Controlled release of n-acetylcysteine (nac) for reduction of systemic and/or vascular inflammation

Abstract

The present invention provides a controlled-release composition which provides a therapeutically effective plasma concentration of N-acetylcysteine over prolonged period of time. The present invention also includes the use of the controlled-release composition, either alone or in combination with at least one additional active agent, for reduction of vascular inflammation marker and treatment of diseases, conditions, and/or symptoms associated with systemic and/or vascular inflammation in a patient. Furthermore, the present invention provides a process of making granules comprising N-acetylcysteine, or a salt, solvate, prodrug, and/or analog thereof.

1 . A composition comprising a sustained release (SR) component, wherein the SR component comprises a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof;
 wherein the composition, upon oral administration, provides a therapeutically effective plasma concentration of N-acetylcysteine over more than about 2 hours following the administration.   
     
     
         2 . The composition of  claim 1 , further comprising
 an immediate release (IR) component, wherein the IR component comprises a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof;   wherein the composition, upon oral administration, provides a therapeutically effective plasma concentration of N-acetylcysteine over about 30 minutes to about 24 hours following the administration.   
     
     
         3 . The composition of  claim 1 , wherein the SR and/or IR component comprises a prodrug or analog of N-acetylcysteine which is less polar than N-acetylcysteine and is absorbable in the lower gastrointestinal tract of a mammal. 
     
     
         4 . The composition of  claim 1 , wherein the SR and/or IR component comprises a prodrug of N-acetylcysteine which has a log P of about 4 or higher. 
     
     
         5 . The composition of  claim 1 , wherein the SR and/or IR component comprises a prodrug of N-acetylcysteine which contains a hydrophobic moiety. 
     
     
         6 . The composition of  claim 1 , wherein the SR and/or IR component comprises a prodrug of N-acetylcysteine selected from the group consisting of an ester prodrug, an amide prodrug, and an anhydride prodrug. 
     
     
         7 . The composition of  claim 1 , wherein the analog of N-acetylcysteine is an amino acid analog. 
     
     
         8 . The composition of  claim 1 , wherein the analog of N-acetylcysteine is selected from the group consisting of DiNAC; N-acetylcysteine L-lysine; Carbocisteine; glutathione; S-nitroso-N-acetylcysteine; S-nitrosothiol-N-acetylcysteine; S-allyl-cysteine; S-alkyl-cysteine; N-acetyl-5-farnesyl-cysteine; N-acetyl-L-arginine-NAC; N-acetyl-L-lysine-NAC; N-acetyl-L-histidine-NAC; N-acetyl-L-ornithine-NAC; thioester of NAC with salicylic acid; 2′4′-difluoro-4-hydroxy-(1,1′-diphenyl)-3-carboxylic derivatives of NAC; S-allymercapto-NAC (ASSNaC); N,N-diacetyl-L-cystine; N-S-diacyl-cysteine; N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC); S-carboxylmethyl-L-cysteine; derivatives of reacting a reactive derivative of p-isobutylphenylpropionic acid and NAC; paraisobutyl NAC; esters of N-acetylcysteine; amides of N-acetylcisteine; anhydrides of N-acetylcistein; and a combination thereof. 
     
     
         9 . The composition of  claim 1 , wherein the SR component, IR component, or both, comprise a prodrug or analog of N-acetyl-D-cysteine, or a salt or solvate thereof. 
     
     
         10 . The composition of  claim 1 , wherein the SR component comprises a matrix, wherein the matrix comprises:
 a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof; and   a release rate controlling polymer.   
     
     
         11 . The composition of  claim 2 , comprising
 a layer of the IR component, and   a layer of the SR component, wherein the SR component comprises a matrix comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof; and a release rate controlling polymer.   
     
     
         12 . The composition of  claim 10 , wherein the rate controlling polymer is a hydrophilic polymer. 
     
     
         13 . The composition of  claim 12 , wherein the hydrophilic polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch, guar gum, sodium alginate, polyvinyl alcohol, chitosan, locust bean gum, amylase and a combination thereof. 
     
     
         14 . The composition of  claim 1 , comprising a release rate controlling membrane disposed over:
 a pull layer comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof, and   an osmotic push layer;   wherein the release rate controlling membrane has an orifice immediately adjacent to the pull layer.   
     
     
         15 . The composition of  claim 14 , wherein the pull layer further comprises a release rate controlling polymer. 
     
     
         16 . The composition of  claim 2 , comprising a release rate controlling membrane disposed over:
 a first pull layer comprising the IR component,   a second pull layer comprising the SR component, and   an osmotic push layer;   wherein the release rate controlling membrane has an orifice immediately adjacent to the first pull layer.   
     
     
         17 . The composition of  claim 16 , wherein the SR component comprises a matrix comprising:
 a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof; and   a release rate controlling polymer.   
     
     
         18 . The composition of  claim 15 , wherein the release rate controlling polymer is a hydrophilic polymer. 
     
     
         19 . The composition of  claim 18 , wherein the hydrophilic polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch, guar gum, sodium alginate, polyvinyl alcohol, chitosan, locust bean gum, amylase and a combination thereof. 
     
     
         20 . The composition of  claim 14 , wherein the release rate controlling membrane comprises a water insoluble and non-erodable polymer. 
     
     
         21 . The composition of  claim 20 , wherein the water insoluble and non-erodable polymer is selected from the group consisting of a cellulose ester, a cellulose ether, a cellulose ester-ether, and a combination thereof. 
     
     
         22 . The composition of  claim 20 , wherein the water insoluble and non-erodable polymer is selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, a monocellulose alkanylate, a dicellulose alkanylate, a tricellulose alkanylate, a monocellulose aroylate, a dicellulose aroylate a tricellulose aroylate, and a combination thereof. 
     
     
         23 . The composition of  claim 14 , wherein the osmotic push layer comprises an osmopolymer. 
     
     
         24 . The composition of  claim 23 , wherein the osmopolymer is selected from the group consisting of poly(hydroxyalkylmethacrylate) having a molecular weight of from about 30,000 to about 5,000,000; poly(vinylpyrrolidone) having molecular weight of from about 10,000 to 360,000 about; anionic and cationic hydrogels; polyelectrolyte complexes; poly(vinyl alcohol); a mixture of methyl cellulose, cross-linked agar, and carboxymethyl cellulose; a copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene; N-vinyl lactams; Carbopol; acidic carboxy polymers having a molecular weight from about 450,000 to about 4,000,000; a sodium salt of Carbopol; acidic carboxy polymers and/or the metal salts thereof; polyethylene oxide polymers having a molecular weight from about 100,000 to about 7,500,000; and combinations thereof. 
     
     
         25 . The composition of  claim 14 , wherein the pull layer comprises an osmagent. 
     
     
         26 . The composition of  claim 25 , wherein the osmagent is selected from the group consisting of a magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, lithium phosphate, sodium phosphate, potassium phosphate, potassium acid phosphate, calcium lactate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, lactose monohydrate, and a blend of fructose glucose. 
     
     
         27 . The composition of  claim 1 , wherein the SR component comprises one or more particles, and each of the particles comprises
 an active core comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof; and   a release rate controlling polymer disposed over the core.   
     
     
         28 . The composition of  claim 1 , wherein the SR component comprises one or more particles, and each of the particles comprises
 an inert core,   an active layer comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof, and   a release rate controlling polymer disposed over the active layer.   
     
     
         29 . The composition of  claim 2 , wherein
 the IR component comprises one or more particles, and   the SR component comprises one or more particles, and each of the particles of the SR component comprises
 an active core comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof; and 
 a release rate controlling polymer disposed over the core. 
   
     
     
         30 . The composition of  claim 2 , wherein
 the IR component comprises one or more particles, and   the SR component comprises one or more particles, and each of the particles of the SR component comprises
 an inert core, 
 an active layer comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof, and 
 a release rate controlling polymer disposed over the active layer. 
   
     
     
         31 . The composition of  claim 27 , wherein the release rate controlling polymer comprises a film-forming, water insoluble polymer in combination with a film-forming, water soluble polymer. 
     
     
         32 . The composition of  claim 31 , wherein the film-forming, water insoluble polymer is 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), polyurethane, and combinations thereof. 
     
     
         33 . The composition of  claim 31 , wherein the film-forming, water soluble polymer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethylene glycol, Pluronic F108, Pluronic F127, Pluronic F68, and combinations thereof. 
     
     
         34 . The composition of  claim 29 , wherein each of the particles of the IR component comprises:
 an inert core, and   a coating disposed over the inert core,   wherein the coating comprises a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof.   
     
     
         35 . A composition comprising a sustained release (SR) component, wherein the SR component comprises
 a modified N-acetylcysteine, or a salt and/or solvate thereof; and   a release rate controlling polymer;   wherein the modified N-acetylcysteine is less polar than N-acetylcysteine.   
     
     
         36 . The composition of  claim 35 , wherein the modified N-acetylcysteine is a prodrug or analog of N-acetylcysteine, or a salt and/or solvate thereof. 
     
     
         37 . A method of reducing a vascular inflammatory marker or mediator in a mammal comprising orally administering to the mammal the composition of  claim 1 . 
     
     
         38 . The method of  claim 37 , wherein the vascular inflammatory marker or mediator is selected from the group consisting of C-reactive protein (CRP); lipoprotein-associated phospholipase A2 (LP-PLA2); lipoprotein Lp(a); myeloperoxidase (MPO); macrophage chemotactic protein 1 (MCP-1); interleukins (IL), such as IL-1,6,8,10; oxidized low-density lipoprotein (oxidized LDL), adiponectin, matrix metaloproteinases (MMP), such as MMP-9,1,2; CD40; homocysteine; cardiovascular risk factor (CVRF); plasminogen activator inhibitor (PAI-1); prostaglandin (PG); tissue polypeptide antigen (TPA); von Willebrand factor (vWF); platelet aggregation; fibrinogen; Factor VII; Factor VIII; tissue factor; phosphoglucose (PGI1); endothelin; metaloproteinases; Lipoxegenase; angiotensin; and a combination thereof. 
     
     
         39 . A method of reducing systemic, organ-specific, and/or vascular inflammation in a mammal comprising orally administering to the mammal the composition of  claim 1 . 
     
     
         40 . A method of treating a disease, condition, or symptom associated with systemic and/or vascular inflammation in a mammal comprising orally administering to the mammal the composition of  claim 1 . 
     
     
         41 . The method of  claim 40 , wherein the disease, condition, or symptom is related to the circulatory system of the mammal. 
     
     
         42 . The method of  claim 40 , wherein the disease, condition, or symptom is selected from the group consisting of liver inflammation; hepatitis; pancreatitis; myocardial hyperthrophy; pulmonary fibrosis; endotoxic shock; uveitis; dementia; Parkinson's disease; brain toxicity; kidney damage from radiographic dyes; cancer drugs toxicity; AIDS; atherosclerosis; arthritis; diabetes; colitis; multiple sclerosis; acute coronary syndrome; acute myocardial infarction; chronic obstructive pulmonary disorder (COPD); and a combination thereof. 
     
     
         43 . The method of  claim 40 , wherein the disease, condition, or symptom is liver inflammation caused by acetaminophen. 
     
     
         44 . A process of making granules comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof, comprising the steps of
 applying forces to loose solids comprising a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof, thereby obtaining a solid sheet; and   reducing the size of the solid sheet, thereby obtaining granules.   
     
     
         45 . The process of  claim 44 , wherein the process the process does not utilize a solvent. 
     
     
         46 . The process of  claim 45 , wherein the applying step is carried out by pressing the loose solids between two counter rotating rolls. 
     
     
         47 . A composition comprising
 (a) a prodrug, or analog of N-acetylcysteine, or a salt or solvate thereof; and   (b) at least one additional active agent.   
     
     
         48 . The composition of  claim 47 , wherein the at least one additional active agent is a statin. 
     
     
         49 . The composition of  claim 48 , wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and a combination thereof. 
     
     
         50 . A method of treating a disease, condition, or symptom associated with systemic and/or vascular inflammation in a mammal comprising co-administering to the mammal (a) N-acetylcysteine, or a salt, solvate, prodrug, and/or analog thereof; and (b) at least one additional active agent. 
     
     
         51 . The composition of  claim 50 , wherein the at least one additional active agent is a statin. 
     
     
         52 . The composition of  claim 51 , wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and a combination thereof. 
     
     
         53 . The composition of  claim 1 , wherein the composition, upon oral administration, provides a therapeutically effective plasma concentration of N-acetylcysteine over more than about 4 hours following the administration. 
     
     
         54 . The composition of  claim 1 , wherein the composition, upon oral administration, provides a therapeutically effective plasma concentration of N-acetylcysteine over about 2 to about 24 hours following the administration. 
     
     
         55 . The composition of  claim 1 , wherein the composition is a solid.