Heparosan polymers and methods of making and using same for the enhancement of therpeutics

Abstract

Compositions, methods, and systems for the development and use of heparosan as a therapeutic modifying agent or vehicle which can modulate drug cargo pharmacokinetics and behavior within a mammalian patient.

What is claimed is: 
     
         1 . A non-immunogenic pharmaceutical drug delivery composition for treating a disease condition in a mammalian patient, the pharmaceutical composition comprising:
 one or more heparosan-drug conjugates, wherein each conjugate comprises:   at least one heparosan polymer, wherein the at least one heparosan polymer is unsulfated; and   at least one therapeutic non-peptide drug conjugated to the at least one heparosan polymer, wherein the at least one therapeutic non-peptide drug treats a mammalian disease condition and remains active when conjugated to the at least one heparosan polymer; and   a pharmaceutically acceptable carrier; and   wherein the pharmaceutical drug delivery composition is a sterile pharmaceutical formulation in a unit dosage format.   
     
     
         2 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one therapeutic non-peptide drug does not increase immunoreactivity of the at least one heparosan polymer. 
     
     
         3 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one therapeutic non-peptide drug is not an adjuvant. 
     
     
         4 . The pharmaceutical drug delivery composition of  claim 1 , wherein each heparosan-drug conjugate comprises a single heparosan polymer conjugated to the at least one therapeutic non-peptide drug. 
     
     
         5 . The pharmaceutical drug delivery composition of  claim 1 , wherein each heparosan-drug conjugate comprises a plurality of heparosan polymers conjugated to the at least one therapeutic non-peptide drug. 
     
     
         6 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer has a mass in a range of from about 600 Da to about 800 kDa. 
     
     
         7 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer is unepimerized. 
     
     
         8 . The pharmaceutical drug delivery composition of  claim 1 , further defined as comprising a plurality of heparosan-drug conjugates, and wherein the plurality of heparosan polymers present in the conjugates is polydisperse in size. 
     
     
         9 . The pharmaceutical drug delivery composition of  claim 1 , further defined as comprising a plurality of heparosan-drug conjugates, and wherein the plurality of heparosan polymers present in the conjugates is substantially monodisperse in size. 
     
     
         10 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer has a linear polymer chain. 
     
     
         11 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer has a branched geometry. 
     
     
         12 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer has a half-life of at least 15 hours within extracellular compartments of the mammalian patient. 
     
     
         13 . The pharmaceutical drug delivery composition of  claim 1 , wherein at least one of:
 (a) the pharmaceutical drug delivery composition exhibits increased retention in blood and/or lymphatic circulation of a mammalian patient when compared to therapeutic non-peptide drug alone;   (b) the pharmaceutical drug delivery composition exhibits reduced occurrence of accumulation in healthy organs and/or tissues of a mammalian patient when compared to therapeutic non-peptide drug alone;   (c) the pharmaceutical drug delivery composition exhibits higher accumulation in tumors and/or diseased tissues of a mammalian patient when compared to therapeutic non-peptide drug alone; and   (d) the at least one heparosan polymer is further characterized as being substantially non-targeting.   
     
     
         14 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer comprises an activated group on the at least one heparosan polymer to effect the conjugation of the at least one heparosan polymer to the therapeutic non-peptide drug, and wherein the reactive group is selected from the group consisting of an aldehyde, alkyne, ketone, maleimide, thiol, azide, amino, carbonyl, sulfhydryl, hydrazide, phosphate, sulfate, nitrate, carbonate, ester, squarate, chelator, and combinations thereof. 
     
     
         15 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one heparosan polymer and the at least one therapeutic non-peptide drug are covalently conjugated. 
     
     
         16 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one therapeutic non-peptide drug is selected from the group consisting of a chemotherapy agent, an antineoplastic agent, a steroid, an antibiotic, an anti-inflammatory agent, an agent that has an action on a central nervous system of the mammalian patient, an antihistaminic, an antiallergic agent, an antipyretic, a respiratory agent, an antimicrobial agent, an antihypertensive agent, a calcium antagonist, an antipsychotic, an agent for Parkinson's disease, a vitamin, an antitumor agent, a cholinergic agonist, a mydriatic, an antidepressant agent, an antidiabetic drug, an anorectic agent, an antimalarial agent, a hormone, an antiulcerative agent, an anticancer agent, a vaccine antigen, a polynucleotide, a nutrient, a small molecule, and combinations thereof. 
     
     
         17 . The pharmaceutical drug delivery composition of  claim 1 , wherein the at least one therapeutic non-peptide drug comprises an anti-cancer agent. 
     
     
         18 . The pharmaceutical drug delivery composition of  claim 17 , wherein the anti- cancer agent comprises cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines or thioxantheres.