Pharmaceutical dosage forms comprising a low-solubility drug and a polymer

Abstract

A dosage form comprises a low-solubility drug, and a precipitation-inhibiting polymer. The drug is in a solubility-improved form and in the form of particles at least partially coated with the precipitation-inhibiting polymer. Exemplified low-solubility drugs are ziprasidone and sildenafil. Exemplified precipitation-inhibiting polymer is HPMCAS.

1 . A dosage form comprising a low-solubility drug and a precipitation-inhibiting polymer, said low-solubility drug being in a solubility-improved form and in the form of particles at least partially coated with said precipitation-inhibiting polymer, wherein when said particles at least partially coated with said precipitation-inhibiting polymer are tested in an in vitro dissolution test, said particles at least partially coated with said precipitation-inhibiting polymer provide concentration enhancement of dissolved drug in an in vitro use environment relative to a control composition consisting of an equivalent amount of said drug in said solubility-improved form alone. 
     
     
         2 . The dosage form of  claim 1  further comprising an excipient. 
     
     
         3 . The dosage form of  claim 1  wherein at least a portion of said particles are completely coated by said precipitation-inhibiting polymer. 
     
     
         4 . The dosage form of  claim 1  wherein at least a portion of said drug is present as aggregated particles bound together by said precipitation-inhibiting polymer. 
     
     
         5 . The dosage form of  claim 1  wherein said particles have a mean particle size of less than about 100 microns. 
     
     
         6 . The dosage form of  claim 1  wherein said solubility-improved form of said drug comprises a cyclodextrin. 
     
     
         7 . The dosage form of  claim 1  wherein a weight ratio of said polymer to said drug is at least 0.11. 
     
     
         8 . The dosage form of  claim 1  wherein said particles at least partially coated with said precipitation-inhibiting polymer, when administered to said in vitro use environment, provide at least one of
 (a) a maximum dissolved concentration of said drug in said use environment that is at least 1.25-fold that provided by said control composition; and   (b) a concentration of said compound in said use environment versus time area under the curve (AUC) for any period of at least 90 minutes between the time of introduction into said use environment and about 270 minutes following introduction to said use environment that is at least 1.25-fold that of said control composition.   
     
     
         9 . The dosage form of  claim 1  wherein said particles at least partially coated with said precipitation-inhibiting polymer, when administered in vivo, provide at least one of
 (c) a concentration of said drug versus time area under the curve (AUC) in the blood plasma or serum that is at least 1.25-fold that of said control composition; and   (d) a maximum concentration of said compound in the blood plasma or serum that is at least 1.25-fold that of said control composition.   
     
     
         10 . The dosage form of  claim 1  wherein said particles at least partially coated with said precipitation-inhibiting polymer provide a maximum flux in a membrane permeation test that is greater than the maximum flux provided by said control composition. 
     
     
         11 . A process for forming a dosage form, comprising:
 (a) providing a low-solubility drug in a solubility-improved form;   (b) at least partially coating said low-solubility drug with a precipitation-inhibiting polymer to form precipitation-inhibiting polymer coated drug particles;   (c) combining said precipitation-inhibiting polymer coated drug particles with an excipient;   (d) forming said precipitation-inhibiting polymer coated drug particles and said excipient into a dosage form.   
     
     
         12 . The process of  claim 11  wherein said step (b) is conducted by spray drying a suspension comprising said precipitation-inhibiting polymer, said solubility-improved form of said drug, and a solvent, wherein said precipitation-inhibiting polymer is substantially dissolved in said solvent, and wherein said solubility-improved form of said drug is substantially not dissolved in said solvent. 
     
     
         13 . The product of the process of  claim 11 . 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The dosage form of  claim 1  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The dosage form of  claim 2  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The dosage form of  claim 3  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The dosage form of  claim 4  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The dosage form of  claim 5  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The dosage form of  claim 6  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The dosage form of  claim 7  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The dosage form of  claim 8  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The dosage form of  claim 9  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The dosage form of  claim 10  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The process of  claim 11  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The process of  claim 12  wherein the low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A product of a process according to  claim 26 .