Directly compressible sustained release formulation containing microcrystalline cellulose

Abstract

The present invention provides an improved process for the preparation of a agglomerated solid dosage form, comprising: (1) preparing an aqueous slurry of (a) microcrystalline cellulose; (b) a microcrystalline cellulose compressibility augmenting agent which (i) physically restricts the proximity of the interface between adjacent cellulose surfaces; (ii) inhibits interactions between adjacent cellulose surfaces, for example, via the creation of a hydrophobic boundary at cellulose surfaces; or (iii) accomplishes both (i) and (ii) above; and (c) an active agent; (2) thereafter drying the resultant aqueous slurry in a manner which inhibits quasi-hornification, thereby obtaining an agglomerated material which is directly compressible into a solid dosage form.

1 - 31 . (canceled)  
     
     
         32 . A sustained release formulation comprising a plurality of spray-dried agglomerated particles, each of said particles comprising: 
 (a) microcrystalline cellulose    (b) a microcrystalline cellulose compressibility augmenting agent which 
 (i) physically restricts the proximity of the interface between adjacent cellulose surfaces;  
 (ii) inhibits interactions between adjacent cellulose surfaces via the creation of a hydrophobic boundary at cellulose surfaces; or  
 (iii) accomplishes both (i) and (ii) above;  
   (c) an active agent; and    (d) an effective amount of a sustained release carrier,    said agglomerated particles being compressed into a solid sustained release matrix which provides release of the active agent over a time period of about 8 to about 24 hours.    
     
     
         33 . The sustained release formulation of  claim 32 , wherein the agglomerated particles are further compressed into a tablet.  
     
     
         34 . The sustained release formulation of  claim 32 , wherein the compressibility augmenting agent is a surfactant having an HLB of at least about 10.  
     
     
         35 . The sustained release formulation of  claim 32 , wherein the compressibility augmenting agent is a surfactant having an HLB of at least about 15.  
     
     
         36 . The sustained release formulation of  claim 32 , wherein the compressibility augmenting agent is a surfactant having an HLB from about 15 to about 40.  
     
     
         37 . The sustained release formulation of  claim 36 , wherein the compressibility augmenting agent is sodium lauryl sulfate.  
     
     
         38 . The sustained release formulation of  claim 36 , wherein the compressibility augmenting agent is polysorbate.  
     
     
         39 . The sustained release formulation of  claim 32 , wherein the compressibility augmenting agent further comprises a silicon dioxide having an average primary particle size from about 1 nm to about 100 μm.  
     
     
         40 . The sustained release formulation of  claim 39 , wherein the silicon dioxide is included in an amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.  
     
     
         41 . The sustained release formulation of  claim 34 , wherein the surfactant is included in an amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.  
     
     
         42 . The sustained release formulation of  claim 40 , wherein the silicon dioxide is colloidal silicon dioxide.  
     
     
         43 . The sustained release formulation of  claim 32 , wherein the sustained release carrier is selected from the group consisting of an alkyl cellulose, an acrylic polymer or copolymer, a cellulose ether, a cellulose ester, and mixtures thereof.  
     
     
         44 . The sustained release formulation of  claim 32 , wherein the sustained release carrier is selected from natural or synthetic gums.  
     
     
         45 . The sustained release formulation of  claim 32 , further comprising a pharmaceutically acceptable filler.  
     
     
         46 . The sustained release formulation of  claim 45 , wherein the pharmaceutically acceptable filler is selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, inorganic phosphates, sulfates, carbonates and mixtures thereof.  
     
     
         47 . The sustained release formulation of  claim 45 , wherein the pharmaceutically acceptable filler is selected from the group consisting of sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, “off-shelf” microcrystalline cellulose and mixtures thereof.  
     
     
         48 . The sustained release formulation of  claim 32 , wherein the sustained release carrier includes a release modifying agent that alters the release rate of the active agent from the formulation upon exposure to an aqueous medium.  
     
     
         49 . The sustained release formulation of  claim 48 , wherein the release modifying agent is selected from the group consisting of calcium sulfate, sodium chloride, potassium sulfate, sodium bicarbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate and sodium fluoride.  
     
     
         50 . The sustained release formulation of  claim 32 , wherein the sustained release carrier is selected from the group consisting of a polylactide, a polyglycolide, a poly(lactide-co-glycolide), a polyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters and polyorthoesters.  
     
     
         51 . The sustained release formulation of  claim 32 , wherein the microcrystalline cellulose compressibility augmenting agent comprises a highly polar dye selected from the group consisting of 3,3′-[[1,1′Biphenyl]-4,4′-diylbis-(azo)]bis[4-amino-1-naphthalenesulfonic acid]disodium salt; disodium salt of 6-hydroxy-5[(2-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid); 5-oxo-1-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3-carboxylic acid, trisodium salt); disodium salt of 1-p-sulphophenylazo-2-naphthol-6-sulfonic acid); trisodium-2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-6,8-disulfonate); disodium 4,4′-(2,4-dihydroxy-5-hydroxymethyl-3,3-phenylene bisazo)di(napthalene-1-sulfonate)); tetrasodium 4-acetamido-5-hyroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo]naphthalene-1,7-disulfonate); disodium 4-hydroxy-3-(4-sulfanato-1-naphythylazo)Naphthalene-1-sulfonate); trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-3,6-disulfonate) and mixtures thereof.