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 particulate constructs wherein said constructs comprise
 an amphiphilic stabilizer, and a conjugate of the formula
   (active−linker) n −hydrophobic moiety  (1) 
   wherein n is an integer of 1-100; and   wherein “active” refers to one or more compounds that have a desired activity;   “linker” is a covalent bond, a divalent residue of an organic molecule or a chelator; and   “hydrophobic moiety” refers to the residue of an organic molecule that is insoluble in aqueous solution; and   (a) wherein the one or more active is other than a pharmaceutical, nutritional compound or diagnostic; or   (b) wherein said constructs comprise at least two different active therapeutic agents; or   (c) wherein said composition is obtainable by rapid micromixing of at least two jet streams, one or more jet streams comprising solution(s) of the amphiphilic stabilizer(s) and the conjugate(s) of formula 1 and the other stream(s) comprising an anti-solvent for the conjugate and the hydrophobic portion of the amphiphilic stabilizer, said jet streams fed at high velocity; or   (d) wherein said hydrophobic moiety is a polymer having a molecular weight>800 Da or is a natural product selected from hydrophobic vitamins, carotenoids, retinols, folic acid, dihydrofolate, cholecalciferol, calcitriol hydroxycholecalciferol, ergocalciferol, α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, and estradiol.   
     
     
         2 - 36 . (canceled) 
     
     
         37 . The composition of  claim 1 , wherein the one or more active is other than a pharmaceutical, nutritional compound or diagnostic. 
     
     
         38 . The composition of  claim 1 , wherein said constructs comprise at least two different active therapeutic agents. 
     
     
         39 . The composition of  claim 1 , wherein said composition is obtainable by rapid micromixing of at least two jet streams, one or more jet streams comprising solution(s) of the amphiphilic stabilizer(s) and the conjugate(s) of formula 1 and the other stream(s) comprising an anti-solvent for the conjugate and the hydrophobic portion of the amphiphilic stabilizer, said jet streams fed at high velocity. 
     
     
         40 . The composition of  claim 1 , wherein said hydrophobic moiety is a polymer having a molecular weight>800 Da or is a natural product selected from hydrophobic vitamins, carotenoids, retinols, folic acid, dihydrofolate, cholecalciferol, calcitriol, hydroxycholecalciferol, ergocalciferol, α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, and estradiol. 
     
     
         41 . The composition of  claim 1 , wherein n is an integer of 2-100. 
     
     
         42 . The composition of  claim 37 , wherein the one or more active is a pigment, an ink, a toner, a pesticide, a viscoelastic agent, an herbicide, a fluorescent probe, a sunscreen, a fragrance, or a flavor compound. 
     
     
         43 . The composition of  claim 1 , wherein the hydrophobic moiety is vitamin E, vitamin A or vitamin K, or a retinol; 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) poly(orthoesters), polyesters, poly(hydroxyvaleric acid), or copolymers thereof, and/or   wherein the amphiphilic stabilizer is methoxypolyethylene glycol (mPEG)-polycaprolactone (PCL), mPEG-polystyrene, mPEG-polybutadiene, polyacrylic acid-polybutylacrylate, or mPEG-polylactate, block copolymers of polyethylene oxide, polypropylene oxide, or polybutylene oxide, or is a copolymer or a gelatin.   
     
     
         44 . The composition of  claim 1 , wherein the linker is the residue of a divalent organic molecule, and said molecule comprises a site for hydrolytic cleavage and/or a site for enzymatic cleavage or a site for photolytic cleavage, or
 wherein the linker is a chelator.   
     
     
         45 . The composition of  claim 38 , wherein said constructs comprise at least two different active therapeutic agents that are maintained at non-antagonistic ratio when administered to a subject. 
     
     
         46 . The composition of  claim 1 , wherein the particulate constructs comprise 10 3 -10 7  conjugates of formula (1). 
     
     
         47 . The composition of  claim 1 , wherein the particulate constructs have an average diameter less than 5μ. 
     
     
         48 . The composition of  claim 1 , which is in the form of an emulsion. 
     
     
         49 . A method to administer a combination treatment to a subject, which method comprises administering a composition of  claim 45  to a subject in need of such treatment.