Oral pharmaceutical compositions of mesalazine

Abstract

Described herein arc pharmaceutical compositions for the oral administration of mesalazine, as well as methods of making such pharmaceutical compositions, and therapeutic methods for using them. The compositions comprise delayed-immediate release and delayed-extended release formulation of mesalazine.

1 .- 41 . (canceled) 
     
     
         42 . A unit dose pharmaceutical product for the oral administration of mesalazine to a subject, comprising:
 (a) a plurality of delayed-immediate release minitablets comprising a compressed matrix comprising mesalazine provided with a pH-dependent enteric coating comprising one or more polymers selected from the group consisting of methacrylic acid and ethyl acrylate copolymer 1:1, hypromellose acetate succinate, and hypromellose phthalate, wherein the delayed-immediate release minitablets selectively release mesalazine at a pH of about 5.5or greater in the distal ileum; and   (b) a plurality of delayed-extended release minitablets comprising a compressed matrix comprising mesalazine provided with an inner pH-independent extended release coating comprising ethyl cellulose and hydroxypropyl methylcellulose and an outer pH-dependent enteric coating comprising one or more polymers selected from the group consisting of methacrylic acid and methyl methacrylate copolymer 1:2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) [7:3:1] and hypromellose acetate succinate, wherein the delayed-extended release minitablets selectively release mesalazine at a pH of about 7 or greater in the colon;   wherein:   the relative amounts of (a) and (b) in the unit dose pharmaceutical product are such that from 10 to 90% w/w of the mesalazine provided in the unit dose pharmaceutical is present in the delayed-extended release minitablets of (b);   the total amount of mesalazine in the unit dose pharmaceutical product is from about 0.4 to 6 g.   
     
     
         43 . The unit dose pharmaceutical product of  claim 42 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer, the delayed-immediate release minitablets exhibit substantially no release of mesalazine at pH 1.2 and pH 4.5, and release substantially all mesalazine within 120 minutes at pH 7.0. 
     
     
         44 . The unit dose pharmaceutical product of  claim 42 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0, the delayed-immediate release minitablets exhibit substantially no release of mesalazine at pH 1.2 and pH 4.5, and release substantially all mesalazine within 90 minutes at pH 7.0. 
     
     
         45 . The unit dose pharmaceutical product of  claim 42 , wherein the delayed-immediate release minitablets of (a) release at least 50% w/w of their total mesalazine content in the distal ileum. 
     
     
         46 . The unit dose pharmaceutical product of  claim 42 , wherein the delayed-immediate release minitablets of (a) release at least 30% w/w of their total mesalazine content in the distal ileum. 
     
     
         47 . The unit dose pharmaceutical product of  claim 42 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, the delayed-extended release minitablets exhibit substantially no release of mesalazine at pH 1.2 and pH 4.5, and exhibit extended release of mesalazine over at least 4 hours at pH 7.0. 
     
     
         48 . The unit dose pharmaceutical product of  claim 42 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, the delayed-extended release minitablets exhibit substantially no release of mesalazine at pH 1.2 and pH 4.5, and exhibit extended release of mesalazine over at least 6 hours at pH 7.0. 
     
     
         49 . The unit dose pharmaceutical product of  claim 42 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, the delayed-extended release minitablets exhibit substantially no release of mesalazine at pH 1.2 and pH 4.5, and exhibit extended release of mesalazine over at least 8 hours at pH 7.0. 
     
     
         50 . The unit dose pharmaceutical product of  claim 42 , wherein, when subject to in vitro dissolution testing according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, the delayed-extended release minitablets exhibit substantially no release of mesalazine at pH 1.2 and pH 4.5, and exhibit extended release of mesalazine over at least 12 hours at pH 7.0. 
     
     
         51 . The unit dose pharmaceutical product of  claim 42 , wherein the delayed-extended release minitablets of (b) release at least 50% w/w of their total mesalazine content in the colon. 
     
     
         52 . The unit dose pharmaceutical product of  claim 42 , wherein the delayed-extended release minitablets of (b) release at least 70% w/w of their total mesalazine content in the colon. 
     
     
         53 . The unit dose pharmaceutical product of  claim 42 , wherein the total amount of mesalazine in the unit dose pharmaceutical product is about 2 g or about 4 g. 
     
     
         54 . The unit dose pharmaceutical product of  claim 42 , wherein the compressed matrix of (a) and the compressed matrix of (b) comprise at least 85% w/w mesalazine and, optionally, one or more selected from a pharmaceutically acceptable binder, a pharmaceutically acceptable filler, and a pharmaceutically acceptable lubricant. 
     
     
         55 . The unit dose pharmaceutical product of  claim 42 , wherein the compressed matrix of (a) and the compressed matrix of (b) comprise micronized mesalazine. 
     
     
         56 . The unit dose pharmaceutical product of  claim 55 , wherein the micronized mesalazine has a particle size distribution such that one or both of (i) the 90 th  percentile, D(v,0.9), is no more than 30 μm and (ii) a typical value D(v,0.9) is about 16-17 μm. 
     
     
         57 . The unit dose pharmaceutical product of  claim 42 , wherein one or both of the minitablets of (a) and the minitablets of (b) further comprise a seal coat exterior to the pH-dependent enteric coating. 
     
     
         58 . The unit dose pharmaceutical product of  claim 42 , wherein the minitablets of (a) and the minitablets of (b) have a longest diameter of 1-4 mm or a length of 1-4 mm. 
     
     
         59 . The unit dose pharmaceutical product of  claim 42 , wherein the minitablets of (a) and the minitablets of (b) are provided in a sachet, capsule, or vial. 
     
     
         60 . A method of administering mesalazine to a subject in need thereof, comprising orally administering to the subject a unit dose pharmaceutical product according to  claim 42 . 
     
     
         61 . A method of treating inflammatory bowel disease, such as ulcerative colitis and mild-to-moderate Crohn's disease, comprising orally administering to the subject a unit dose pharmaceutical product according to  claim 42 .