Dihydroxy open-acid and salts of HMG-Co-A reductase inhibitors

Abstract

The instant invention provides methods and pharmaceutical compositions for inhibiting HMG-CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, comprising orally administering a therapeutically effective amount of a compound selected from a dihydroxy open acid statin and a pharmaceutically acceptable salt or ester thereof in a delayed-release pharmaceutical dosage form to a patient in need of such treatment wherein substantial release of the compound from the dosage form is delayed until after passage of the dosage form through the stomach.

What is claimed is:  
     
         1 . An oral pharmaceutical composition comprising a therapeutically effective amount of a compound selected from a dihydroxy open acid statin and a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier, formulated as a delayed-release dosage form wherein substantial release of the compound from the dosage form after oral administration to a patient is delayed until after passage of the dosage form through the stomach.  
     
     
         2 . The pharmaceutical composition of  claim 1  wherein at most 10% by weight of the statin is released into the stomach of a patient after administration.  
     
     
         3 . The pharmaceutical composition of  claim 2  wherein at most 5% by weight of the statin is released into the stomach of a patient after administration.  
     
     
         4 . The pharmaceutical composition of  claim 3  wherein at most 1% by weight of the statin is released into the stomach of a patient after administration.  
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the composition is enterically coated.  
     
     
         6 . The pharmaceutical composition of  claim 5  wherein the dosage form is surrounded by an enteric coating.  
     
     
         7 . The pharmaceutical composition of  claim 5  wherein the dosage form comprises enterically coated granules of the dihydroxy open acid statin or a pharmaceutically acceptable salt or ester thereof.  
     
     
         8 . The pharmaceutical composition of  claim 5  wherein the dosage form comprises enterically coated granules of dihydroxy open acid simvastatin or a pharmaceutically acceptable salt or ester thereof.  
     
     
         9 . The pharmaceutical composition of  claim 5  wherein the dosage form comprises enterically coated granules of the dihydroxy open acid statin or a pharmaceutically acceptable salt or ester thereof, provided that the dosage form does not contain granules of aspirin.  
     
     
         10 . The pharmaceutical composition of  claim 5  wherein the composition is formulated in an enterically coated rapid-release pharmaceutical dosage form.  
     
     
         11 . The pharmaceutical composition of  claim 5  wherein the composition is formulated in an enterically coated time controlled-release pharmaceutical dosage form.  
     
     
         12 . The pharmaceutical composition of  claim 1  wherein the composition is formulated in a drug delivery device comprised of: 
 (A) a compressed core prepared from an admixture comprising: 
 (i) a therapeutically effective amount of the compound; and  
 (ii) a polymer which upon hydration forms gelatinous microscopic particles; and  
 
 (B) a water insoluble, water impermeable polymeric coating comprising a polymer and a plasticizer, which surrounds and adheres to the core, the coating having a plurality of formed apertures exposing between about 1 and about 75% of the core surface;  
 and wherein the release rate of the compound from the device is a function of the number and size of the apertures.  
 
     
     
         13 . The pharmaceutical composition of  claim 12  wherein the drug delivery device is additionally comprised of an enteric overcoat exterior to the water insoluble, water impermeable polymeric coating.  
     
     
         14 . The composition of  claim 1  wherein the statin is selected from the dihydroxy open acid forms of lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin and ZD-4522 and the pharmaceutically acceptable salts and esters thereof.  
     
     
         15 . The composition of  claim 1  wherein the statin is selected from the dihydroxy open acid form of lovastatin, simvastatin and the pharmaceutically acceptable salts and esters thereof.  
     
     
         16 . The composition of  claim 1  wherein the statin is selected from the dihydroxy open acid form of simvastatin and the pharmaceutically acceptable salts and esters thereof.  
     
     
         17 . The composition of  claim 1  wherein the statin is a pharmaceutically acceptable salt of dihydroxy open acid simvastatin.  
     
     
         18 . The composition of  claim 1  wherein the statin is a calcium salt of dihydroxy open acid simvastatin.  
     
     
         19 . The composition of  claim 1  wherein the statin is an ammonium salt of dihydroxy open acid simvastatin.  
     
     
         20 . The composition of  claim 1  wherein the statin is a crystalline hydrated calcium salt of dihydroxy open acid simvastatin having an x-ray powder diffraction pattern obtained using CuKα radiation characterized by reflections at d-spacings of 30.7, 24.6, 15.9, 11.2, 8.58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.93, 3.84, 3.67, 3.51 and 3.28 Å.  
     
     
         21 . The composition of  claim 5  wherein the statin is selected from the dihydroxy open acid form of lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin and ZD-4522 and the pharmaceutically acceptable salts and esters thereof.  
     
     
         22 . The composition of  claim 5  wherein the statin is selected from the dihydroxy open acid form of lovastatin, simvastatin and the pharmaceutically acceptable salts and esters thereof.  
     
     
         23 . The composition of  claim 5  wherein the statin is selected from the dihydroxy open acid form of simvastatin and the pharmaceutically acceptable salts and esters thereof.  
     
     
         24 . The composition of  claim 5  wherein the statin is a pharmaceutically acceptable salt of simvastatin.  
     
     
         25 . The composition of  claim 5  wherein the statin is a calcium salt of dihydroxy open acid simvastatin.  
     
     
         26 . The composition of  claim 5  wherein the statin is an ammonium salt of dihydroxy open acid simvastatin.  
     
     
         27 . The composition of  claim 5  wherein the statin is a crystalline hydrated calcium salt of dihydroxy open acid simvastatin having an x-ray powder diffraction pattern obtained using CuKα radiation characterized by refelections at d-spacings of 30.7, 24.6, 15.9, 11.2, 8.58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.93, 3.84, 3.67, 3.51 and 3.28 Å.  
     
     
         28 . The composition of  claim 27  further comprising BHA.  
     
     
         29 . The composition of  claim 27  further comprising propyl gallate.  
     
     
         30 . The composition of  claim 27  further comprising BHA and propyl gallate.  
     
     
         31 . An oral pharmaceutical composition made by combining a therapeutically effective amount of a compound selected from a dihydroxy open acid statin and a pharmaceutically acceptable salt or ester thereof with a pharmaceutically acceptable carrier in a delayed-release dosage form.  
     
     
         32 . A process for preparing an oral pharmaceutical composition comprising combining a compound selected from a dihydroxy open acid statin and a pharmaceutically acceptable salt or ester thereof with a pharmaceutically acceptable carrier in a delayed-release dosage form.  
     
     
         33 . The composition of  claim 18  wherein the composition is coated with SURETERIC WHITE®.  
     
     
         34 . The composition of  claim 33  wherein the coating of SURETERIC WHITE® surrounds the dosage form.  
     
     
         35 . The composition of  claim 20  wherein the composition is coated with SURETERIC WHITE®.  
     
     
         36 . The composition of  claim 35  wherein the coating of SURETERIC WHITE® surrounds the dosage form.  
     
     
         37 . The composition of  claim 28  wherein the composition is coated with SURETERIC WHITE®.  
     
     
         38 . The composition of  claim 29  wherein the composition is coated with SURETERIC WHITE®.  
     
     
         39 . The composition of  claim 30  wherein the composition is coated with SURETERIC WHITE®.  
     
     
         40 . The composition of  claim 1  wherein the dosage form is comprised of a core tablet, a sub-coat applied over the core tablet and an enteric coat applied over the sub-coat, wherein the core tablet is comprised of a crystalline hydrated calcium salt of dihydroxy open acid simvastatin having an x-ray powder diffraction pattern obtained using CuKα radiation characterized by reflections at d-spacings of 30.7, 24.6, 15.9, 11.2, 8.58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.93, 3.84, 3.67, 3.51 and 3.28 Å, the sub-coat is comprised of a 1:1 ratio hydroxypropyl cellulose:hydroxypropyl methyl cellulose mixture, and the enteric coat is comprised of SURETERIC WHITE®.  
     
     
         41 . The composition of  claim 40  wherein the core tablet is further comprised of an anti-oxidant agent selected from the group consisting of BHA, propyl gallate and combinations thereof.