Particulate drug delivery

Abstract

Methods for efficient preparation of drug-polymer (or oligomer) conjugates which are useful in the preparation of particles, including microparticles and nanoparticles, for delivery of the drug in vivo for therapeutic applications. The invention additionally provides certain drug-polymer and drug-oligomer conjugates which are useful in the preparation of particles for delivery of the drug in vivo. The invention also provides nanoparticles of this invention prepared by nanoprecipitation using drug-polymer/oligomer conjugates of the invention. The drug conjugates are formed during polymerization of the polymer or oligomer in which the drug is employed as an initiator of the polymerization of the monomers which form the polymer and/or oligomer. More specifically, the drug conjugates are formed by ring-opening polymerization of cyclic monomers in the presence of an appropriate ring-opening polymerization catalyst and the initiator (the drug). The method is particularly useful for formation of polymer/oligomer conjugates with drugs and other chemical species containing one or more hydroxyl groups or thiol groups.

1 . A method for preparing particles for in vivo delivery of a drug which comprises the steps of:
 (a) providing a drug the structure of which comprises one or more hydroxyl or thiol groups;   (b) conducting ring-opening polymerization of one or more cyclic monomers selected from cyclic esters, cyclic carbonates, cyclic phosphate, cyclic silicone, cyclic peptides or amino acid derivative, or cyclic phosphazane, or a combination thereof in anhydrous, water-miscible solvent in the presence of the drug as a polymerization initiator and a polymerization catalyst to form a covalent drug-oligomer or drug-polymer conjugate; and   (c) forming particles comprising the drug-oligomer or drug-polymer conjugate ranging in size from 2 nanometers to 100 microns.   
     
     
         2 . The method of  claim 1  wherein the particles are nanoparticles having particle size ranging from 2 nm to 300 nm. 
     
     
         3 . The method of  claim 1  wherein the particles are microparticles ranging in particle size from 0.200 micrometers to 400 micrometers. 
     
     
         4 . The method of  claim 1  further comprising the step of modifying the surface of the particle. 
     
     
         5 . The method of  claim 4  wherein the particle surface is modified by providing a coating layer of a polymer which may be the same or different from that of the conjugate. 
     
     
         6 . The method of  claim 5  wherein the particle surface is modified with surface pegylation with PEG chain length ranging from PEG 400 to PEG 40,000. 
     
     
         7 . The method of  claim 6  wherein the surface pegylation is provided by forming covalent particle-PEG linkages. 
     
     
         8 . The method of  claim 6  wherein the surface pegylation is provided through non-covalent interactions using hydrophobic polymer-b-PEG. 
     
     
         9 . The method of  claim 4  wherein the surface of the particle formed is modified with a hydrophilic or hydrophobic surface modifier. 
     
     
         10 . The method of  claim 4  wherein the surface of the particle formed is modified with an amphiphilic polymer. 
     
     
         11 . The method of  claim 10  wherein the amphiphilic polymer comprises PEG. 
     
     
         12 . The method of  claim 10  wherein the amphiphilic polymer is a copolymer comprising PEG. 
     
     
         13 . The method of  claim 9  wherein the surface of the particle formed is modified by covalent or non-covalent attachment to one or more of a peptide, protein, saccharide, carbohydrate, nucleic acid or a combination thereof. 
     
     
         14 . The method of  claim 1  wherein the terminal groups of the polymer or oligomer are selected from the group consisting of hydroxyl, thiol, amine, azide, alkyne, alkene, ketone, phenol, halides, imidazole, guanidinium, carboxylate, or phosphate groups. 
     
     
         15 . The method of  claim 14  wherein the surface of the particle formed is modified by coating or conjugation of one or more targeting ligands. 
     
     
         16 . The method of  claim 1  wherein the particles have a drug concentration gradient. 
     
     
         17 . The method of  claim 1  wherein the particles have a multilayer structure with different drug concentrations or different types of drugs in different layers. 
     
     
         18 . The method of  claim 17  wherein at least one layer of the particles is formed from the drug-oligomer or drug-polymer conjugate. 
     
     
         19 . The method of  claim 1  wherein the drug is a drug selected from the drugs in  FIG. 13 . 
     
     
         20 . The method of  claim 1  wherein the drug is a drug selected from Darunavir (TMC-114), Tipranavir (TPV), Saquinavir (SQV), Ritonavir (RTV), Indinavir, Nelfinavir (NFV), Amprenavir (APV), Lopinavir (ABT-378), Atazanavir (ATV), Vinorelbine bitartrate, fulvestrant, Sarcodictyins, camptothecins, Vinblastine, bryostatin 1, (+)-Cylindricine, (+)-Lactacystin, Aeruginosin 298-A, (+)-Fostriecin, Garsubellin A/Hyperforin, (S)-Oxybutynin, Epothilone A, Zidovudine (AZT), Lamivudine (3TC), Didanosine (ddI), Abacavir (ABC), Emtricitabine (FTC), bamethane, ethamivan, hexachlorophene, salicylanilide, pyrocatechin, thymol, pentazocine, phloroglucinol, eugenol, niclosamide, terbutaline, dopamine, methyldopa, norepinephrine, eugenol, α-naphthol, polybasic phenols, adrenaline, dopamine, phenylephrine, metaraminol, fenoterol, bithionol, alpha-tocopherol, isoprenaline, adrenaline, norepiniphrine, salbutamol, fenoterol, bithionol, chlorogenic acid/esters, captopril, amoxicillin, betaxolol, masoprocol, genistein, daidzein, daidzin, acetylglycitin, equol, glycitein, iodoresiniferatoxin, SB202190, or tyrphostin SU1498. 
     
     
         21 . The method of  claim 1  wherein the nanoparticles formed range in size on average from 2 nm to 400 μm. 
     
     
         22 . The method of  claim 1  wherein the catalyst is an organometallic catalyst or an organo catalyst of a ring-opening polymerization reaction. 
     
     
         23 . The method of  claim 1  wherein the polymerization reaction is performed in a solvent selected from THF, acetone, methylene chloride, chloroform, dimethylformamide, DMSO, acetonitrile or mixtures thereof. 
     
     
         24 . The method of  claim 1  wherein nanoparticles are formed by combining a solution of the covalent drug-polymer conjugate or the drug-oligomer conjugate in a water-miscible solvent with an excess of water. 
     
     
         25 . The method of  claim 1  wherein the molar ratio of cyclic monomer to drug initiator ranges from 5000/1 to 2/1. 
     
     
         26 . The method of  claim 1  wherein the drug is a hydroxyl-containing small organic molecule. 
     
     
         27 . The method of  claim 1  wherein the drug is a macromolecule. 
     
     
         28 . The method of  claim 1  wherein the drug is a peptide, saccharide or nucleic acid. 
     
     
         29 . The method of  claim 1  wherein the cyclic monomer is a cyclic ester, cyclic carbonate or a combination thereof. 
     
     
         30 . The method of  claim 1  wherein the catalyst is an orgaometallic catalyst. 
     
     
         31 . A covalent drug-oligomer or drug-polymer conjugate prepared by polymerizing one or more cyclic monomers selected from the group consisting of cyclic esters, cyclic carbonates, cyclic phosphates, cyclic siloxanes, cyclic peptides or amino acid derivative, or cyclic phosphazanes, in the presence of a drug the structure of which comprises one or more hydroxyl groups and a ring-opening polymerization catalyst wherein the drug comprising the one or more hydroxyl groups is the initiator of the polymerization reaction. 
     
     
         32 . The covalent drug-polymer conjugate of  claim 31  wherein the oligomer comprises 5000 or fewer repeating units of the ring-opened monomer. 
     
     
         33 . The covalent drug-polymer conjugate of  claim 31  wherein the oligomer comprises 500 or fewer repeating units of the ring-opened monomer. 
     
     
         34 . The covalent drug-oligomer conjugate of  claim 31  wherein the oligomer comprises 50 or fewer repeating units of the ring-opened monomer. 
     
     
         35 . The covalent drug-oligomer conjugate of  claim 31  wherein the oligomer comprises 20 or fewer repeating units of the ring-opened monomer. 
     
     
         36 . The covalent drug-oligomer conjugate of  claim 31  wherein the oligomer comprises 10 or fewer repeating units of the ring-opened monomer. 
     
     
         37 . A pharmaceutical composition comprising particles made by the method of  claim 1 . 
     
     
         38 . A pharmaceutical composition comprising particles made from a covalent drug-oligomer or drug-polymer conjugate of  claim 31 . 
     
     
         39 . A nanoparticle comprising a core/shell structure or a multiple layer structure wherein at least one of the core or shell or one of the layers is formed from a drug-polymer or a drug-oligomer conjugate which is prepared by conducting ring-opening polymerization of one or more cyclic monomers selected from cyclic esters, cyclic carbonates, cyclic phosphate, cyclic silicone, cyclic peptides or amino acid derivative, or cyclic phosphazane, or a combination thereof in an anhydrous, water-miscible solvent in the presence of the drug as a polymerization initiator and a polymerization catalyst to form the drug-oligomer or drug-polymer conjugate. 
     
     
         40 . A method for delivery of a drug to an individual in need thereof which comprises administering to the individual nanoparticles of  claim 39  and which comprise the drug covalently conjugated to an oligomer or polymer comprising ring-opened monomer repeating units. 
     
     
         41 . The method of  claim 40  wherein the monomers are selected from lactides, glycolides or a combination thereof. 
     
     
         42 . A method for delivery of a drug to an individual in need thereof which comprises administering to the individual nanoparticles prepared by the method of  claim 1  and which comprise the drug covalently conjugated to an oligomer or polymer comprising ring-opened monomer repeating units. 
     
     
         43 . A method for making a medicament comprising a drug whose structure comprises one or more hydroxyl groups or thiol groups which comprises covalently attaching the drug to an oligomer or polymer formed by rein-opening polymerization by introducing the drug into the ring-opening polymerization reaction to function therein as the initiator of polymerization. 
     
     
         44 . A method for preparing particles for in vivo delivery of a chemical species which has at least one hydroxyl group or thiol group which comprises the steps of:
 (a) conducting ring-opening polymerization of one or more cyclic monomers selected from cyclic esters, cyclic carbonates, cyclic phosphate, cyclic silicone, cyclic peptides or amino acid derivative, or cyclic phosphazane, or a combination thereof in anhydrous, water-miscible solvent in the presence of the chemical species having at least one hydroxyl group as a polymerization initiator and a polymerization catalyst to form a covalent drug-oligomer or drug-polymer conjugate; and   (c) forming particles comprising the drug-oligomer or drug-polymer conjugate ranging in size from 2 nanometers to 100 microns.   
     
     
         45 . A covalent oligomer or polymer conjugate prepared by polymerizing one or more cyclic monomers selected from the group consisting of cyclic esters, cyclic carbonates, cyclic phosphates, cyclic siloxanes, cyclic peptides or amino acid derivative, or cyclic phosphazanes, in the presence of a chemical species the structure of which comprises one or more hydroxyl groups and a ring-opening polymerization catalyst wherein the drug comprising the one or more hydroxyl groups is the initiator of the polymerization reaction. 
     
     
         46 . The conjugate of  claim 45  wherein the chemical species is selected from the groups consisting of a diagnostic reagent, a peptide, a saccharide, a carbonhydrate, an inorganic species, a contrast agent, a vitamin, a nutrient, a nucleic acid, an RNA molecule, an siRNA, or a DNA molecule.