# US 8,784,865 B2 · Long term drug delivery devices with polyurethane-based polymers and their manufacture

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,784,865 B2
- Document ID: US8784865B2
- Status: Granted
- Kind: B2
- Application number: 13/892,946
- Filed: 2013-05-13
- Published: 2014-01-09
- Granted: 2014-07-22
- Earliest claimed: 2008-09-30
- Assignees: Endo Pharmaceuticals Solutions Inc.
- Applicants: Endo Pharmaceuticals Solutions Inc.
- Inventors: Petr Kuzma; Harry Quandt
- Web page: https://patentgrep.com/patent/US8784865B2

## CPC

- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/0092: {Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/4168: having a nitrogen attached in position 2, e.g. clonidine
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 38/09: Luteinising hormone-releasing hormone [LHRH] {, i.e. Gonadotropin-releasing hormone [GnRH]}; Related peptides
- A61M 31/002: {Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time (artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50)}
- A61M 37/00: Other apparatus for introducing media into the body (for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30); Percutany, i.e. introducing medicines into the body by diffusion through the skin (salt baths A61H33/04)
- Y10T 29/49826: Assembling or joining
- 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)
- 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)}
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

This invention is related to the use of polyurethane-based polymer as a drug delivery device to deliver biologically active compounds at a constant rate for an extended period of time and methods of manufactures thereof. The device is very biocompatible and biostable, and is useful as an implant in patients (humans and animals) for the delivery of appropriate bioactive substances to tissues or organs.

## Claims

### Claim 1

An implantable drug delivery device, comprising a polyurethane-based polymer having polyether-based polyol segments represented by the formula —[O—(CH2)n]x—O—, said polyurethane-based polymer configured to provide a cylindrically shaped reservoir, wherein the reservoir is sealed after being charged with an effective amount of solid formulation comprising an active agent and one or more pharmaceutically acceptable carriers, such that the release of the active agent at a substantially zero order rate in vitro by diffusion through the polyurethane-based polymer generally increases as the equilibrium water content (% EWC) of the polymer increases, wherein the active agent is histrelin, risperidone, dexamethasone, naltrexone, metolazone, clonidine, or selegiline.

### Claim 2 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is histrelin.

### Claim 3 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is risperidone.

### Claim 4 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is dexamethasone.

### Claim 5 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is naltrexone.

### Claim 6 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is metolazone.

### Claim 7 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is clonidine.

### Claim 8 (depends on 1)

The drug delivery device of claim 1, wherein the active agent is selegiline.

### Claim 9 (depends on 1)

The drug delivery device of claim 1, wherein the polyurethane-based polymer has a % EWC of between about 5%-43%.

### Claim 10 (depends on 1)

The drug delivery device of claim 1, wherein the one or more pharmaceutically acceptable carriers is selected from the group consisting of croscarmellose, stearic acid, and a combination thereof.

### Claim 11 (depends on 10)

The drug delivery device of claim 10, wherein the one or more pharmaceutically acceptable carriers are croscarmellose and stearic acid.

### Claim 12 (depends on 11)

The drug delivery device of claim 11, wherein the croscarmellose comprises 10% of the solid drug formulation, and stearic acid comprises 2% of the solid drug formulation.

### Claim 13 (depends on 1)

The drug delivery device of claim 1, wherein the reservoir has a wall thickness of 0.2 mm.

### Claim 14

A method of delivering an active agent to a subject, comprising implanting an implantable device into the subject, wherein the implantable device comprises a polyurethane-based polymer having polyether-based polyol segments represented by the formula —[O—(CH2)n]x—O—, said polyurethane-based polymer configured to provide a cylindrically shaped reservoir, wherein the reservoir is sealed after being charged with an effective amount of solid formulation comprising an active agent and one or more pharmaceutically acceptable carriers, such that the release of the active agent at a substantially zero order rate in vitro by diffusion through the polyurethane-based polymer generally increases as the equilibrium water content (% EWC) of the polymer increases, wherein the active agent is histrelin, risperidone, dexamethasone, naltrexone, metolazone, clonidine, or selegiline.

### Claim 15 (depends on 14)

The method of claim 14, wherein the active agent is histrelin.

### Claim 16 (depends on 14)

The method of claim 14, wherein the active agent is risperidone.

### Claim 17 (depends on 14)

The method of claim 14, wherein the active agent is dexamethasone.

### Claim 18 (depends on 14)

The method of claim 14, wherein the active agent is naltrexone.

### Claim 19 (depends on 14)

The method of claim 14, wherein the active agent is metolazone.

### Claim 20 (depends on 14)

The method of claim 14, wherein the active agent is clonidine.

### Claim 21 (depends on 14)

The method of claim 14, wherein the active agent is selegiline.

### Claim 22 (depends on 14)

The method of claim 14, wherein the polyurethane-based polymer has a % EWC of between about 5%-43%.

### Claim 23 (depends on 14)

The method of claim 14, wherein the one or more pharmaceutically acceptable carriers is selected from the group consisting of croscarmellose, stearic acid, and a combination thereof.

### Claim 24 (depends on 23)

The method of claim 23, wherein the one or more pharmaceutically acceptable carriers are croscarmellose and stearic acid.

### Claim 25 (depends on 24)

The method device of claim 24, wherein the croscarmellose comprises 10% of the solid drug formulation, and stearic acid comprises 2% of the solid drug formulation.

### Claim 26 (depends on 14)

The method of claim 14, wherein the reservoir has a wall thickness of 0.2 mm.

### Claim 27

A process for manufacturing a drug delivery device comprising: supplying a polyurethane-based polymer formed as a hollow tube; loading a solid formulation comprising one or more active ingredients into the tube; and sealing the tube; wherein the one or more active ingredients and the polyurethane-based polymer are selected such that either: (i) both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophilic characteristics, or (ii) both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophobic characteristics; and wherein the drug delivery device delivers the one or more active ingredients by diffusion through the polyurethane-based polymer at a substantially zero order release rate in vitro and wherein the polyurethane-based polymer is formed from one or more polyols, wherein the general polyol structure is selected from the group consisting of:
—[O—(CH2)n]x—O—;
O—(CH2—CH2—CH2—CH2)x—O—; and
O—[(CH2)6—CO3]n—(CH2)—O—.

### Claim 28 (depends on 27)

The process of claim 27, wherein the sealing of the hollow tube comprises inserting a pre-fabricated plug into an open end and applying heat or solvent to the pre-fabricated plug and polyurethane-based polymer.

### Claim 29 (depends on 27)

The process of claim 27, wherein the sealing comprises inserting a pre-fabricated end plug at an open end of the hollow tube; applying an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation into an interface formed between the pre-fabricated end plug and the open end; and curing the polyurethane formulation with light and/or heat to seal the pre-fabricated plug in the end of the tube.

### Claim 30 (depends on 27)

The process of claim 27 further comprising conditioning and priming comprises selecting a parameter selected from the group consisting of time, temperature, and medium to influence the substantially zero order release rate in vitro of the one or more active ingredients through the polyurethane-based polymer.

### Claim 31 (depends on 27)

The process of claim 27, wherein the one or more active ingredients and the polyurethane-based polymer are selected such that both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophilic characteristics.

### Claim 32 (depends on 27)

The process of claim 27, wherein the one or more active ingredients and the polyurethane-based polymer are selected such that both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophobic characteristics.

### Claim 33 (depends on 27)

The process of claim 27, wherein the solid formulation includes one or more pharmaceutically acceptable carriers that are not required for the substantially zero order release rate in vitro of the one or more active ingredients through the polyurethane-based polymer.

### Claim 34 (depends on 33)

The process of claim 33, wherein the one or more pharmaceutically acceptable carriers are not required for the substantially zero order release rate in vitro of the one or more active ingredients as governed by Fick's Law of Diffusion.

### Claim 35 (depends on 27)

The process of claim 27, wherein the hollow tube is formed by extrusion molding, injection molding, or spin-casting of the polyurethane-based polymer.

### Claim 36 (depends on 27)

The process of claim 27, wherein the hollow tube is formed with two open ends.

### Claim 37 (depends on 27)

The process of claim 27, wherein the hollow tube is formed with two open ends, and one end is sealed prior to the loading.

### Claim 38 (depends on 27)

The process of claim 27, wherein the hollow tube is formed with one open end and one closed end.

### Claim 39 (depends on 31)

The process of claim 31 in which the at least one active ingredient is selected from drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, and antiparasitic.

### Claim 40 (depends on 32)

The process of claim 32 in which the at least one active ingredient is selected from drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, and antiparasitic.

### Claim 41 (depends on 27)

The process of claim 27, wherein the at least one active ingredient is selected from the group consisting of histrelin, risperidone, dexamethasone, naltrexone, metolazone, clonidine, and selegiline.