BIODEGRADABLE BIOACTIVE AGENT RELEASING MATRICES WITH PARTICULATES
The present invention is directed to biodegradable polymeric matrices for the controlled release of a hydrophilic bioactive agent. Generally, the biodegradable matrices include an aliphatic polyester copolymer and microparticulates that include the hydrophilic bioactive agent. In some embodiments, the matrix includes a second biodegradable polymer comprising hydrophilic and hydrophobic portions. Exemplary matrix forms are device coatings and medical implants. Matrices of the invention demonstrated high bioactive agent loading, were able to modulate release of the bioactive agent in a therapeutic manner, and also maintained high levels of activity for therapeutically useful large molecule bioactive agents, such as proteins.
1 . A biodegradable bioactive agent-releasing matrix, comprising a polymeric matrix comprising:
a biodegradable aliphatic polyester copolymer comprising monomeric units of formula I:
wherein R 1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms, and wherein the monomeric units of formula I are present in the biodegradable aliphatic polyester copolymer in an amount of greater than 17% by weight; and
a plurality of microparticles dispersed within the matrix; wherein the microparticles comprise a hydrophilic bioactive agent,
wherein the biodegradable bioactive agent-releasing matrix comprises a surface that is placed in direct contact with body fluid and/or body tissue.
2 . A biodegradable bioactive agent-releasing matrix, comprising a polymeric matrix comprising:
a first biodegradable copolymer comprising a biodegradable aliphatic polyester copolymer comprising monomeric units of formula II:
wherein R 2 is a divalent saturated or unsaturated hydrocarbon group that includes four or five carbon atoms, and wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount of greater than 15% by weight;
a second biodegradable copolymer comprising hydrophobic and hydrophilic portions; and
a plurality of microparticles dispersed within the matrix; wherein the microparticles comprise a hydrophilic bioactive agent.
3 . The biodegradable bioactive agent-releasing matrix of claim 2 , wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 15% to 80% by weight.
4 . The biodegradable bioactive agent-releasing matrix of claim 3 , wherein the monomeric units of formula I are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 25% to 75% by weight.
5 . The elution control matrix of claim 2 , wherein the monomeric units of formula II are derived from the polymerization of caprolactone.
6 . The biodegradable bioactive agent-releasing matrix of claim 2 , wherein the biodegradable aliphatic polyester copolymer further comprises monomeric units of formula I:
wherein R 1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms.
7 . The biodegradable bioactive agent-releasing matrix of claim 6 , wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 20% to 85% by weight.
8 . The biodegradable bioactive agent-releasing matrix of claim 7 , wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 25% to 75% by weight.
9 . The biodegradable bioactive agent-releasing matrix of claim 6 , wherein the monomeric units of formula I are derived from the polymerization of lactide.
10 . The biodegradable bioactive agent-releasing matrix of claim 2 , wherein the first biodegradable polymer and second biodegradable polymer are present in the matrix in a ratio in the range of 1:10 to 10:1 by weight.
11 . The biodegradable bioactive agent-releasing matrix of claim 10 , wherein the first biodegradable polymer and second biodegradable polymer are present in the matrix in a ratio in the range of 1.5:10 to 10:1.5 by weight.
12 . The biodegradable bioactive agent-releasing matrix of claim 2 wherein the second biodegradable polymer includes hydrophilic polymeric blocks and hydrophobic polymeric blocks, with one or both blocks including degradable linkages
13 . The biodegradable bioactive agent-releasing matrix of claim 2 wherein the second biodegradable polymer includes polyethylene glycol blocks.
14 . The biodegradable bioactive agent-releasing matrix of claim 2 wherein the second biodegradable copolymer comprises a polyether ester copolymer.
15 . The biodegradable bioactive agent-releasing matrix of claim 14 wherein the second biodegradable copolymer comprises a poly(ether ester) block copolymer comprising poly(ethylene glycol) (PEG) and poly(butylene terephthalate) (PBT) blocks.
16 . The biodegradable bioactive agent-releasing matrix of claim 14 wherein the second biodegradable copolymer comprises a block copolymer comprising poly(ethylene glycol) (PEG) and poly(lactic acid) (PLA) blocks.
17 . The biodegradable bioactive agent-releasing matrix of claim 2 wherein the microparticles are present in the matrix in an amount in the range of 1% to 50% by weight of a total solids content of the matrix.
18 . The biodegradable bioactive agent-releasing matrix of claim 16 wherein the microparticles are present in the matrix in an amount in the range of 20% to 40% by weight of a total solids content of the matrix.
19 . The biodegradable bioactive agent-releasing matrix of claim 2 wherein the microparticles comprise a polypeptide.
20 . The biodegradable bioactive agent-releasing matrix of claim 19 , wherein the microparticles comprises a polypeptide that is an antibody or fragment thereof.
21 . The biodegradable bioactive agent-releasing matrix of claim 20 , wherein the microparticles comprises a Fab fragment.
22 . The biodegradable bioactive agent-releasing matrix of claim 2 , wherein the microparticles are formed predominantly of the hydrophilic bioactive agent.
23 . The biodegradable bioactive agent-releasing matrix of claim 2 , which is in the form of a coating on an implantable medical device.
24 . A method for affecting a condition in a subject comprising the steps of introducing the biodegradable bioactive agent-releasing matrix of claim 2 in a subject, and allowing hydrophilic bioactive agent to be released from the elution control matrix which affects the condition in a subject.