Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use

Abstract

Symmetrically and asymmetrically branched homopolymers are modified at the surface level with functional groups that enable forming aggregates with water insoluble or poorly water soluble pharmaceutically active agents (PAA). The aggregates formed are specifically induced by interaction of PAA and homopolymer and are different from aggregates that are formed by the polymer alone in the absence of the PAA or by the PAA alone in the absence of the polymer. Such aggregates can be used to improve drug solubility, stability, delivery and efficacy.

We claim: 
     
         1 . An aggregate comprising
 a) a branched homopolymer, wherein said homopolymer is modified with a surface group and wherein said surface modified branched homopolymer comprises symmetrically branched polymers, asymmetrically branched polymer or a combination thereof, and   b) a water insoluble or poorly water soluble pharmaceutically active agent (PAA),   
       wherein the size of said aggregate is different from the size of aggregates formed of said surface modified branched homopolymer alone. 
     
     
         2 . The aggregate of  claim 1 , wherein said surface modified branched homopolymer comprises a hydrophobic surface group. 
     
     
         3 . The aggregate of  claim 1 , wherein said PAA is associated with a surface group of said branched polymer. 
     
     
         4 . The aggregate of  claim 2 , wherein said surface modified branched polymer comprises a polyoxazoline, a poly(2-substituted oxazoline), a polyethyleneglycol, a polyethyleneoxide, a polyacrylamide, a polyphosphate, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyethyleneimine, a polypropyleneimine, a polyamidoamine or a combination thereof. 
     
     
         5 . The aggregate of  claim 2 , wherein said surface modified branched polymer comprises an aliphatic and/or saturated or unsaturated hydrocarbons comprising from 1 to about 22 carbons, aromatic hydrocarbons, polyethylene polymers, polystyrene polymers, perfluoropolymers, polydimethylsiloxanes, polyacrylates, polymethylmethacrylates or a combination thereof. 
     
     
         6 . The aggregate of  claim 1 , wherein said water insoluble or poorly water soluble PAA comprises an antiinfective agent or an antineoplastic agent. 
     
     
         7 . The aggregate of  claim 1 , wherein said water insoluble or poorly water soluble PAA comprises paclitaxel, docetaxel, taxotere, vinblastine, vincristine, vindesine, vinorelbine, irinotecan, topotecan, camptothecin, camptothecin derivatives (such as, irinotecan, topotecan etc.), doxorubin, cisplatin, carboplatin, oxaliplatin, satraplatin, dolargin, loperamide, tubocurarine, ibuprofen, diazepam, naproxen, carbamazepine, griseofulvin, nifedipine, phytosterol, omeprazol, domperidone, zidovudine, amphotericin B, chlormethine, chlorambucil, busulfan, thiotepa, cyclophosphamide, estramustine, ifosfamide, meclilorethamine, melphalan, uramustine, lonuistine, streptozotocin, dacarbazine, procarbazine, temozolamide, (SP-4-3)-(cis)-aminedichloro-[2-methylpyridine]-platinum (II), methotrexate, permetrexed, raltitrexed, trimetrexate, cladribine, chlorodeoxyadenosine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, azacitidine, capecitabine, cytarabine, edatrexate, floxuridine, 5 fluorouracil, gemcitabine, troxacitabine, bleomycin, dactinomycin, adriamycin, actinomycin, mithramycin, mitomycin, mitoxantrone, porfiromycin, daunorubicin, epirubicin, idarubicin, valrubicin, phenesterine, tamoxifen, piposulfancamptothesin, amsacrine, etoposide, teniposide, fluoxymesterone, testolactone, bicalutamide, cyproterone, flutamide, nilutamide, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, dexamethasone, prednisone, diethylstilbestrol, fulvestrant, raloxifene, toremifene, buserelin, goserelin, leuprolide, triptorelin, medroxyprogesterone acetate, megestrol acetate, levothyroxine, liothyronine, altretamine, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, methoxsalen, sodium porfimer, bortezomib, erlotinib hydrochloride, gefitinib, imatinib mesylate, semaxanib, adapalene, bexarotene, trans-retinoic acid, 9-cis-retinoic acid and N-(4-hydroxyphenyl) retinamide or a combination thereof. 
     
     
         8 . The aggregate of  claim 1 , further comprising a targeting moiety covalently linked to said homopolymer, wherein said moiety comprises antibody, antigen-binding portion thereof, antigen, cell receptor, cell receptor ligand or lectin ligand. 
     
     
         9 . The aggregate of  claim 1 , further comprising a contrast reagent. 
     
     
         10 . The aggregate of  claim 4 , wherein said poly(2-substituted oxazoline) comprises poly(2-methyloxazoline, poly(2-ethyloxazoline), poly(2-propyloxazoline) or poly(2-butyloxazoline). 
     
     
         11 . The aggregate of  claim 9 , wherein said contrast agent comprises a magnetic resonance imaging contrast agent. 
     
     
         12 . The aggregate of  claim 9 , wherein said contrast agent comprises a radionuclide.