# US 9,005,649 B2 · Methods for making controlled delivery devices having zero order kinetics

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- Number: US 9,005,649 B2
- Document ID: US9005649B2
- Status: Granted
- Kind: B2
- Application number: 13/383,820
- Filed: 2010-07-14
- Published: 2012-07-12
- Granted: 2015-04-14
- Earliest claimed: 2009-07-14
- Assignees: Board of Regents, The University of Texas System
- Applicants: Paul S. Ho; Salomon Stavchansky; Phillip Bowman; Zhiquan Luo; Zhuojie Wu; Ashish Rastogi
- Inventors: Paul S. Ho; Salomon Stavchansky; Phillip Bowman; Zhiquan Luo; Zhuojie Wu; Ashish Rastogi
- Web page: https://patentgrep.com/patent/US9005649B2

## CPC

- A61B 5/4839: {combined with drug delivery}
- A61B 5/076: {Permanent implantation}
- A61B 5/686: {Permanently implanted devices, e.g. pacemakers, other stimulators, biochips (A61B5/6861 takes precedence)}
- A61B 17/06166: {Sutures (suture materials A61L17/00; manufacture of artificial threads D01D; treatment of threads D06M)}
- A61B 90/30: Devices for illuminating a surgical field, the devices having an interrelation with other surgical devices or with a surgical procedure
- A61F 2/0063: {Implantable repair or support meshes, e.g. hernia meshes}
- A61F 2/06: Blood vessels
- 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)
- A61F 2/91: made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
- A61F 2/915: with bands having a meander structure, adjacent bands being connected to each other
- A61F 9/0017: {implantable in, or in contact with, the eye, e.g. ocular inserts}
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61L 17/005: {containing a biologically active substance, e.g. a medicament or a biocide}
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61L 29/16: Biologically active materials, e.g. therapeutic substances {(A61L29/048 takes precedence)}
- A61L 31/06: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds {(A61L31/041 takes precedence)}
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- A61M 25/001: {Forming the tip of a catheter, e.g. bevelling process, join or taper}
- A61M 25/0017: {specially adapted for long-term hygiene care, e.g. urethral or indwelling catheters to prevent infections}
- A61M 25/0043: {characterised by structural features}
- 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)}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/10: Antimycotics
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61B 2560/0219: of externally powered implanted units
- A61F 2220/005: using adhesives
- A61F 2230/0013: Horseshoe-shaped, e.g. crescent-shaped, C-shaped, U-shaped
- A61F 2230/0054: V-shaped
- A61F 2240/001: Designing or manufacturing processes
- A61F 2250/0002: for data transfer
- A61F 2250/0068: the pharmaceutical product being in a reservoir
- A61F 2310/00017: Iron- or Fe-based alloys, e.g. stainless steel
- A61F 2310/00179: Ceramics or ceramic-like structures
- A61F 2310/00329: Glasses, e.g. bioglass
- A61L 2300/43: Hormones, e.g. dexamethasone
- A61L 2300/602: Type of release, e.g. controlled, sustained, slow
- A61M 2025/0057: {Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings}
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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 of a non-planer enclosure 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 a non-planer enclosure having a series of passageways that connect an outer surface and an inner area for the delivery of the one or more active agents through the series of passageways with a zero order release kinetics.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 1)

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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 14)

The method of claim 14, wherein the polymer coating is poly(methacrylates), 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.

### Claim 16 (depends on 14)

The method of claim 14, 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.

### Claim 17

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 wherein the silicon-wafer mold forms a non-planer cylindrical enclosure;
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, wherein the first substrate comprises a polyimide polymer; 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 a non-planer enclosure having a series of passageways that connect an outer surface and an inner area for the delivery of the one or more active agents through the series of passageways with a zero order release kinetics.

### Claim 18 (depends on 17)

The method of claim 17, 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.

### Claim 19 (depends on 17)

The method of claim 17, 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.