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WO1993012817A1 - Combinaisons therapeutiques utiles dans le traitement du reflux gastro-×sophagien - Google Patents

Combinaisons therapeutiques utiles dans le traitement du reflux gastro-×sophagien Download PDF

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Publication number
WO1993012817A1
WO1993012817A1 PCT/US1992/010692 US9210692W WO9312817A1 WO 1993012817 A1 WO1993012817 A1 WO 1993012817A1 US 9210692 W US9210692 W US 9210692W WO 9312817 A1 WO9312817 A1 WO 9312817A1
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WO
WIPO (PCT)
Prior art keywords
amino
oxo
methyl
gastrin
cck
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Application number
PCT/US1992/010692
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English (en)
Inventor
David Christopher Horwell
John Cureton Hunter
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Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Publication of WO1993012817A1 publication Critical patent/WO1993012817A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • gastrin exerts many pharmacological effects throughout the gastrointestinal (GI) tract, it appears that its main physiological functions are stimulation of acid secretion in the stomach, and stimulation of mucosal growth in the stomach, small intestine, and colon.
  • GI gastrointestinal
  • the secretory activity of the gastrin-producing G-cell of the gastric antru depen s on the intragastric pH, on the presence c . absence of food in the stomach lumen, and on the activity of several epigastric endocrine, paracrine, or neuronal systems.
  • abolition of acid secretion, as in the achlorhydria of pernicious anemia is accompanied by a marked hypergastrinemia where gastrin levels may reach those seen in patients with gastrinoma, or with Zollinger Ellison syndrome (Yalow, R. S. and Berson, S. A., Radioimmunoassay of gastrin, Gastroenteroloqy 58:1-14 (1970); McGuigan, J. E.
  • Hyperfunction of the G-cell in achlorhydria of pernicious anemia or after vagotomy is associated with increases in G-cell number in the antral mucosa, but the hyperplasia of the G-cell is a consequence of achlorhydria itself, and is independent of the degree of hypergastrinemia.
  • gastric mucosal cells such as the acid-secreting parietal cell, or the histamine-for ing enterochromaffin-like cell (ECL-cel ) , where gastrin has a trophic function
  • the hyperplasia of achlorhydria will be dependent on hypergastrinemia (Becker, H. D., Arnold, R., B ⁇ rger, H.
  • the action of the former class of agent is by antagonism of the receptors for the histamine that has a dominant role in producing secretion of H + -ions by the parietal cell; the latter group inhibit acid secretion by a direct action at sulphydryl groups of the H + /K + -ATPase of the parietal cell membrane.
  • Treatment with either class of compound will produce achlorhydria, and a resulting hypergastrinemia; this in turn will affect the growth of GI mucosal cells.
  • the instant invention concerns pharmaceutical compositions containing a CCK-B/gastrin antagonist or a long-acting and potent H 2 antagonist and an ATP'ase proton pump inhibitor with or without a pharmaceutically acceptable carrier.
  • CCK B antagonists include but are not limited to: L-365-091 which is 1-( (3-( ( ( (4-chlorophenyl)- amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-l-yl)acetyl)-pyrrolidine; and (S)-5-[ (10,ll-dihydrodibenzo[a,d]cyclohepten- 5-yl)amino] -[ (lH-indol-2-yl)carbonyl]amino]-5-oxo- pentanoic acid.
  • L-365,260 which is (R)-N-(2,3-dihydro-l-methyl-2- oxo-5-phenyl-lH-l, -benzodiazepine-3-yl)-N'-(3- methyIpheny1)urea,
  • LY—262,690 which is fcrans-l-Pyrazolidinecarboxa- mide, 5-(2-chlorophenyl) -3-oxo-4-phenyl-N- [A-(tri- luoromethyl)pheny1]-,
  • LY-262,691 which is trans-5-(2-chlorophenyl)- 3-oxo-4-phenyl-N-[4-(bromo)phenyl]-1-pyrazolidine- carboxamide, and trans—l-pyrazolidinecarboxamide-N-(4- bromophenyl)-5-(2-chlorophenyl)-3-oxo-4-phenyl-.
  • R 1 is 2,3-dichloro, 3,4-(CH 2 ) 4 , 4-CF 3 , or 4-Br;
  • R 2 is hydrogen, 2-chloro, 2,3—dichloro, or CN; and R 3 is hydrogen -trans or -cis.
  • X 0 is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl
  • X j! is hydrogen, fluorine, chlorine, bromine, methyl ethyl isopropyl, methoxy, trifluoromethyl, propoxy, isopropoxy, cyclopentyloxyl, MeS, or NMe 2 ;
  • X p is hydrogen, methoxy, ethoxy, isopropoxy, isopropyl, MeS, or NMe 2 ; or X_, and X_ together are -OCH 2 0-; Y is hydrogen, methyl, methoxy, fluorine, chlorine, or bromine; and
  • R is hydrogen or methyl
  • Proton pump inhibitors include but are not limited to: omeprazole, BY308, SK&F 95601 which is 2-[[ (3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]- 5-methoxy-(IH)-benzimidazole; and SK&F 96067 which is 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline.
  • the instant invention also includes a method of treating peptic disorders such as gastroesophageal reflux disease and ulcers.
  • the instant invention also includes a method of treating Zollinger-Ellison Syndrome.
  • compositions of the instant invention contain from 0.1 mg/kg to 10 mg/kg of a CCK-B antagonist and from 10 mg to 360 g of an ATP'ase proton pump inhibitor.
  • Figure I shows serum gastrin levels in venous blood from rats.
  • Figure II shows enterochromaffin-like cell (ECL) proliferation in the corpus of rat gastric mucosa.
  • Irreversible proton pump inhibitors such as omeprazole, BY308, and others are extremely effective in gastroesophageal reflux disease (GERD) , as indeed are the longer acting and potent H 2 antagonists, as well as in all other peptic disorders caused or aggravated by gastric acid.
  • GFD gastroesophageal reflux disease
  • a long-acting H 2 antagonist means dosing usually is once per day; that is once in 24 hours, usually nocturnally.
  • the compounds cause carcinoid tumors in animals because of the elevated levels of gastrin. This problem means that the duration of treatment with, for example, omeprazole in GERD is restricted.
  • Gerd is a chronic problem and the relief to sufferers provided by existing treatments renders them dependent on permanent therapy.
  • Proton pump inhibitors are also useful in the treatment of ulcers but the same problems pertain to the use of the drugs for ulcer treatment.
  • Proton pump inhibitors are also useful in the long-term treatment of Zollinger-Ellison syndrome.
  • the pharmaceutical compositions of the instant invention that contain combinations of an ATP'ase proton pump inhibitor and a CCK-B antagonist are useful for all of the above problems.
  • a CCK-B antagonist blocks the cellular hypertrophy of gastric mucosal cells.
  • Gastrin has been implicated as a growth factor in many areas of the gastrointestinal and respiratory tracts.
  • G-cell mass in the gastric mucosa.
  • ECL enterochromaffin-like cells
  • gastric carcinoid tumors formed from ECL cell hyperplasia in omeprazole-treated rats are related to the achlorhydria and secondary hypergastrinemia produced by the drug. If this is the case then treatment with gastrin antagonists should- inhibit this omeprazole—induced phenomeno .
  • gastrin-dependent tumors include a human small cell carcinoma of the lung, which was recently reported to contain CCK-B/gastrin receptors, and a mouse carcinoid tumor of the colon.
  • CCK-B/gastrin antagonist compounds of the instant invention are able to block acid secretion in the rat in response to stimulation by pentagastrin
  • Proton pump inhibitors such as omeprazole, 5-methoxy-2-[ [ (4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]sulfinyl]-IH-benzimidazole, which are described and claimed in United States Patent 4,255,431, are useful in the instant invention.
  • the patent is hereby incorporated by reference.
  • proton pump inhibitors include but are not limited to: [[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl]- methyl]sulfenamide;
  • Figure I concerns serum gastrin levels. It shows levels of gastrin-like immunoreactivity in venous blood from rats, before and after 1, 4, 7, or 14 days of treatment with vehicles (veh/veh: isotonic saline 3 subcutaneous injections at 8-hour intervals, methocel orally at 8:00 a.m.)
  • Compound 1 which is [R-[R*,S*-(E) ] ] ] -A-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.l 3,7 ]dec-2-yloxy)- carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4- oxo-2-butenoic acid, 18 mg/kg thrice daily (veh/1189) , BY 308 40 mg/kg orally in methocel (308/veh) or BY 30
  • Figure II concerns ECL-cell proliferation in the corpus. It shows the uptake of 3 H-thymidine into enterochromaffin-like cells (ECL-cell) of rat gastric mucosa after 14 days of treatments (as Figure 1) ; and labelled ECL-cells as a percentage of total ECL-cell count in the field ("labelling index") .
  • I ⁇ M is Methocel/NaCl; &22Z229 i- s Methocel/compound 1; is BY308/NaCl; and ⁇ g is BY308/compound 1.
  • Fe ale Sprague-Dawley rats were used with free access to lab diet and water. Groups of 10 animals were treated three times daily with 18 mg/kg of compound 1 for 14 days as follows:
  • Blood was drawn from the retro-orbital venous plexus before treatment on Days 0, 1, 4, 7, and 14 for assay of serum gastrin and CCK levels.
  • H-thymidine was infused into a tail vein (1 ⁇ ci/g body weight as a bolus injection, followed by continuous infusion for 8 hours of 0.25 ⁇ Ci/g/h) , for subsequent measurement of ECL-cel labeling index by autoradiography.
  • Optimal tissue preservation was achieved by perfusion fixation in Bouin's fixative for 8 minutes, and by fixation for 24 hours of excised tissue blocks in Bouin's solution, with embedding in paraffin wax.
  • 5 ⁇ m sections were cut; 2 ⁇ m for autoradiography (Eissele, R., Rosskopf, B., Koop, H., Adler, G., and Arnold, R.,
  • Antral G-cells were visualized after removal of the paraffin wax by immunostaining for gastrin using the avidin-biotin-peroxidase complex technique (Hsu, S. M., Raine, L., and Fanger, H., Use of avidin- biotin-peroxidase complex (ABC) in immunoperoxidase techniques; a comparison between ABC and unlabeled antibody (PAP) procedures, J Histochem Cvtochem 29:577-780 (1981)) .
  • avidin-biotin-peroxidase complex technique Hsu, S. M., Raine, L., and Fanger, H., Use of avidin- biotin-peroxidase complex (ABC) in immunoperoxidase techniques; a comparison between ABC and unlabeled antibody (PAP) procedures, J Histochem Cvtochem 29:577-780 (1981)
  • ECL-cell density was evaluated in sections of oxyntic mucosa by the silver impregnation method or by immunostaining for chromogranin for autoradiographic studies (Grimelius, L., A silver nitrate stain for A 2 cells of human pancreatic islets, Acta Soc Med Ups 73:271-294 (1968) ) .
  • Gastrin levels in unfixed sections of antrum and somatostatin in the fundus were measured by radioimmunoassay. Unfixed samples of pancreas were taken to assay for enzyme and DNA levels by standard methods. .
  • Antral mucosal G-cells were increased from 56/mm (saline + methocel), or 60 ⁇ mm ( ( [R-[R*,S*-(E) ] ]-4-[ [2- [[3-(lH-indol-3-yl)-2-methyl-l-oxo-2-[ [ (tricyclo- [3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]amino]propyl]amino]-3- phenylpropyl]amino]-4-oxo-2-butenoic acid, + methocel) to 75/mm and 88/mm in the corresponding groups given BY 308.
  • the increases by BY 308 were statistically significant at the 2% level. That is, the increase in G-cell number is attributable to the achlorhydria, and is obtained in either group treated with BY 308.
  • CCK B /gastrin antagonists are expected to have clinical utility in the periphery, in the management of gastrin-dependent hyperplasias.
  • compositions or combinations of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides pharmaceutical compositions comprising a compound which is a CCK-B/gastrin antagonist (or a long-acting and potent H 2 antagonist) or a pharmaceutically acceptable salt thereof and a proton pump inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, if desired.
  • composition can be given orally formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules, and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound of pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, nonaqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, nonaqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose, and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates, or oils, and the dispersion or suspension, then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil.
  • a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins, or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • composition is in unit dose form such as a tablet or capsule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains pre erably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the pharmaceutically acceptable compositions of the invention will normally be administered to a subject for the treatment of peptic disorders and other conditions caused or exacerbated by gastric acidity.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example, for a week or more.
  • composition of the present invention can be coadministered with further active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminum hydroxide) , nonsteroidal antiinflammatory drugs (for example, indomethacin, aspirin, or naproxen) , steroids, or nitrite scavengers (for example, ascorbic acid or aminosulphonic acid) , or other drugs used for treating gastric ulcers (for example, pirenzepine, prostanoids, for example, 16, 16-dimethyl PGE 2 , or histamine H 2 -antagonists (for example, cimetidine, ranitidine, famotidine, and mareatidine) .
  • active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminum hydroxide) , nonsteroidal antiinflammatory drugs (for example, indomethacin, aspirin, or naproxen) , steroids, or nitrite scavengers (for example, as
  • a syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:
  • Flavoring agent 0.1 g
  • Phenylacetic acid (54.46 g, 0.4 M) was dissolved in acetic anhydride (80 mL) .
  • O-chlorobenzaldehyde (56.23 g, 0.4 M) was added slowly, with stirring. This was followed by the slow addition of triethylamine (40 mL) .
  • the reaction mixture was stirred at reflux for 5 hours.
  • the reaction mixture was steam distilled until the distillate was no longer cloudy.
  • the distillate was discarded.
  • the aqueous residue was cooled.
  • the solution was decanted from the gummy solid. This solid was dissolved in a 10% K 2 C0 3 solution.
  • the basic solution was charcoaled then filtered through a pooled Super cell.
  • the filtrate was made acidic (pH 1) with 10% HC1, cooled, and the solid filtered.
  • the product was recrystallized from 50% ethanol/H 2 0 to yield 52.14 g of white solid, mp 158
  • Step 2 Preparation of c-phenyl-2-chlorocinnamic acid methyl ester oPhenyl-2-chlorocinnamic acid (26.29 g (0.102 M) was dissolved in ethanol (300 cc) . Anhydrous HC1 was bubbled through the reaction mixture with stirring for 15 minutes. The reaction mixture was refluxed for 2 hours, then HC1 was bubbled through the reaction mixture for another 15 minutes. The reaction was stirred at reflux overnight. The methanol was removed in vacuo and the residue taken up in ether. The ether solution was washed with H 2 0, saturated NaHC0 3 solution, and brine. It was then dried over MgS0 4 . The ether solution was concentrated in vacuo to yield an oil that quickly solidified to yield 27.13 g of product, mp 67-69°C.

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Abstract

L'invention concerne des combinaisons d'inhibiteurs de pompage de protons et d'antagonistes de la gastine/CCK-B dans les compositions pharmaceutiques qui sont utiles dans le traitement de troubles peptiques tels que des ulcères et reflux gastro-÷sophagiens ainsi que dans le traitement du syndrome Zollinger-Ellison.
PCT/US1992/010692 1991-12-20 1992-12-11 Combinaisons therapeutiques utiles dans le traitement du reflux gastro-×sophagien WO1993012817A1 (fr)

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US81148791A 1991-12-20 1991-12-20
US811,487 1997-03-05

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069438A1 (fr) * 1999-05-13 2000-11-23 Astrazeneca Ab Combinaison pharmaceutique d'antagoniste du recepteur de la neurokinine et d'inhibiteur de la pompe a protons
WO2000071122A1 (fr) * 1999-05-20 2000-11-30 Par Pharmaceutical, Inc. Composition stabilisee a base de pyridinyl-sulfinyl-benzimidazole et procede associe
US6303644B1 (en) 1997-07-25 2001-10-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Proton pump inhibitor in therapeutic combination with antibacterial substances
WO2001085724A1 (fr) * 2000-05-08 2001-11-15 James Black Foundation Limited Ligands (iii) des recepteurs de la cholecystokinine et de la gastrine
WO2001085167A1 (fr) * 2000-05-08 2001-11-15 James Black Foundation Limited Compositions pharmaceutiques comprenant des inhibiteurs de la pompe a protons et des ligands du recepteur des gastrines/cholecystokinines
WO2001077685A3 (fr) * 2000-04-10 2002-07-25 Gen Hospital Corp Diagnostique et traitement de maladie gastro-intestinale
US6926907B2 (en) 2001-06-01 2005-08-09 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
WO2006051312A1 (fr) * 2004-11-15 2006-05-18 James Black Foundation Limited Ligands de récepteur de la gastrine et de la cholécystokinine
EP1747800A1 (fr) * 2005-07-29 2007-01-31 Rottapharm S.p.A. Combinaison d'itriglumide et de PPI pour traiter des conditions gastro-intestinales et reliées
CN100348196C (zh) * 2001-11-13 2007-11-14 詹姆士布莱克基金会有限公司 作为胃泌激素和缩胆囊肽受体配体的苯并三氮杂䓬
US7524837B2 (en) 2003-05-12 2009-04-28 Janssen Pharmaceutica N.V. Benzotriazapinone salts and methods for using same
US7736666B2 (en) 2000-03-08 2010-06-15 Nicox S.A. Self emulsifying drug delivery system
US7815933B2 (en) 2001-09-07 2010-10-19 Nicox S.A. Self emulsifying drug delivery system
US7863330B2 (en) 2006-06-14 2011-01-04 Rottapharm S.P.A. Deloxiglumide and proton pump inhibitor combination in the treatment of gastrointestinal disorders
US8852636B2 (en) 2001-06-01 2014-10-07 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8945621B2 (en) 2009-06-25 2015-02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer
WO2015077572A1 (fr) * 2013-11-22 2015-05-28 CL BioSciences LLC Antagonistes de gastrine (eg yf476, nétazépide) pour le traitement et la prévention de l'ostéoporose
US9220698B2 (en) 2008-09-09 2015-12-29 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid

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Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6303644B1 (en) 1997-07-25 2001-10-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Proton pump inhibitor in therapeutic combination with antibacterial substances
WO2000069438A1 (fr) * 1999-05-13 2000-11-23 Astrazeneca Ab Combinaison pharmaceutique d'antagoniste du recepteur de la neurokinine et d'inhibiteur de la pompe a protons
WO2000071122A1 (fr) * 1999-05-20 2000-11-30 Par Pharmaceutical, Inc. Composition stabilisee a base de pyridinyl-sulfinyl-benzimidazole et procede associe
US7736666B2 (en) 2000-03-08 2010-06-15 Nicox S.A. Self emulsifying drug delivery system
WO2001077685A3 (fr) * 2000-04-10 2002-07-25 Gen Hospital Corp Diagnostique et traitement de maladie gastro-intestinale
WO2001085724A1 (fr) * 2000-05-08 2001-11-15 James Black Foundation Limited Ligands (iii) des recepteurs de la cholecystokinine et de la gastrine
WO2001085167A1 (fr) * 2000-05-08 2001-11-15 James Black Foundation Limited Compositions pharmaceutiques comprenant des inhibiteurs de la pompe a protons et des ligands du recepteur des gastrines/cholecystokinines
GB2377442A (en) * 2000-05-08 2003-01-15 Black James Foundation Gastrin and cholecystokinin receptor ligands (III)
GB2379387A (en) * 2000-05-08 2003-03-12 Black James Foundation Pharmaceutical compositions comprising proton pump inhibitors and gastrin/cholecystokinin receptor ligands
GB2377442B (en) * 2000-05-08 2004-08-04 Black James Foundation Gastrin and cholecystokinin receptor ligands (III)
GB2379387B (en) * 2000-05-08 2004-10-06 Black James Foundation Pharmaceutical compositions comprising proton pump inhibitors and gastrin/cholecystokinin receptor ligands
US7034048B2 (en) 2000-05-08 2006-04-25 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands (III)
US9345695B2 (en) 2001-06-01 2016-05-24 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US6926907B2 (en) 2001-06-01 2005-08-09 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9707181B2 (en) 2001-06-01 2017-07-18 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9198888B2 (en) 2001-06-01 2015-12-01 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8865190B2 (en) 2001-06-01 2014-10-21 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8858996B2 (en) 2001-06-01 2014-10-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDS
US8852636B2 (en) 2001-06-01 2014-10-07 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9161920B2 (en) 2001-06-01 2015-10-20 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9364439B2 (en) 2001-06-01 2016-06-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US7815933B2 (en) 2001-09-07 2010-10-19 Nicox S.A. Self emulsifying drug delivery system
CN100348196C (zh) * 2001-11-13 2007-11-14 詹姆士布莱克基金会有限公司 作为胃泌激素和缩胆囊肽受体配体的苯并三氮杂䓬
US7524837B2 (en) 2003-05-12 2009-04-28 Janssen Pharmaceutica N.V. Benzotriazapinone salts and methods for using same
WO2006051312A1 (fr) * 2004-11-15 2006-05-18 James Black Foundation Limited Ligands de récepteur de la gastrine et de la cholécystokinine
GB2435190A (en) * 2004-11-15 2007-08-15 Black James Foundation Gastrin and cholecystokinin receptor ligands
US7846921B2 (en) 2005-07-29 2010-12-07 Rottapharm, S.P.A. Method of relieving symptoms of gastroesophageal reflux disease
WO2007014872A1 (fr) * 2005-07-29 2007-02-08 Rottapharm S.P.A. Combinaison d'itriglumide et d’inhibiteurs de la pompe à proton dans le traitement de troubles gastro-intestinaux et apparentés
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EP3071206B1 (fr) 2013-11-22 2021-02-17 CL Biosciences LLC Antagonistes du gastrin (par exemple yf476, netazepide) pour le traitement et la prevention de l' osteoporose
KR102254957B1 (ko) 2013-11-22 2021-05-25 씨엘 바이오사이언시즈 엘엘씨 골다공증 치료 및 예방을 위한 가스트린 길항제(ｅｇ ｙｆ476, 네타제피드)

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