Targeted and high density drug loaded polymeric materials

Abstract

Polymeric delivery devices have been developed which combine high loading/high density of molecules to be delivered with the option of targeting. As used herein, “high density” refers to microparticles having a high density of ligands or coupling agents, which is in the range of 1000-10,000,000, more preferably between 10,000 and 1,000,000 ligands per square micron of microparticle surface area. A general method for incorporating molecules into the surface of biocompatible polymers using materials with an HLB of less than 10, more preferably less than 5, such as fatty acids, has been developed. Because of its ease, generality and flexibility, this method has widespread utility in modifying the surface of polymeric materials for applications in drug delivery and tissue engineering, as well other fields. Targeted polymeric microparticles have also been developed which encapsulate therapeutic compounds such as drugs, cellular materials or components, and antigens, and have targeting ligands directly bound to the microparticle surface. Preferred applications include use in tissue engineering matrices, wound dressings, bone repair or regeneration materials, and other applications where the microparticles are retained at the site of application or implantation. Another preferred application is in the use of microparticles to deliver anti-proliferative agents to the lining of blood vessels following angioplasty, transplantation or bypass surgery to prevent or decrease restenosis, and in cancer therapy. In still another application, the microparticles are used to treat or prevent macular degeneration when administered to the eye, where agents such as complement inhibitors are administered.

1 . Polymeric microparticles for delivery of a therapeutic, nutritional, diagnostic or prophylactic agent incorporated in a high density on or within the microparticles, the microparticles comprising ligands present in a density of between about which is preferably in the range of 1,000 to 10,000,000, more preferably 10,000-1,000.000, ligands per square micron of microparticle surface area. 
   
   
       2 . The microparticles of  claim 1  wherein the ligands have a first end incorporated into the surface of the microparticle and a second end facing outwardly from the surface of the microparticle. 
   
   
       3 . The microparticles of  claim 2  wherein the polymer is a hydrophobic polymer and the ligands are materials with an HLB of less than 10, more preferably less than 5, which insert into the surface of the microparticles. 
   
   
       4 . The microparticles of  claim 3  comprising a hydrophobic polymer having fatty acid conjugates inserted therein and extending outwardly from the polymeric surface. 
   
   
       5 . The microparticles of  claim 1  wherein the ligands are, or are bound to, an agent to be delivered selected from the group consisting of therapeutic, nutritional, diagnostic, and prophylactic agents, attachment molecules, targeting molecules, and mixtures thereof. 
   
   
       6 . The microparticles of  claim 5  having bound thereto targeting molecules. 
   
   
       7 . The microparticles of  claim 6  wherein the targeting molecules are physically or chemically attached to the ligands. 
   
   
       8 . The microparticles of  claim 5  further comprising agent encapsulated within the polymer. 
   
   
       9 . The microparticles of  claim 8  for delivery of the same or different agents in the form of a two phase delivery or pulsed delivery. 
   
   
       10 . The microparticles of  claim 5  wherein targeting molecules are bound to the surface of the microparticles or to the ligands. 
   
   
       11 . The microparticles of  claim 10  wherein the targeting molecules are selected from the group consisting of specific targeting molecules and non-specific targeting molecules. 
   
   
       12 . The microparticles of  claim 10  wherein the density and means of attachment, whether covalent or ionic, direct or via the means of linkers, of the ligands is used to modulate targeting of the microparticles. 
   
   
       13 . The microparticles of  claim 10  wherein the targeting molecules are selected from the group consisting of antibodies and fragments thereof, sugars, peptides, and ligands for cell surface receptors. 
   
   
       14 . The microparticles of  claim 5  wherein the ligands are attachment molecules. 
   
   
       15 . The microparticles of  claim 14  wherein the ligand is, or is bound to, an attachment molecule selected from the group consisting of strepavidin and biotin. 
   
   
       16 . The microparticles of  claim 1  further comprising linkers attached to the ligands. 
   
   
       17 . The microparticles of  claim 16  wherein the linkers are branched and multiple agents to be delivered or attachment molecules are attached via the linkers to each of the ligands. 
   
   
       18 . The microparticles of  claim 16  wherein the linkers are polyethyleneglycol star polymers. 
   
   
       19 . The microparticles of  claim 5  wherein the agent to be delivered is a therapeutic or nutritional agent selected from the group consisting of drugs, proteins, peptides, sugars, polysaccharides, nucleotide molecules, and nucleic acid molecules. 
   
   
       20 . The microparticles of  claim 5  wherein the agent to be delivered is a diagnostic agent selected from the group consisting of paramagnetic molecules, fluorescent compound, magnetic molecules, and radionuclides, 
   
   
       21 . The microparticles of  claim 18  wherein the agent to be delivered inhibits calcification. 
   
   
       22 . The microparticles of  claim 5  wherein the agent to be delivered is a cytotoxic or antiproliferative agent. 
   
   
       23 . The microparticles of  claim 5  wherein the linkers are polyethyleneglycol and the attachment molecules are strepavidin, avidin or biotin. 
   
   
       24 . The microparticles of  claim 1  having a diameter that is between 0.5 and 20 microns. 
   
   
       25 . The microparticles of  claim 1  in the form of nanoparticles having a diameter between 50 and 500 nanometers. 
   
   
       26 . The microparticles of  claim 25  wherein the nanoparticles have a diameter of less than 100 nm. 
   
   
       27 . The microparticles of  claim 1  encapsulated in a liposome. 
   
   
       28 . A method for making a microparticle for delivery of a therapeutic, nutritional, diagnostic or prophylactic agent comprising
 Providing a solution of a hydrophobic polymer or the polymer in liquid form,   Adding materials with an HLB of less than 10, more preferably less than 5, to the polymer, which insert into the surface of the microparticles when the polymer is solidified to form microparticles under conditions wherein one end of the material with an HLB of less than 10 inserts into the polymer and the other extends outwardly from the polymeric surface of the microparticle.   
   
   
       29 . The method of  claim 28  wherein the hydrophobic polymer and material with an HLB of less than 10 is added to the polymer in a water in oil in water emulsion. 
   
   
       30 . The method of  claim 28  wherein the material with an HLB of less than 10 is first conjugated to a targeting or attachment molecule or therapeutic, prophylactic or diagnostic agent. 
   
   
       31 . The method of  claim 28  wherein the material with an HLB of less than 10 is a fatty acid, lipid or detergent. 
   
   
       32 . Microparticles formed of a hydrophobic or lipophilic polymer with a first end of a material with an HLB of less than 10 as a ligand interspersed therein and a second end of the material with an HLB of less than 10 facing outwardly from the surface of the microparticles. 
   
   
       33 . The microparticles of  claim 32  wherein material with an HLB of less than 10 is selected from the group consisting of fatty acids, lipids and detergents.