Parenteral formulations of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea
AssigneeBoehringer Ingelheim Pharmaceuticals, Inc.
InventorsMichael L. Cappola, Susan Lynn Way
Life of this patent
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Abstract
Disclosed are formulations and compositions comprising, and process for preparing, improved parenteral dosage forms of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea. Also disclosed are methods of treating cytokine mediated diseases using such formulations and compositions.
Claims27
A pharmaceutical parenteral dosage formulation comprising:
- (a) a pharmaceutically effective amount of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
- (b) a pharmaceutically non-toxic amount of an oligosaccharide capable of forming an association or complex with 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea in its aqueous state.
A dry powder formulation for parenteral administration upon reconstitution with a diluent, said powder comprising 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and β-cyclodextrin.
A pharmaceutical composition comprising a pharmaceutically acceptable vehicle and a lyophilized 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and cyclodextrin fraction, said lyophilized fraction being produced by a process comprising:
- (a) combining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea with a cyclodextrin compound in a pharmaceutically acceptable solvent;
- (b) freezing the mixture of step (a) at a temperature of about −10° C. to about −196° C. to form a frozen fraction;
- and
- (c) lyophilizing said frozen fraction to obtain a lyophilized 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and cyclo-dextrin fraction.
A pharmaceutical composition in the form of a dry powder comprising 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and cyclodextrin, wherein said dry powder contains less than 25% water.
A lypholized powder comprising 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and a cyclodextrin in a ratio of greater than 1:1.
A dry powder comprising 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and a cyclodextrin in a ratio of greater than 1:1 made by the method comprising the steps of:
- a. combining the cyclodextrin with a solvent to form a first solution;
- b. admixing the 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea into said first solution;
- c. drying the resultant solution of step b.
A method for parenterally delivering 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea comprising the steps of admixing a cyclodextrin and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea in a solvent, removing the solvent by drying to produce a dry powder formulation, and reconstituting the dry powder formulation with a pharmaceutically-acceptable solvent.
A parenteral pharmaceutical formulation of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea which is stabilized against decomposition said formulation comprising 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea in aggregation with stabilizing amounts of a cyclodextrin wherein said 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and cyclodextrin are present in a weight ratio of about 1:1 to about 1:1000.
Dependencies are inferred from the claim text.