Pharmaceuticals formulation

Abstract

A solid, oral, controlled release pharmaceutical dosage form comprising a pharmaceutically active ingredient having a solubility in water of greater than 1 gm in 250 ml water at 25° C., the active ingredient dispersed in a matrix wherein the dosage form provides, as tested by the Ph. Eur. Basket method at 100 rpm 900 ml aqueous buffer (pH 6.5) containing 0.05% w/w Polysorbate 80 at 37° C., an essentially zero order rate of release of the pharmaceutically active ingredient over a period of 8 hours, the amount of pharmaceutically active ingredient released over eight hours being in the range of 15% to 45%, and when tested in a group of at least five healthy humans the median tmax, based on blood sampling at half hourly intervals, is in the range of from about 2.5 to about 6 hours, and the ratio of mean Cmax to the mean plasma level at 24 hours is in the range of about 1.5 to about 3.5.

1 . A solid, oral, controlled release pharmaceutical dosage form which comprises a pharmaceutically active ingredient having a solubility in water of greater than 1 gm in 250 ml water at 25° C. dispersed in a matrix and wherein the dosage form when tested by the Ph. Eur Basket method at 100 rpm 900 ml aqueous buffer (pH 6.5) containing 0.05% w/w Polysorbate 80 at 37° C. has an essentially zero order rate of release of the pharmaceutically active ingredient over a period of 8 hours, the amount of pharmaceutically active ingredient released over eight hours being in the range of 15% to 45%, and when tested in a group of at least five healthy humans the median tmax, based on blood sampling at half hourly intervals, is in the range of from 2.5 to 6 hours, and the ratio of mean Cmax to the mean plasma level at 24 hours is in the range of 1.5 to 3.5.  
     
     
         2  A pharmaceutical dosage form according to  claim 1 , wherein the median tmax is in the range from 2.5 to 3.5 hours  
     
     
         3  A pharmaceutical dosage form, according to any one of the preceding claims which has a W 50  in the range from 15 to 35 hours, preferably from 20 to 30 hours, when tested in vivo as set forth in  claim 1 .  
     
     
         4  A pharmaceutical dosage form according to  claim 1 ,  2  or  3 , wherein the matrix comprises a mixture of an hydrophobic, fusible material having a melting point of greater than 40° c and a hydrophilic, organic, polymeric fusible wicking agent  
     
     
         5  A pharmaceutical dosage form according to any one of  claim 4  wherein the weight ratio of hydrophobic fusible material to hydrophilic, organic polymeric wicking agent in the said mixture is in the range from 8:1 to 16.1  
     
     
         6  A pharmaceutical dosage form according to any one of the preceding claims, in which the pharmaceutically active ingredient is a pharmaceutically acceptable salt of morphine, preferably morphine sulphate or morphine hydrochloride.  
     
     
         7  A pharmaceutical dosage form according to  claim 5 , which is suitable for once a day dosing.  
     
     
         8  A pharmaceutical dosage form according to any one of the preceding claims, in the form of a tablet or a capsule containing multiparticulates.  
     
     
         9  A process for preparing a dosage form according to any one of the preceeding claims comprising: 
 (a) mechanically working in a high shear mixer a mixture of hydrophobic fusible binder and a minor amount of an organic, fusible, polymeric material which in the finished dosage form is capable of functioning as a wicking agent at a speed and temperature at which the binder melts or softens and the mixture forms agglomerates;  
 (b) extruding the agglomerates whereby the extrudate is obtained as extruded pieces or an elongate extrudate is formed into pieces;  
 (c) continuing mechanically working the pieces in a high shear mixer; and  
 (d) continuing mechanically working with additional binder material at a temperature and speed at which the additional binder melts or softens.  
 
     
     
         10  A process according to  claim 8 , wherein in stage (d) the additional binder melts or softens and binds with the particles  
     
     
         11  A solid, oral, controlled release pharmaceutical dosage form which comprises a pharmaceutically active ingredient having a solubility in water of greater than 1 gm in 250 ml water at 25° C. dispersed in a matrix, the dosage form being obtainable by a process as defined in  claim 9  or claim  10 .