Methods for Making Controlled Delivery Devices Having Zero Order Kinetics

Abstract

A method of making an injectable or implantable active agent delivery device capable of delivering a diagnostic, therapeutic, and/or prophylactic agent to a desired targeted site having orifice(s) on the surface is disclosed herein providing unidirectional release of the agent at a controlled desirable rate. The agent may include, but is not limited to, drugs, proteins, peptides, biomarkers, bioanalytes, and/or genetic material. The technology of the invention is based on parallel processing to fabricate micro-holes on tubes employing photo-lithography and reactive ion etching techniques and also incorporates a simple molding method to form the micro-holes on flexible polymer tubes, including bio-degradable tubes. The parallel processing method of the instant invention is fast, economical and well suited for mass production. The developed device, due to its composite structure, has the ability to combine several release mechanisms, leading to zero-order release kinetics for most of the time.

1 - 79 . (canceled) 
     
     
         80 . A device for delivery of one or more active agents capable of zero-order delivery kinetics comprising:
 a housing formed from one impermeable, biocompatible material encompassing a hollow core;   one or more passageways of micrometer scale fabricated in the housing and connecting the hollow core and an outer space;   a drug supply loaded in the hollow core via a first end of the housing, wherein the drug supply comprises the one or more active agents; and   a biocompatible material sealing the first end of the housing.   
     
     
         81 . The device of  claim 80 , wherein the housing is a tubular housing encompassing the hollow core and the one or more passageways extend through the tubular housing. 
     
     
         82 . The device of  claim 80 , wherein the homogenous, impermeable, biocompatible housing is smaller than 5 mm in diameter. 
     
     
         83 . The device of  claim 80 , wherein the one or more passageways have an inner diameter in the range of 1-100 μm, 10-50 μm or 20-30 μm. 
     
     
         84 . The device of  claim 80  further comprising multiple housings, each of which comprise one or more passageways to enable individual release rates of therapeutic agents from the housings. 
     
     
         85 . The device of  claim 80 , wherein the housing comprises multiple partitioned compartments each of which comprises one or more passageways to enable individual release rates of therapeutic agents from the compartments. 
     
     
         86 . The device of  claim 80 , wherein the passageways are coated or sealed with a biodegradable material to control the timing of the onset of drug release. 
     
     
         87 . The device of  claim 80 , wherein the device comprises a plurality of enclosures each of which contains an active agent and the release rate from each of which can be controlled by the dimensions of the critical features, such as the size and shape of the enclosure and the number and the size of the passages, and affected by the drug solubility and drug loading density. 
     
     
         88 . The device of  claim 80 , wherein the device comprises an enclosure which is loaded with multiple active agents and each of the active agents may have an individual release rate as a result of the composite interactions of the drug solubility, drug loading density, dimensions of the critical features, such as the size and shape of the enclosure and the number and the size of the passages. 
     
     
         89 . The device of  claim 80 , wherein the shape of the one or more holes or perforations is selected from the group consisting of a triangle, a polygon, an undecagon, a trapezium or trapezoid, a quadrilateral, an icosagon, a star polygon, an annulus, a circle, a crescent, an ellipse, an oval, an arbelos, a Reuleaux triangle, a semicircle, a sphere, an Archimedean spiral, an astroid, a deltoid, a super ellipse, and a tomahawk. 
     
     
         90 . The device of  claim 80 , wherein the hollow core is loaded with a composition or formulation of one or more therapeutic agents which are to be released at their individual release rates 
     
     
         91 . The device of  claim 80 , wherein the device may optionally be integrated with a microelectronic circuit, wherein the microelectronic circuit comprises at least one of a sensor, a transmitter, a receiver, a transceiver, a switch, a power supply or a light, and wherein the microelectronic circuit is capable of monitoring body analytes and controlling the release of chemical agents or medications. 
     
     
         92 . The device of  claim 91 , wherein the sensor comprises an analyte sensor wherein the analyte may be selected from the group consisting of an inorganic ion, a small organic molecule, a protein, and a steroid hormone. 
     
     
         93 . The device of  claim 92 , wherein the protein comprises an insulin protein. 
     
     
         94 . The device of  claim 91 , wherein a signal from the transmitter is received by a remote detector. 
     
     
         95 . The device of  claim 80 , wherein the hollow core is filled with one or more active agents in a dosage form selected from the group consisting of a solid dosage form, a liquid dosage form, a semi-solid dosage, a powder, or a hydrogel with or without the use of a polymer, wherein the polymer is a natural polymer, a synthetic polymer or a combination thereof. 
     
     
         96 . The method of  claim 95 , wherein the natural polymer is selected from the group consisting of anionic polymers, alg-inic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, cationic polymers, chitosan, polylysine, amphipathic polymers, collagen, carboxymethyl chitin, fibrin, and neutral polymers, dextran, agarose, pullulan, and combinations and modifications thereof. 
     
     
         97 . The method of  claim 95 , wherein the synthetic polymer is selected from the group consisting of poly (vinyl alcohol), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (N-iso-propylacrylamide), poly-(caprolactone), poly(hydroxybutyrate), HEMA (hydroxyethylmethacrylate), PMMA (poly(methyl methacrylate), PEMA (poly(ethyl methacrylate), PAAm (polyacrylamide), cyclodextrin, and combinations and modifications thereof. 
     
     
         98 . The device of  claim 80 , wherein the housing matrix is selected from the group consisting of a polymer, a rubber, a metal, a mineral, a ceramic or a glass, and wherein the passage-way is selected from the group consisting of a hole, a perforation, a channel, an orifice, an aperture, a bore or combinations thereof, and wherein the active agent is selected from the group consisting of a therapeutic drug, a vitamin, a mineral, a saccharide, a lipid, a nucleic acid, a protein, a peptide, and combinations thereof. 
     
     
         99 . The device of  claim 80 , wherein the therapeutic drug is selected from the group consisting of an analgesic agent, an anti-inflammatory agent, an antihistaminic agent, an antiallergic agent, a central nervous system drug, an antipyretic agent, a respiratory agent, a steroid, a local anesthetic, a sympatho-mimetic agent, an antihypertensive agent, an antipsychotic agent, a calcium antagonist, a muscle relaxant, a vitamin, a cholinergic agonist, an antidepressant, an antispasmodic agent, a mydriatic agent, an anti-diabetic agent, an anorectic agent, an antiulcerative agent, an anti-tumor agent or combinations modifications thereof and, wherein the proteins are selected from the group consisting of an immunoglobulin or fragments thereof, a hormone, an enzyme, a cytokine, a bio-molecule, and combinations and modifications thereof. 
     
     
         100 . The device of  claim 80 , wherein the device is attached to a medical device. 
     
     
         101 . The device of  claim 100 , wherein the medical device is selected from the group consisting of a stent, a urinary catheter, an intravascular catheter, a dialysis shunt, a wound drain tube, a skin suture, a vascular graft, an implantable mesh, an intraocular device, an eye buckle, a heart valve, and combinations and modifications thereof. 
     
     
         102 . The device of  claim 80 , wherein the device is coated with a coating that prevents release of the one or more active agents until the coating is removed, which then causes release of the one or more active agents at a substantially constant rate. 
     
     
         103 . The device of  claim 80 , wherein the device has a geometrical shape selected from the group consisting of a cuboid, a cube, a sphere, a cone, an oval, and a cylinder. 
     
     
         104 . The device of  claim 80 , wherein the device may optionally be coated by a polymer, wherein the polymer is selected from the group consisting of polysaccharides, proteins, poly (ethylene glycol), poly(methacrylates), poly(ethylene-co-vinyl acetate), poly(DL-lactide), poly(glycolide), copolymers of lactide and glycolide, polyanhydride copolymers, and combinations and modifications thereof. 
     
     
         105 . The device of  claim 80 , wherein the device comprises a biocompatible material selected from the group consisting of a polymer, a metal, a mineral, a ceramic, a glass, and combinations and modifications thereof. 
     
     
         106 . The device of  claim 80 , wherein a number and a size of at least one passageway modulates a rate and an extent of release of the drug. 
     
     
         107 . The device of  claim 80 , wherein the rate and the extent of drug release is dependent on one or more parameters selected from the group consisting of drug solubility, device dimensions, passageway dimensions, and drug density and wherein the drug release rate is manipulated by changing a parameter selected from the group consisting of one or more holes on the surface, diameter of the holes, distance between the holes, diameter of the tube, length of the tube, solubility of the drug, and the amount of drug supply. 
     
     
         108 . The device of  claim 80 , wherein the drug supply is selected from a drug depot or a drug reservoir comprising a solid, a liquid, a semi-solid, and a suspension. 
     
     
         109 . The device of  claim 108 , wherein the drug supply is a member of a biopharmaceutical classification system (BCS) class selected from the group consisting of Class I (High permeability, High solubility); Class II (Low solubility, Low Permeability); Class III (High Solubility, Low Permeability), and Class IV (Low solubility, Low permeability). 
     
     
         110 . The device of  claim 108 , wherein the drug supply is selected from the group consisting of paclitaxel, rapamycin, sirolimus, zota rolimus, and tacrolimus. 
     
     
         111 . The device of  claim 108 , wherein the drug supply is selected from the group consisting of digitoxin, digoxin, quinidine, procainamide, propafenone, lidocaine, propanolol, verapamil, diltiazem, nitrogylcerine, isosorbide dinitrate, captopril, enalapril, thiazides, furosemide, spironolactone, pclitaxel, rapamycin, zotarolimus, and tacrolimus and combinations and modifications thereof. 
     
     
         112 . The device of  claim 108 , wherein the drug supply is selected from the group of opioid agonists consisting of morphine, codeine, thebaine and its derivatives, buprenorphine, papaverine, noscapine, and opioid antagonists consisting of naloxone and naltrexone, and combinations and modifications thereof.