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 particles which would result from forming said particle from a mixture of
 a) an amphiphilic stabilizer,   b) a conjugate of the formula
   (active-linker) n -hydrophobic moiety  (1)
 
   wherein n is an integer of 1-100; and   wherein “active” refers to at least a first therapeutic agent;   “linker” is a covalent bond, a divalent residue of an organic molecule or a chelator which comprises a bond that is selectively cleavable to control release of said active; and   “hydrophobic moiety” refers to the residue of an organic molecule that is insoluble in aqueous solution; and   c) a second therapeutic agent different from the first therapeutic agent.   
     
     
         2 . The composition of  claim 1 , wherein n is an integer of 2-100. 
     
     
         3 . 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.   
     
     
         4 . The composition of  claim 1 , wherein the amphiphilic stabilizer is methoxypolyethylene glycol (mPEG)-polycaprolactone (PCL), mPEG-polystyrene, mPEG-polybutadiene, mPEG-polylactate, block copolymers of polyethylene oxide, and polypropylene oxide, or block copolymers of polyethylene oxide and polybutylene oxide. 
     
     
         5 . The composition of  claim 1 , wherein the linker is the residue of a divalent organic molecule, and said residue of a divalent organic 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.   
     
     
         6 . The composition of  claim 1 , wherein said first and second therapeutic agents are maintained at non-antagonistic ratio when administered to a subject. 
     
     
         7 . The composition of  claim 1 , wherein the particulate constructs comprise 10 3 -10 7  conjugates of formula (1). 
     
     
         8 . The composition of  claim 1 , wherein the particulate constructs have an average diameter less than 5μ. 
     
     
         9 . The composition of  claim 1 , which is in the form of an emulsion. 
     
     
         10 . The composition of  claim 1  wherein said first and second therapeutic agents are coupled in conjugates of formula (1) to separate hydrophobic moieties. 
     
     
         11 . The composition of  claim 10  wherein the separate hydrophobic moieties are different. 
     
     
         12 . The composition of  claim 10  wherein said first and second therapeutic agent conjugates comprise a paclitaxel polylactic acid conjugate of formula (1) and a cis-diaminedichloroplatinum(II) polylactic acid diacid diethyl ester terminated polymer conjugate of formula (1). 
     
     
         13 . The composition of  claim 1  wherein said first therapeutic agent is present in the form of formula (1) and the second therapeutic agent is in unbound form. 
     
     
         14 . The composition of  claim 13  wherein the agent in the form of formula (1) is cis-diaminedichloroplatinum(II) and the agent in unbound form is paclitaxel. 
     
     
         15 . The composition of  claim 1  wherein said first and second therapeutic agents are coupled in a conjugate of formula (1) to the same hydrophobic moiety. 
     
     
         16 . A method to administer a combination treatment to a subject, which method comprises administering a composition of  claim 6  to a subject in need of such treatment.