Methods for Making Controlled Delivery Devices Having Zero Order Kinetics

• US 20120177716A1
• Filed: 07/14/2010
• Published: 07/12/2012
• Est. Priority Date: 07/14/2009
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Ho, Paul S., Bowman, Phillip, Luo, Zhiquan, Rastogi, Ashish, Stavchansky, Salomon, Wu, Zhuojie
• Granted Patent: US 9,005,649 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61B 17/06166 Sutures suture materials A61L17/00; manufacture of artificial threads D01D; treatment of threads D06M
• CPC Class Codes: A61B 2560/0219 of externally powered implanted units
• CPC Class Codes: A61B 5/076 Permanent implantations telemetry using implanted circuitry A61B5/0031; implanted stimulators for therapy A61N1/3605, A61N1/362, A61N1/372
• CPC Class Codes: A61B 5/4839 combined with drug delivery
• CPC Class Codes: A61B 5/686 Permanently implanted devices, e.g. pacemakers, other stimulators, biochips A61B5/6861 takes precedence
• CPC Class Codes: A61B 90/30 Devices for illuminating a surgical field, the devices having an interrelation with other surgical devices or with a surgical procedure
• CPC Class Codes: A61F 2/0063 Implantable repair or support meshes, e.g. hernia meshes
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2/91 made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• CPC Class Codes: A61F 2/915 with bands having a meander structure, adjacent bands being connected to each other
• CPC Class Codes: A61F 2220/005 using adhesives
• CPC Class Codes: A61F 2230/0013 Horseshoe-shaped, e.g. crescent-shaped, C-shaped, U-shaped
• CPC Class Codes: A61F 2230/0054 V-shaped
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0002 for data transfer
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61F 2310/00017 Iron- or Fe-based alloys, e.g. stainless steel
• CPC Class Codes: A61F 2310/00179 Ceramics or ceramic-like structures
• CPC Class Codes: A61F 2310/00329 Glasses, e.g. bioglass
• CPC Class Codes: A61F 9/0017 : implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 31/573 : substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61L 17/005 : containing a biologically active substance, e.g. a medicament or a biocide
• CPC Class Codes: A61L 2300/43 : Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/16 : Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/06 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61M 2025/0057 : Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
• CPC Class Codes: A61M 25/001 : Forming the tip of a catheter, e.g. bevelling process, join or taper
• CPC Class Codes: A61M 25/0017 : specially adapted for long-term hygiene care, e.g. urethral or indwelling catheters to prevent infections
• CPC Class Codes: A61M 25/0043 : characterised by structural features
• CPC Class Codes: A61M 27/002 : Implant devices for drainage of body fluids from one part of the body to another intraocular A61F9/00781; middle ear A61F11/202
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives

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.

Claims

1. A method for making a device for delivery of one or more active agents with

zero-order kinetics comprising the steps of:

providing a mold comprising a first surface and a second surface, wherein the first surface comprises one or more trenches, cavities or depressions, wherein each of the one or more trenches, cavities or depressions comprise one or more holes or perforations;

placing a first substrate in the trenches, cavities or depressions, wherein the substrate may optionally be held in place in the trench by using an adhesive; and

transferring a shape of the holes or the perforations in the one or more trenches, cavities or depressions to the first substrate by one or more microfabrication techniques to make the device for the delivery of the one or more active agents.

2. The method of claim 1, 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.

3. The method of claim 1, wherein the one or more microfabrication techniques are selected from the group consisting of physical etching, chemical etching, reactive ion etching, physical vapor deposition, chemical vapor deposition, liftoff, electroplating, electroless plating, ion milling, laser ablation, plasma torch cutting, lithography, and combinations and modifications thereof.

4. The method of claim 1, further comprising the optional step of pushing the substrate to the bottom of the trench by using a second substrate, wherein the second substrate is selected from the group consisting of silicon, glass, polymer, stainless steel, metals, alloys, ceramics, semiconductors, dielectrics, and combinations and modifications thereof.

5. The method of claim 1, further comprising the optional step of flipping the mold prior to the step of transferring the shape, wherein the flipping results in the second surface facing the one or more microfabrication or etching sources, wherein the etching sources are selected from the group consisting of ions, etching gases, plasma, laser beams, and combinations or modifications thereof.

6. The method of claim 1, wherein the first substrate material is selected from the group consisting of a polymer, a rubber, a metal, a semiconductor, a dielectric, a mineral, a ceramic, and a glass.

7. The method of claim 1, wherein the method further comprising the step of loading an active agent supply in the device by a method selected from the group consisting of capillary action, dipping, injection, and pressure loading using positive or negative pressures.

8. The method of claim 1, wherein the one or more active agents comprise a solid, a liquid dosage, a semi-solid, a powder or a hydrogel.

9. The method of claim 1, wherein the device may optionally be attached to a medical device or 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.

10. The method of claim 9, wherein the medical device is selected from the group consisting of a stent, an 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.

11. The method of claim 1, wherein the one or more holes or perforations are circular.

12. The method of claim 11, wherein the circular holes or the perforations range from 1 nanometer-1 centimeter, 100 nanometers-100 microns, 1 micron-50 microns, 10-30 microns, 15-25 microns or 20 microns.

13. The method of claim 1, wherein the first substrate is a polymer tube and the technique is reactive ion etching using a plasma.

15. The method of claim 1, further comprising the optional step of polymer coating the device thereby preventing a 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.

16. The method of claim 15, wherein the polymer coating 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 and one or more active agents are selected from the group consisting of drugs, proteins, vitamins, minerals, saccharides, lipids, nucleic acid, peptides, manure, plant nutrients, chemicals, perfumes, fragrances, flavoring agents, animal feed, effervescent gas releasing agents, and combinations and modifications thereof.

21. A method for making the mold of claim 1, comprising the steps of:

providing a substrate comprising a first surface and a second surface;

forming one or more trenches on the first surface or on the second surface by one or more microfabrication techniques; and

forming one or more holes or perforations on the one or more trenches by one or more microfabrication techniques.

22. The method of claim 21, wherein the substrate comprises a material selected from the group consisting of semiconductors, metals, dielectrics, polymers, rubbers, minerals, and ceramics.

23. The method of claim 21, wherein the first surface or the second surface is planar or non-planar.

25. The method of claim 21, wherein the one or more trenches are made by one or more microfabrication techniques selected from the group consisting of physical etching, chemical etching, reactive ion etching, ion milling, laser ablation, plasma torch cutting, thin film deposition, lithography, mechanical drilling, sand blasting, photolithography, wet anisotropic etching, and combinations and modifications thereof.

26. The method of claim 21, wherein the substrate is a silicon wafer.

28. The method of claim 21, wherein one or more trenches are made by a method comprising the steps of:

depositing at least one layer on the first surface of the substrate, wherein the layer serve as etching mask layer, wherein the deposition is done by physical vapor deposition;

coating a photo-resist layer onto the etching mask layer;

creating a trench structure on the photo-resist layer by using photo-lithography;

aligning a desired trench direction and creating one or more alignment marks on the substrate;

transferring the trench structure through the etching mask layer to the substrate or substrate layer by using one or more microfabrication techniques; and

removing any residual substrate or substrate-layer materials from the formed trenches.

29. The method of claim 28, wherein the etching mask layer is selected from the group consisting of silicon dioxide, silicon nitride, silicon carbide, silicon oxynitride, silicon carbonitride, chromium, nickel, aluminum, Al2O3, and combinations and modifications thereof and the photo-resist layer is selected from the group consisting of Poly(methyl methacrylate) (PMMA), Poly(methyl glutarimide) (PMGI), Phenol formaldehyde resin, SU-8, and combinations and modifications thereof.

32. The method of claim 28, wherein the method further comprises the additional step of forming one or more holes or perforations on the one or more trenches comprising the steps of:

depositing at least one etching mask layer on the second surface of the substrate or the substrate layer;

defining a window pattern by photolithography on the second surface of the substrate or the substrate layer;

aligning the window pattern to the trench on the first surface of the substrate or the substrate layer using the one or more alignment marks;

transferring the window pattern onto the substrate or the substrate layer by a combination of reactive ion and wet anisotropic etching;

defining the hole or perforation structure by lithography; and

forming the hole or the perforation by reactive ion etching.

14. (canceled)

17. (canceled)

18. The method of claim 17, wherein the drugs are selected from the group consisting of an analgesic agent, an antiinflammatory agent, an antihistaminic agent, an antiallergic agent, a central nervous system drug, an antipyretic agent, a respiratory agent, a steroid, a local anesthetic, a sympathomimetic 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 the proteins are selected from the group consisting of an immunoglobulin or fragments thereof, a hormone, an enzyme, a cytokine, a biomolecule, and combinations and modifications thereof.

19-20. -20. (canceled)

24. (canceled)

27. (canceled)

30-31. -31. (canceled)

33-34. -34. (canceled)

35. A method for making a device for delivery of one or more active agents with zero-order kinetics by a reactive ion etching technique comprising the steps of:

providing a silicon-wafer mold comprising a first surface and a second surface, wherein the first surface comprises one or more trenches, cavities or depressions, wherein each of the one or more trenches, cavities or depressions comprise one or more holes, perforations or patterns;

placing a first substrate in the trenches, cavities or depressions, wherein the substrate may optionally be held in place in the trench by using an adhesive; and

transferring a shape of the holes, the perforations or the patterns in the one or more trenches, cavities or depressions to the first substrate by using a reactive plasma to make the device for the delivery of the one or more active agents.

36. The method of claim 35, further comprising the optional step of pushing the first substrate to the bottom of the trenches, cavities or depressions by using a second substrate, wherein the second substrate is selected from the group consisting of silicon, glass, polymer, stainless steel, metals, alloys, ceramics, semiconductors, dielectrics, and combinations and modifications thereof.

37. The method of claim 35, further comprising the optional step of flipping the mold prior to the step of transferring the shape, wherein the flipping results in the second surface facing the reactive plasma.

38. The method of claim 35, wherein the first substrate is a planar or a non-planar substrate, the first substrate is a cylindrical polymer tube and the polymer is polyimide.

41. A method for making the silicon-wafer mold of claim 35, comprising the steps of:

providing the silicon-wafer substrate comprising a first surface and a second surface;

forming one or more trenches on the first surface or on the second surface by a method comprising the steps of;

depositing at least one etching mask layer on the silicon-wafer substrate by a physical vapor deposition, wherein the etching mask layer comprises a silicon nitride layer and a chromium layer;

spin-coating a photo-resist layer onto the etching mask layer;

creating a trench structure on the photo-resist layer by using a photolithographic technique;

aligning a desired trench direction and creating of one or more alignment marks on the substrate, wherein the alignment marks are used to position the first substrate;

transferring the trench structure through the one or more etching mask layers to the silicon-wafer substrate by the reactive ion etching technique using a reactive plasma; and

fabricating the trench structure by removal of any residual substrate or substrate-layer materials from the formed trenches by a wet anisotropic etching step; and

forming one or more holes, perforations or patterns on the one or more trenches by a method comprising the steps of;

defining a window pattern by a photolithographic technique aligned to the formed trenches on the surface of the silicon-wafer not containing the formed trench structures;

transferring the window pattern onto the trench structure by a combination of reactive ion etching and wet anisotropic etching; and

forming one or more holes, perforations or patterns on the one or more trenches by a combination of lithography and reactive ion etching.

42. The method of claim 41, wherein a selection of the silicon-wafer substrate is dependent on the shape of the trench structure to be transferred, wherein a depth and a width of the trench structure is dependent on a geometry of the photo-resist layer and a duration of the anisotropic etching step.

44. The method of claim 41, wherein the method comprises an optional step of hardening the silicon-wafer mold by an application of a silicon-nitride layer to the surface.

63. The method of claim 41, wherein the one or more active agents comprise a solid, a liquid dosage, a semi-solid, a powder or a hydrogel.

39-40. -40. (canceled)

43. (canceled)

45-62. -62. (canceled)

64-68. -68. (canceled)

69. A method for treating a medical condition in a patient comprising the steps of:

identifying the a patient exhibiting at least one symptom of the medical condition; and

implanting an impermeable therapeutic agent delivery device comprising a therapeutic agent supply capable of providing an effective dose for the medical condition symptom, wherein the delivery device releases the therapeutic agent with zero-order kinetics.

70. The method of claim 69, wherein the medical condition is selected from the group consisting of a cardiovascular disease, diabetes, epilepsy, Parkinson'"'"'s disease, pain, cancer, ocular disease, and a fungal infection, wherein the cardiovascular disease is selected from the group consisting of stenosis, restenosis, late stent thrombosis, stroke, myocardial infarction, congestive heart disease, high blood pressure, angina, atherosclerosis or thrombosis.

78. The method of claim 70, wherein the therapeutic agent delivery device is made by the method comprising the steps of:

providing a mold comprising a first surface and a second surface, wherein the first surface comprises one or more trenches, cavities or depressions, wherein a shape of the trench is selected from the group consisting of a cylinder, an oval, a cone, a sphere, and a cuboid, wherein each of the one or more trenches comprise one or more holes or perforations;

placing a first substrate in the trench, wherein the substrate may optionally be held in place in the trench by using an adhesive; and

transferring a shape of the holes or the perforations in the one or more trenches to the first substrate by one or more micro fabrication techniques to make the device for the delivery of the therapeutic agent 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.

71-79. -79. (canceled)

79. (canceled)