrointestinal inflammatory diseases such as, for example, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, gastroesophageal reflux disease (GERD) and ulcerative colitis
  • non- gastrointestinal inflammatory diseases in particular arthritis, including but not limited to rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis
  • asthma bronchitis and skin related disorders
  • Inflammation associated disorders which may be mentioned are, for example, pain (both chronic and acute), migraine, fever and headaches.
  • agents seleded from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids can be combined beneficially with (S)-pantoprazole and/or its salts to enhance or to improve safety and tolerability of the mono therapy, i.e.
  • the mono therapy using only said agents seleded from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids unpartnered with (S)-pantoprazole and/or its salts, by reducing the risk of adverse effects, such as medicament-associated gastrointestinal disorders or medicament-caused gastrointestinal diseases, associated conventionally with the mono therapy.
  • agents seleded from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids unpartnered with (S)-pantoprazole and/or its salts by reducing the risk of adverse effects, such as medicament-associated gastrointestinal disorders or medicament-caused gastrointestinal diseases, associated conventionally with the mono therapy.
  • the combination therapy according to this invention can be applied to treat diseases, disorders or conditions typically treated, ameliorated or prevented by NSAIDs and/cir COX-2 inhibitors, such as, for example, inflammatory diseases (in particular all kind of arthritis, including rheumatosis arthritis or degenerative joint diseases including osteoarthritis) or inflammation associated disorders, and/or particularly symptoms caused by arthritis, such as inflammation, swelling , stiffness and joint pain, or other kinds of pain or painful conditions, such as gout attacks, bursitis, tendonitis, touthache, lower back and neck pain, myositis, sprains, strains or other injuries, or symptoms associated with influenza or other viral infections or common cold.
  • inflammatory diseases in particular all kind of arthritis, including rheumatosis arthritis or degenerative joint diseases including osteoarthritis
  • inflammation associated disorders and/or particularly symptoms caused by arthritis, such as inflammation, swelling , stiffness and joint pain, or other kinds of pain or painful conditions, such as gout attacks, bursitis, tendonitis
  • disorders or conditions which can be treated, ameliorates d or prevented by NSAIDs and/or, particularly, COX-2 inhibitors within the combination therapy according to this invention, can be mentioned 1 , without being restricted thereto, neuropathic pains, (inflammatory) I ver diseases, stroke, epilepsy, dysmenorrhoea, ophthalmic diseases, cognitive disorders such as dementia, particularly degenerative dementia (such e.g. Alzheimer's disease) or, in more particular, cellular and neoplastic transformation and metastatic tumour growth, such e.g. certain cancerous diseases, for example colonic cancer and prostate cancer, or cancer associated with overexpression of HER-2/neu (e.g. breast cancer), or adenomatous coloredal polyps (and to reduce herewith the risk of developing colon cancer), or other conditions mediated by COX-2.
  • neuropathic pains such as dementia, particularly degenerative dementia (such e.g. Alzheimer's disease) or, in more particular, cellular and neoplastic transformation and metastatic tumour growth, such
  • disorders or conditions which can be treated, ameliorated or preventeded by bisphosphonates within the combination therapy according to this invention, can be mentioned, without being restricted thereto, disorders associated with abnormal bone resorption such as, for example, osteoporosis, multiple myeloma or metastatic bone diseases.
  • administering refers - with regard to the NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates or corticosteroids - preferably to oral application.
  • parenterale e.g. intravenous
  • percutaneous application can be also advantageous.
  • (S)-pantoprazole and/or its salts oral or intravenous application is preferred.
  • the dosage of the active compounds is in a customary order of magnitude comparable with the mono dosage, whereby, due to the additive and/or super-additive synergism of the single effects, the relevant doses of the active compounds in the combined dosage can be reduced compared to norm, or whereby- while maintaining the customary doses of the single components - a surprisingly higher and prolonged effect is obtained.
  • the person skilled in the art is aware on the base of his expert knowledge of the total daily dosage of the NSAIDs, the COX-2 inhibitors, the NO-NSAIDs, the bisphosphonates or the corticosteroids, which are comprised in the abovementioned pharmaceutical compositions, pharmaceutical produds, formulations, combinations, preparations, commercial packages or kits according to this invention.
  • Said total daily dosage can vary within a wide range.
  • the daily doses are in a range from 100-2000 ⁇ g/kg.
  • the adive compounds are preferably employed in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the adive compound content advantageously being between 0.1 and 95%.
  • the person skilled in the art can develop, on the basis of his her knowledge, by appropriate choice of the excipients and the auxiliaries different galenic forms precisely tailored to the active ingredients) (such as, for example, retard forms or gastric acid resistant forms).
  • 'medicament' or 'pharmaceutical composition shall be taken to refer to a composition comprising both (S)-pantoprazole and/or its salts and the other active ingredient in a fixed combination (fixed unit dosage form), or a medicament pack comprising the two active ingredients as discrete separate dosage forms.
  • the adive ingredients are preferably packed into blister cards which are suited for improving compliance.
  • Each blister card preferably contains the medicaments to be taken on one day of treatment. If the medicaments are to be taken at different times of day, the medicaments can be disposed in different sedions on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening).
  • the blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day.
  • the various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times.
  • the daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column.
  • Medicaments which must be taken together at a particular time of day are placed together at the ap- « intestinalte time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.
  • the title compound can also be prepared from organic-aqueous solvent mixtures
  • (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution is dissolved in an organic solvent, for example warm acetone.
  • a magnesium salt for example magnesium chloride hexahydrate
  • water 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added drop by drop, and the mixture is cooled with stirring.
  • the precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant This gives the title compound as a colourless to beige powder.

Abstract

The present invention relates to new combinations and new use of (S)-pantoprazole and/or its salts in the prevention or treatment of medicament caused gastrointestinal diseases.

Description

PHARMACEUTICAL COMBINATIONS OF ( S ) -PANTOPRAZOLE WITH NSAID OR CORTICOSTEROIDS
Field of application of the invention
The invention relates to the new use of (S)-pantoprazole and its salts in the prevention or treatment of medicament caused gastrointestinal diseases and/or medicament associated gastrointestinal disorders and to new use of (S)-pantoprazole and its salts in combination therapy, and to new combinations comprising (S)-pantoprazole and its salts.
Known technical background
In U. S. Patent 6,544,556 pharmaceutical formulations containing a non-steroidal anti-inflammatory drug (NSAID) and a proton pump inhibitor are disclosed. - In European Patent Application 1 352660 oral pharmaceutical dosage forms comprising a proton pump inhibitor and an NSAID are described and claimed. - U. S. Patent Application 2003/069255 is directed to drug dosage forms that release an agent that raises the pH of a patient's gastrointestinal tract, for example a proton pump inhibitor, followed by an NSAID. - International Patent Application WO 03/075884 provides effervescent composition comprising a bisphosphonate, an acidic compound, an alkaline effervescing component, and optionally an anti-ulcer agent, such as a proton pump inhibitor, and methods of treating osteoporosis in a mammal using the effervescent compositions. - In U. S. Patent 5,888,535, according to the abstract of said patent "methods and compositions are disclosed utilizing optically pure (-)-pantoprazole for the treatment of ulcers in humans while substantially reducing the concomitant liability of adverse effects associated with the racemic mixture of pantoprazole." - In U. S. Patent 6,410,569 the dihydrate of the magnesium salt of pantoprazole is disclosed.
Description of the invention
It has now been found that (S)-pantoprazole and its salts, which are described in greater detail below, have, as a first aspect (aspect 1) of the present invention, advantageous gastro-protective action against certain medicaments (such as, for example, those medicaments mentioned below in the description of this invention, especially antiinflammatoriies and antirheumatics, and/or, in particular, those medicaments which cause erosive changes and/or lesions in the gastrointestinal system) and/or are well useful and effective in prevention or treatment of gastrointestinal disorders associated with certain medicaments indicated below and/or are particularly useful and effective in prevention or treatment of gastrointestinal diseases caused by certain medicaments selected from the group consisting of NSAIDs (non-steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO- NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids, and/or can be used, as a second aspect (aspect 2) of the present invention, in combination therapy of diseases and/or disorders which can be treated, ameliorated or prevented with said certain medicaments mentioned above in aspect 1, particularly with those medicaments selected from the group consisting of NSAIDs (non- steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO-NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids, whereby said combination therapy is characterised by improved gastrointestinal safety and tolerance compared to mono therapy.
Unexpectedly it has been found, that the gastrointestinal safety and tolerability of a combination comprising (a) (S)-pantoprazole and/or its salts as defined herein, and (b) an agent selected from the group consisting from NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids is greater than that, which can be achieved with said agent (b) alone, i.e. greater than the gastrointestinal safety and tolerability of a mono therapy using only said agent (b) unpartnered with (S)- pantoprazole and/or its salts.
Within the scope of this invention, "(S)-pantoprazole and/or its salts" is understood to include:
- (S)-pantoprazole and/or its salts [which is the same as (-)-pantoprazole and its salts]
- (S)-pantoprazole [(-)-pantoprazole]
- salts of (S)-pantoprazole [(-)-pantoprazole]
- (S)-pantoprazole [(-)-pantoprazole] and/or its salts being substantially free of (R)-pantoprazole [(+)- pantoprazole] and /or its salts
- (S)-pantoprazole [(-)-pantoprazole] being substantially free of (R)-pantoprazole [(+)-pantoprazole]
- salts of (S)-pantoprazole [(-)-pantoprazole] being substantially free of salts of (R)-pantoprazole [(+)- pantoprazole].
"Salts" in the context of the invention means all pharmaceutically acceptable salts prepared by reacting (S)-pantoprazole [(-)-pantoprazole] with a suitable inorganic or organic base. Examples of salts with bases which may be mentioned are aluminium, sodium, potassium, lithium, magnesium, zinc or calcium salts. Particularly preferred is the magnesium salt. If (S)-pantoprazole and/or its salts are isolated in crystalline form, the crystals may contain variable amounts of solvent Accordingly, according to the invention, the term "(S)-pantoprazole and/or its salts" also includes all solvates, in particular all hydrates, of (S)-pantoprazole and/or its salts. An exemplary hydrate of (S)-pantoprazole and/or its salts, which may be mentioned, is (S)-pantoprazole-sodium sesquihydrate [= (S)-pantoprazole-sodium x 1.5 H20]. A particularly preferred hydrate of (S)-pantoprazole and/or its salts is the (S)- pantoprazole-magnesium dihydrate.
"Substantially free" in the context of the invention means that (S) -pantoprazole and/or its salts contains less than 10 % by weight of (R)-pantoprazole. Preferably, "substantially free" means that (S)- pantoprazole and/or its salts contains less than 5 % by weight of (R)-pantoprazole. In the most preferred embodiment, "substantially free" means that (S)-pantoprazole and/or its salts contains less than 1 % by weight of (R)-pantoprazole. Within the scope of this invention the terms "medicament caused gastrointestinal diseases" and "gastrointestinal diseases caused by certain medicaments" refer to gastrointestinal diseases which are induced and/or caused by certain medicaments selected from the group consisting of NSAIDs (non- steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO-NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids, whereby NSAIDs, COX-2 inhibitors, NO- NSAIDs and bisphosphonates are particularly worthy to be mentioned; NSAIDs, COX-2 inhibitors and NO-NSAIDs are to be emphasized, NSAIDs and COX-2 inhibitors are more to be emphasized, and NSAIDs are particularly to be emphasized.
Exemplary NSAIDs within the meaning of the present invention are, in an embodiment (embodiment 1) according to the present invention, glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-methoxyphenyl- alpha-methyl-4-(isobutyl)phenylacetate [Research Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN: ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN: ALMINOPROFEN], 2- amino-3-benzoylphenylacetic acid [INN: AMFENAC], (plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2- pyridyl-2H-1,2-benzothiazine-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN: AMPIROXICA ], 2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate [INN: AMTOLMETINGUACIL], (plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1 H pyrrolizine-1-carboxylic acid [INN: ANIROLAC], 2-[4-(alpha,alpha,alpha-trifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7- trifluoromethyl-4-quinolyl)anthranilate [INN: ANTRAFENINE], 5-(dimethylamino)-9-methyl-2-propyl- 1H-pyrazolo[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE], 4-acetamidophenyl salicylate acetate [INN: BENORILATE], 2-(8-methyl-10,11-dihydro-11-oxodibenz[blfJoxepin-2- yl)propionic acid [INN: BERMOPROFEN], 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid [INN: BROMFENAC], 3-(3- chloro-4-cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN: BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC], butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyl-4-(2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN], 2-(4-biphenylyl)butyric acid, trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE], 2-(acetyloxy)-benzoic acid, calcium salt, 'compound with urea (1:1) [INN: CARBASALATE CALCIUM], (plus/minus)-6-chloro-alpha-methylcarbazole-2-acetic acid [INN: CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid [INN: CINMETACIN], N-(2- pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide [INN: CINNOXI- CAM], 6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC], 2-[4-(p- chlorophenyl)benzyloxy]-2-methylpropionic acid [INN: CLOBUZARIT], 5-methoxy-2-methyl-3- indolylacetohydroxamic acid [INN: DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN], (+)-(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN], 2-[(2,6-di- chlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], 2',4'-Difluoro-4-hydroxy-3- biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN: EL- TENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide [INN: ETERSALATE], 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4- b]indole-1 -acetic acid [INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid 2-(2- hydroxyethoxy)-ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic acid, ester with 4-butyl-4- (hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN: FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC], 3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4- dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC], (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], (plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl alcohol [INN: FEPRADINOL], 4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbutanoic acid [INN: FLOBUFEN], 2,3-dihydroxypropyl N-[8-(trifluoromethyl)-4-quinoly]anthranilate [INN: FLOCTAFENINE], N-(alpha,alpha,alpha-trifluoro-m- tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benz- oxazoleacetic acid [INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biphenylacetic acid [INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL], 2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC], 2-[4-(2'- furoyl)phenyl]propionic acid [INN: FURPROFEN], 2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol- 3-yl]acetamido]-2-deoxy-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic acid 4-nitrooxybutylester [Research Code: HCT-1026], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl 4-(3-thienyl)phenyl-alpha- methylacetate [Research Code: IDPH-8261], (plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, 3,7,11-trimethyl- 2,6,10-dodecatrienyl ester [INN: INDOMETACIN FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropicacid [INN: INDOPROFEN], 2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic acid [INN: KETOPROFEN], (DL)-5-benzoyl-3H- 1,2-dihydropyrrolo[1,2-a]pyrrole-1-carboxylic acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2- (hydroxymethyl)cinnamyl]benzoflιran [Research Code: L-651896], N-(2-carboxyphenyl)-4- chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1-phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN: LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic acid [Research Code: M-5010], N-(2,3- xylyl)anthranilic acid [INN: MEFENAMIC ACID], 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN: MESA- LAZINE], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-acetic acid [Research Code: ML-3000], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], 4-(6- methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE], (plus)-6-methoxy-alpha-methyl-2- naphthalineacetic acid [INN: NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN: NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE], 4,5-diphenyl-2-oxazolepropionic acid [INN: OXAPROZIN], alpha-methyl-4-[(2-oxocyclohexylidene)methyl]benzene acetic acid [INN: PELUBIPRO- FEN], 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione [INN: PHENYLBUTAZONE], 2-(p- isobutylphenyl)propionic acid 2-pyridyl-methyl ester [INN: PIMEPROFEN], 4-(p-chlorophenyl)-1-(p- fluorophenyl)pyrazole-3-acetic acid [INN: PIRAZOLAC], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2- benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], 3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid [INN: PIRPROFEN], 2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN], 2,6-di-tert-butyi-4-(2,-thenoyl)phenoi [INN: PRIFELONE], alpha-cyano-1-methyl- beta-oxopyrrole-2-propionanilide [INN: PRINOMIDE], 3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L- 4-benzamido-N,N-dipropylglutaramat 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (ester) [INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-2(1H)quinazolinone [INN: PRO- QUAZONE], 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid [INN: PROTIZINIC] ACID], 2- [[2-(p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT], o- hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC ACID], N-acetyl-L-cysteine sal icy late (ester), acetate (ester) [INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN: SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN: SALSALATE], 4-[1-(2- fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine [Research Code: SM-8849], (Z)-5-fluoro-2-methyl- 1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid [Research Code: TA-60], phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN: TALNIFLUMATE], (Z)-5-chloro-3-(2- thenoyl)-2-oxoindole-1-carboxamide [INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide [INN: TENOXICAM], 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3- propionamide [INN: TEPOXALIN], alpha-(5-benzoyl-2-thienyl)propionicacid [INN: TIAPROFENIC ACID], 5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiazolin one [INN: TIARAMIDE], 2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-propionic acid N,N- dimethylcarbamoylmethyl ester [INN: TlbNOPROFEN ARBAMEL], 1-Cyclohexyl-2-(2-methyl-4- quinolyl)-3-(2-thiazolyl)guanidine [INN: TIMEGADINE], 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine [INN: TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID], 1- methyl-5-(4-methylbenzoyl)-1H-py ole-2-aceticacid [INN: TOLMETIN], hydroxybis[alpha-methyl-4-(2- methylpropyl)benzene acetato-0]-aluminium [Research Code: U-18573-G], N-(3- trifluoromethylpheny -anthranilic acid n-butyl ester [INN: UFENAMATE], 2-[4-[3- (hydroxyimino)cyclohexyl]phenyl]propionic acid [INN: XIMOPROFEN], 2-(10,11-dihydro-10-oxo- dibenz[b,f]thiepin-2-yl-propionic acid [INN: ZALTOPROFEN] and 2-[4-(2-thiazolyloxy)phenyl]-propionic acid [INN: ZOLIPROFEN], as well as the pharmaceutically acceptable derivatives of these compounds.
Exemplary NSAIDs according to embodiment 1 which are to be emphasized are: ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, ME- FENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds. In an alternative embodiment, exemplary NSAIDs according to embodiment 1 which are to be emphasized are: DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.
Preferred exemplary NSAIDs according to embodiment 1, which are selected from the above-defined group of exemplary NSAIDs, are 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineaceticacid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], as well as the pharmaceutically acceptable derivatives of these compounds.
In an alternative embodiment, preferred exemplary NSAIDs according to embodiment 1, which are selected from the above-defined group of exemplary NSAIDs, are 2-[(2,6-dichlorophenyl)amino]- benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1- (4-chlorabenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6- methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2- pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], as well as the pharmaceutically acceptable derivatives of these compounds.
Particularly preferred exemplary NSAIDs according to embodiment 1 are 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], as well as the pharmaceutically acceptable derivatives of these compounds.
A selected, particular preferred exemplary NSAID according to embodiment 1 is 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable derivative thereof.
Examples of NO-NSAIDs to be used in the present invention include, but are not limited to, those disclosed, particularly those individualized or disclosed as examples, in WO 96/32946, WO 96/35416, WO 96/38136, WO 96/39409, WO 00/50037, US 6,057,347, WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641, WO 97/31654, WO 99/44595, WO 99/45004 and WO 01/45703, as well as the pharmaceutically acceptable derivatives of these compounds.
As exemplary COX-2 inhibitors within the scope of this invention can be mentioned in one embodiment (embodiment 2) according to the present invention, without being restricted to: 5-chloro-6'- methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine [INN: ETORICOXIB], 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide [INN: CELECOXIB], 4-[p- (methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone [INN: ROFECOXIB], N-[[p-(5-methyl-3-phenyl-4- isoxazolyl)phenyl]sulfonyl]propion-amide [INN: PARECOXIB], p-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulfonamide [INN: VALDECOXIB], 2-[2-(2-chloro-6-fluorophenylamino)-5- methylphenyl]acetic acid [INN: LUMIRACOXIB], 4-(4-cyclohexyl-2-methyloxazoI-5-yl)-2- fluorobenzene-sulfonamide [INN: TILMACOXIB], 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)-1H- imidazol-1-yl]benzene-sulfonamide [INN: CIMICOXIB], 4'-nitro-2'-phenoxymethanesulfonanilide [INN: NIMESULIDE], 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone [INN: FLOSULIDE], 5- bromo-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-thiophene [DUP-697], 4-acetyl-2-(2,4- difluorophenoxy)methanesulfonanilide [FK-3311], N-[2-(cyclohexyloxy)-4- nitrophenyf]methanesulfonamide [NS-398], 5-methanesulfonamido-6-(2,4-difluorophenylthio)-1 - in anone [L-745337], 8-acetyl-3-(4-fluorophenyl)-2-[4-(methanesulfonyI)phenyl]imidazo[1 ,2-a]- pyridine [GR-253035], 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfon-amide [SC- 58236], 4-(2,3-dihydro-2-oxo-3-phenyl-4-oxazolyl)-benzenesulfonamide [LAS-33815], CS-502, 2-(3,4- difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone [ABT- 963], or GW-406381, or those COX-2 inhibitors disclosed in the applications WO 02096427, WO 02096886 or WO 02096885, which are all incorporated by reference into the specification of the present invention in their entirety for all purposes, as well as the pharmaceutically acceptable derivatives of these compounds.
COX-2 inhibitors according to embodiment 2 of this invention which are to be emphasized include, but are not limited to, 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine [INN: ETORICOXIB], 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide [INN: CELECOXIB], 4- [p-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone [INN: ROFECOXIB], N-[[p-(5-methyl-3-phenyl-4- isoxazolyl)phenyl]sulfonyl]propion-amide [INN: PARECOXIB], p-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulfonamide [INN: VALDECOXIB], 2-[2-(2-chloro-6-fluorophenylamino)-5- methylphenyfjacetic acid [INN: LUMIRACOXIB], 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2- fluorobenzene-sulfonamide [INN: TILMACOXIB], and 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)-1H- imidazol-1-yl]benzene-sulfonamide [INN: CIMICOXIB], as well as the pharmaceutically acceptable derivatives of these compounds.
As exemplary COX-2 inhibitors within the scope of this invention can be also mentioned in another embodiment (embodiment 2') according to the present invention, without being restricted to: CELECOXIB ROFECOXIB, as well as the pharmaceutically acceptable derivatives of these compounds.
As examples of bisphosphonates within the meaning of this invention can be mentioned in one embodiment (embodiment 3) according to the present invention, without being restricted to, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLEDRONIC ACID, CLODRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, PAMIDRONIC ACID and ETIDRONIC ACID, as well as the pharmaceutically acceptable derivatives of these compounds.
Examples of bisphosphonates to be used in the present invention include also in another embodiment (embodiment 3') according to the present invention, but are not limited to, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLEDRONIC ACID and ETIDRONIC ACID, as well as the pharmaceutically acceptable derivatives of these compounds.
As examples of corticosteroids within the meaning of this invention can be mentioned in one embodiment (embodiment 4) according to the present invention, without being restricted to, HYDROCORTISONE, PREDNISONE, PREDNISOLONE, METHYLPREDNISOLONE,
TRIA CINOLONE ACETONIDE, AMCINONIDE, CLOBETASONE, CLOBETASOL, DEFLAZACORT, DESONIDE, CLOPREDNOL, DEXAMETHASONE, DIFLORASONE, DIFLUCORTOLONE, DIFLUPREDNATE, FLUDROXYCORTIDE, FLUDROCORTISONE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUOCORTIN BUTYL, CLOCORTOLONE, FLUOCINOLONE ACETONIDE, FLUOCORTOLONE, FLUOROMETHOLONE, FLUPREDNIDENE, FLUPREDNISOLONE, BETA ETHASONE, HALCINONIDE, BUDESONIDE, HALOMETASONE, RIMEXOLONE, PARAMETHASONE, PREDNYLIDENE, LOTEPREDNOL ETABONATE, PREDNICARBATE, as well as the pharmaceutically acceptable derivatives of these compounds.
Examples of preferred corticosteroids to be used in the present invention include also in another embodiment (embodiment 4') according to the present invention, but are not limited to, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE, as well as the pharmaceutically acceptable derivatives of these compounds.
A particularly preferred corticosteroid to be used in the present invention is BETAMETHASONE, DEXAMETHASONE, FLUOCORTOLONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, HYDROCORTISONE, BUDESONIDE, TRIAMCINOLONE ACETONIDE, as well as the pharmaceutically acceptable derivatives of these compounds.
In the context of the present invention, the term "pharmaceutically acceptable derivative" means a pharmaceutically acceptable salt, ester or solvate (e.g. hydrate) or a pharmaceutically acceptable solvate of such salt or ester.
Within the scope of this invention the term "gastrointestinal diseases" in the context of "medicament caused gastrointestinal diseases" or "gastrointestinal diseases caused by certain medicaments" refers to those gastrointestinal diseases, which are known to the art-skilled person on the base of his/her expert knowledge, to be caused by certain medicaments such as, for example, art-known gastrointestinal inflammatory diseases and lesions, particularly gastric ulcer (e.g. stomach ulcer or duodenal ulcer), heartburn, bleeding or medicament related functional gastropathy, whereby gastric ulcer is particularly to be emphasized.
In the meaning of this invention, the terms "medicament associated gastrointestinal disorders" and "gastrointestinal disorders associated with certain medicaments" refer to gastrointestinal disorders known to the person skilled in the art (such as e.g. indigestion, mild forms of heartburn, stomach irritation or pain) which are associated with certain medicaments such as, for example, those mentioned above, particularly NSAIDs, as well as e.g. chloroquine, theophylline, dihydralazine, salazosulfapyri- dine, thiazides, iodine-containing contrast media, gold preparations or antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol).
In this connection, it is to be understood for the skilled person that the abovementioned gastrointestinal diseases or disorders are caused or associated mainly with the active agents or ingredients of the abovementioned medicaments.
Any or all of the listed combination partners as defined herein can be suitable to be used in the combination therapy or in the combinations according to the present invention.
In a further aspect, this invention relates to the use of (S)-pantoprazole and/or its salts in the prevention or treatment of medicament caused gastrointestinal diseases and/or medicament associated disorders.
A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the prevention and/or treatment of medicament induced gastric ulcer.
A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for the prevention and/or treatment of medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer.
A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for the prevention of medicament associated gastrointestinal disorders.
A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for the well-tolerated treatment and/or prevention of inflammatory diseases and/or inflammation associated disorders. A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions for treating and/or preventing of gastrointestinal or, particularly, non-gastrointestinal inflammatory diseases and/or inflammation associated disorders, and for reducing the risk of medicament associated gastrointestinal disorders or, particularly, for reducing medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer.
A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts in the manufacture of pharmaceutical compositions comprising an antiinflammatory or antirheumatic ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids for use in combination therapy, e.g. for use in the treatment and/or prevention of diseases or disorders conventionally treated, ameliorated or prevented monotherapeutically with said antiinflammatory or antirheumatic ingredient, particulariy those diseases or disorders mentioned in the specification of this invention.
A further aspect of the present invention is the use of said selected tricyclic imidazo[1,2-a]pyridine compounds in the manufacture of pharmaceutical compositions comprising an active ingredient which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids for treating and/or preventing of diseases or disorders which can be treated, ameliorated or prevented by said active ingredient, particularly those diseases or disorders mentioned in the specification of this invention, and for reducing the risk of medicament associated gastrointestinal disorders or, particularly, for reducing medicament caused gastrointestinal diseases, particularly those mentioned in this invention.
A further aspect of the present invention is the simultaneous, separate or sequential co-administration of a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, preferably a NSAID, with (S)-pantoprazole and/or its salts to prevent medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer.
A further aspect of the present invention is the simultaneous, separate or sequential co-administration of a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid with (S)- pantoprazole and/or its salts to treat, ameliorate or prevent diseases or disorders which can be treated, ameliorated or prevented by this NSAID, COX-2 inhibitor, NO-NSAID or bisphosphonate.
A further aspect of the present invention is a method for prevention and/or treatment of medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer, comprising administering a therapeutically effective amount of one or more of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid to a mammal. A further aspect of the present invention is a method for prevention and/or treatment of medicament associated gastrointestinal disorders comprising administering a therapeutically effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with said medicament to a human in need thereof.
A further aspect of the present invention is a method for treatment or prevention of inflammatory diseases and/or inflammation assodated disorders comprising administering a therapeutically effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid to a mammal.
A further aspect of the present invention is a method for amelioration the gastrointestinal tolerance of the therapy of inflammatory diseases and/or inflammation associated disorders comprising administering a therapeutically effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid to a mammal.
A further aspect of the present invention is a method for treating, ameliorating or preventing of di s- eases or disorders, which can be treated, ameliorated or prevented by an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and reducing the risk of gastrointestinal diseases caused by said agent or reducing the risk of gastrointestinal disorders associated with said agent, in a human patient in need of such treatment, amelioration or prevention and at risk of gastrointestinal diseases caused by said agent or gastrointestinal disorders associated with said agent comprising administering to said patient an;agent selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids in an amount effective to treat, to ameliorate or to prevent diseases or disorders, which can be treated, ameliorated or prevented by said agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, simultaneously, separately or sequentially with (S)- pantoprazole and/or its salts an amount effective to reduce the risk of gastrointestinal diseases caused by said agent or gastrointestinal disorders associated with said agent.
A further aspect of the present invention is a method for treating, ameliorating or preventing of diseases or disorders, which can be treated, ameliorated or prevented by an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and reducing the risk of gastrointestinal diseases or disorders caused by or assodated with said agent in a patient in need thereof comprising administering to said patient a combination or a composition according to this invention.
A further aspect of the present invention is a preferably orally applicable pharmaceutical composition for simultaneous administration comprising, in admixture, a first active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticoster- oids, and a second active ingredient, which is (S)-pantoprazole and/or its salts, to prevent medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer, in a mammal.
A further aspect of the present invention is a pharmaceutical composition comprising a first active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates or corticosteroids, and a second active ingredient which is (S)-pantoprazole and/or its salts, to prevent and/or treat medicament caused gastrointestinal diseases, particularly medicament induced gastric ulcer, in a mammal.
A further aspect of the present invention is a pharmaceutical composition comprising a first active ingredient, which is selected from a group consisting of chloroquine, theophylline, dihydralazine, sala- zosulfapyridine, thiazides, iodine-containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol), and a second active ingredient, which is (S)- pantoprazole and/or its salts, to prevent medicament associated gastrointestinal disorders in a human.
A further aspect of the present invention is a pharmaceutical composition for simultaneous administration comprising a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salts.
A further aspect of the present invention is a composition comprising a first active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, and a second active ingredient which is (S)-pantoprazole and/or its salts, for simultaneous, sequential or separate use in therapy in any order.
A further aspect of the present invention is a preferably orally applicable pharmaceutical composition in unit dosage comprising a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salts for use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further aspect of the present invention is a pharmaceutical composition comprising a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salts, wherein the NSAID, the COX-2 inhibitor, the NO-NSAID, the bisphosphonate or the corticosteroid and (S)-pantoprazole and/or its salts are administered in a single dosage form, such that the NSAID, the COX-2 inhibitor, the NO-NSAID, the bisphosphonate or the corticosteroid and (S)- pantoprazole and/or its salts are physically separated from each other.
A further aspect of the present invention is a composition comprising a first active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and a second adive ingredient which is (S)-pantoρrazole and/or its salts, together with a pharmaceutically acceptable carrier. A further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts; and (b) a pharmaceutically effective amount of at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid.
A further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts; and (b) a pharmaceutically effective amount of at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid; wherein component (a) and component (b) are maintained in the same delivery vehicle.
A further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts; and (b) a pharmaceutically effective amount of at least one NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate or corticosteroid; wherein component (a) and component (b) are maintained in different delivery vehicles.
A further aspect of the present invention is a preferably orally applicable pharmaceutical formulation comprising a first active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, a second active ingredient, which is (S)- pantoprazole and/or its salts, and a pharmaceutically acceptable carrier, diluent, adjuvant, auxiliary or excipient for use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further aspect of the present invention is a first pharmaceutical formulation comprising (S)- pantoprazole and/or its salts and a pharmaceutically acceptable carrier or diluent; and a second pharmaceutical formulation comprising a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid and a pharmaceutically acceptable carrier or diluent.
A further aspect of the present invention is a combination comprising a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid and (S)-pantoprazole and/or its salts for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further aspect of the present invention is a combination comprising a medicament selected from a group consisting of chloroquine, theophylline, dihydralazine, salazosulfapyridine, thiazides, iodine- containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotri- moxazol), and (S)-pantoprazole and/or its salts, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament associated gastrointestinal disorders in a human. A further aspect of the present invention is a combination, particularly a pharmaceutical combination, such as, for example, a combined preparation, e.g. a kit of parts, or a composition, particulariy a pharmaceutical composition, comprising a first active ingredient which is an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and a second active ingredient which is (S)-pantoprazole and/or its salts as mentioned in the present invention and, optionally, at least one pharmaceutically acceptable carrier for simultaneous, sequential, separate or chronologically staggered use in therapy, and/or for use as combined unit dosage form or as separate unit dosage forms in therapy, and/or for use as fixed combination in therapy, and/or for use as admixture in therapy, e.g. to treat, to ameliorate or to prevent in a mammal, including human, diseases or disorders, which can be treated, ameliorated or prevented by said first active ingredient, and, in combination therewith, to reduce, to treat, to ameliorate or to prevent in a mammal, including human, gastrointestinal diseases caused by said first active ingredient or to reduce, to treat, to ameliorate or to prevent gastrointestinal disorders associated with said first active ingredient.
A further aspect of the present invention relates to combining separate pharmaceutical compositions in kit form.
A further aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazoIe and/or its salts, and a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further aspect of the present invention is a commercial package comprising as active ingredients a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid as well as (S)- pantoprazole and/or its salts together with instructions for simultaneous, sequential or separate use in therapy.
A further aspect of the present invention is a commercial package comprising (S)-pantoprazole and/or its salts as adive ingredient together with instructions for simultaneous, sequential or separate use with a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid.
A further aspect of the present invention is a commercial package comprising a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid as active ingredient together with instructions for simultaneous, sequential or separate use with (S)-pantoprazole and/or its salts.
A further aspect of the present invention is a commercial package comprising a medicament selected from the group consisting of chloroquine, theophylline, dihydralazine, salazosulfapyridine, thiazides, iodine-containing contrast media, gold preparations and antibiotics (e.g. tetracyclines, sulfonamides or cotrimoxazol) together with instructions for simultaneous, sequential or separate use with (S)- pantoprazole and/or its salts.
A further aspect of the present invention is a pharmaceutical product, such as, for example, a commercial package, comprising a combination, such as, for example, a combined preparation, e.g. a kit of parts, or a pharmaceutical composition, comprising a first active ingredient which is an agent selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and a second active ingredient which is (S)-pantoprazole and/or its salts as mentioned in the present invention and, optionally, at least one pharmaceutically acceptable carrier for simultaneous, sequential, separate or chronologically staggered use in therapy, and/or for use as combined unit dosage form or for use as separate unit dosage forms in therapy, and/or for use as fixed combination in therapy, and/or for use as admixture in therapy; together with standard packaging material, and together with instructions for simultaneous, sequential, separate or chronologically staggered use in therapy, e.g. to treat, to ameliorate or to prevent in a mammal, including human, diseases or disorders, which can be treated, ameliorated or prevented by said first active ingredient, and, in combination therewith, to treat, to ameliorate or to prevent in a mammal, including human, gastrointestinal diseases caused by said first adive ingredient or to treat, to ameliorate or to prevent gastrointestinal disorders associated with said first active ingredient.
A further aspect of the present invention is a kit comprising at least one dosage unit of a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid as well as at least one dosage unit of (S)-pantoprazole and/or its salts for simultaneous, sequential or separate use in therapy. Optionally, abovementioned kit can be provided with instructions for use:«?
A further aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A further aspect of the present invention is the use of a pharmaceutical composition, pharmaceutical product, formulation, preparation, combination, commercial package or kit according to the invention in the manufacture of a medicament for the treatment of an inflammatory disease and/or inflammation assodated disorder.
A further aspect of the present invention is the use of the pharmaceutical compositions, formulations, preparations, combined preparations, combinations or kits according to this invention in the manufacture of a pharmaceutical product, such as e.g. a commercial package, for the treatment or prevention of diseases or disorders which can be conventionally treated by NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates or corticosteroids. A further aspect of the present invention is the use of the pharmaceutical compositions, formulations, preparations, combined preparations, combinations or kits according to this invention in the manufacture of a pharmaceutical produd, such as e.g. a commercial package, for the treatment or prevention of gastrointestinal diseases or disorders caused by or associated with NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates or corticosteroids.
A further aspect of the present invention is the use of the pharmaceutical compositions, formulations, preparations, combined preparations, combinations or kits, particularly pharmaceutical compositions and kits, according to this invention in the manufacture of a medicament for treating or preventing of diseases or disorders which can be treated by agents selected from NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates and corticosteroids, and for treating or preventing of gastrointestinal diseases or disorders caused by or associated with the therapeutic use of said agents.
A further aspect of the present invention is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
A further aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further aspect of the present invention is a k'rt comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A preferred aspect of the present invention is a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
A further preferred aspect of the present invention is a pharmaceutical product (such as, for example, a commercial package) comprising a first active ingredient which is (S)-pantoprazole magnesium, and a second active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates and corticosteroids; together with instructions for simultaneous, sequential or separate use, e.g. to treat or prevent gastrointestinal diseases caused by said second active ingre- dient and/or to treat or prevent diseases which can be treated or prevented by said second active ingredient.
A further preferred aspect of the present invention is a kit comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient selected from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids; together with instructions for simultaneous, sequential or separate use in therapy, e.g. to treat or prevent gastrointestinal diseases caused by said second active ingredient and/or to treat or prevent diseases which can be treated or prevented by said second active ingredient.
A more preferred aspect of the present invention is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazoIe magnesium dihydrate, and a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
A further more preferred aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of (S)-pantoprazole magnesium dihydrate, and a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further more preferred aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
Another preferred aspect of the present invention is a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-aspect, a NSAID, such as e.g. one of those NSAIDs mentioned exemplarily above, or, in a second sub-asped, a COX-2 inhibitor, such as e.g. one of those COX-2 inhibitors mentioned exemplarily above, or, in a third sub-asped, a bisphosphonate, such as e.g. one of those bisphosphonates mentioned exemplarily above, or, in a fourth sub-asped a corticosteroid, such as e.g. one of those corticosteroids mentioned exemplarily above, or, in a more detailed sub-aspect, an agent selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, CLODRONIC ACID, PAMIDRO NIC ACID, ETIDRONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE or a pharmaceutically acceptable derivative thereof.
A more preferred aspect of the present invention is a pharmaceutical composition comprising a first adive ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a NSAID, such as e.g. one of those NSAIDs mentioned exemplarily above, or, in a more detailed sub- aspect a NSAID selected from the group consisting of
ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID AND TOLMETIN, or a pharmaceutically acceptable derivative thereof.
A further more preferred asped of embodiment a of the present invention is a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a COX-2 inhibitor, such as e.g. one of those COX-2 inhibitors mentioned exemplarily above, or, in a more detailed sub-asped, a COX-2 inhibitor selected from the group consisting of
ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB and CIMICOXIB, or a pharmaceutically acceptable derivative thereof.
A further more preferred asped of the present invention is a pharmaceutical composition comprising a first adive ingredient which is (S)-pantoprazole and/or its salts; and a second adive ingredient which is a bisphosphonate, such as e.g. one of those bisphosphonates mentioned exemplarily above, or, in a more detailed sub-aspect a bisphosphonate selected from the group consisting of
ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID,
ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID,
CLODRONIC ACID, PAMIDRONIC ACID and ETIDRONIC ACID, or a pharmaceutically acceptable derivative thereof.
A further more preferred aspect of the present invention is a pharmaceutical composition comprising a first adive ingredient which is (S)-pantoprazole and/or its salts; and a second active ingredient which is a corticosteroid, such as e.g. one of those corticosteroids mentioned exemplarily above, or, in a more detailed sub-aspect a corticosteroid seleded from the group consisting of
BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE,
PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE,
FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT,
BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE, or a pharmaceutically acceptable derivative thereof.
A particulariy preferred aspect of embodiment a of the present invention is a pharmaceutical composition comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-asped, a NSAID, such as e.g. one of those NSAIDs mentioned above, or, in a second sub-asped, a COX-2 inhibitor, such as e.g. one of those COX-2 inhibitors mentioned above, or, in a third sub- asped, a bisphosphonate, such as e.g. one of those bisphosphonates mentioned above, or, in a fourth sub- aspect, a corticosteroid, such as e.g. one of those corticosteroids mentioned above, or, in a more detailed sub- aspect, an agent selected from the group consisting of
ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, CLODRONIC ACID, PAMIDRONIC ACID, ETIDRONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE or a pharmaceutically acceptable derivative thereof.
A yet further particularly preferred asped of embodiment a of the present invention is a pharmaceutical produd (such as, for example, a commercial package) comprising a first adive ingredient which is (S)-pantoprazole magnesium; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-asped, a NSAID, such as e.g. one of those NSAIDs mentioned above, or, in a second sub-asped, a COX-2 inhibitor, such as e.g. one of those COX-2 inhibitors mentioned above, or, in a third sub- asped, a bisphosphonate, such as e.g. one of those bisphosphonates mentioned above, or, in a fourth sub- aspect, a corticosteroid, such as e.g. one of those corticosteroids mentioned above, or, in a more detailed sub- aspect, an agent selected from the group consisting of
ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, CLODRONIC -ACID, PAMIDRONIC ACID and ETIDRONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE, or a pharmaceutically acceptable derivative thereof, together with instrudions for simultaneous, sequential or separate use, e.g. to treat or prevent gastrointestinal diseases caused by said second active ingredient and/or to treat or prevent diseases which can be treated or prevented by said second active ingredient. A still further particularly preferred aspect of embodiment a of the present invention is a kit comprising a first active ingredient which is (S)-pantoprazole magnesium; and a second active ingredient which is a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid, or, in particular, a NSAID, a COX-2 inhibitor, a bisphosphonate or a corticosteroid, or, in a first sub-asped, a NSAID, such as e.g. one of those NSAIDs mentioned above, or, in a second sub-asped, a COX-2 inhibitor, such as e.g. one of those COX-2 inhibitors mentioned above, or, in a third sub- asped, a bisphosphonate, such as e.g. one of those bisphosphonates mentioned above, or, in a fourth sub- asped, a corticosteroid, such as e.g. one of those corticosteroids mentioned above, or, in a more detailed sub- asped, an agent selected from the group consisting of
ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, ME- CLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, CLODRONIC ACID, PAMIDRONIC ACID and ETIDRONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE, or a pharmaceutically acceptable derivative thereof, together with instrudions for simultaneous, sequential or separate use, e.g. to treat or prevent gastrointestinal diseases caused by said second adive ingredient and/or to treat or prevent diseases which can be treated or prevented by said second active ingredient.
A particulariy preferred aspect of the present invention is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium, and a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, ETIDRONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE and the pharmaceutically acceptable derivatives of these compounds.
A further particularly preferred asped of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from t ie group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXA.PROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, ETIDRONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE and the pharmaceutically acceptable derivatives of these compounds, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further particularly preferred asped of the present invention is a kit comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium, a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, R OFECOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, ZOLANDRONIC ACID, ETID RONIC ACID, BETAMETHASONE, HYDROCORTISONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, TRIAMCINOLONE ACETONIDE, DEXAMETHASONE, DESONIDE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUDROCORTISONE, DEFLAZACORT, BUDESONIDE, LOTEPREDNOL ETABONATE, FLUOCORTOLONE and the pharmaceutically acceptable derivatives of these compounds, and in- strudions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof. A particulariy preferred aspect of the present invention to be especially emphasized is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium, and a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these compounds.
A further particularly preferred aspect of the present invention to be especially emphasized is a pharmaceutical produd comprising, in combination, a preparation of a first adive ingredient, which is (S)- pantoprazole magnesium, and a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID seleded from the group consisting of ACETYLSALICYLIC AC ID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these compounds, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further particularly preferred aspect of the present invention to be especially emphasized is a kit comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium, a preparation of a second adive ingredient which is a NSAID or a COX-2 inhibitor or a NO-NSAID selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these compounds, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A selected particularly preferred aspect of the present invention is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, ETIDRONIC ACID BETAMETHASONE, DEXAMETHASONE, FLUOCORTOLONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, HYDROCORTISONE, BUDESONIDE, TRIAMCINOLONE ACETONIDE and the pharmaceutically acceptable derivatives of these compounds.
A further selected particularly preferred aspect of the present invention is a pharmaceutical produd comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, ZOLANDRONIC ACID, ETIDRONIC ACID, BETAMETHASONE, DEXAMETHASONE, FLUOCORTOLONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, HYDROCORTISONE, BUDESONIDE, TRIAMCINOLONE ACETONIDE and the pharmaceutically acceptable derivatives of these compounds, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further selected particulariy preferred asped of the present invention is a kit comprisingxa preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, ETIDRONIC ACID, BETAMETHASONE, DEXAMETHASONE, FLUOCORTOLONE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, HYDROCORTISONE, BUDESONIDE, TRIAMCINOLONE ACETONIDE and the pharmaceutically acceptable derivatives of these compounds, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A selected particulariy preferred aspect of the present invention to be especially emphasized is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO- NSAID selected from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these compounds.
A further selected particularly preferred aspect of the present invention to be especially emphasized is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a preparation of a second adive ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these compounds, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further selected particulariy preferred asped of the present invention to be especially emphasized is a kit comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second active ingredient, which is a NSAID or a COX-2 inhibitor or a NO- NSAID seleded from the group consisting of ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, CELECOXIB, ROFECOXIB and the pharmaceutically acceptable derivatives of these compounds, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A seleded particulariy preferred asped of the present invention to be especially emphasized is a pharmaceutical composition comprising, in admixture, a first adive ingredient, which is (S)-pantoprazole magnesium, and a second adive ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound.
A further selected particularly preferred asped of the present invention to be especially emphasized is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole magnesium, and a preparation of a second adive ingredient which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal. A further seleded particularly preferred aspect of the present invention to be especially emphasized is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole magnesium, a preparation of a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, and instrudions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A selected particularly preferred asped of the present invention to be especially emphasized is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound.
A further selected particularly preferred asped of the present invention to be especially emphasized is a pharmaceutical produd comprising, in combination, a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium dihydrate, and a preparation of a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, for simultaneous, sequential or separate use in therapy, e.g. to prevent medicament induced gastric ulcer in a mammal.
A further selected particularly preferred asped of the present invention to be especially emphasized is a kit comprising a preparation of a first adive ingredient, which is (S)-pantoprazole magnesium dihydrate, a preparation of a second active ingredient, which is DICLOFENAC or a pharmaceutically acceptable derivative of this compound, and instrudions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
Within the scope of this invention, "inflammatory diseases" which may be mentioned are gastrointestinal inflammatory diseases such as, for example, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, gastroesophageal reflux disease (GERD) and ulcerative colitis, or non- gastrointestinal inflammatory diseases, in particular arthritis, including but not limited to rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis; or asthma, bronchitis and skin related disorders such as psoriasis, eczema, bums and dermatitis.
"Inflammation associated disorders" which may be mentioned are, for example, pain (both chronic and acute), migraine, fever and headaches.
Furthermore, the person skilled in the art knows on the basis of his/her expert knowledge which diseases, disorders or conditions can be treated, ameliorated or prevented by NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids. According to the present invention, agents seleded from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids can be combined beneficially with (S)-pantoprazole and/or its salts to enhance or to improve safety and tolerability of the mono therapy, i.e. the mono therapy using only said agents seleded from the group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids unpartnered with (S)-pantoprazole and/or its salts, by reducing the risk of adverse effects, such as medicament-associated gastrointestinal disorders or medicament-caused gastrointestinal diseases, associated conventionally with the mono therapy.
In this context, the skilled person knows therefore on the basis of his/her expert knowledge and/or on the basis of the disclosure of the present invention which diseases, disorders or conditions conventionally treated, ameliorated or prevented monotherapeutically with NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates or corticosteroids can be now beneficially treated, ameli rated or prevented with the combination therapy according to the present invention.
In more detail, the combination therapy according to this invention can be applied to treat diseases, disorders or conditions typically treated, ameliorated or prevented by NSAIDs and/cir COX-2 inhibitors, such as, for example, inflammatory diseases (in particular all kind of arthritis, including rheumatosis arthritis or degenerative joint diseases including osteoarthritis) or inflammation associated disorders, and/or particularly symptoms caused by arthritis, such as inflammation, swelling , stiffness and joint pain, or other kinds of pain or painful conditions, such as gout attacks, bursitis, tendonitis, touthache, lower back and neck pain, myositis, sprains, strains or other injuries, or symptoms associated with influenza or other viral infections or common cold.
As further diseases, disorders or conditions, which can be treated, ameliorates d or prevented by NSAIDs and/or, particularly, COX-2 inhibitors within the combination therapy according to this invention, can be mentioned1, without being restricted thereto, neuropathic pains, (inflammatory) I ver diseases, stroke, epilepsy, dysmenorrhoea, ophthalmic diseases, cognitive disorders such as dementia, particularly degenerative dementia (such e.g. Alzheimer's disease) or, in more particular, cellular and neoplastic transformation and metastatic tumour growth, such e.g. certain cancerous diseases, for example colonic cancer and prostate cancer, or cancer associated with overexpression of HER-2/neu (e.g. breast cancer), or adenomatous coloredal polyps (and to reduce herewith the risk of developing colon cancer), or other conditions mediated by COX-2.
As diseases, disorders or conditions, which can be treated, ameliorated or prevenied by bisphosphonates within the combination therapy according to this invention, can be mentioned, without being restricted thereto, disorders associated with abnormal bone resorption such as, for example, osteoporosis, multiple myeloma or metastatic bone diseases.
Within the meaning of this invention the terms "use", "administration", "co-administπation" or "administering" refer - with regard to the NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates or corticosteroids - preferably to oral application. However in some cases, parenterale (e.g. intravenous) or percutaneous application can be also advantageous. With regard to (S)-pantoprazole and/or its salts, oral or intravenous application is preferred. The dosage of the active compounds is in a customary order of magnitude comparable with the mono dosage, whereby, due to the additive and/or super-additive synergism of the single effects, the relevant doses of the active compounds in the combined dosage can be reduced compared to norm, or whereby- while maintaining the customary doses of the single components - a surprisingly higher and prolonged effect is obtained.
The person skilled in the art is aware on the base of his expert knowledge of the total daily dosage of the NSAIDs, the COX-2 inhibitors, the NO-NSAIDs, the bisphosphonates or the corticosteroids, which are comprised in the abovementioned pharmaceutical compositions, pharmaceutical produds, formulations, combinations, preparations, commercial packages or kits according to this invention. Said total daily dosage can vary within a wide range. For example, in the case of Diclofenac the daily doses are in a range from 100-2000 μg/kg.
In general, it has proven advantageous in human medicine to administer (S)-pantoprazole and/or its salts in the case of oral administration in a daily dose from approximately 10 to approximately 80, preferably 20 to 40 mg as calculated for the free acid (S)-pantoprazole. In the case of parenteral treatment, similar or [in particular in the case of intravenous administration of (S)-pantoprazole and/or its salts], as a rule, lower doses can be used.
The optimal dose and manner of administration of the active compounds necessary in each case can easily be determined by any person skilled in the art on the basis of his/her expert knowledge.
The person skilled in the art is familiar, on the basis of his/her knowledge, with carriers, diluents, adjuvants, auxiliaries or excipients which are suitable for the desired pharmaceutical formulations and/or preparations. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex- ing agents (e.g. cyclodextrines).
In medicines, the adive compounds are preferably employed in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the adive compound content advantageously being between 0.1 and 95%. Thus, for example with regard to the desired mode and site of adion, the person skilled in the art can develop, on the basis of his her knowledge, by appropriate choice of the excipients and the auxiliaries different galenic forms precisely tailored to the active ingredients) (such as, for example, retard forms or gastric acid resistant forms).
All patents and patent applications referred to herein are herein incorporated by reference into the specification in their entirety for all purposes. It is to be understood that the invention covers all combinations of single aspeds or embodiments of the invention as described herein.
It is to be understood that when used herein, 'medicament' or 'pharmaceutical composition' shall be taken to refer to a composition comprising both (S)-pantoprazole and/or its salts and the other active ingredient in a fixed combination (fixed unit dosage form), or a medicament pack comprising the two active ingredients as discrete separate dosage forms. In case of a medicament pack comprising the two adive ingredients, the adive ingredients are preferably packed into blister cards which are suited for improving compliance.
Each blister card preferably contains the medicaments to be taken on one day of treatment. If the medicaments are to be taken at different times of day, the medicaments can be disposed in different sedions on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening). The blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day. The various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times.
The daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column.
Medicaments which must be taken together at a particular time of day are placed together at the ap-« propriate time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.
Having described the invention in detail and by reference to the embodiments or aspects thereof, the scope of the present invention is not limited only to those described embodiments or aspects. As will be apparent to persons skilled in the art, modifications, analogies, variations, derivations, homologisa- tions and adaptations to the above-described invention can be made on the base of art-known knowledge and/or on the base of the disclosure (e.g. the explicit, implicit or inherent disclosure) of the present invention without departing from the spirit and scope of this invention. Examples
1. Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H- benzimidazolide} dihydrate
At 20-25°C, 20.2 g (52.7 mmol) of (-)-pantoprazole {(-)-[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyri- dinyl)methylsulphinyl]-1H-benzimidazole} were suspended in 200 ml of purified water. A solution of (55.2 mmol) sodium hydroxide in 10 ml of water was added, and the mixture was stirred at 20-30°C for 30 min. With addition of a filter aid (1 g Hyflo-Super-Cel), the turbid solution was filtered.6.32 g (31.2 mmol) of magnesium dichloride hexahydrate in 150 ml of water were then added drop by drop with stirring over a period of 30 min. After a further 30 min., the precipitated solid was filtered off with su c- tion using a sudion filter, stirred with water (2x 50 ml) and again filtered off with suction. Drying under reduced pressure at 50-60°C gave, in a yield of 17.36 g (80%), a hydrate of magnesium (-)-bis{[5- (difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide} having a water content of 4.5-4.7 % as a colourless to beige powder (m. p. 158-161 °C, with decomposition).
Specific rotation: αo20° = -114° (c = 0.5, measured in methanol)
For recrystallisation, 1.88 g of the hydrate were, at 55°C, dissolved in 6 ml of methanol, and 20 ml of water were added with stirring. A colourless to beige solid crystallized out. This gave the title compound of m. p. 160-163°C (with decomposition) having a water content of 4.3-4.4 %.
Alternatively, the title compound can also be prepared from organic-aqueous solvent mixtures To this end, (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution, is dissolved in an organic solvent, for example warm acetone. 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added drop by drop, and the mixture is cooled with stirring. The precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant This gives the title compound as a colourless to beige powder.
2. Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H- benzimidazolide} dihydrate
A. (-)-Pantoprazole-Na
36 g of (-)-pantoprazole were suspended in 180 ml of methyl isobutyl ketone (MIBK) and 18 ml of 2-propanol and heated to an internal temperature of 45°C. The suspension was stirred at this temperature for 15 min. At 50°C, 11 g of 30% (w/w) aqueous sodium hydroxide solution were slowly added drop by drop to this suspension. A clear to slightly turbid solution resulted. This solution was stirred for a bit longer and then filtered to give a clear solution. The clear filtrate was slowly cooled to room temperature. Between 45°C and 30°C, crystallization, which could be accelerated by seeding with (-)-pantoprazole sodium, began. The resulting suspension was stirred at an internal temperature of < 20°C for another 2 h. The suspension was then filtered, and the crystals were washed with 40 ml of MIBK.
Drying was carried out in a vacuum drying cabinet at < 50 mbar and 40-45°C. [It is also possible to dispense with drying and to use the moist product (having an MIBK content of 10-20 %) directly for step B]. The white-beige crystalline product obtained after drying was hygroscopic. The water content was from 2 to 12 %. The absorption and release of water were reversible. Yield: 34 g = 90 % of theory (based on anhydrous produd). Specific rotation: OD 0° = - 95 (c = 0.5, measured in methanol, sodium salt having a water content of 12%). m. p.: 145-165°C (decomposition, sodium salt having a water content of 2 %); 02-109°C (decomposition, sodium salt having a water content of 12 %).
B. (-)-Pantoprazole-Mg
30 g of (-)-pantoprazole sodium salt (calculated anhydrous substance) were suspended in 260 ml of water. The suspension was heated to 35-40°C and stirred at 35-40°C for another 10 min. This gave a clear solution. The clear solution was cooled to 22-27°C. 14.3 g of magnesium chloride hexahydrate were dissolved in 100 ml of water, and at room temperature and with stirring, the solution was slowly added dropwise to the (-)-pantoprazole sodium salt solution. The resulting suspension was then stirred at room temperature for another 4 h. The suspension was, under pressure, filtered through a Nutsche filter, and the produd was, a little at a time, washed twice with 300 ml of water. Drying in a vacuum drying cabinet at < 50 mbar and 40-45°C gave 27.5 g (90 %) of the title compound of m. p. 160- 163°C. Water content 4.3-4.4 %; specific rotation: αD 20° = *429 (c= 0.5, measured in methanol).
Recrystallisation of (-)-pantoprazole-Mg
For recrystallisation, 6.0 g of the (-)-pantoprazole-Mg-dihydrate were, at 55°C, dissolved in 18 ml of methanol. After 15 min, 90 ml of water were added with stirring to the orange-brown-solution. A colourless to beige solid crystallised out The resulting suspension was then stirred at 20-25°C for another 1 hour. The solid was filtered off, washed with 10 ml of water and dried under vacuum for 20 hours at 50°C. The yield for the title compound was 88 % (5.26 g) with the following data:
M.P.: 161-165°C (with decomposition)
Specific rotation: αD Z0° = -130° (c = 0.5, measured in methanol)

Claims

Patent Claims
1. A pharmaceutical composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salt; and a second active ingredient, which is selected from a group consisting of NSAIDs, COX-2 inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
2. A pharmaceutical composition according to claim 1 , comprising in admixture for simultaneous administration a NSAID, a COX-2 inhibitor, a NO-NSAID, a bisphosphonate or a corticosteroid together with (S)-pantoprazole and/or its salt.
3. A pharmaceutical composition according to claim 1 , comprising a first active ingredient, which is a NSAID or a COX-2 inhibitor or a NO-NSAID or a bisphosphonate or a corticosteroid, and a second active ingredient, which is (S)-pantoprazole and/or its salt, for simultaneous, sequential or separate use in therapy in any order.
4. A pharmaceutical composition according to any of the preceding claims, wherein (S)-pantoprazole is present in the form of its magnesium salt.
5. A pharmaceutical composition according to any of the preceding claims, wherein (S)-pantoprazole is present in the form of the dihydrate of its magnesium salt.
6. A pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5, wherein the second active ingredient is
- a NSAID selected from the group consisting of glycolic acid [o-(2,6- dichloroanilino)phenyf|acetate(ester) [INN: ACECLOFENAC]; 1-(4-chlorobenzoyl)-5-methoxy-2- methyl-1H-indole-3-acetic acid carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylacetate [Research Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN: ALCLOFENAC], p-[(2- methylallyl)amino]hydratropic acid [INN: ALMINOPROFEN], 2-amino-3-benzoylphenylaceticacid [INN: AMFENAC], (plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-car- ' boxamide ethylcarbonate (ester), 1,1-dioxide [INN: AMPIROXICAM], 2-methoxyphenyl-1-methyl-5-(p- methylbenzoyl)pyrrol-2-acetamido-acetate [INN: AMTOLMETINGUACIL], (plus/minus)-2,3-dihydro-5- (4-methoxybenzoyl)-1H pyrrolizine-1-carboxylic acid [INN: ANIROLAC], 2-[4-(alpha,alpha,alpha- trifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthranilate [INN: ANTRAFENINE], 5-(dimethylamino)-9-methyl-2-propyl-1 H-pyrazolo[1 ,2-a][1 ,2,4]benzo-triazine-1 ,3(2H)-dione [INN: AZA- PROPAZONE], 4-acetamidophenyl salicylate acetate [INN: BENORILATE], 2-(8-methyl-10,11- dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid [INN: BERMOPROFEN], 2-[(1-benzyl-1H-indazol- 3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyfjacetic acid [INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN: BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC], butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyi-4- (2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN], 2-(4-biphenylyl)butyric acid, trans-4- phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE], 2-(acetyloxy)-benzoic acid, calcium salt, compound with urea (1:1) [INN: CARBASALATE CALCIUM], (plus/minus)-6-chloro-alpha-methylcarbazole- 2-acetic acid [INN: CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid [INN: CIN- METACIN], N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1 -dioxide [INN: CINNOXICAM], 6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC], 2-[4-(p- chlorophenyl)benzyloxy]-2-methylpropionic acid [INN: CLOBUZARIT], 5-methoxy-2-methyl-3- indolylacetohydroxamic acid [INN: DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN], (+)-(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN], 2-[(2,6-di- chlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], 2',4'-Difluoro-4-hydroxy-3- biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN: EL- TENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide [INN: ETERSALATE], 1 ,8-diethyl-1 ,3,4,9-tetrahydropyrano[3,4- b]indole-1 -acetic acid [INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid 2-(2- hydroxyethoxy)-ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic acid, ester with 4-butyl-4- (hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN: FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC], 3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4- dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC], (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], (plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl alcohol [INN: FEPRADINOL], 4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbutanoic acid [INN: FLOBUFEN], 2,3-dihydroxypropyl N-[8-(trifluoromethyl)-4-quinoly]anthranilate [INN: FLOCTAFENINE], N-(alpha,alpha,alpha-trifluoro-m- tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benz- oxazoleacetic acid [INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biphenylacetic acid [INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL], 2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC], 2-[4-(2'- furoyl)phenyl]propionic acid [INN: FURPROFEN], 2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol- 3-yl]acetamido]-2-deoxy-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionicacid 4-nitrooxybutylester [Research Code: HCT-1026], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl 4-(3-thienyl)phenyl-alpha- methylacetate [Research Code: IDPH-8261], (plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, 3,7,11-trimethyl- 2,6,10-dodecatrienyl ester [INN: INDOMETACIN FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN: INDOPROFEN], 2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic acid [INN: KETOPROFEN], (DL)-5-benzoyl-3H- 1,2-dihydropyrrolo[1,2-a]pyrrole-1-carboxylic acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2- (hydroxymethyl)cinnamyl]benzofuran [Research Code: L-651896], N-(2-carboxyphenyl)-4- chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1-phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN: LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic acid [Research Code: M-5010], N-(2,3- xylyl)anthranilic acid [INN: MEFENAMIC ACID], 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN: MESA- LAZINE], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-acetic acid [Research Code: ML-3000], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], 4-(6- methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE], (plus)-6-methoxy-alpha-methyl-2- naphthalineacetic acid [INN: NAPROXEN], 2-[3-(trifluoromethyI)anilino]nicotinic acid [INN: NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE], 4,5-diphenyl-2-oxazolepropionic acid [INN: OXAPROZIN], alpha-methyl-4-[(2-oxocydohexylidene)methyl]benzene acetic acid [INN: PELUBIPRO- FEN], 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione [INN: PHENYLBUTAZONE], 2-(p- isobutylphenyl)propionic acid 2-pyridyl-methyl ester [INN: PIMEPROFEN], 4-(p-chlorophenyl)-1-(p- fluorophenyl)pyrazole-3-acetic acid [INN: PIRAZOLAC], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2- benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], 3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid [INN: PIRPROFEN], 2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN: PRIFELONE], alpha-cyano-1-methyl- beta-oxopyrrole-2-propionanilide [INN: PRINOMIDE], 3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L- 4-benzamido-N,N-dipropylglutaramat 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (ester) [INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-2(1H)quinazolinone [INN: PRO- QUAZONE], 7-methoxy-alpha,10-dimethylphenothiazine-2-aceticacid [INN: PROTIZI NIC ACID], 2-[[2- (p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT], o- hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester) [INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN: SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyI ester [INN: SALSALATE], 4-[1-(2- fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine [Research Code: SM-8849], (Z)-5-fluoro-2-methyl- 1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid [Research Code: TA-60], phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN: TALNIFLUMATE], (Z)-5-chloro-3-(2- thenoyl)-2-oxoindole-1-carboxamide [INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide [INN: TENOXICAM], 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3- propionamide [INN: TEPOXALIN], alpha-(5-benzoyl-2-thienyl)propionicacid [INN: TIAPROFENIC ACID], 5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiazolin one [INN: TIARAMIDE], 2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-propionic acid N,N- dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL], 1-Cyclohexyl-2-(2-methyl-4- quinolyl)-3-(2-thiazolyl)guanidine [INN: TIM EGADINE], 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine [INN: TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID], 1- methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-aceticacid [INN: TOLMETIN], hydroxybis[alpha-methyl-4-(2- methylpropyl)benzene acetato-0]-aluminium [Research Code: U-18573-G], N-(3- trifluoromethylphenyl)-anthranilic acid n-butyl ester [INN: UFENAMATE], 2-[4-[3- (hydroxyimino)cyclohexyl]phenyl]propionic acid [INN: XIMOPROFEN], 2-(10,11-dihydro-10-oxo- dibenz[b,f]thiepin-2-yl-propioπic acid [INN: ZALTOPROFEN] and 2-[4-(2-thiazolyloxy)phenyl]-propionic acid [INN: ZOLIPROFEN]; or
- a NO-NSAID such as, for example, a NO-NSAID seleded from the group consisting of those NO- NSAIDs which are disclosed in WO 96/32946, WO 96/35416, WO 96/38136, WO 96/39409, WO 00/50037, US 6,057,347, WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641, WO 97/31654, WO 99/44595, WO 99/45004 or WO 01/45703; or
- a COX-2 inhibitor seleded from the group consisting of 5-chloro-6'-methyl-3-[4- (methylsulfonyl)phenyl]-2,3'-bipyridine [INN: ETORICOXIB], 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl]benzene-sulfonamide [INN: CELECOXIB], 4-[p-(methylsulfonyl)phenyl]-3-phenyl- 2(5H)-furanone [INN: ROFECOXIB], N-[[p-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propion- amide [INN: PARECOXIB], p-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide [INN: VALDECOXIB], 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]acetic acid [INN: LUMIRACOXIB], 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzene-sulfonamide [INN: TILMACOXIB], 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzene-sulfonamide [INN: CIMICOXIB], 4'-nitro-2*-phenoxymethanesulfonanilide [INN: NIMESULIDE], 6-(2,4-difluorophenoxy)-5- methylsulfonylamino-1-indanone [INN: FLOSULIDE], 5-bromo-2-(4-fluoro-phenyl)-3-(4- methanesulfonyl-phenyl)-thiophene [DUP-697], 4-acetyl-2-(2,4-difluorophenoxy)methanesulfonanilide [FK-3311], N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide [NS-398], 5-methanesulfonamido- 6-(2,4-difluorophenylthio)-1 -indanone [L-745337], 8-acetyl-3-(4-fluorophenyl)-2-[4- (methanesulfonyl)phenyl]imidazo[1,2-a]- pyridine [GR-253035], 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)pyrazol-1-yl]beFizenesulfon-amide [SC- 58236], 4-(2,3-dihydro-2-oxo-3-phenyl-4-oxazolyl)-benzenesulfonamide [LAS-33815], CS-502, 2-(3,4- difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone [ABT- 963], and GW^t06381, and those COX-2 inhibitors disclosed in WO 02096427, WO 02096886 or WO 02096885; or
- a bisphosphonate selected from the group consisting of ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, CLODRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, PAMIDRONIC ACID and ETIDRONIC ACID; or
- a corticosteroid seleded from the group consisting of HYDROCORTISONE, PREDNISONE, PREDNISOLONE, METHYLPREDNISOLONE, TRIAMCINOLONE ACETONIDE, AMCINONIDE, CLOBETASONE, CLOBETASOL, DEFLAZACORT, DESONIDE, CLOPREDNOL, DEXAMETHASONE, DIFLORASONE, DIFLUCORTOLONE, DIFLUPREDNATE, FLUDROXYCORTIDE, FLUDROCORTISONE, FLUMETASONE, TIXOCORTOL PIVALATE, FLUOCORTIN BUTYL, CLOCORTOLONE, FLUOCINOLONE ACETONIDE, FLUOCORTOLONE, FLUOROMETHOLONE, FLUPREDNIDENE, FLUPREDNISOLONE, BETAMETHASONE, HALCINONIDE, BUDESONIDE, HALOMETASONE, RIMEXOLONE, PARAMETHASONE, PREDNYLIDENE, LOTEPREDNOL ETABONATE, PREDNICARBATE, or a pharmaceutically acceptable derivative of any of these second ingredients.
7. A pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5, wherein the second active ingredient is seleded from the group consisting of glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; 1-(4-chlorobenzoyl)- 5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester [INN: ACEMETACIN]; 2- (acetyloxyjbenzoic acid [ACETYLSALICYLIC ACID], 2-methoxyphenyl-alpha-methyl-4- (isobutyl)phenylacetate [Research Code: AF-2259], (4-allyloxy-3-chlorophenyl)aceticacid [INN: ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN: ALMINOPROFEN], 2-amino-3- benzoylphenylacetic acid [INN: AMFENAC], (plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl- 2H-1,2-benzothiazine-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN: AMPIROXICAM], 2- methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate [INN: AMTOLMETINGUA- CIL], (plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H pyrrolizine-1-carboxylic acid [INN: ANIRO- LAC], 2-[4-(alpha,alpha,alpha-trifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4- quinolyl)anthranilate [INN: ANTRAFENINE], 5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2- a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE], 4-acetamidophenyl salicylate acetate [INN: BENORILATE], 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid [INN: BERMOPROFEN], 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid [INN: BROMFENAC], 3-(3-chloro-4- cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN: BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC], butylmalonic acid mono- (1,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyl-4-(2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN], 2-(4-biphenylyl)butyric acid, trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIX- IRATIJ; 2-(acetyloxy)-benzoic acid, calcium salt, compound with urea (1:1) [INN: CARBASALATE CALCIUM], (plus/minus)-6-chloro-alpha-methylcarbazole-2-acetic acid [INN: CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid [INN: CINMETACIN], N-(2-pyridyl)-2-methyl-4- cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM], 6-chloro-5- cydohexyl-1-indancarboxylic acid [INN: CLIDANACJ, 2-[4-(p-chlorophenyl)benzyloxy]-2- methylpropionic acid [INN: CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN: DEBOXAMET], (S)-(+)-p-isobutylhydratropic add [INN: DEXIBUPROFEN], (+)-(S)-m- benzoylhydratropic acid [INN: DEXKETOPROFEN], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], ^'-Difluoro^-hydroxy-S-biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6- dichloroanilino)-3-thiopheneacetic acid [INN: ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide [INN: ETERSALATE], 1 ,8-diethyl-1 ,3,4,9-tetrahydropyrano[3,4-b]indole-1 -acetic acid [INN: ETODOLAC], 2- [[3-(trifluoromethyl)phenyl]amino]benzoic acid 2-(2-hydroxyethoxy)-ethyl ester [INN: ETO- FENAMATE], p-chlorobenzoic acid, ester with 4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5- pyrazolidinedione [INN: FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC], 3-(4- biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC], (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)- 2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], (plus/minus)-alpha-[[(2-hydroxy-1,1- dimethylethyl)amino]methyl]-benzyl alcohol [INN: FEPRADINOL], 4-(2',4'-difluorobiphenylyl)-4-oxo-2- methylbutanoic acid [INN: FLOBUFEN], 2,3-dihydroxypropyl N-[8-(trifluoromethyl)-4- quinoly]anthranilate [INN: FLOCTAFENINE], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid [INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biphenylacetic acid [INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL], 2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC], 2-[4-(2'- furoyl)phenyl]propionic acid [INN: FURPROFEN], 2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol- 3-yl]acetamido]-2-deoxy-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic acid 4-nitrooxybutylester [Research Code: HCT-1026], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl 4-(3-thienyl)phenyl-alpha- methylacetate [Research Code: IDPH-8261], (plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, 3,7,11-trimethyl- 2,6,10-dodecatrienyl ester [INN: INDOMETACIN FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN: INDOPROFEN], 2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic acid [INN: KETOPROFEN], (DL)-5-benzoyl-3H- 1,2-dihydropyrrolo[1,2-a]pyrrole-1-carboxylic acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2- (hydroxymethyl)cinnamyl]benzofuran [Research Code: L-651896], N-(2-carboxyphenyl)-4- chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1-phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN: LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic acid [Research Code: M-5010], N-(2,3- xylyl)anthranilic acid [INN: MEFENAMIC ACID], 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN: MESA- LAZINE], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-acetic acid [Research Code: ML-3000], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], 4-(6- methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE], (plus)-6-methoxy-alpha-methyl-2- naphthalineacetic acid [INN: NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN: NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE], 4,5-diphenyl-2-oxazolepropionic acid [INN: OXAPROZIN], alpha-methyl-4-[(2-oxocyclohexylidene)methyl]benzene acetic acid [INN: PELUBIPRO- FEN], 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione [INN: PHENYLBUTAZONE], 2-(p- isobutylphenyl)propionic acid 2-pyridyl-methyl ester [INN: PIMEPROFEN], 4-(p-chlorophenyl)-1-(p- fluorophenyl)pyrazole-3-acetic acid [INN: PIRAZOLAC], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2- benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], 3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid [INN: PIRPROFEN], 2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN], 2,6-di-teιt-butyl-4-(2'-thenoyl)phenol [INN: PRIFELONE], alpha-cyano-1-methyl- beta-oxopyrrole-2-propionanilide [INN: PRINOMIDE], 3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L- 4-benzamido-N,N-dipropylglutaramat 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (ester) [INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-2(1H)quinazolinone [INN: PRO- QUAZONE], 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid [INN: PROTIZI NIC ACID], 2-[[2- (p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT], o- hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester) [INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN: SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN: SALSALATE], 4-[1-(2- fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine [Research Code: SM-8849], (Z)-5-fluoro-2-methyl- 1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid [Research Code: TA-60], phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN: TALNIFLUMATE], (Z)-5-chloro-3-(2- thenoyl)-2-oxoindole-1-carboxamide [INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide [INN: TENOXICAM], 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1 H-pyrazole-3- propionamide [INN: TEPOXALIN], alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID], 5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiazolin one [INN: TIARAMIDE], 2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-propionic acid N,N- dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL], 1-Cyclohexyl-2-(2-methyl-4- quinolyl)-3-(2-thiazolyl)guanidine [INN: TIMEGADINE], 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine [INN: TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID], 1- methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN: TOLMETIN], hydroxybis[alpha-methyl-4-(2- methylpropyl)benzene acetato-0]-aluminium [Research Code: U-18573-G], N-(3- trifluoromethylphenyl)-anthranilic acid n-butyl ester [INN: UFENAMATE], 2-[4-[3- (hydroxyimino)cyclohexyl]phenyl]propionicacid [INN: XIMOPROFEN], 2-(10,11-dihydro-10-oxo- dibenz[b,f]thiepin-2-yl-propionic acid [INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]-propionic acid [INN: ZOLIPROFEN], and
5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine [INN: ETORICOXIB], 4-[5-(4- methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide [INN: CELECOXIB], 4-[p- (methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone [INN: ROFECOXIB], N-[[p-(5-methyl-3-phenyl-4- isoxazolyl)phenyl]sulfonyl]propion-amide [INN: PARECOXIB], p-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulfonamide [INN: VALDECOXIB], 2-[2-(2-chloro-6-fluorophenylamino)-5- methylphenyl]acetic acid [INN: LUMIRACOXIB], 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2- fluorobenzene-sulfonamide [INN: TILMACOXIB], 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)-1H- imidazol-1-yl]benzene-sulfonamide [INN: CIMICOXIB], 4'-nitro-2'-phenoxymethanesulfonanilide [INN: NIMESULIDE], 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone [INN: FLOSULIDE], 5- bromo-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-thiophene [DUP-697], 4-acetyl-2-(2,4- difiuorophenoxy)methanesulfonanilide [FK-3311], N-[2-(cyclohexyloxyH- nitrophenyl]methanesulfonamide [NS-398], 5-methanesulfonamido-6-(2,4-difluorophenylthio)-1- indanone [L-745337], 8-acetyl-3-(4-fluorophenyl)-2-[4-(methanesulfonyl)phenyl]imidazo[1 ,2-a]- pyridine [GR-253035], 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)pyrazol-1 -yl]benzenesulfon-amide [SC- 58236], 4-(2,3-dihydro-2-oxo-3-phenyl-4-oxazolyl)-benzenesulfonamide [LAS-33815], CS-502, 2-(3,4- difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone [ABT-
963], GW-406381, and
ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, INCADRONIC ACID, OLPADRONIC
ACID, MINODRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, CLODRONIC ACID,
PAMIDRONIC ACID and ETIDRONIC ACID; or a pharmaceutically acceptable derivative of any of these second ingredients.
8. A pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5, wherein the second adive ingredient is seleded from the group consisting of
ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, FLOCTAFENINE, FLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, MECLOFENAMATE, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, SULINDAC, TENOXICAM, TIAPROFENIC ACID, TOLMETIN, ETORICOXIB, CELECOXIB, ROFECOXIB, PARECOXIB, VALDECOXIB, LUMIRACOXIB, TILMACOXIB, CIMICOXIB, ALENDRONIC ACID, RISEDRONIC ACID, TILUDRONIC ACID, IBANDRONIC ACID, ZOLANDRONIC ACID, INCADRONIC ACID, OLPADRONIC ACID, MINODRONIC ACID, CLODRONIC ACID, PAMIDRONIC ACID and ETIDRONIC ACID, or a pharmaceutically acceptable derivative of any of these second ingredients.
9. A pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5, wherein the second active ingredient is DICLOFENAC or a pharmaceutically acceptable derivative of this compound.
10. A method for prevention of gastrointestinal diseases caused by NSAIDs, COX-2 inhibitors, NO- NSAIDs, bisphosphonates and/or corticosteroids, which comprises administering to a mammal being in need of a NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate and/or corticosteroid therapy, a therapeutically effective amount of (S)-pantoprazole and/or its salt, simultaneously, separately or sequentially with the NSAID, COX-2 inhibitor, NO-NSAID, bisphosphonate and/or corticosteroid.
PCT/EP2005/050335 2004-01-28 2005-01-27 Pharmaceutical combinations of (s) -pantoprazole with nsaid or corticosteroids WO2005074930A1 (en)

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US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
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US8945621B2 (en) 2009-06-25 2015-02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer
US9987231B2 (en) 2011-12-28 2018-06-05 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US10603283B2 (en) 2011-12-28 2020-03-31 Genus Lifesciences, Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid

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