Particulate constructs for release of active agents

Abstract

Particulate constructs stabilized by amphiphilic copolymers and comprising at least one active coupled to a hydrophobic moiety provide sustained release of the active in both in vitro and in vivo environments.

1 . A composition comprising nanoparticulate constructs wherein said nanoparticulate constructs comprise:
 a) an amphiphilic stabilizer, and   b) a conjugate of the formula
   (active−linker) n −hydrophobic moiety   (1)
 
   wherein n is an integer of 1-100;   “active” refers to a compound that has a desired activity;   “linker” is a divalent residue of an organic molecule, which divalent residue is selectively cleavable by reduction or hydrolysis upon exposure to a predefined stimulus to, thereby, control the release of said active from the hydrophobic moiety and the nanoparticulate construct, the cleavage being either within the divalent residue, at the bond that couples the linker to the active, or at the bond that couples the linker to the hydrophobic moiety; and   “hydrophobic moiety” refers to the residue of an organic molecule that is insoluble in aqueous solution; and   i) wherein the one or more active is a therapeutic agent or a diagnostic agent; or   ii) wherein the one or more active is a compound other than a pharmaceutical agent and other than a diagnostic agent;   wherein the hydrophobic moiety is a polymer having a molecular weight between 800 and 200,000 g/mole or is a natural product selected from the group consisting of hydrophobic vitamins, carotenoids, retinols, cholecalciferol, calcitriol, hydroxycholecalciferol, ergocalciferol, α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, and estradiol, and   the amphiphilic stabilizer is a copolymer having a hydrophilic region and a hydrophobic region, which copolymer is a graft, block or random amphiphilic copolymer and has a molecular weight between1,000 g/mole and 50,000 g/mole.   
     
     
         2 . The composition of  claim 1 , wherein the hydrophobic moiety is a polymer selected from the group consisting of a polymer of: an acrylate, an acrylonitrile, a methacrylonitrile, vinyl acetate, vinylversatate, vinylpropionate, vinylformamide, vinylacetamide, vinylpyridine, vinylimidazole, an aminoalkylacrylate, an aminoalkylmethacrylate, an aminoalkyl(meth)acrylamide, a styrene, cellulose acetate phthalate, cellulose acetate succinate, and hydroxypropylmethylcellulose phthalate, and the polymers: poly(D,L lactide), poly(L-lactic acid), poly(D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutyrate), poly(alkylcarbonate), a poly(orthoester), a polyester, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), a polyanhydride, a polyphosphazene, a poly(amino acid),an amino acid copolymer, poly(ethylene-vinyl acetate), a poly(ethylene-vinyl acetate) (“EVA”) copolymer, silicone rubber, polyethylene, polypropylene, a polydiene, a hydrogenated form of a polydiene, a maleic anhydride copolymer of vinyl-methylether and other vinyl ethers, a polyamide (nylon 6,6), polyurethane, a poly(ester urethane), a poly(ether urethane), poly(ester-urea), polycaproic acid, polymethylbenzylate, poly(caprolactone), poly(valerolactone), a copolymer of poly(caprolactone) and poly(lactic acid), or
 is vitamin E, vitamin K, vitamin A, beta carotene, astaxanthin, trans- and cis-retinal, retinoic acid, retinyl acetate, retinyl palmitate, cholecalciferol, calcitriol, hydroxycholecalciferol, ergocalciferol, α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, or estradiol, and/or 
 wherein, in said amphiphilic stabilizer, a hydrophilic polymeric block is coupled to a hydrophobic polymeric block, wherein: 
 the hydrophobic block is selected from the group consisting of a polymer of: an acrylate, an acrylonitrile; methacrylonitrile, vinyl acetate, vinylversatate, vinylpropionate, vinylformamide, vinylacetamide, vinylpyridine, vinylimidazole, an aminoalkylacrylate, an aminoalkylmethacrylate, an aminoalkyl(meth)acrylamide, styrene, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, 
 and the polymers: poly(D,L lactide), poly(L-lactic acid), poly (D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutyrate), poly(alkylcarbonate), a poly(orthoester), a polyester, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), a polyanhydride, a polyphosphazene, a poly(amino acid), an amino acid copolymer, poly(ethylene-vinyl acetate), a poly(ethylene-vinyl acetate) (“EVA”) copolymer, silicone rubber, polyethylene, polypropylene, a polydiene, a hydrogenated form of polydiene, a maleic anhydride copolymer of vinyl methylether and other vinyl ethers, a polyamide (nylon 6,6), polyurethane, a poly(ester urethane), a poly(ether urethane), poly(ester-urea), poly(caprolactone), poly(valerolactone), and a copolymer of poly(caprolactone) and poly(lactic acid); and 
 the hydrophilic block is selected from the group consisting of a polymer of a carboxylic acid, a polyoxyethylene, a polyacrylamide; a copolymer of acrylamide with dimethylaminoethylmethacrylate, diallyldimethylammonium chloride, vinylbenzylthrimethylammonium chloride, acrylic acid, methacrylic acid, 2-acrylamido-2-methylpropane sulfonic acid, and styrene sulfonate; polyvinyl pyrrolidone, starch, a starch derivative, dextran, a dextran derivative, a polypeptide, poly hyaluronic acid, an alginic acid, a polylactide, a polyethyleneimine, a polyionene, a polyacrylic acid, a polyiminocarboxylate, and gelatin. 
 
     
     
         3 . The composition of  claim 2 , wherein the hydrophobic moiety is vitamin E, vitamin A or vitamin K; or
 wherein the hydrophobic moiety is polycaprolactone, polylactic acid, polystyrene, polybutadiene, polycaproic acid, polymethylbenzylate, poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutyrate), poly(alkylcarbonate), a poly(orthoester), a polyester, or poly(hydroxyvaleric acid), or   wherein the amphiphilic stabilizer is methoxypolyethylene glycol (mPEG)-polycaprolactone (PCL), mPEG-polystyrene, mPEG-polybutadiene, polyacrylic acid-polybutylacrylate, mPEG-polylactate, and block copolymers of polyoxyethylene.   
     
     
         4 . The composition of  claim 1 , wherein said composition is obtainable by Nano Precipitation. 
     
     
         5 . The composition of  claim 1 , wherein the one or more active is a therapeutic agent. 
     
     
         6 . The composition of  claim 5 , wherein said particulate constructs comprise at least two different actives, which different actives are therapeutic agents. 
     
     
         7 . The composition of  claim 6 , wherein said therapeutic agents are present in the composition at a non-antagonistic ratio. 
     
     
         8 . The composition of  claim 5  for use as a medicament. 
     
     
         9 . The composition of  claim 1 , wherein the one or more active is a compound other than a pharmaceutical agent and other than a diagnostic agent. 
     
     
         10 . The composition of  claim 9 , wherein the one or more active is a pigment, an ink, a toner, a pesticide, a herbicide, a fungicide, a fluorescent probe, a UV-absorbing ingredient for a sunscreen, a fragrance, or a flavor compound.