POLYMER-ENCAPSULATED DRUG PARTICLES
Various embodiments disclosed relate to polymer-encapsulated drug particles and a drug-releasing coating including the same, as well as drug-coated balloon catheters for treating, preventing, or reducing the recurrence of strictures in body lumens and methods of using the same. A drug-coated balloon catheter for delivering a therapeutic agent to a target site of a body lumen stricture includes an elongated balloon. The balloon catheter includes a coating layer overlying an exterior surface of the balloon. The coating layer includes the polymer-encapsulated drug particles; or a drug-releasing coating including the polymer-encapsulated drug particles; or a therapeutic agent and a first and/or second additive; or a combination thereof.
1 . A polymer-encapsulated drug particle comprising:
a therapeutic agent; and
one or more polymers that encapsulate the therapeutic agent, the one or more polymers comprising poly(lactide-co-glycolide) (PLGA);
wherein the therapeutic agent is crystalline, partially crystalline, amorphous, partially amorphous, or a combination thereof.
2 . The polymer-encapsulated drug particle of claim 1 , wherein the PLGA comprises a first PLGA having a weight ratio of lactic acid to glycolic acid of about 85:15 and a second PLGA having a weight ratio of lactic acid to glycolic acid of about 75:25.
3 . The polymer-encapsulated drug particle of claim 1 , wherein the therapeutic agent is chosen from paclitaxel, docetaxel, taxol, an mTOR inhibitor, rapamycin, sirolimus, zotarolimus, everolimus, tacrolimus, umirolimus, daunorubicin, doxorubicin, and combinations thereof.
4 . The polymer-encapsulated drug particle of claim 1 , wherein the therapeutic agent comprises paclitaxel, sirolimus, or a combination thereof.
5 . The polymer-encapsulated drug particle of claim 1 , wherein the polymer-encapsulated drug particle has a largest dimension of 0.2 micron to 30 microns.
6 . The polymer-encapsulated drug particle of claim 1 , wherein the one or more polymers further comprise polyarginine, an amino dextran, a polycation-containing cyclodextrin, an amino cyclodextrin or a derivative thereof, a histone, a protamine, cationized human serum albumin, an aminopolysaccharide, chitosan, a peptide, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), a polyethylenimine, a polyallylamine, a polypropylenimine, a polyamidoamine dendrimer, a cationic polyoxazoline, a poly(beta-aminoester), a PEG-PEI copolymer, a PLGA-PEI copolymer, a positively charged gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid-modified branched polyethylenimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate), poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, poly(N,N-dimethylaminoethyl methacrylate), a cationic copolymer of dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate, an anionic copolymer of methacrylic acid/methyl methacrylate, a copolymer of ethyl acrylate/methyl methacrylate/methacrylic acid ester with quaternary ammonium groups, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), butylated hydroxytoluene (BHT), or a combination thereof.
7 . The polymer-encapsulated drug particle of claim 1 , further comprising a first ionic or zwitterionic additive, wherein the first ionic or zwitterionic additive is coated on a surface of the polymer-encapsulated drug particle.
8 . The polymer-encapsulated drug particle of claim 7 , wherein the first ionic or zwitterionic additive comprises at least one of: a charged polymer, a charged lipid, a phospholipid, a phosphocholine, a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidylinositol, and combinations thereof.
9 . The polymer-encapsulated drug particle of claim 7 , wherein the first ionic or zwitterionic additive comprises polyarginine, an amino dextran, a polycation-containing cyclodextrin, an amino cyclodextrin or a derivative thereof, a histone, a protamine, cationized human serum albumin, an aminopolysaccharide, chitosan, a peptide, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), a polyethylenimine, a polyallylamine, a polypropylenimine, a polyamidoamine dendrimer, a cationic polyoxazoline, a poly(beta-aminoester), a PEG-PEI copolymer, a PLGA-PEI copolymer, a positively charged gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid-modified branched polyethylenimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate), poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, poly(N,N-dimethylaminoethyl methacrylate), a cationic copolymer of dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate, an anionic copolymer of methacrylic acid/methyl methacrylate, a copolymer of ethyl acrylate/methyl methacrylate/methacrylic acid ester with quaternary ammonium groups, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), or a combination thereof.
10 . The polymer-encapsulated drug particle of claim 7 , wherein the first ionic or zwitterionic additive comprises poly-L-lysine, polylysine, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), or a combination thereof.
11 . A drug-releasing coating comprising:
the polymer-encapsulated drug particle of claim 1 ; and
a release matrix comprising a second ionic or zwitterionic additive and optionally comprising butylated hydroxytoluene (BHT).
12 . The drug-releasing coating of claim 11 , wherein the second ionic or zwitterionic additive comprises a water-soluble polymer.
13 . The drug-releasing coating of claim 11 , wherein the second ionic or zwitterionic additive comprises polyvinyl alcohol (PVA), a polypeptide, a protein, a water-soluble surfactant, a water-soluble vitamin, polyethylene glycol, polyvinylpyrrolidinone, polyarginine, an amino dextran, a polycation-containing cyclodextrin, an amino cyclodextrin or a derivative thereof, a histone, a protamine, cationized human serum albumin, an aminopolysaccharide, chitosan, a peptide, poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), a polyethylenimine, a polyallylamine, a polypropylenimine, a polyamidoamine dendrimer, a cationic polyoxazoline, a poly(beta-aminoester), a PEG-PEI copolymer, a PLGA-PEI copolymer, a positively charged gelatin, hydroxy-terminated poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), stearic acid-modified branched polyethylenimine, branched PEI-g-PEG, poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate), poly(1-vinylpyrrolidone)-graft-(1-triacontene), polylysine, poly(N,N-dimethylaminoethyl methacrylate), a cationic copolymer of dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate, an anionic copolymer of methacrylic acid/methyl methacrylate, a copolymer of ethyl acrylate/methyl methacrylate/methacrylic acid ester with quaternary ammonium groups, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (DPePC), or a combination thereof.
14 . The drug-releasing coating of claim 11 , wherein the second ionic or zwitterionic additive comprises poly-L-lysine, polylysine, polyvinyl alcohol (PVA), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (DPePC), or a combination thereof.
15 . The drug-releasing coating of claim 11 , wherein the polymer-encapsulated drug particle comprises 10 wt % to 90 wt % of the drug-releasing coating.
16 . The drug-releasing coating of claim 11 , wherein the release matrix further comprises particles of the therapeutic agent that are free of encapsulation by the one or more polymers.
17 . A medical device comprising:
a balloon; and
the drug-releasing coating of claim 11 on at least a portion of the balloon.
18 . The medical device of claim 17 , further comprising:
a base coat comprising the second ionic or zwitterionic additive between the balloon and the drug-releasing coating; and
a top coat comprising polyvinyl alcohol, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (DPePC), butylated hydroxytoluene (BHT), or a combination thereof, over the drug-releasing coating.
19 . The medical device of claim 17 , wherein the second ionic or zwitterionic additive between the balloon and the drug-releasing coating comprises polyvinyl alcohol (PVA), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-disteroyl-sn-glycero-3-phosphatidylcholine (DSPC), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (DPePC), or a combination thereof.
20 . The medical device of claim 17 , wherein the medical device releases at least 3% of the therapeutic agent upon inflation of the balloon and at least about 2 ng of the therapeutic agent per mg of tissue 72 hours after inflation of the balloon.