Controlled Absorption Water-Soluble Pharmaceutically Active Organic Compound Formulation for Once-Daily Administration

Abstract

The present disclosure provides a once-daily water-soluble pharmaceutically active formulation for oral administration. In certain embodiments, the composition comprises a watersoluble pharmaceutically active organic compound incorporated into a small particulate, each particulate having a core of the water-soluble pharmaceutically active organic compound or an acceptable salt thereof in reversible association with a pharmaceutically acceptable drug-binding polymer. The core of the composition being surrounded by an insoluble water permeable membrane that is capable of delaying the dissolution of the pharmaceutically active compound therewithin and providing for extended release of the pharmaceutically active compound. In some embodiments, the formulation of the invention are designed to extend release of the pharmaceutically active organic compound liar about 3 hours to about 8 hours, thereby enabling preparation of an extended release formulation for any pharmaceutically active compound with a half-life of from about 16 hours to about 21 hours.

1 . A particulate composition comprising:
 (a) a biologically active core, said biologically active core comprising a pharmaceutically active substance and a set of one or more drug binding polymers, wherein said pharmaceutically active substance being in reversible association with said set of one or more drug binding polymers; and   (b) a coat, said coat comprising a membrane-forming polymer, said membrane-forming polymer surrounding said core, wherein said pharmaceutically active substance comprises a pharmaceutically active compound, a pharmaceutically acceptable salt of said pharmaceutically active compound or a combination thereof.   
     
     
         2 . A particulate composition comprising:
 (a) a biologically inert core, said biologically inert core comprising a set of one or more drug binding polymers; and   (b) a coat, said coat comprising a membrane-forming polymer, said membrane-forming polymer surrounding said core.   
     
     
         3 . The particulate composition according to  claim 1 , wherein said set of one or more drug binding polymers are selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly (ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) or polyurethane and combinations thereof. 
     
     
         4 . The particulate composition according to  claim 1 , wherein said pharmaceutically active substance and said set of one or more drug binding polymers respectively being present in said biologically active core in a weight ratio of from about 20:1 to about 1:2. 
     
     
         5 . The particulate composition according to  claim 1 , wherein said reversible association between said pharmaceutically active substance and said set of one or more drug binding polymers comprises chemical bonding, ionic bonding, complexation, van der Waals interaction, hydrogen bonding, or combinations thereof. 
     
     
         6 . The particulate composition according to  claim 1 , wherein at least one of said set of one or more drug binding polymers is insoluble in water. 
     
     
         7 . The particulate composition according to  claim 1 , wherein at least one of said set of one or more polymers is soluble in water. 
     
     
         8 . The particulate composition according to  claim 1 , wherein said coat comprises a water-insoluble, water-permeable polymer capable of retarding drug release. 
     
     
         9 . The particulate composition according to  claim 1 , wherein said biologically active core comprises a powder, said powder comprising particles of said pharmaceutically active substance mixed with particles of said set of one or more drug binding polymers, and wherein said coat comprises a water-insoluble, water-permeable polymer. 
     
     
         10 . The particulate composition according to  claim 1 , wherein said biologically active core comprises a powder, said powder comprising particles of said pharmaceutically active substance mixed with particles of said set of one or more drug binding polymers, wherein said set of one or more drug binding polymers comprise at least one pharmaceutically acceptable water insoluble polymer, and wherein said coat comprises a water-insoluble, water-permeable polymer. 
     
     
         11 . A method of making the particulate composition according to  claim 1 , said method comprising:
 (a) blending a powder, said powder comprising particles of a pharmaceutically active substance and particles of a set of one or more polymers to form a homogenous powdered drug-polymer blend;   (b) shaping a portion of said homogenous powdered drug-polymer blend to form a central core; and   (c) applying a polymer binding solution to said central core to form a layered structure on said central core, wherein said a pharmaceutically active substance comprises a pharmaceutically active compound, a pharmaceutically acceptable salt of said pharmaceutically active compound or a combination thereof.   
     
     
         12 . A method of making a particulate composition according to  claim 2 , comprising:
 (a) blending a powder, said powder comprising particles of a set of one or more polymers to form a homogenous powdered drug-polymer blend;   (b) shaping a portion of said homogenous powdered drug-polymer blend to form a central inert core; and   (c) applying a polymer binding solution to said central inert core to form a layered structure on said central core.   
     
     
         13 . A controlled release pharmaceutical composition comprising the particulate composition according to  claim 1 , and having a dissolution rate which when measured in a type 1 dissolution basket apparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH 7.2 and at 75 r.p.m. corresponds to the following dissolution pattern:
 (a) from 15 to 30% of the total pharmaceutically active chemical is released after 0.5 hours of measurement in said apparatus;   (b) from 25 to 60% of the total pharmaceutically active chemical is released after 1 hour of measurement in said apparatus; and   (c) not less than 65% of the total pharmaceutically active chemical is released after 4 hours of measurement in said apparatus.   
     
     
         14 . The controlled release pharmaceutical composition according to  claim 13 , wherein the composition is a once daily solid controlled-release oral dosage form. 
     
     
         15 . The controlled release pharmaceutical composition according to  claim 13 , wherein the composition is a twice a day solid controlled-release oral dosage form. 
     
     
         16 . A method for extending delivery of a single dose of a pharmaceutically active substance to once daily or to beyond one day from administration of the dose to a subject, comprising:
 (a) blending a powder, said powder comprising particles of said pharmaceutically active substance and particles of a set of one or more polymers, to form a homogenous powder drug-polymer blend,   wherein said a homogenous powder drug-polymer blend comprises said pharmaceutically active substance in a reversible association with said set of one or more drug binding polymers,   wherein said pharmaceutically active substance comprises a pharmaceutically active compound, a pharmaceutically acceptable salt of said pharmaceutically active compound or a combination thereof;   (b) shaping a portion of said homogenous powder drug-polymer blend to form a central core; and   (c) applying a polymer binding solution to said central core to form a layered structure on said central core to form a controlled realse pharmaceutical composition, wherein said controlled release pharmaceutical composition delivers said pharmaceutically active substance to said subject for at least one or more days from administration of a single dose of said pharmaceutical composition.   
     
     
         17 . A particulate composition according to  claim 1 , wherein said particulate composition comprises microparticles/microparticulates having average diamter of from about 100 μm to about 900 μm. 
     
     
         18 . The particulate composition of  claim 17 , wherein said particulate composition comprises microparticles/microparticulates having average diamter selected from the group consisting of: from 100 μm to about 150 μm; from about 150 μm to about 200 μm; from about 200 μm to about 250 μm; from about 250 μm to about 300 μm; from about 300 μm to about 350 μm; from about 350 μm to about 400 μm; from about 400 μm to about 450 μm; from about 450 μm to about 500 μm; from about 500 μm to about 550 μm; from about 550 μm to about 600 μm; from about 600 μm to about 650 μm; from about 650 μm to about 700 μm; from about 700 μm to about 750 μm; from about 750 μm to about 800 μm; from about 800 μm to about 850 μm; from about 850 μm to about 900 μm; from about 150 μm to about 200 μm; from about 200 μm to about 250 μm; from about 250 μm to about 300 μm; from about 300 μm to about 350 μm; from about 350 μm to about 400 μm; from about 400 μm to about 450 μm; from about 450 μm to about 500 μm; from about 500 μm to about 550 μm; from about 550 μm to about 600 μm; from about 600 μm to about 650 μm; from about 650 μm to about 700 μm; from about 700 μm to about 750 μm; from about 750 μm to about 800 μm; from about 800 μm to about 850 μm; from about 200 μm to about 250 μm; from about 250 μm to about 300 μm; from about 300 μm to about 350 μm; from about 350 μm to about 400 μm; from about 400 μm to about 450 μm; from about 450 μm to about 500  82  m; from about 500 μm to about 550 μm; from about 550 μm to about 600 μm; from about 600 μm to about 650 μrn; from about 650 μm to about 700 μm; from about 700 μm to about 750 μm; from about 750 μm to about 800 μm; from about 250 μm to about 300 μm; from about 300 μm to about 350 μm; from about 350 μm to about 400 μm; from about 400 μm to about 450 μm; from about 450 μm to about 500 μm; from about 500 μm to about 550 μm; from about 550 μm to about 600 μm; from about 600 μm to about 650 μm; from about 650 μm to about 700 μm; from about 700 μm to about 750 μm; from about 300 μm to about 350 μm; from to about 350 μm to about 400 μm; from to about 400 μm to about 450 μm; from to about 450 μm to about 500 μm; from to about 350 μm to about 400 μm; from to about 400 μm to about 450 μm; from to about 450 μm to about 500 μm and combinations thereof. 
     
     
         19 . A pharmaceutical formulation, said pharmaceutical formulation comprising the particulate composition of  claim 1  filled into capsules or compressed into tablets. 
     
     
         20 . The pharmactuical formuation of  claim 19 , wherein said tablets rapidly dissolve in any aqueous medium to release microparticulates of said particulate composition. 
     
     
         21 . The pharmactuical formuation of  claim 19 , wherein said capsules rapidly dissolve in any aqueous medium to release microparticulates of said particulate composition. 
     
     
         22 . The pharmaceutical formulation according to  claim 18 , wherein said pharmaceutically active substance is released in a controlled manner having a release profile that is substantially the same/identical to the release profile of said microparticulates alone. 
     
     
         23 . The pharmaceutical formulation of  claim 18 , wherein said pharmaceutical formulation comprises said particulate composition filled into capsules. 
     
     
         23 . The pharmaceutical formulation of  claim 18 , wherein said pharmaceutical formulation comprises said particulate composition compressed into tablets. 
     
     
         24 . The composition of  claim 1 , wherein said particulate composition has a particle size distribution selected from the group consisting of: about 60% of the particles having a particle diameter of about 1267 μm or less; 58% of particles having a particle diameter of about 1055 μm or less; about 53% of particles having a particle diameter of about 949 μm or less; about 52% of particles having a particle diameter of about 737 μm or less; about 50% of particles having a particle diameter of about 631 μm or less; about 47% of particles having a particle diameter of about 525 μm or less; about 37% of particles having a particle diameter of about 419 μm or less; about 21% of particles having a particle diameter of about 313 μm or less; about and 6% of particles having a particle diameter of about 207 μm or less. 
     
     
         25 . The composition of  claim 1 , wherein said particulate composition has a particle size distribution selected from the group consisting of: about 80% of the particles having a diamter of about 860 μm or less; about 77% of particles having a particle diameter of about 798 μm or less; about 75% of particles having a particle diameter of about 736 μm or less; about 69% of particles having a particle diameter of about 674 μm or less; about 65% of particles having a particle diameter of about 612 μm or less; about 61% of particles having a particle diameter of about 550 μm or less; about 52% of particles having a particle diameter of about 488 μm or less; about 37% of particles having a particle diameter of about 426 μm or less; about 26% of particles having a particle diameter of about 364 μm or less; about 10% of particles having a particle diameter of about 302 μm or less; about and 5% of particles having a particle diameter of about 240 μm or less.