WO2011139594A2

WO2011139594A2 - Artificial bursa for intra-articular drug delivery

Info

Publication number: WO2011139594A2
Application number: PCT/US2011/033540
Authority: WO
Inventors: Laurie Yunker; Andrew James Lowenthal Walsh
Original assignee: Medtronic, Inc.
Priority date: 2010-04-27
Filing date: 2011-04-22
Publication date: 2011-11-10
Also published as: WO2011139594A3

Abstract

The invention describes methods and devices for treating a tissue within a synovial joint in a patient in need of such treatment. The methods and devices involve inserting a drug delivery device through the synovial joint and anchoring the drug delivery device within the synovial joint capsule so that the drug delivery device does not substantially interfere with movement of the joint. The drug delivery device comprises a deformable polymeric delivery device having a reservoir portion and a dispensing portion extending from the reservoir portion and at least one pharmaceutical agent contained within the drug delivery device.

Description

ARTIFICIAL BURSA FOR INTRA-ARTICULAR DRUG DELIVERY

FIELD OF THE INVENTION

The invention relates generally to methods and devices for treating a tissue within a synovial joint in a patient in need of such treatment. The methods and devices involve inserting a drug delivery device through the synovial joint and anchoring the drug delivery device within the synovial joint capsule so that the drug delivery device does not substantially interfere with movement of the joint. The drug delivery device comprises a deformable polymeric delivery device having a reservoir portion and a dispensing portion extending from the reservoir portion and at least one pharmaceutical agent contained within the drug delivery device.

BACKGROUND OF THE INVENTION

Synovial joints, such as the knee, are joints of the body where two adjacent bones are coupled and encapsulated within a synovial membrane or capsule. Ligaments connect bones together while tendons connect bone to muscle. Some joints have cartilage between two or more bones. A synovial membrane substantially surrounds the joint and encapsulates the synovial fluid that fills the joint, thereby forming the joint capsule. The synovial fluid functions to both lubricate and nourish the joint. A synovial joint functions to facilitate full range of normal articulation and movement of the joint that is unique to each patient. As such, maintaining the integrity of the joint allows performance of the patient's day-to-day activities.

There are numerous traumas and/or acute or chronic disorders, which affect the normal workings of a synovial joint and require therapeutic intervention. Examples of joint disorders include, but are not limited to, osteoarthritis, chondromalacia and rheumatoid arthritis, carpal tunnel syndrome, tarsal tunnel syndrome or the like.

Additionally, the joint could simply be infected from a post-surgical or prior joint injury. In each of these disorders and traumas the joint is mechanically compromised, either acutely or chronically, causing the body to elicit an immune response. Such a response typically manifests itself as inflammation and/or persistent pain in the joint area. An example of a joint is a knee joint which contains the tibia and the fibula extending up from the lower leg, the femur extending down from the thigh and the patella as the knee cap over the joint. The medial collateral ligament and the lateral collateral ligament connect the femur to the tibia and fibula, respectively, and restrict the sideways motion of the joint. The posterior cruciate ligament connects the femur to the tibia and restricts backward movement of the joint away from the patella. The anterior cruciate ligament connects the femur to the tibia and restricts the joint rotation and forward motion toward the patella. Examples of traumas to the knee joint include, but are not limited to, tearing and/or fracturing of the anterior cruciate ligament, posterior cruciate ligament, the medial collateral ligament, the lateral collateral ligament, the patellar ligament, the medial meniscus, the lateral meniscus and chondral fractures.

Inflammation can be an acute response to trauma or a chronic response to the presence of inflammatory agents brought about by any number of processes or events which trigger tissue damage within the synovial joint. For example, when tissues are damaged, tumor necrosis factor-alpha (hereinafter "TNF-alpha") attaches to cells causing them to release other cytokines leading to an increase in inflammation. One type of recruited immune system cell is the macrophage. Macrophages release interleukin-1 beta ("IL-1 beta") and tumor necrosis factor-alpha ("TNF-alpha"), pro- inflammatory cytokines heavily involved in orchestrating the immediate and local physiological effects of injury or infection. For instance, once released, proinflammatory cytokines promote inflammation. The purpose of the inflammatory cascade is to promote healing of the damaged tissue. However, once the tissue is healed, the inflammatory process does not necessarily end. Left unchecked, the inflammatory process can lead to degradation of surrounding tissues and associated chronic pain. Thus, pain can become a disease state in itself. That is, when this pathway is activated, inflammation and pain ensue. Cycles of inflammation and associated pain often occur long after the initial trauma has or should have resolved.

Current treatment methods of inflammation of the joints include the use of pharmaceutical agents, which are designed to reduce inflammation such that the pain associated with the inflammation subsides and the subject regains at least partial use of the joint. Such pharmaceutical agents include, but are not limited to, analgesics and anti-inflammatory drugs. These drugs can be administered systemically and/or injected directly into the inflamed joint. However, these types of treatments only reduce inflammation for a limited time span. Thus, they are required to be administered regularly by the subject or his/her attending physician.

Recently, however, there have been a number of attempts to develop implants that administer pharmaceutical agents gradually and continuously over a longer time frame. One development has been to use a non-injectable implants such as a drug delivery device. A drug delivery device is a device that contains and gradually releases a pharmaceutical agent to a targeted region over time. One example of a drug delivery device is a capsule that contains the pharmaceutical agent within a biocompatible housing where the end caps of the capsule are comprised of a biodegradable polymer.

A second example of a drug delivery device is a biodegradable capsule wherein the pharmaceutical agent is distributed homogenously throughout the capsule. With both types of drug delivery devices, as the biodegradable polymer degrades in the body, the pharmaceutical agent is gradually released.

Some drug delivery devices can interfere in the movement of the parts of the joints if the drug delivery device is placed inside the joint capsule. When that happens, the drug delivery device can injure the bone or soft connective tissue within the joint capsule. Instead of alleviating pain and promoting healing, the drug delivery device becomes the cause of pain and injury.

BRIEF SUMMARY OF THE INVENTION

A need exists for a delivery device, which has a shape and is positioned within the joint or next to the joint and can release at least one pharmaceutical agent over a period of time so that the device allows unfettered movement of the joint while helping the joint heal. In addition, the device may help prevent or reduce the likelihood of adverse systemic effects of the pharmaceutical agent by having the pharmaceutical agent located at or near the site of injury rather than being administered systemically.

New drug delivery devices and methods of use are provided, which allow for accurate and precise implantation of the drug delivery device with minimal physical and psychological trauma to a patient. One advantage of the drug delivery device and methods is that the drug delivery device can now be easily delivered to the target tissue site (e.g., synovial joint) with little physical or psychological trauma to the patient. In this way, accurate and precise implantation of a drug delivery device in a minimally invasive procedure can be accomplished. In various embodiments, the drug delivery device comprises one or more anchoring members (e.g., barbs, hooks, wire, etc.) that allows accurate placement of the device in a manner to optimize location, accurate spacing, and drug distribution within the joint capsule.

In one embodiment, a method is provided for treating a tissue within a synovial joint in a patient in need of such treatment, the method comprising inserting a drug delivery device through the synovial joint and attaching (anchoring) the device to the inside of the synovial joint capsule so that the drug delivery device does not

substantially interfere with movement of the joint, wherein the drug delivery device comprises a compressible reservoir and drug dispensing portion comprising a polymeric structure and at least one pharmaceutical agent contained therein.

In another embodiment, an implantable drug delivery device is provided that is useful for treating tissue within a synovial joint in a patient in need of such treatment. The implantable drug delivery device comprises a therapeutically effective amount of a pharmaceutical agent contained within a compressible polymeric reservoir and/or a drug dispensing portion. The drug delivery device is capable of being anchored to an inside of a synovial joint capsule so that the drug delivery device does not substantially interfere with movement of the joint and the drug delivery device is capable of releasing the pharmaceutical agent over a period of at least three days.

In one exemplary embodiment, a method of reducing pain and/or inflammation of tissue within a synovial joint is provided. The method includes inserting a drug delivery device through the synovial joint and anchoring the drug delivery device to the inside of the synovial joint capsule so that the drug delivery device allows normal articulation of the synovial joint and does not substantially interfere with movement of the joint. The drug delivery device includes a compressible polymeric reservoir and a drug dispensing portion and at least one analgesic and/or anti-inflammatory agent. The at least one analgesic and/or anti-inflammatory agent can be coated within the interior of the compressible polymeric reservoir and/or the dispensing portion. Alternatively, the at least one analgesic and/or anti-inflammatory agent can be integrated into the polymer for extended release. The device, therefore, is capable of releasing the at least one analgesic and/or anti-inflammatory agent over a period of at least three days, more particularly 1 month to about 3 months. In another exemplary embodiment, an implantable drug delivery device is provided that is useful for treating tissue within a synovial joint in a patient in need of such treatment, the implantable drug delivery system comprising a therapeutically effective amount of a pharmaceutical agent contained within a compressible polymeric reservoir and/or a drug dispensing portion of the device. The device further includes one or more anchoring members capable of being anchored to an inside of a synovial joint capsule so that the drug delivery device does not substantially interfere with movement of the joint. The drug delivery device is capable of releasing the

pharmaceutical agent over a period of at least three days.

While multiple embodiments are disclosed, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description. As will be apparent, the invention is capable of modifications in various obvious aspects, all without departing from the spirit and scope of the present invention. Accordingly, the detailed descriptions are to be regarded as illustrative in nature and not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates a side sectional view of a joint capsule with different tissue types that are treatable with the one or more drug delivery devices described herein.

Figure 2 illustrates a side sectional view of a joint capsule with different tissue types that are treatable with the one or more drug delivery devices described herein. In this view a drug delivery device containing barbs as the anchoring member is implanted within the infra-patella fat pad of the joint capsule.

Figure 3 illustrates an enlarged sectional view of a drug delivery device.

DETAILED DESCRIPTION

In the specification and in the claims, the terms "including" and "comprising" are open-ended terms and should be interpreted to mean "including, but not limited to. . . . " These terms encompass the more restrictive terms "consisting essentially of and "consisting of."

It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. As well, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising",

"including", "characterized by" and "having" can be used interchangeably.

For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing quantities of ingredients, percentages or proportions of materials, reaction conditions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth, the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range of " 1 to 10" includes any and all subranges between (and including) the minimum value of 1 and the maximum value of 10, that is, any and all subranges having a minimum value of equal to or greater than 1 and a maximum value of equal to or less than 10, e.g., 5.5 to 10.

The present invention provides a unique compressible drug delivery device, an artificial bursa, suitable for positioning within a synovial joint capsule. The

compressible polymeric delivery device includes a drug delivery portion and a drug. The compressible polymeric drug delivery portion includes a drug containing reservoir portion and a drug dispensing portion extending from the drug containing reservoir portion. The drug dispensing portion comprises a dispensing port to provide delivery of the drug from the drug delivery device into the synovial capsule and synovial fluid.

In one embodiment, the drug delivery device is positioned within a fat pad adjacent to the synovial capsule such that the dispensing port is in communication with the synovial fluid. The drug delivery device can simply be positioned, for example, within the fat pad or can be further anchored to the desired position by one or more anchoring members located about the surface of the drug delivery device.

In another embodiment, the drug delivery device can be anchored to surrounding fibrous tissues (ligaments, bone, etc.) about the synovial capsule.

As the joint undergoes movement, the compressible polymeric delivery device is compressed and released by the pressure exerted upon the joint and fat pat with extension and compression of the joint. This compressing and decompressing of the compressible polymeric drug delivery device helps to promote movement of synovial fluid into and out of the device. As the fluid moves in and out of the device, a drug is dispensed from within the reservoir of the device. One advantage of this is that since the drug is administered directly into the synovial joint, an increased amount of synovial fluid is produced, helping to alleviate pressure and discomfort in the joint often associated after surgery, injury or inflammation of the joint.

The phrase "drug delivery device" refers to the apparatus as described herein, and shown in the figures, that is constructed with a polymeric material, that is compressible, and includes a reservoir portion, a drug dispensing portion and a dispensing port. In one aspect, the drug delivery device is collapsible for ease of insertion into the synovial capsule. In one embodiment, the drug delivery device is constructed of a biostable polymeric material. In another embodiment the drug delivery device is constructed of a biodegradable polymeric material.

The phrase "compressible drug delivery portion" refers to the apparatus of the invention that includes a reservoir portion, a drug dispensing portion and a dispensing port separate from the drug.

The phrase "drug containing reservoir" refers to a portion of the drug delivery device which can be bulb like in configuration and generally contains the drug. The drug can be coated within the walls of the reservoir and/or can be part of the reservoir itself. That is, where the polymer of the drug delivery device is biodegradable, then the drug can be entrapped within the polymer itself and is delivered as the polymer degrades. Alternatively, the drug can be entrained within the polymer of the drug delivery device and can simply diffuse from the polymeric network by diffusion or other physiological/physical interactions where the polymer is not necessarily degradable. The phrase "drug dispensing portion" refers to a portion of the drug delivery device that extends from the reservoir portion of the device. Like the drug containing reservoir, the drug can also be coated or entrapped within the drug dispensing portion of the drug delivery device. In one embodiment, the drug dispensing portion can be elongated and can be considered a pipette. In another embodiment, the drug dispensing portion of the drug delivery device can simply be a flanged portion of the reservoir. The phrase "dispensing port" is intended to refer to opening of the drug delivery device. The port helps facilitate delivery of the drug into the synovial fluid and can be

"flanged" so as to help secure the drug delivery device in place to inhibit movement about the synovial capsule. Synovial fluid enters the dispensing port. Dissolution or migration of the drug from within the drug containing reservoir thus occurs and is delivered through the port into the synovial space and fluid.

The term "treating" or "treatment" of a disease refers to executing a protocol, which may include administering one or more pharmaceutical agents to a patient (human or otherwise), in an effort to alleviate signs or symptoms of the disease.

Alleviation can occur prior to signs or symptoms of the disease appearing, as well as after their appearance. Thus, "treating" or "treatment" includes "preventing" or

"prevention" of disease. In addition, "treating" or "treatment" does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient.

The term "drug" as used herein is generally meant to refer to any substance that alters the physiology of a patient. The term "drug" may be used interchangeably herein with the terms "therapeutic agent," "therapeutically effective amount," and "active pharmaceutical ingredient" or "API." It will be understood that unless otherwise specified a "drug" formulation can include more than one therapeutic agent, wherein exemplary combinations of therapeutic agents include a combination of two or more drugs. The drug provides a concentration gradient of the therapeutic agent for delivery to the site. In various embodiments, the drug delivery device described herein provides an optimal drug concentration gradient of the therapeutic agent at a distance of up to about 0.1 cm to about 5 cm from the implant site, and comprises at least one agent or its pharmaceutically acceptable salt. The dosage administered to an individual, as single or multiple doses, can vary depending upon numerous factors, including the

pharmaceutical agent's pharmacokinetics, the route of administration, the patient's condition and characteristics (sex, age, body weight, health, size, etc.), symptoms, concurrent treatments, frequency of treatment, and the effect desired.

"Localized" delivery is defined herein as non-systemic delivery wherein a pharmaceutical agent is deposited within a tissue, for example, inside a joint capsule, or in close proximity thereto.

One or more "anchoring member(s)" or "attachment member(s)" holds the drug delivery device in place within the joint capsule or on the interior of the capsular bursae. The anchoring member comprises an exterior and interior surface, the exterior surface of the anchoring member capable of contacting the tissue in the joint capsule. In various embodiments, the anchoring member comprises barbs, clips, latch, staples, rivets, adhesives, sutures, or the like that retain the drug delivery device to the inside of the joint capsule. Suitable attachment members are included in US publications 2009/0259306, 2009/0319037, 2002/0151970, 2006/0287717, 2008/0161911, or US Patent Nos. 5,893,369, 6,113,612, 6,514,265, or 6,945,980, the contents of which are incorporated herein by reference in their entirety.

Not withstanding the above, use of self-closing clips as a replacement for sutures in performing an anastomosis procedure is highly desired by surgeons. In this regard, the design and construction of self-closing clips or fasteners has greatly improved as described, for example in U.S. Pat. No. 6,945,980 (the teachings of which are incorporated herein by reference). Along these same lines, efforts have been made to develop surgical tools or instruments that can simultaneously deliver or deploy two or more of the self-closing clips in a simple, consistent fashion. One such instrument is available from Medtronic, Inc., of Minneapolis, Minn, under the trade name Spyder™. The Spyder™ device provides fast, automated proximal anastomotic connection by simultaneous delivery of multiple U-Clip™ self-closing surgical clips (or other self- closing clips) without the use of a side-biting clamp or second manipulation of the tissue. Other instruments for delivering self-closing clips are described, for example, in U.S. Publication Nos. 2004/0068276 and 2005/0070924, the teachings of both of which are incorporated herein by reference in their entirety.

In various embodiments, the anchoring member has radially compressed and radially expanded support frame configurations. Such an anchoring member can be implanted at a point of treatment within the joint capsule by minimally invasive techniques, such as a delivery and deployment through a catheter or arthroscopic device. In various embodiments, the entire drug delivery device can be folded, rolled, and/or compressed in a delivery system and when deployed at the implant site, expands to hold itself at the desired site. For example, the anchoring member can exert a radially outward force on the interior of the tissue at the point of implantation in the body. Examples of metals suitable for use in the anchoring member include, but are not limited to, molybdenum alloys, stainless steel, spring steel (e.g. Elgiloy®), shape memory alloy, and/or nitinol, which are considered desirable materials for use in the anchoring member due at least to their biocompatibility, shapeability, and well- characterized nature.

"Substantially interfere" includes moderate to severe interference with the articular movement of the joint, which causes pain and/or inflammation. In various embodiments, after the drug delivery device is implanted, there may be mild or no interference with articulating movement of the joint. This can be accomplished, by, among other things, placing the drug delivery device at the desired location (e.g., inside the synovial membrane), using a drug delivery device of the appropriate size and shape. In various embodiments, an apparatus and methods for providing treatment within a synovial joint are provided. The treatment comprises administering to the synovial joint of the subject in need of treatment a pharmaceutically effective amount of at least one pharmaceutical agent, which are contained in an implant (referred to here as a "drug delivery device"). The drug delivery device can release the at least one pharmaceutical agent in a sustained-release manner (i.e., over long period of time) or in a non-sustained release manner (i.e., over a short period of time).

In a particular embodiment of the present invention, the at least one

pharmaceutical agent includes, but is not limited to, anti-inflammatory agents, anti- infective agents (such as, antibiotics, antiviral agents, anti-protozoal agents, anti-fungal agents, and anti-parasitic agents), analgesics, growth factors, cytokines, lubricants, nutrients, or other joint therapy agents. As discussed herein, a drug delivery device can be inserted into a synovial joint capsule such as, but not limited to, the knee, through the synovial membrane. The drug delivery device can be secured to the inside of synovial membrane by a variety of attachment devices, such as sutures, barbs, tacks, staples, tethers, and adhesives.

The drug device can be implanted so as not to substantially interfere with movement of the joint. One example is the synovial joint for the knee. However, it will be understood that the drug delivery device may be implanted in any synovial joint (e.g., fingers, toes, etc.). Exemplary areas to implant the drug delivery device, include, but are not limited to, fat tissue, tendon, lateral gutter, supra-patellar or prepatellar bursa, infra-patellar fat pad, patella, infra-patellar bursa, intra-patellar bursa, anterior cruciate ligament, posterior cruciate ligament, trochlear groove, meniscus, or region around the meniscus, cartilage, femur, tibia and/or synovial membrane of a knee (which surrounds the synovial joint) so long as the drug deliver device does not substantially interfere with movement of the joint.

Alternatively, the drug delivery device can be anchored to the outside of the synovial membrane and release the pharmaceutical agent into the surrounding tissue.

Then the pharmaceutical agent can diffuse through the synovial membrane to provide therapeutic affects within the joint capsule. Diffusion of the pharmaceutical agent may also occur into the surrounding synovial fluid of the joint space. The drug delivery device can be manufactured to allow for diffusion only into the capsular region or only into the joint space.

In another embodiment, the drug delivery device can be placed inside the joint capsule such that the drug delivery device does not move, for example, by placement in the supra-patella or prepatella bursa or inner membrane of the joint cavity of the knee. When appropriate, the implant may be placed in the subpatellar fat or intrapatellar bursa (e.g., to treat inflammation in the areas around these sites).

The drug delivery device has a shape and is positioned inside or outside the joint in such a manner as to allow for normal joint articulation. Normal joint articulation may be defined as, but is not limited to, the range of motion of the joint if the drug delivery device was not present (interfering with the movement of the joint). The drug delivery device will be capable of carrying at least one pharmaceutical agent in quantities sufficient for therapeutic or prophylactic treatment over a pre-selected period of time. The drug delivery device can also protect the at least one pharmaceutical agent from premature degradation by body processes (such as proteases) for the duration of treatment. The sustained-release of the at least one pharmaceutical agent will result in local, biologically effective concentrations of the at least one pharmaceutical agent in or around an inflamed or infected joint.

The drug delivery devices and methods provided herein, in various embodiments, allow for long term, sustained release of at least one pharmaceutical agent. The release of the pharmaceutical agent can be over 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, 20 days, or 30 days. In an alternative embodiment, the release of the at least one pharmaceutical agent can be over 30 days, 60 days, 90 days, 180 days, 6 months, 9 months, 12 months, 14 months, 16 months, or 18 months. In another embodiment, the drug delivery device can contain two or more pharmaceutical agents, each one being released over different number of days or months.

In various embodiments, the drug delivery device is designed for long term use to treat diseases of a joint. In particular the drug delivery device's shape and place of attachment allow for unfettered movement of the bones, ligaments, tendons and other body parts within the joint. The device contains at least one pharmaceutical agent.

Because the device is located inside or adjacent to the joint capsule, the effective dose of the pharmaceutical agent can be lower than the effective dose of the same pharmaceutical agent administered systemically. This ability to use a lower effective dose and to have the pharmaceutical agent localized to the site of the injury or disease results in a reduction of the likelihood of adverse effects of the pharmaceutical agent. It is known that systemic, long-term administration of some pharmaceutical agents results in adverse effects, such as liver toxicity, weight gain, weight loss, muscle wasting, kidney damage, and cardiac damage. By locating a drug delivery device at or near the site of injury or disease, the localized drug level may be sufficiently high to treat the injured or diseased joint tissue, but sufficiently low enough in tissue distant from the site to prevent side effects or toxicity.

In one embodiment, the drug delivery device can be "reloaded" with a

pharmaceutical agent by insertion of a needle into the device to deliver a subsequent amount of pharmaceutical agent. The syringe can be inserted through the dispensing port and the pharmaceutical agent can be delivered in a carrier. An appropriate carrier can be selected such that the pharmaceutical agent and carrier can coat the inner walls of the reservoir and "cure". Thus, the drug delivery device can be used for extended periods of time without the need to remove the device when the pharmaceutical agent has been depleted.

In various embodiments, the pharmaceutical agent is provided in the drug delivery device to deliver about 1 pg/kg/day to 1 mg/kg/day of the drug.

The dosage of pharmaceutical agent may be from approximately 0.0005 to

approximately 100 μg/day Additional dosages of pharmaceutical agent include from approximately 0.0005 to approximately 50 μ§/ο^; approximately 0.0005 to

approximately 25 μ§/ο^; approximately 0.0005 to approximately 10 μ§/ο^;

approximately 0.0005 to approximately 5 μ§/ο^; approximately 0.0005 to

approximately 1 μ§/ο^; approximately 0.0005 to approximately 0.75 μ§/ο^;

approximately 0.0005 to approximately 0.5 μ§/ο^; approximately 0.0005 to

approximately 0.25 μ§/ο^; approximately 0.0005 to approximately 0.1 μ§/ο^;

approximately 0.0005 to approximately 0.075 μ§/ο^; approximately 0.0005 to approximately 0.05 μ§/ο^; approximately 0.001 ίομ§/ο^ approximately 0.025 μ§/(^; approximately 0.001 to approximately 0.01 μ§/ο^; approximately 0.001 to

approximately 0.0075 μ§/ο^; approximately 0.001 to approximately 0.005 μ§/ο^; approximately 0.001 to approximately 0.025 μ§/ο^; and approximately 0.002 μg/day. In another embodiment, the dosage of pharmaceutical agent is from approximately 0.001 to approximately 15 μg/day. In another embodiment, the dosage of

pharmaceutical agent is from approximately 0.001 to approximately 10 μg/day. In another embodiment, the dosage of pharmaceutical agent is from approximately 0.001 to approximately 5 μg/day. In another embodiment, the dosage of pharmaceutical agent is from approximately 0.001 to 2.5 μg/day. In some embodiments, the amount of pharmaceutical agent is between 40 and 600 μg/day. In some embodiments, the amount of pharmaceutical agent is between 200 and 400 μg/day.

In various embodiments, provided are methods, systems and compositions for decreasing, eliminating, or managing pain, especially pain of neuromuscular or skeletal origin, by providing direct and controlled delivery, i.e., targeted delivery of at least one pharmaceutical agent to one or more sites of inflammation and sources of pain. A pharmaceutical agent itself may be on a continuum of rapid acting to long acting compositions. Generally, the pharmaceutical agent is a component of a pharmaceutical composition, which can range in a continuum of rapid release to sustained release. Still further, the delivery of that pharmaceutical composition via a drug deliver device can include, for example, rapid and repeating delivery at intervals or continuous delivery.

The delivery can be local, direct, and controlled. A pharmaceutical composition contains at least one pharmaceutical agent, diluents, carriers, and excipients. Diluents, carriers, and excipients are well-known the art. The drug delivery device of this invention has a "low profile" shape, which allows for unrestricted movement of the joint. In various embodiments, the low profile of the drug delivery device minimizes volume displacement if placed in the synovial space. The "low profile" shape of the drug delivery device means that the device's height is minimized. The length and width of the device can range from about 1 centimeter (cm) to about 3 cm, more particularly from about 1.2 cm to about 2.5 cm and even more particularly from about 1.5 to about 2 cm. The width of the device can range from about 5 millimeters (mm) to about 1.5 cm, more particularly from about 25 mm to about 1 cm and even more particularly from about 50 mm to about 900 mm.

The volume of the reservoir portion of the drug delivery device can be from about

200 μΐ to about 5 milliliters (ml), more particularly from about 500 μΐ to about 3 ml and more particularly from about 0.75 ml to about 1.5 ml.

Because the height is minimized as compared to the length and width, the device's shape can be referred to as a balloon, bulb, capsule, shell, or other similar shapes.

When anchored to the inside of the joint membrane or placed in the upper lateral gutter of the knee (the lateral gutter of the knee is the region posterior to the patella, this low profile drug delivery device allows for normal articulation of the joint.

One can place the drug delivery device in any part of a synovial joint, along the internal side of the capsular membrane or on the outside of the capsular membrane. When placed next to the membrane, it may be advantageous to anchor the drug delivery device to the membrane so that the device remains securely anchored to the membrane to allow for normal articulation of the joint. The device can be secured to the synovial membrane by a variety of anchoring devices, such as sutures, barbs, tacks, staples, tethers, and adhesives. Certain anchoring devices, such as sutures, barbs, tacks, staples, and tethers, can be attached to the drug deliver device prior to inserting the drug delivery device into the patient, and then passed through the synovial membrane in such a manner as to secure the device to the synovial membrane. Alternatively, one can place the attachment devices through the joint membrane and the drug delivery device in order to securely anchor the drug delivery device to the joint membrane.

In addition, attachment devices such as sutures, barbs, tacks, staples, and tethers, can absorb fluid when inside the body and swell, thereby helping to secure the device to the membrane. The drug delivery device, and/or the attachment devices can be made of polymers, monomers, starches, gums, poly(amino acids) or a combination thereof that swell upon contact with fluid (water, saline, body fluids, etc). In various embodiments, the amount of swelling can range from 5 to 100 percent, 5 to 40 percent, or 5 to 20 percent. The time to reach maximum swelling can be designed into the design of the product. In practice, the time to reach maximum swelling can occur within a period of 5 days, 3 days, 2 days or within a period of 24 hours.

Nonlimiting list of swellable materials from which the drug delivery device and/or anchoring member may be made include polyvinyl alcohol (PVA), PVA modified with hydrophilic co-monomers, e.g. AMPS, PVA modified with fast crosslinking groups, e.g. NAAADA, PVA modified with polyvinylpyrroline (PVP), polyethylene glycol (PEG), poly( vinyl ether), co-polymers of PVA and PEG, polypropylene glycol (PPG), co-polymers of PEG and PPG, co-polymers of PVA or PPG, polyacrylonitrile, hydrocolloids, e.g. agar, alginates, carboxymethylcellulose (CMC), collagen, elastin, chitin, chitosan, gelatin, or the like. In various embodiments, the swellable material includes, for example, poly(N-isopropylacrylamide-co-acrylic acid)-poly(L-lactic acid) (NAL); poly(N-isopropyl acrylamide) (PNIPAM) grafted to other polymers such as carboxymethylcellulose (CMC) copolymers or polymers including block copolymers and end-functionalized polymers, composites or copolymers containing thermo- sensitive poly(2-ethoxyethyl vinyl ether) and/or poly(hydroxyethyl vinyl ether) and/or (EOVE200-HOVE400), whose sol-gel transition temperature is 20.5°C. The swellable material, in various embodiments, may be used to control release of the drug into the tissue and/or the synovial space.

The polymers can be crosslinked, lightly crosslinked hydrophilic polymers.

Although these polymers may be non-ionic, cationic, zwitterionic, or anionic, in various embodiments, the swellable polymers are cationic or anionic. In various embodiments, the swellable polymer can contain a multiplicity of acid functional groups, such as carboxylic acid groups, or salts thereof. Examples of such polymers suitable for use herein include those which are prepared from polymerizable, acid-containing monomers, or monomers containing functional groups which can be converted to acid groups after polymerization. Examples of such polymers also include polysaccharide- based polymers such as carboxymethyl starch and cellulose, and poly(amino acid) polymers such as poly(aspartic acid). Some non-acid monomers may also be included, usually in minor amounts, in preparing the absorbent polymers. Such non-acid monomers include, for example, monomers containing the following types of functional groups: carboxylate or sulfonate esters, hydroxyl groups, amide groups, amino groups, nitrile groups, quaternary ammonium salt groups, and aryl groups (e.g. phenyl groups, such as those derived from styrene monomer). Other potential non-acid monomers include unsaturated hydrocarbons such as ethylene, propylene, 1-butene, butadiene, or isoprene.

The swellable drug delivery device and/or anchoring member can be dehydrated and swell after implantation in response to fluid uptake. The drug delivery device can be fully dehydrated or only partially dehydrated. Upon exposure to liquid (water, saline, body fluids, etc.), the drug delivery device will absorb the liquid and swell. In some instances, the design of the drug delivery device can allow the device to swell with sufficient force despite being constrained to provide both space filling and expansion to hold the device in place. In some embodiments, the drug delivery device can swell by incorporating fluid having differences in ionic strength between the exterior and interior of the anchoring member.

In various embodiments, the body of the drug delivery device is swellable and/or the anchoring members are swellable to elute the API, when the device is injected, implanted and/or deployed at or near the target tissue site.

In one embodiment, the drug delivery device is manufactured with the attachment devices as an integral part of the drug delivery device. In another embodiment, the attachment devices are connected to the drug delivery device prior to insertion of the device into a patient. In the third embodiment, the attachment devices are connected to the drug delivery device after the device is placed in the patient's body.

The drug delivery device may be made from polymers; biodegradable (also referred to as "resorbable" polymers) and/or non-biodegradable polymers can be used. These polymers are useful because of their versatile degradation kinetics, safety, and biocompatibility profiles. The polymers can be manipulated to modify the

pharmacokinetics of the least one pharmaceutical agent contained within the drug delivery device, to shield the pharmaceutical agent from enzymatic attack, as well as degrade over time at the site of attachment such that the pharmaceutical agent is released over time. Natural biodegradable polymers include, but are not limited to, proteins (e.g., collagen, albumin, elastin, silk, glycosaminoglycans, chondroitin sulfate, or gelatin);

polysaccharides (e.g., cellulose, cellulose starch, starch, alginates, chitin, chitosan, cyclodextrins, polydextrose, dextrans, glucosamine, hyaluronic acid, or hyaluronic acid esters) or lipids.

Examples of resorbable polymers include, but are not limited to, poly(alpha- hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PLG), polyethylene glycol (PEG), PEG conjugates of poly(alpha-hydroxy acids), polyorthoesters, polyaspirins, polyphosphazenes, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, polyethylene glycol-terephthalate and polybutylene- terephthalate (PEGT-PBT) copolymer(polyactive), methacrylates, poly(N- isopropylacrylamide), polyethylene oxides (as known as polyoxyethylene or PEO), poly-propylene oxide (also known as polyoxypropylene or PPO), poly(aspartic acid) (PAA), PEO-PPO-PEO (Pluronics®, BASF), PEO-PPO-PAA copolymers, PLGA- PEO-PLGA, polyphosphoesters, polyanhydrides, polyester-anhydrides, polyamino acids, polyurethane-esters, polyphosphazines, polycaprolactones, polytrimethylene carbonates, polydioxanones, polyamide-esters, polyketals, polyacetals, polyethylene- vinyl acetates, silicones, polyurethanes, polypropylene fumarates,

polydesaminotyrosine carbonates, polydesaminotyrosine arylates,

polydesaminotyrosine ester carbonates, polydesaminotyrosine ester arylates, polyorthocarbonates, polycarbonates, or copolymers or physical blends thereof or combinations thereof.

More examples of synthetic biodegradable polymers include, but are not limited to, various polyesters, copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al, 1983, Biopolymers 22:547-556), polyphosphagenes, various hydrogels (see, for example, Langer et al, 1981, J. Biomed. Mater. Res. 15: 167-277; Langer, 1982, Chem. Tech. 12:98-105), and poly-D-(-)-3-hydroxybutyric acid (EP 133,988). Polylactide (PLA) and its copolymers with glycolide (PLGA) have been well known in the art since the commercialization of the Lupron Drug delivery device™, approved in 1989 as the first parenteral sustained-release formulation utilizing PLA polymers.

Additional examples of products which utilize PLA and PLGA as excipients to achieve sustained-release of the active ingredient include Atridox (PLA; periodontal disease), Nutropin Drug delivery device (PLGA; with hGH), and the Trelstar Drug delivery device (PLGA; prostate cancer).

Other synthetic polymers include, but are not limited to, poly(epsilon- caprolactone), poly(3-hydroxybutyrate), poly(beta-malic acid) and poly(dioxanone), polyanhydrides, polyurethane (see WO 2005/013936), polyamides, polyorthoesters, n- vinyl alcohol, polyethylene oxide/polyethylene terephthalate or Dacron®,

polyphosphate, polyphosphonate, polydihydropyran, and polyacytal.

In various embodiments, the drug delivery device comprises poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-epsilon-caprolactone, D,L-lactide-glycolide-epsilon-caprolactone, glycolide-caprolactone or a combination thereof.

Examples of non-biodegradable polymers include, but are not limited to, various cellulose derivatives (carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyalkyl methyl celluloses, and alkyl celluloses), silicon and silicon-based polymers (such as

polydimethylsiloxane), polyethylene-co-(vinyl acetate), poloxamer,

polyvinylpyrrolidone, poloxamine, polypropylene, polyamide, polyacetal, polyester, poly ethylene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or "Teflon™"), styrene butadiene rubber, polyethylene, polypropylene, polyphenylene oxide- polystyrene, poly-alpha-chloro-p-xylene, polymethylpentene, polysulfone, non- degradable ethylene-vinyl acetate (e.g., ethylene vinyl acetate disks and poly(ethylene- co-vinyl acetate)), and other related biostable polymers.

Non-resorbable polymers can also include, but are not limited to, delrin, polyurethane, copolymers of silicone and polyurethane, polyolefms (such as

polyisobutylene and polyisoprene), acrylamides (such as polyacrylic acid and poly(acrylonitrile-acrylic acid)), neoprene, nitrile, acrylates (such as polyacrylates, poly(2-hydroxy ethyl methacrylate), methyl methacrylate, 2-hydroxyethyl methacrylate, and copolymers of acrylates with N-vinyl pyrrolidone), N-vinyl lactams,

polyacrylonitrile, glucomannan gel, vulcanized rubber and combinations thereof.

Examples of polyurethanes include thermoplastic polyurethanes, aliphatic polyurethanes, segmented polyurethanes, hydrophilic polyurethanes, polyether- urethane, polycarbonate-urethane and silicone polyether-urethane. The vulcanized rubber described herein may be produced, for example, by a vulcanization process utilizing a copolymer produced as described, for example, in U.S. Pat. No. 5,245,098 to Summers et al. from 1-hexene and 5-methyl-l,4-hexadiene.

Other suitable non-resorbable material include, but are not limited to, lightly or highly cross-linked biocompatible homopolymers and copolymers of hydrophilic monomers such as 2-hydroxyalkyl acrylates and methacrylates, N-vinyl monomers, and ethylenically unsaturated acids and bases; polycyanoacrylate, polyethylene oxide- polypropylene glycol block copolymers, polygalacturonic acid, polyvinyl pyrrolidone, polyvinyl acetate, polyalkylene glycols, polyethylene oxide, collagen, sulfonated polymers, vinyl ether monomers or polymers, alginate, polyvinyl amines, polyvinyl pyridine, and polyvinyl imidazole. Depending on the amount of crosslinking within the bioresorbable polymers, the degradation time of the polymer can be reduced, thus making the polymer, for the purpose of this invention, appear to be non-resorbable over the time frame of the use of the material for this invention.

The drug delivery device may also contain shape memory polymers so that the drug delivery device can be compressed or folded prior to and during insertion through the capsule member and then be able to uncompress or unfold after the drug delivery device is within the joint. For example, a multi-block copolymer of oligo(epsilon- caprolactone)diol and crystallisable oligo(rho-dioxanone)diol can be used to create a shape memory polymer. This shape memory polymer features two block-building segments, a hard segment and a "switching" segment, which are linked together in linear chains. The higher-temperature shape is the polymer's ^"permanent^" form, which it assumes after heating. One component, oligo(epsilon-caprolactone)dimethacrylate, furnishes the crystallizable "switching" segment that determines both the temporary and permanent shape of the polymer. By varying the amount of the comonomer, n-butyl acrylate, in the polymer network, the cross-link density can be adjusted. In this way, the mechanical strength and transition temperature of the polymers can be tailored such that it can be used in the present invention. The shape memory polymers can be generated such that they return to their original shape with the application of an external stimulus. The external stimulus can be temperature, an electric or magnetic field, light, or a change in pH.

The drug delivery device can be inserted into position in a closed or folded, which can expand or unfold using memory shape fibers. Further, the drug delivery device can include radiographic markers to aid in visualization. The expanded drug delivery device will lodge at or near the target tissue and will be held in place by the expansion. This design allows the drug delivery device to be folded in the device for administering the drug delivery device and allows the drug delivery device to expand after the drug delivery device is deployed from the delivery device (e.g., catheter, needle, etc.) As noted above, in various embodiments, radiopaque material or markers can be positioned in or on or coated on the drug delivery device to assist in determining the position of the drug delivery device relative to the inflamed tissue being treated.

Examples of radiopaque material include, but are not limited to, barium sulfate, calcium phosphate, iopamidol, iodixanol, gadodiamide, Hypaque® sodium (diatrizoate sodium, Amersham Health, Inc., Princeton, N.J.), Hypaque®-76 (diatrizoate meglumine and diatrizoate sodium, Amersham Health, Inc., Princeton, N.J.), and Hypaque®

Meglumine (combination of diatrizoic acid dehydrate, water and meglumine,

Amersham Health, Inc., Princeton, N.J.).

Other types of radiopaque material include radioisotopes that can be linked to the drug delivery device. Examples of radioisotopes include, ¹⁸F, ³H, ¹²⁴I, ¹²⁵I, ¹³¹1, ³⁵S, ¹⁴C, and ^UC. Radioisotopes may be attached using a chelating agent such as EDTA or DTP A, and can be detected by gamma counter, scintillation counter, PET scanning, or autoradiography.

Alternatively, one can link a fluorescent molecule to the drug delivery device. Examples of fluorescent molecules include cy5, cy5.5, fluorescein, fluorescamine, dansyl compounds, ICG, phycoerythryn, phycocyanin, allophycocyanin, o- phthaladehyde, red fluorescent protein, green fluorescent protein and other near infrared or infra-red fluorophores.

As discussed above, the at least one pharmaceutical agent contained in the drug delivery device of this invention can be anti-inflammatory agents, anti-infective agents (such as, antibiotics, antiviral agents, anti-protozoal agents, anti-fungal agents, and antiparasitic agents), analgesics, growth factors, cytokines, nutraceutical, lubricants, nutrients, or other joint therapy agents.

Anti-inflammatory agents can include cytokines, steroids, non-steroidal anti- inflammatories, and agents that inhibit inflammatory cytokines. Of course, these groups can overlap. Examples of agents that inhibit inflammatory cytokines include, but are not limited to, tumor necrosis factor alpha (TNF-alpha) inhibitors (for example, onercept, adalimumab, infliximab, etanercept, pegsunercept (PEG sTNF-Rl), sTNF-Rl, CDP-870, CDP-571, CNI-1493, RDP58, ISIS 104838, 1→ 3-beta-D-glucans, lenercept, PEG-sTNFRl 1 Fc mutein, D2E7, afelimomab and antibodies or antibody fragments that bind to TNF-alpha or that bind to its receptor), inhibitors of TNF-alpha production or release (for example, thalidomide, tenidap, and phosphodiesterase inhibitors, such as, but not limited to, pentoxifylline and rolipram, and TNF-alpha converting enzyme inhibitors (TACE)), inhibitors of interleukin-1 (IL-1) (for example, anakinra, a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL- lRa); Orthokine® (IL-IRa obtained from human serum), AMG 108 (a monoclonal antibody that blocks IL-1 activity), and any other antibody or antibody fragment that binds to IL-1 or its receptors), inhibitors of IL-6 (for example, tocilizumab (a humanized anti-IL-6 mAb produced by Chugai Pharma USA, LLC, Bedminster, N.J.) or any other antibody or fragment that binds to IL-6 or its receptor), inhibitors of IL-8 (for example, any antibody or antibody fragment that binds to IL-8 or its receptor), and inhibitors of classical or non-classical nuclear factor kappa B (NFKB) pathways (for example, ureido-thiophenecarboxamide derivatives, diferuloylmethane, IK -1 and

IKK-2 inhibitors, proteosomal inhibitors such as Bortezomib, sulindac, dexamethasone, fluocinolone, dithiocarbamate, and sulfasalazine), or clonidine.

Cytokines that have anti-inflammatory activity include but are not limited to

interleukin-4 (IL-4) IL-10, IL-11, and IL-13.

The at least one pharmaceutical agent in the drug delivery device can also be an inhibitor of a matrix metalloprotease (MMP). Most MMP inhibitors are thiols or hydroxamates. Non-limiting examples of MMP inhibitors include TAPI-1 (TNF-alpha protease inhibitor) which blocks cleavage of cell surface TNF; TAPI-0, an analog of TAPI-1 that possesses similar efficacy in vitro; TAPI-2 which is inhibits both the activation-induced shedding of L-selectin from neutrophils, eosinophils, and

lymphocytes and also inhibits phenylarsine oxide-induced L-selectin shedding; Ac- SIMP-1; Ac-SIMP-2; SIMP-1; SIMP-2; doxycycline; marimastat (Vemalis Pic, Winnersh, United Kingdom); cipemastat (F. Hoffmann-La Roche Ltd, Basel,

Switzerland); and tissue inhibitor of metalloproteinases (TIMPs) which include TIMP- 1, TIMP-2, TIMP-3 and TIMP-4. Synthetic inhibitors of MMPs generally contain a chelating group which binds the catalytic zinc atom at the MMP active site tightly. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Examples of steroidal anti-inflammatory agents include but are not limited to hydrocortisone, Cortisol, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone -phosphate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene(fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluocinolone, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone,

beclomethasone dipropionate, and triamcinolone.

Non-limiting examples of non-steroidal anti-inflammatory compounds include acetaminophen, paracetamol, nabumetone, celecoxib, etodolac, nimesulide, apasone, gold, oxicams, such as piroxicam, isoxicam, meloxicam, tenoxicam, sudoxicam, and CP-14,304; the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, ketorolac, sulfasalazine, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.

Suitable analgesics include, without limitation, non-steroid anti-inflammatory drugs, non-limiting examples of which have been recited above. Analgesics also include other types of compounds, such as, for example, opioids (such as, for example, morphine naloxone, codeine, oxycodone, hydrocodone, diamorphine, pethidine, tramadol, tapentadol, or buprenorphine), local anaesthetics (such as, for example, bupivacaine, ropivacaine, mupivacaine, lidocaine and capsaicin), glutamate receptor antagonists, alpha-adrenoreceptor agonists (for example, clonidine), beta one receptor antagonists (e.g., HOE- 140), adenosine, sodium or calcium channel blockers, neurotoxins (BoNT/A Botulinum toxin), TrkA receptor antagonists, canabinoids, cholinergic and GABA receptors agonists, and different neuropeptides.

Examples of antibiotics include but are not limited to amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, tobramycin and apramycin, streptovaricins, rifamycins, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, piperacillin,

pivampicillin, ticarcillin, cefacetrile, cefadroxil, cefalexin, cefaloglycin cefalotin, cefapirin cefazolin, cephradine, cefaclor, ceforanide, cefotiam cefprozil, cefuroxime, cefdinir, cefditoren, cefixime, cefmenoxime, cefoperazone cefotaxime, cefpiramide, cefpodoxime, ceftazidime, ceftibuten, ceftriaxone, cefepime, cefquinome, doxycycline, sulbactam, tazobactam, clavulanic acid, ampicillin/sulbactam(sultamicillin), co- amoxicillin/clavulanate (or clavulanic acid) and combinations thereof.

Antiviral agents can include, but are not limited to, vidarabine, acyclovir, famciclovir, valacyclovir, gancyclovir, valganciclovir, nucleoside-analog reverse transcriptase inhibitors (such as AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), and 3TC (lamivudine)), nevirapine, delavirdine, protease inhibitors (such as, saquinavir, ritonavir, indinavir, and nelfinavir), ribavirin, amantadine, rimantadine, neuraminidase inhibitors (such as zanamivir and oseltamivir), pleconaril, cidofovir, foscarnet, and/or interferons.

In various embodiments, the active pharmaceutical ingredient includes osteoporosis drugs or drugs that will block/modify bone remodeling. Examples of such drugs include, but are not limited to, calcitonin, bisphosphonates, such as for example, alendronate, risedronate, zoledronic acid, ibandronate, etidronate, synthetic hormones for treating osteoporosis, (e.g., teriparatide), Dehydroxymethylepoxyquinomicin (DHMEQ), estrogen receptor agonists/antagonists, such as for example, arzoxifene, genistein, TSE-424, raloxifene, lasofoxifene, basedoxifene. Other drugs such as, for example, MMP inhibitors, such as for example, BB-3364, Ilomastat (GM 6001;

Galardin), marimastat, TMI-1 (sulfonamide hydroxamate), neovastat, BAY12-9566, Ro32-3555, SC44463 or combinations thereof. Active pharmaceutical may include HIV-protease inhibitors, such as for example, agenerase, aptivus, crixivan, invirase, kaletra, lexiva, norvir, prezista, reyataz, viracept or a combination thereof. Exemplary active pharmaceutical ingredients include toll-like receptors antagonists, chaperonin 10, superoxide dismutase mimetics, poly(adp)ribose polymerase inhibitors (PARP-1), caspase-1 or interleukin (IL)-lb converting enzyme (ICE) inhibitors, triterpenoids (synthetic or natural), jesterones, cathepsin inhibitors (e.g., OST-4077; Relacitib), dipeptidyl Peptidase IV Inhibitors (DPP-IV), cartilage repair stimulators (e.g., RNI 249, vincaria, reparagen, etc.), leflunomide, boswellic acid, curcumin, withanolides, biolimus, everolimus, zotarolimus, IKK inhibitors, manumycin A, arthritis disease modifying drugs of any sort, including but not limited to calcium fructaborate, anthraquinone derivatives diacerein or rhein, or a combination thereof. Exemplary active pharmaceutical agents also include blockers of nitric oxide synthesis (e.g., L- NAME, L-NMMA, or haloperadol), and blockers of apoptosis (e.g. Aralia cordata or other blockers of p38 MAP -kinase).

Anti-fungal agents can include, but are not limited to, fluconazole, itraconazole, ketoconazole, miconazole, ciclopirox, clotrimazole, econazole, miconazole, nystatin, oxiconazole, terconazole, and tolnaftate.

Anti-protozoal agents can include, but are not limited to, chloroquine,

hydroxychloroquine, quinine, primaquine, denzimidazole, piperazine, pyrentel pamoate, praziquantel, ivermectin, diloxanide furoate, metronidazole, eflornithine, furazolidone, idoquinol, paromomycin, emetines, atovaquone, pyrimethamine combined with sulfadiazine, sodium stibogluconate, amphotericin B, nifurtimox, melarsoprol, suramin, and pentamidine.

The at least one pharmaceutical agent of the present invention may be a growth factor. The growth factor may be an osteoinductive and/or cartilage forming protein or molecule that may be used alone or in combination with any of the above agents to stimulate or induce bone or cartilage growth within the joint. Platelet-derived growth factors (PDGFs), bone morphogenetic proteins (BMPs), insulin-like growth factors (IGFs), basic fibroblast growth factor (bFGF), cartilage derived morphogenetic protein (CDMP), and various other bone and cartilage regulatory proteins, such as CD-RAP, are all growth factors that are successful in bone and cartilage regeneration. BMPs and CDMPs, in particular, induce new cartilage and bone formation though a signal cascade that, ultimately, leads to morphogenesis of precursor cells into bone or cartilage cells. CD-RAP is also known in the art to be a regulatory protein synthesized by chondrocytes involved in the formation of type II collagen and, ultimately, cartilage. BMPs, CDMPs, and CD-RAP may be contained within the drug delivery device and released from the drug delivery device such that the proteins or molecules induce the formation of bone and/or cartilage. Such formation of bone and/or cartilage is useful for the treatment of the degeneration of cartilage and bone associated with osteoarthritis, chondromalacia, rheumatoid arthritis, or any other bone or cartilage degenerative condition.

Examples of such BMPs and CDMPs may include, but are not limited to, BMP-2, BMP-4, BMP-6, BMP-7, BMP-8, and CDMP-1. The BMPs or CDMPs may be available from Genetics Institute, Inc., Cambridge, Mass. and may also be prepared by one skilled in the art as described in U.S. Pat. No. 5,187,076 to Wozney et al; U.S. Pat. No. 5,366,875 to Wozney et al; U.S. Pat. No. 4,877,864 to Wang et al; U.S. Pat. No. 5,108,922 to Wang et al; U.S. Pat. No. 5,116,738 to Wang et al; U.S. Pat. No.

5,013,649 to Wang et al; U.S. Pat. No. 5,106,748 to Wozney et al; and PCT Patent Nos. WO93/00432 to Wozney et al; W094/26893 to Celeste et al; and W094/26892 to Celeste et al. All osteoinductive factors are contemplated whether obtained as above or isolated from bone. Methods for isolating BMP from bone are described in U.S. Pat. No. 4,294,753 to Urist and in Urist et al, 81 PNAS 371, 1984.

The present application is not limited to the above embodiments of BMPs,

CDMPs, and CD-RAP. Rather, any natural or synthetic BMP, CDMP or other osteoinductive or cartilage producing protein or molecule is contemplated by the present invention such as, but not limited to, BMP-1, BMP-2, rhBMP-2, BMP-3, BMP- 4, rhBMP-4, BMP-5, BMP-6, rhBMP-6, BMP-7 (also called OP-1), rhBMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP- 18, GDF-5 (also called CDMP-1), rfiGDF-5, and mimetics thereof. Additionally, the present invention may include, separately or in combination with any of the above embodiments, any other protein or molecule that induces bone or cartilage regeneration such as, but not limited to, platelet-derived growth factors (PDGFs), insulin-like growth factors (IGFs), fibroblast growth factor (FGF), LIM mineralization proteins, transforming growth factors (TGF), fibroblast growth factor (FGF), growth

differentiation factors (GDF), and mimetics thereof. A more detailed discussion as to how each of these growth factors and/or proteins induce bone and cartilage regeneration may be found in Rengachary, Neurosurg. Focus, 13: 1-6, 2002; Reddi, Arthritis Res, 3:1-5, 2001; and Varkey et al, Expert Opin. Drug Deliv., 1 : 19-36, 2004.

In various embodiments, the therapeutic agent comprises botulinum toxin, TGF beta, fibroblast growth factor 18, or a combination thereof.

The drug delivery device manufactured in the above example can be administered to a patient using minimally invasive procedures or using a full surgical procedure. Using minimally invasive procedures, such as an arthroscopy, one can make an incision in the skin and muscle of the patient near joint. The endoscope can be pushed through the tissue until it reaches the capsular membrane. An incision can be made in the membrane.

The drug delivery device can be rolled or folded or otherwise compressed into a smaller shape. It can be inserted into the proximal opening of the endoscope and pushed until it exits the distal end of the endoscope inside the synovial joint. Once inside the synovial joint, one can unfold, unroll or otherwise uncompress the drug delivery device. If the drug delivery device has shape memory polymer attached to it, the shape memory polymer may be sufficient to uncompress the drug delivery device.

If the drug delivery device has a lattice similar to an umbrella, one can

uncompress the drug delivery device by extending the lattice. Alternatively, if one had compressed the drug delivery device into a smaller size around an uninflated balloon and placed the drug delivery device and the uninflated balloon inside the synovial joint, then one could inflate the balloon, thereby uncompressing the drug delivery device. Alternatively, one can use forceps or similar tools to careful unfold, unroll or otherwise uncompress the drug delivery device. The use of a tool to open up the drug delivery device could occur prior to attachment of some of the drug delivery device to the synovial membrane or after attachment of the drug delivery device to the synovial membrane at one or more points.

Alternatively, the drug delivery device can have a guide wire attached to the drug delivery device prior to folding, rolling or compressing the drug delivery device. The folded drug delivery device and the guide wire can be moved into the synovial joint via the endoscope. Once inside the synovial joint, one can use the guidewire to position the drug delivery device to the desired location. The drug delivery device can then be attached to the synovial membrane and the guide wire can be used to unroll, unfold, or otherwise uncompress the drug delivery device. Alternatively, the guide wire can be used to unroll, unfold, or otherwise uncompress the drug delivery device and then position the drug delivery device to the desired location for anchoring to the synovial membrane.

The drug delivery device can be anchored to the synovial membrane by any of the attachment devices mentioned above. Sutures, barbs, tacks, staples, tethers, and the like can be passed through the drug delivery device and the synovial membrane at various points on the drug delivery device to securely anchor the drug delivery device to the synovial membrane. Some of the adhesive devices can be made from polymers that absorb body fluids and swell, thereby providing an additional mechanism to secure the drug delivery device to the synovial membrane. Alternatively, an adhesive can be applied to the surface of the synovial membrane or to the side of the drug delivery device which faces the synovial membrane. The surgeon applies pressure to the drug delivery device and the synovial membrane until the adhesive cures, thereby securing the drug delivery device to the synovial membrane.

In an alternative embodiment, after an incision has been made in the synovial membrane, the physician can replace, wash or flush out the synovial joint by suctioning out the fluids and adding a physiologically neutral solution such as saline, dextrose solution, phosphate buffered saline, Ringer lactate, Sydny's ringers, or Ringer-Locke solution, HT-FRS (BioLife), Synvisc®, Orthovisc®, hyaluronic acids or derivatives thereof or the like. The suctioning of fluids and addition of the physiologically neutral solution can be repeated any number of times for any length of time. The steps can occur simultaneously or as distinctly different steps. Not wishing to be bound to a particular hypothesis, it is believed that the synovial fluid of an inflamed joint contains a myriad of pro-inflammatory cytokines and other pro-inflammatory molecules.

Washing, replacing or flushing out the inflamed joint removes most or all of these pro-inflammatory cytokines and other pro-inflammatory molecules and benefits the treatment regimen. Many anti-inflammatory agents, such as antibodies or receptors that specifically bind to pro-inflammatory molecules, exert their action in a sacrificial manner, they are consumed generally stoichiometrically relative to their targets. Thus, removal of the targets of the anti-inflammatory agents from an inflamed synovial joint prior to administration of the pharmaceutical agent provides benefits in such specific binding modes of action as well as with other anti-inflammatory agents. Washing, flushing or replacing the synovial fluid of the joint with suitable substitutes for synovial fluid of a joint may even help the joint heal faster, thereby lessening the amount of time and the dose of pharmaceutical agents necessary for treatment. After the washing, flushing or replacing the joint fluid, the physician can insert the drug delivery device through the endoscope into the joint. In addition, after the joint has been washed, the physician can administer into the joint a dosage of an at least one pharmaceutical agent to help start the treatment, and dosage separate from the pharmaceutical agent which will be released by the drug delivery device.

In another embodiment, if one is inserting the drug delivery device into a knee, the drug delivery device can be placed in the upper lateral gutter of the knee after the drug delivery device has been unrolled, unfolded or otherwise uncompressed. Placement of the drug delivery device into the upper lateral gutter occurs by inserting the catheter or guidewire during image-guided arthroscopy into the upper compartment of the supra patellar bursa. The compressed or rolled drug delivery device is then deployed using SMA springs or an expandable, retractable, frame. After placing the drug delivery device in the upper lateral gutter, one secures the drug delivery device to the synovial membrane by any of the attachment devices discussed above.

In an alternative embodiment, the physician inserts the endoscope into the patient's body until the distal end is adjacent to the synovial membrane of the joint to be treated. The folded, rolled, compressed drug delivery device is inserted into the proximal end of the endoscope and moves through the distal end of the endoscope into the patient's body, adjacent to the synovial membrane. The drug delivery device can be unfolded, unrolled, or otherwise uncompressed and placed next to the outside of the synovial membrane. Then the physician can securely anchor the drug delivery device to the outside of the synovial membrane using any of the attachment devices discussed above. The at least one pharmaceutical agent will dissolve and can pass through the synovial membrane into the synovial joint. One has the option of washing out the synovial fluid even if one anchors the drug delivery device to the outside of the synovial membrane.

In another embodiment, an adhesive (listed above) is sprayed onto the synovial membrane in the upper lateral gutter (e.g., supra patellar compartment), using an endoscopic spray device, prior to insertion and deployment of the folded polymer drug delivery device onto the surface. The drug delivery device which has been securely anchored to the synovial membrane can be left in place for the pre-determined time. If the drug delivery device is not completely biodegradable, one may have to reopen the patient's body to remove the non-resorbable components of the drug delivery device.

After the drug delivery device is securely anchored to the synovial membrane, the physician repairs the hole in the synovial membrane, if any, and removes the endoscope, repairing any tissue that was cut during the procedure. The drug delivery device releases the at least one pharmaceutical agent over the pre-determined period of time at the pre-determined rate. If the drug delivery device is made from resorbable polymers, there may not be a need to remove it from the patient. If the drug delivery device is made from non-biodegradable polymers, then the physician may need to remove the drug delivery device from the patient using minimally invasive techniques or using open surgical techniques.

In various embodiments, the drug delivery device comprising the active ingredients can be made by combining a biocompatible polymer and a therapeutically effective amount of the active ingredients or pharmaceutically acceptable salts thereof and forming the implantable compressible drug delivery device from the combination. Alternatively, the active ingredient can be coated onto at least the interior of the reservoir portion of the drug delivery device by various methods known in the art.

In yet another embodiment, the active ingredient can be coated onto at least the exterior of the drug delivery device.

Various techniques are available for forming at least a portion of a drug delivery device from the biocompatible polymer(s), therapeutic agent(s), and optional materials, including solution processing techniques and/or thermoplastic processing techniques. Where solution processing techniques are used, a solvent system is typically selected that contains one or more solvent species. The solvent system is generally a good solvent for at least one component of interest, for example, biocompatible polymer and/or therapeutic agent. The particular solvent species that make up the solvent system can also be selected based on other characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spin coating techniques, web coating techniques, solvent spraying techniques, dipping techniques, techniques involving coating via mechanical suspension, including air suspension (e.g., fluidized coating), ink jet techniques and electrostatic techniques. Where appropriate, techniques such as those listed above can be repeated or combined to build up the drug delivery device to obtain the desired release rate and desired thickness.

n various embodiments, a solution containing solvent and biocompatible polymer are combined and placed in a mold of the desired size and shape. In this way, polymeric regions, including barrier layers, lubricious layers, and so forth can be formed. If desired, the solution can further comprise, one or more of the following: other therapeutic agent(s) and other optional additives such as radiographic agent(s), etc. in dissolved or dispersed form. This results in a polymeric matrix region containing these species after solvent removal. In other embodiments, a solution containing solvent with dissolved or dispersed therapeutic agent is applied to a pre-existing polymeric region, which can be formed using a variety of techniques including solution processing and thermoplastic processing techniques, whereupon the therapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the drug delivery device or portions thereof include molding techniques (for example, injection molding, rotational molding, and so forth), extrusion techniques (for example, extrusion, co-extrusion, multi-layer extrusion, and so forth) and casting.

Thermoplastic processing in accordance with various embodiments comprises mixing or compounding, in one or more stages, the biocompatible polymer(s) and one or more of the following: the active ingredients, optional additional therapeutic agent(s), radiographic agent(s), and so forth. The resulting mixture is then shaped into an implantable drug delivery device. The mixing and shaping operations may be performed using any of the conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for the therapeutic agent(s) to degrade, for example, due to elevated temperatures and/or mechanical shear that are associated with such processing. For example, certain therapeutic agents may undergo substantial degradation under ordinary thermoplastic processing conditions. Hence, processing is preferably performed under modified conditions, which prevent the substantial degradation of the therapeutic agent(s). Although it is understood that some degradation may be unavoidable during thermoplastic processing, degradation is generally limited to 10% or less. Among the processing conditions that may be controlled during processing to avoid substantial degradation of the therapeutic agent(s) are temperature, applied shear rate, applied shear stress, residence time of the mixture containing the therapeutic agent, and the technique by which the polymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s) and any additional additives to form a substantially homogenous mixture thereof may be performed with any device known in the art and conventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formed by heating the biocompatible polymer, which can be mixed with various additives (e.g., therapeutic agent(s), inactive ingredients, etc.) to form a mixture. A common way of doing so is to apply mechanical shear to a mixture of the biocompatible polymer(s) and additive(s). Devices in which the biocompatible polymer(s) and additive(s) may be mixed in this fashion include devices such as single screw extruders, twin screw extruders, banbury mixers, high-speed mixers, ross kettles,

Any of the biocompatible polymer(s) and various additives may be premixed prior to a final thermoplastic mixing and shaping process, if desired (e.g., to prevent substantial degradation of the therapeutic agent among other reasons).

For example, in various embodiments, a biocompatible polymer is

precompounded with a radiographic agent (e.g., radio-opacifying agent) under conditions of temperature and mechanical shear that would result in substantial degradation of the therapeutic agent, if it were present. This precompounded material is then mixed with therapeutic agent under conditions of lower temperature and mechanical shear, and the resulting mixture is shaped into the active ingredient containing drug delivery device. Conversely, in another embodiment, the

biocompatible polymer can be precompounded with the therapeutic agent under conditions of reduced temperature and mechanical shear. This precompounded material is then mixed with, for example, a radio-opacifying agent, also under conditions of reduced temperature and mechanical shear, and the resulting mixture is shaped into the drug delivery device or coated onto the reservoir portion of the preformed device.

The conditions used to achieve a mixture of the biocompatible polymer and therapeutic agent and other additives will depend on a number of factors including, for example, the specific biocompatible polymer(s) and additive(s) used, as well as the type of mixing device used. As an example, different biocompatible polymers will typically soften to facilitate mixing at different temperatures. For instance, where a drug delivery device is formed comprising PLGA or PLA polymer, a radio-opacifying agent (e.g., bismuth

subcarbonate), and a therapeutic agent prone to degradation by heat and/or mechanical shear (e.g., clonidine), in various embodiments, the PGLA or PLA can be premixed with the radio-opacifying agent at temperatures of about, for example, 150°C to 170°C.

The therapeutic agent is then combined with the premixed composition and subjected to further thermoplastic processing at conditions of temperature and mechanical shear that are substantially lower than is typical for PGLA or PLA compositions. For example, where extruders are used, barrel temperature, volumetric output are typically controlled to limit the shear and therefore to prevent substantial degradation of the therapeutic agent(s). For instance, the therapeutic agent and premixed composition can be mixed/compounded using a twin screw extruder at substantially lower temperatures (e.g., 100-105°C), and using substantially reduced volumetric output (e.g., less than 30% of full capacity, which generally corresponds to a volumetric output of less than 200 cc/min). It is noted that this processing temperature is well below the melting points of certain active ingredients, such as an antiinflammatory and analgesic compounds, because processing at or above these temperatures will result in substantial therapeutic agent degradation. It is further noted that in certain embodiments, the processing temperature will be below the melting point of all bioactive compounds within the composition, including the therapeutic agent. After compounding, the resulting drug delivery device is shaped into the desired form, also under conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or more therapeutic agents are premixed using non-thermoplastic techniques. For example, the

biocompatible polymer can be dissolved in a solvent system containing one or more solvent species. Any desired agents (for example, a radio-opacifying agent, a therapeutic agent, or both radio-opacifying agent and therapeutic agent) can also be dissolved or dispersed in the solvents system. Solvent is then removed from the resulting solution/dispersion, forming a solid material. The resulting solid material can then be granulated for further thermoplastic processing (for example, extrusion) if desired. As another example, the therapeutic agent can be dissolved or dispersed in a solvent system, which is then applied to a pre-existing drug delivery device (the preexisting drug delivery device can be formed using a variety of techniques including solution and thermoplastic processing techniques, and it can comprise a variety of additives including a radio-opacifying agent and/or viscosity enhancing agent), whereupon the therapeutic agent is imbibed on or in the drug delivery device. The application (coating) can be performed multiple times to increase the thickness of the coating containing the therapeutic agent.

It should be understood that the therapeutic agent can be dissolved in a system that, upon coating, deposits not only the therapeutic agent, but a coating layer as well of a suitable polymeric material such as those disclosed herein. For example, the therapeutic agent could be dissolved in a system that includes PLGA. The system then can be coated onto the delivery device, in particular within the reservoir portion of the device, and dried to remove solvent. The process can be performed multiple times to increase the coating thickness with the therapeutic agent. Furthermore, it should be understood that the coating process can be by dip coating, spray, and other conventional methods known in the art. Additionally, the multiple coatings can be effected with different carrier/polymeric systems to provide different rates of dissolution. For example, the drug delivery device can be coated with a therapeutic dissolved with PLGA, coated, and dried. A subsequent layer can then be applied with either the same therapeutic or a different therapeutic and a different polymer, such as PLA.

Typically, an extrusion processes may be used to form the drug delivery device comprising a biocompatible polymer(s), therapeutic agent(s) and radio-opacifying agent(s). Co-extrusion may also be employed, which is a shaping process that can be used to produce a drug delivery device comprising the same or different layers or regions (for example, a structure comprising one or more polymeric matrix layers or regions that have permeability to fluids to allow immediate and/or sustained drug release). Multi-region drug delivery devices can also be formed by other processing and shaping techniques such as co-injection or sequential injection molding technology.

In various embodiments, the drug delivery device that may emerge from the thermoplastic processing (e.g., pellet, strip, etc.) is cooled and molded into the delivery apparatus that includes the reservoir portion, drug dispensing portion and dispensing port, often by blow molding. Examples of cooling processes include air cooling and/or immersion in a cooling bath. In some embodiments, a water bath is used to cool the extruded drug delivery device. However, where a water-soluble therapeutic agent such as active ingredients, is used, the immersion time should be held to a minimum to avoid unnecessary loss of therapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use of ambient or warm air jets after exiting the bath will also prevent re-crystallization of the drug on the drug delivery device surface, thus controlling or minimizing a high drug dose "initial burst" or "bolus dose" upon implantation or insertion if this release profile is not desired.

In various embodiments, the drug delivery device can be prepared by molding the drug delivery device to the desired shape (with or without anchoring members) and then mixing or spraying the drug within the reservoir portion.

Referring now to the figures, Figure 1 illustrates a side sectional view of a joint capsule with different tissue types that are treatable with the one or more drug delivery devices.

Figure 1 illustrates an exemplary synovial joint where the drug delivery device may be implanted so as not to substantially interfere with movement of the joint.

Shown is the synovial joint for the knee. However, it will be understood that the drug delivery device may be implanted in any synovial joint (e.g., fingers, toes, etc.).

Exemplary areas to implant the drug delivery device, include, but are not limited to, fat tissue, tendon, lateral gutter, supra-patellar or prepatellar bursa, infra-patellar fat pad, infra-patellar bursa, intra-patellar bursa, anterior cruciate ligament, posterior cruciate ligament, trochlear groove, meniscus, or region around the meniscus, cartilage, femur, tibia and/or synovial membrane of a knee (which surrounds the synovial joint) so long as the drug delivery device does not substantially interfere with movement of the joint.

Figure 2 illustrates a side sectional view of a joint capsule with different tissue types that are treatable with the one or more drug delivery devices. In this view a drug delivery device containing barbs as the anchoring member is implanted within the infrapatellar fat pad of the joint capsule.

Figure 3 provides a compressible drug delivery device 10 shown in Figure 2 that includes a drug containing reservoir portion 20, a drug dispensing portion 30 with a dispensing port 40 with attachment members 50 (barbs). The compressible polymeric drug delivery portion 80 can be coated with a coating layer 60 of various polymers described herein. Coating layer 60 further includes drug 70 also as disclosed herein. It should be understood that in an alternative embodiment, drug 70 could be entrapped within the drug delivery device polymeric material 90 and/or within coating 60.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications and patents specifically mentioned herein are incorporated by reference in their entirety for all purposes including describing and disclosing the chemicals, instruments, statistical analyses and methodologies which are reported in the publications which might be used in connection with the invention. All references cited in this specification are to be taken as indicative of the level of skill in the art. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

The following paragraphs enumerated consecutively from 1 through 13 provide for various aspects of the present invention. In one embodiment, in a first paragraph (1), the present invention provides an implantable drug delivery device including a compressible polymeric drug delivery portion and a drug, wherein the compressible polymeric drug delivery portion comprises a drug containing reservoir portion and a drug dispensing portion extending from the drug containing reservoir portion, wherein the drug dispensing portion comprises a dispensing port to provide delivery of the drug from the drug delivery device.

2. The drug delivery device of paragraph 1, wherein the drug containing reservoir portion comprises a bulb configuration.

3. The drug delivery device of either of paragraph 1 or paragraph 2, wherein the drug dispensing portion comprises a pipette or tube configuration.

4. The drug delivery device of any of paragraphs 1 through 3, wherein the drug is coated on the interior surface of the drug containing reservoir portion and or the drug dispensing portion.

5. The drug delivery device of any of paragraphs 1 through 3, wherein the drug is integrated with the polymer of the drug delivery device.

6. The drug delivery device of any of paragraphs 1 through 5, wherein the drug delivery device comprises a biodegradable polymer.

7. The drug delivery device of paragraph 6, wherein the biodegradable polymer degrades over a period of about 3 to about 6 months. 8. The drug delivery device of any of paragraphs 1 through 7, wherein the drug delivery device comprises one or more anchoring members to anchor the device to the inside of the joint capsule.

9. The drug delivery device of paragraph8, wherein one or more anchoring members comprise barbs, hooks, cork screws, staples, tethers, clips, sutures, compressible and expandable shape memory alloys, nitinol wires, adhesives or a combination thereof.

10. A method of reducing pain and/or inflammation of tissue within a synovial joint in a patient in need of such treatment, the method comprising inserting a drug delivery device through the synovial joint and anchoring the drug delivery device to the inside of the synovial joint capsule so that the drug delivery device allows normal articulation of the synovial joint and does not substantially interfere with movement of the joint, wherein the drug delivery device comprises a compressible polymeric drug delivery portion, wherein the compressible polymeric drug delivery portion comprises a drug containing reservoir portion and a drug dispensing portion extending from the drug containing reservoir portion, wherein the drug dispensing portion comprises a dispensing port to provide delivery of the drug from the drug delivery device and the drug comprises at least one analgesic and/or anti-inflammatory agent and/or

antimicrobial and the drug delivery device is capable of releasing the at least one analgesic and/or anti-inflammatory agent and/or antimicrobial over a period of at least three days.

11. A method of treating a tissue within a synovial joint in a patient in need of such treatment, the method comprising inserting a drug delivery device through the synovial joint and anchoring the drug delivery device to the inside of the synovial joint capsule so that the drug delivery device does not substantially interfere with movement of the joint, wherein the drug delivery device comprises a drug and a compressible polymeric drug delivery portion, wherein the compressible polymeric drug delivery portion comprises a drug containing reservoir portion and a drug dispensing portion extending from the drug containing reservoir portion, wherein the drug dispensing portion comprises a dispensing port to provide delivery of the drug from the drug delivery device.

12. The method of paragraph 11, wherein the drug is delivered into the synovial fluid.

13. The method of paragraph 12, wherein synovial fluid flows into and out of the drug delivery device. Although the present invention has been described with reference to preferred embodiments, persons skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention. All references cited throughout the specification, including those in the background, are incorporated herein in their entirety. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

P0034445.01 O 2011/139594 PCT/US2011/033540 CLAIMS What is claimed is:

1. An implantable drug delivery device comprising:

a compressible polymeric drug delivery portion and a drug, wherein the compressible polymeric drug delivery portion comprises a drug containing reservoir portion and a drug dispensing portion extending from the drug containing reservoir portion, wherein the drug dispensing portion comprises a dispensing port to provide delivery of the drug from the drug delivery device.

2. The drug delivery device of claim 1, wherein the drug containing reservoir portion comprises a bulb configuration.

3. The drug delivery device of either of claim 1 or claim 2, wherein the drug dispensing portion comprises a pipette or tube configuration.

4. The drug delivery device of any of claims 1 through 3, wherein the drug is coated on the interior surface of the drug containing reservoir portion and or the drug dispensing portion.

5. The drug delivery device of any of claims 1 through 3, wherein the drug is integrated with the polymer of the drug delivery device.

6. The drug delivery device of any of claims 1 through 5, wherein the drug delivery device comprises a biodegradable polymer.

7. The drug delivery device of claim 6, wherein the biodegradable polymer degrades over a period of about 3 to about 6 months.

8. The drug delivery device of any of claims 1 through 7, wherein the drug delivery device comprises one or more anchoring members to anchor the device to the inside of a joint capsule. P0034445.01

O 2011/139594 PCT/US2011/033540

9. The drug delivery device of claim 8, wherein one or more anchoring members comprise barbs, hooks, cork screws, staples, tethers, clips, sutures, compressible and expandable shape memory alloys, nitinol wires, adhesives or a combination thereof.

10. A method of reducing pain and/or inflammation of tissue within a synovial joint in a patient in need of such treatment, the method comprising inserting a drug delivery device through the synovial joint and anchoring the drug delivery device to the inside of the synovial joint capsule so that the drug delivery device allows normal articulation of the synovial joint and does not substantially interfere with movement of the joint, wherein the drug delivery device comprises a compressible polymeric drug delivery portion, wherein the compressible polymeric drug delivery portion comprises a drug containing reservoir portion and a drug dispensing portion extending from the drug containing reservoir portion, wherein the drug dispensing portion comprises a dispensing port to provide delivery of the drug from the drug delivery device , wherein the drug comprises at least one analgesic and/or anti-inflammatory agent and/or antimicrobial and the drug delivery device is capable of releasing the at least one analgesic and/or anti-inflammatory agent and/or antimicrobial over a period of at least three days.

12. The method of claim 11, wherein the drug is delivered into the synovial fluid. P0034445.01

O 2011/139594 PCT/US2011/033540

13. The method of claim 12, wherein synovial fluid flows into and out of the drug delivery device.