Polymer particle delivery compositions and methods of use

Abstract

The present invention provides biodegradable polymer particle delivery compositions based on polymers, such as polyester amide (PEA) and polyester urethane (PEUR) polymers, that contain amino acids in the polymer. The polymer particle delivery compositions can be formulated as a liquid dispersion of polymer particles with the bioactive agents dispersed in the particle or conjugated attached to polymer molecules or particle surfaces. The bioactive agents can include drugs, polypeptides, DNA and cells for cell-based therapies using particles sized for local, mucosal or circulatory delivery. Methods of treating a disease by administering to a subject the polymer particle delivery composition, which incorporates a bioactive agent suitable for treatment of the disease, or its symptoms, are also included.

1 . A polymer particle delivery composition in which a therapeutically effective amount of at least one bioactive agent is dispersed in a biodegradable polymer, wherein the polymer is a PEA having a chemical formula described by structural formula (I),  
       
         
           
           
               
               
           
         
         wherein n ranges from about 5 to about 150; R 1 is independently selected from residues of α,ω-bis(4-carboxyphenoxy)-(C 1 -C 8 ) alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid or 4,4′-(alkanedioyldioxy)dicinnamic acid, (C 2  - C 20 ) alkylene, (C 2 -C 20 ) alkenylene or a saturated or unsaturated residues of therapeutic di-acids; the R 3 s within an individual n monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, -(CH 2 )C 3 , and -CH 2 )C 2 S(CH 2 ); and R 4  is independently selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy, (C 2 -C 20 ) alkylene, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of general structural formula(II), and combinations thereof, (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene and saturated or unsaturated therapeutic di-acid residues;  
         
           
             
             
                 
                 
             
           
         
         
           
             
             
                 
                 
             
           
         
         wherein n ranges from about 5 to about 150, m ranges about 0.1 to 0.9: p ranges from about 0.9 to 0. 1; wherein R 1 is independently selected from residues of α,ω)-bis(4-carboxyphenoxy)-(C 1 -C 8 ) alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid or 4,4′-(alkanedioyldioxy) dicinnamic acid, (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or a saturated or unsaturated residues of therapeutic di-acids; each R 2  is independently hydrogen, (C 1 -C 12 ) alkyl or (C 6 -C 10 ) aryl or a protecting group; the R 3 S within an individual m monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, -CH 2 )C 3 , and -CH 2 ) 2 S(CH 2 ); and R 4  is independently selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy, (C 2 -C 20 ) alkylene, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula(II), and combinations thereof, and residues of saturated or unsaturated therapeutic diols;  
         or a PEUR polymer having a chemical formula described by structural formula (IV),  
         
           
             
             
                 
                 
             
           
         
         and wherein n ranges from about 5 to about 150; wherein the R  3 s within an individual n monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl(C 1 -C 6 ) alkyl, -(CH 2 ) 3 , and -(CH 2 ) 2 S(CH 2 ); R 4  is selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, and bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II); and R 6  is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of general formula (II), a residue of a saturated or unsaturated therapeutic diol, and mixtures thereof.  
         or a PEUR polymer having a chemical structure described by general structural formula (V)  
         
           
             
             
                 
                 
             
           
         
         wherein n ranges from about 5 to about 150, m ranges about 0.1 to about 0.9: p ranges from about 0.9 to about 0.1; R 2  is independently selected from hydrogen, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, or a protecting group; the R 3 s within an individual m monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl(C 1 -C 6 ) alkyl, -CH 2 ) 3 − as pyrrolidine-2-carboxylic acid and -CH 2 ) 2 S(CH 2 ); R 4  is selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, and bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II); and R 6  is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of general formula (II), a residue of a saturated or unsaturated therapeutic diol, and mixtures thereof.  
         or a biodegradable PEU polymer having a chemical formula described by general structural formula (VI):  
         
           
             
             
                 
                 
             
           
         
         wherein n is about 10 to about 150; the R 3 s within an individual n monomer are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, -CH 2 ) 3 , and -CH 2 ) 2 S(CH 2 ); R 4  is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II), and mixtures thereof;  
         or PEU having a chemical formula described by structural formula (VII)  
         
           
             
             
                 
                 
             
           
         
         wherein m is about 0.1 to about 1.0; p is about 0.9 to about 0.1; n is about 10 to about 150; each R 2  is independently hydrogen, (C 1 -C 12 ) alkyl or (C 6 -C 10 ) aryl; the R 3 s within an individual m monomer are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6  -C 10 ) aryl (C 1 -C 6 )alkyl, -(CH 2 ) 3 , and -CH 2 ) 2 S(CH 2 ); each R 4  is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II), and mixtures thereof.  
       
     
     
         2 . The composition of  claim 1 , wherein the composition is formulated for administration in the form of a liquid dispersion of the polymer particles.  
     
     
         3 . The composition of  claim 1 , wherein the composition is lyophilized.  
     
     
         4 . The composition of  claim 1 , wherein the polymer comprises at least one hydrophilic side functional group.  
     
     
         5 . The composition of  claim 4 , wherein the side functional group is -COOH.  
     
     
         6 . The composition of  claim 1 , wherein the polymer has the chemical formula described by structural formula (I), (IV) or (VII) and R 3 s in at least one monomer n is CH 2 Ph.  
     
     
         7 . The composition of  claim 1 , wherein  
       
         
           
           
               
               
           
         
       
     
     
         8 . The composition of  claim 7 , wherein R 1 is selected from −CH 2 -CH=CH−CH 2 −,-(CH 2 ) 4 −,-(CH 2 ) 6 −, and -(CH 2 ) 8 −.  
     
     
         9 . The composition of claim I, wherein the 1 ,4:3,6-dianhydrohexitol of structural formula (II) is derived from D-glucitol, D-mannitol, or L-iditol.  
     
     
         10 . The composition of  claim 1 , wherein the composition forms a time release polymer depot when administered in vivo.  
     
     
         11 . The composition of  claim 1 , wherein the composition biodegrades over a period of twenty-four hours, about seven days, about thirty days, or about 90 days.  
     
     
         12 . The composition of  claim 1 , wherein the composition is in the form of particles having an average diameter in the range from about 10 nanometers to about 1000 microns.  
     
     
         13 . The composition of  claim 1 , wherein the at least one bioactive agent is conjugated to the polymer on the exterior of the particles.  
     
     
         14 . The composition of  claim 13 , wherein the bioactive agent is selected from the group consisting of a targeting ligand, a drug, an antigen and an antibody.  
     
     
         15 . The composition of  claim 1 , further comprising a covering water soluble molecule conjugated to the polymer on the exterior of the particles.  
     
     
         16 . The composition of  claim 15 , wherein the covering water soluble molecule is selected from the group consisting of poly(ethylene glycol) (PEG); phosphoryl choline (PC); glycosaminoglycans; polysaccharides; poly(ionizable or polar amino acids); chitosan and alginate.  
     
     
         17 . The composition of  claim 16 , wherein the glycosaminoglycan is heparin and the polysaccharide is polysialic acid.  
     
     
         18 . The composition of  claim 1 , wherein a particle includes from about 5 to about 150 molecules of bioactive agent per polymer molecule chain.  
     
     
         19 . The composition of  claim 1 , wherein a polymer molecule in the particles has an average molecular weight in range from about 5,000 to about 300,000.  
     
     
         20 . The composition of  claim 1 , wherein the at least one bioactive agent is conjugated to a polymer molecule in the particles.  
     
     
         21 . The composition of  claim 1 , wherein a polymer molecule has from about 5 to about 70 molecules of bioactive agents attached thereto.  
     
     
         22 . The composition of  claim 1 , wherein the polymer is contained in a polymer-bioactive agent conjugate having structural formula VIII:  
       
         
           
           
               
               
           
         
       
       wherein n, m, p, R 1 , R 3 , and R 4  are as above, R 5  is selected from the group consisting of —O-, -S-, and -NR 8 -, wherein R 8  is H or (C 1 -C 8 )alkyl; and R 7  is the bioactive agent.  
     
     
         23 . The composition of  claim 22 , except that two or more molecules of the polymer are crosslinked to provide an -R 5 -R 7 - R 5  conjugate.  
     
     
         24 . The composition of  claim 22 , except that the bioactive agent is covalently linked to two parts of a single polymer molecule of structural formula IV through the -R 5 -R 7 -R 5 -conjugate and R 5  is independently selected from the group consisting of—O-, -S-, and -NR 8 -, wherein R 8  is H or (C 1 -C 8 ) alkyl; and R 7  is the bioactive agent.  
     
     
         25 . The composition of  claim 23 , except that R 1  is independently (C 2 -C 20 ) alkylene or (C 2 -C 20 ) alkenylene, and wherein one of R 5  is —X-Y-, 
 wherein X is selected from the group consisting of (C 1 -C 18 ) alkylene, substituted alkylene, (C 3 -C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group consisting of O, N, and S, substituted heterocyclic, (C 2 -C 18 ) alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6  and C 10  aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylkynyl and wherein the substituents are selected from the group consisting of H, F, Cl, Br, I, (C 1 -C 6 ) alkyl, -CN, -NO 2 , -OH, -O(C 1 -C 4 ) alkyl, -S(C 1 -C 6 ) alkyl, -S[(=O)(C 1 -C 6 ) alkyl], -S[(O 2 )(C 1‘-C   6 ) alkyl],-C[(=O)(C 1 -C 6 ) alkyl], CF 3 ,-O[(CO)-(C 1 -C 6 ) alkyl], -S(OC 2 )[N(R 9 R 10  )], -NH[(C=O)(C 1 -C 6 ) alkyl],-NH(C=O)N(R 9 R 10 ), and -N(R 9 R 10 ); wherein R 9  and R 10  are independently H or (C 1 -C 6 ) alkyl; and    Y is selected from the group consisting of —O-, -S-, -S-S-, -S(O)-,-S(O 2 )-, -NR 8 -, -C(=O)-,-OC(=O)-,-C(=O)O-,-OC(=O)NH-,-NR 8 C(=O)-,-C(=O)NR 8 -,-NR 8 C(=O)NR 8 -, -NR 8 C(=O)NR 8 -, and-NR 8 C(=S)NR 8 -.    
     
     
         26 . The composition of  claim 25 , except that each R 5  is -X-Y-.  
     
     
         27 . The composition of  claim 22 , comprising four molecules of the polymer, except that only two of the repeating units omit R 7  and are crosslinked to provide a single -R 5 -X-R 5 -conjugate, 
 wherein X is selected from the group consisting of (C 1 -C 18 ) alkylene, substituted alkylene, (C 3 -C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group consisting of O, N, and S, substituted heterocyclic, (C 2 -C 18 ) alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6  and C 10 aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylkynyl and wherein the substituents are selected from the group consisting of H, F, Cl, Br, I, (C 1 -C 6 ) alkyl, -CN, -NO 2 , -OH, -O(C 1 -C 4 ) alkyl, -S(C 1 -C 6 ) alkyl, -S[(=O)(C 1 -C 6 ) alkyl], -S[(O 2 )(C 1 -C 6 ) alkyl], -C[(=O)(C 1 -C 6 ) alkyl], CF 3 ,-O[(CO)-(C 1 -C 6 ) alkyl)], -S(O 2 )[N(R 9 R 10 )], -NH[(C=O)(C 1 -C 6 ) alkyl], -NH(C=O)N(R 9 R 10 ), and -N(R 9 R 10 ); wherein R 9  and R 10  are independently H or (C 1 -C 6 ) alkyl.    
     
     
         28 . The composition of  claim 22 , except that two molecules of the polymer are partially crosslinked to provide an -R 5 -X-Y-R 7 -R 5 -conjugate.  
     
     
         29 . The composition of  claim 24 , except that one molecule of the polymer is covalently linked to the bioactive agent through an -R 5 -R 7 -Y-X- R 5 -bridge, (Formula XI).  
       
         
           
           
               
               
           
         
       
       wherein, X is selected from the group consisting of (C 1 -C 18 ) alkylene, substituted alkylene, (C 3 -C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group consisting of O, N, and S, substituted heterocyclic, (C 2 -C 18 ) alkenyl 1, substituted alkenyl, alkynyl, substituted alkynyl, C 6  and C 10 ) aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylkynyl, wherein the substituents are selected from the group consisting of H, F, Cl, Br, I, (C 1 -C 6 ) alkyl, -CN, -NO 2,  -OH, -O(C 1 -C 4 ) alkyl, -S(C 1 -C 6 ) alkyl, -S[(=O)(C 1 -C 6 ) alkyl], -S[(O 2 )(C 1 -C 6 ) alkyl], -C[(=O)(C 1 -C 6 ) alkyl], CF 3 ,-O[(CO)-(C 1 -C   6 )alkyl], -S(O 2 )[N(R 9 R 10 )], -NH[(C=O)(C 1 -C 6 )alkyl], -NH(C=O)N(R 9 R 10 ), and -N(R 11 R 12 ), wherein R 1  is independently (C 2  -C 20 ) alkylene or (C 2 -C 20 ) alkenylene, and R 11  and R 12  are independently H or (C 1 -C 6 ) alkyl.  
     
     
         30 . The composition of  claim 28 , except that one molecule of the polymer is covalently linked to the bioactive agent through the conjugate and R 1  is (C 2 - C 20 ) alkylene or (C 2 -C 20 ) alkenylene.  
     
     
         31 . The composition of  claim 1 , wherein the composition forms a time release polymer depot when administered in vivo.  
     
     
         32 . The composition of  claim 1 , wherein the composition the particles have an average diameter in the range from about 10 nanometers to about 1000 microns and the at least one bioactive agent is dispersed in the particles.  
     
     
         33 . The composition of  claim 32 , wherein the particles further comprise a covering of the polymer.  
     
     
         34 . The composition of  claim 1 , wherein a particle has from about 5 to about 150 molecules of the bioactive agent per polymer molecule.  
     
     
         35 . The composition of  claim 1 , wherein a polymer molecule has from about 5 to about 70 molecules of bioactive agents attached thereto.  
     
     
         36 . The composition of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable vehicle.  
     
     
         37 . The composition of  claim 1 , wherein the composition is in the form of disperse droplets containing the particles in a mist.  
     
     
         38 . The composition of  claim 37 , wherein the mist is produced by a nebulizer.  
     
     
         39 . The composition of  claim 1 , wherein the composition is contained within a nebulizer actuatable to produce a mist comprising dispersed droplets of the vehicle.  
     
     
         40 . The composition of  claim 1 , wherein the composition is contained within an injection device that is actuatable to administer the composition by injection.  
     
     
         41 . The composition of  claim 1 , wherein the bioactive agent is hydrophilic and is selected from the group consisting of a hydrophilic drug, peptide, protein, lipid, sugar, RNA and DNA.  
     
     
         42 . The composition of  claim 41 , wherein the DNA is a gene contained in an expression system suitable for expression of the gene.  
     
     
         43 . The composition of  claim 42 , wherein the expression system comprises an adenovirus vector.  
     
     
         44 . The composition of  claim 1 , wherein the particles encapsulate an aqueous solution containing at least one smaller particle of the polymer in which the at least one bioactive agent is dispersed.  
     
     
         45 . The composition of  claim 1 , wherein the particles encapsulate an aqueous solution containing the at least one bioactive agent.  
     
     
         46 . The composition of  claim 1 , wherein the bioactive agent is contained in a polymer/bioactive agent mixture and the particles further comprise a covering formed by a different polymer in which the mixture is not soluble.  
     
     
         47 . The composition of  claim 1 , wherein the polymer forms a covering for the particles and the particles further comprise a mixture of the bioactive agent and a different polymer in which the mixture is not soluble.  
     
     
         48 . The composition of  claim 1 , wherein the bioactive agent is hydrophobic and is selected from the group consisting of a hydrophobic drug, peptide, protein, lipid, fat and sugar.  
     
     
         49 . A micelle-forming polymer particle delivery composition comprising at least one bioactive agent dispersed in a biodegradable polymer comprising 
 a) a hydrophobic section comprising a biodegradable polymer having a chemical structure described by structural formula (I), and    b) a water soluble section comprising at least one block of ionizable poly(amino acid), or the water soluble section comprises repeating alternating units of: 
 i) polyethylene glycol, polyglycosaminoglycan, or polysaccharide; and  
 ii) at least one ionizable or polar amino acid, wherein the repeating alternating units have substantially similar molecular weights and wherein the molecular weight of the polymer is in the range from about 10 kD to 300kD.  
   
     
     
         50 . The composition of  claim 49 , wherein the molecular weight of the polymer is over 10 kD and at least one of the amino acid units is an ionizable or polar amino acid selected from the group consisting of serine, glutamic acid, aspartic acid, lysine and arginine.  
     
     
         51 . The composition of  claim 49  wherein the repeating alternating units have substantially similar molecular weights in the range from about 300 D to about 700 D.  
     
     
         52 . The composition of  claim 49 , further comprising a pharmaceutically acceptable aqueous media with a pH value at which at least a portion of the ionizable amino acids in the water soluble chain are ionized, and wherein the composition forms micelles.  
     
     
         53 . The composition of  claim 49 , wherein the micelles have an average size in the range from about 20 nm to about 200 nm.  
     
     
         54 . The composition of  claim 49 , wherein the bioactive agent is selected from the group consisting of a small molecule drug, a peptide, a protein, lipid, sugar, DNA, cDNA or RNA.  
     
     
         55 . The composition of  claim 49 , wherein the water soluble section of the polymer has a molecular weight in the range from about 5 kD to about 100 kD.  
     
     
         56 . The composition of  claim 49 , wherein the complete water soluble section of the polymer comprises ionizable or polar water soluble poly(amino acids).  
     
     
         57 . The composition of  claim 49 , wherein the hydrophobic section of the polymer has a chemical structure described by structural formula I.  
     
     
         58 . The composition of  claim 57 , wherein the polymer comprises a moiety selected from carboxylate phenoxy propene (CPP), leucine-1,4:3,6-dianhydro-D-sorbitol (DAS), and combinations thereof.  
     
     
         59 . A method for treating a disease of interest in a subject by administering to the subject in vivo a invention polymer particle delivery composition of  claim 1  in the form of a liquid dispersion of polymer particles that incorporate at least one bioactive agent selected to treat the disease, which particles biodegrade by enzymatic action to release the bioactive agent over time.  
     
     
         60 . A method of delivering polymer particles containing one or more bioactive agents to a local site in the body in a subject in need thereof, said method comprising 
 injecting a dispersion of the polymer particles to an in vivo site in the body of the subject where the injected particles agglomerate to form a polymer depot of particles of increased size,    wherein the particles comprise a polymer containing at least one amino acid and a non-amino acid moiety per repeat unit of the polymer.    
     
     
         61 . The method of  claim 60 , wherein the particles have an average diameter in the range from about 1 μm to about 200 μm.  
     
     
         62 . The method of  claim 60 , wherein the polymer has a chemical formula described by structural formula (I).  
     
     
         63 . The method of  claim 60 , wherein the injection is administered intramuscularly, subcutaneously, intravenously, into the Central Nervous System (CNS), into the peritoneum or intraorgan.  
     
     
         64 . The composition of  claim 1 , wherein the composition is formulated for intrapulmonary or gastroenteral delivery.