WO2012047931A1 - Device for local drug delivery and treatment of cerebral edema and other brain-related diseases - Google Patents

Device for local drug delivery and treatment of cerebral edema and other brain-related diseases Download PDF

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Publication number
WO2012047931A1
WO2012047931A1 PCT/US2011/054818 US2011054818W WO2012047931A1 WO 2012047931 A1 WO2012047931 A1 WO 2012047931A1 US 2011054818 W US2011054818 W US 2011054818W WO 2012047931 A1 WO2012047931 A1 WO 2012047931A1
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WIPO (PCT)
Prior art keywords
drug
device
reservoir
housing
method
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Application number
PCT/US2011/054818
Other languages
French (fr)
Inventor
Michael J. Cima
Fred Hochberg
Urvashi Upadhyay
Qunya Ong
Kamal A. Shair
Original Assignee
Massachusetts Institute Of Technology
Massachusetts General Hospital
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Publication date
Priority to US38959410P priority Critical
Priority to US61/389,594 priority
Application filed by Massachusetts Institute Of Technology, Massachusetts General Hospital filed Critical Massachusetts Institute Of Technology
Publication of WO2012047931A1 publication Critical patent/WO2012047931A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00Anatomical parts of the body
    • A61M2210/06Head
    • A61M2210/0693Brain, cerebrum

Abstract

Methods and device for treatment of cerebral edema are provided. The method may include implanting within a cranial cavity of a patient in need treatment or prophylaxis of cerebral edema a device for the local controlled release of a drug, which may be a steroid, such as a corticosteroid, for treating cerebral edema; and releasing an effective amount of the drug from the reservoir into the cranial cavity at a controlled rate. The device may include an implantable housing defining a reservoir, a solid drug formulation, including a water-soluble drug, disposed in the reservoir, the housing having a means for receiving a liquid vehicle to solubilize the drug when the device is implanted in a patient; and a tissue interfacing member operably connected to the reservoir for conducting the solubilized drug to an intracranial site and configured to controllably release the solubilized drug to the intracranial site.

Description

DEVICE FOR LOCAL DRUG DELIVERY AND TREATMENT OF CEREBRAL EDEMA AND OTHER BRAIN-RELATED DISEASES

Cross-Reference to Related Applications

This application claims priority to U.S. Provisional Patent Application No.

61/389,594, filed October 4, 2010, which is incorporated herein by reference.

Background

The present disclosure generally pertains to implantable drug delivery systems and methods, including but not limited to devices and methods for reducing cerebral edema, such as tumor-related cerebral edema.

Edema is a condition marked by swelling within the body. Cerebral edema in particular is marked by swelling within or about the brain. Because the cranial cavity is a relatively confined space, swelling may increase the pressure in the cranial cavity to unsafe levels. Headache, drowsiness, seizure, herniation, brain damage, loss of consciousness, and even death may result.

Often, cerebral edema results from head conditions such as head injury, stroke, or brain tumor. Cerebral edema is of particular significance for patients with brain tumor, whether primary in nature or metastasized from another location in the body. In fact, the main cause of death in patients with brain tumor is cerebral edema, not the tumor itself. These patients may experience edema as a direct result of the brain tumor or as an indirect result of treatments such as brain surgery, chemotherapy, and radiation therapy. Notably, the edema associated with a tumor may have a volume that is three times that of the tumor itself, which is especially consequential given the confined space in the cranial cavity.

Thus, it is not uncommon to treat patients with brain tumors or other head conditions in a manner to mitigate brain swelling. Steroids are often used for this purpose. For example, brain cancer patients are often treated with corticosteriods, such as

methylprednisolone, dexamethasone, or other glucocorticoids. These steroids are usually delivered systemically in large doses for extended periods, either orally or parenterally.

However, continued systemic steroid delivery may result in complications, such as myopathic changes, infections, blood clots, and bone softening, which negatively impact the patient's recovery or quality of life.

The complications associated with systemic delivery of corticosteriods potentially may be avoided by injecting an extended release depot formulation of corticosteroids directly into the brain. However, formulating an effective extended release depot formulation has proved elusive to date, at least in part due to the limited aqueous solubility of such

corticosteroids and their incompatibility with conventional polymer matrix formulations.

A significant need therefore exists for new systems and methods of reducing swelling and inflammation, such as cerebral edema caused by brain tumor, brain tumor therapy, or other conditions associated with brain swelling and inflammation. In particular, there is a need for such treatment systems and methods that can reduce or avoid the undesirable side effects associated with systemic steroid delivery.

One device known in the art is referred to as an Ommaya reservoir. It is a device that is implanted in the brain for administering drug or withdrawing fluid from the brain. A typical Ommaya reservoir includes a reservoir and a catheter. The reservoir is usually a dome-shaped housing, and the catheter is usually an elongated tube extending from the dome- shaped housing. A distal tip of the catheter includes a number of holes or openings, which are in fluid communication with the reservoir by way of an internal lumen through the catheter.

In use, the Ommaya reservoir is implanted in the brain in a surgical procedure. An incision is made in the scalp, and a hole is drilled through the skull. The reservoir is subcutaneously positioned just below the surface of the scalp above the skull, and the catheter is passed through the hole in the skull until its distal tip is positioned in a ventricle of the brain. The incision is closed, and the device remains implanted in the brain for an extended time period. When so implanted, the device provides a flow path between the surface of the scalp and the cerebrospinal fluid in the ventricle of the brain. The flow path extends from the reservoir through the internal lumen of the catheter to the openings or holes in its distal tip. The reservoir is readily accessible from the scalp via a needle or other medical instrument for removing fluid from, or directing fluid into, the device. For example, cerebrospinal fluid in the ventricle may be drawn through the catheter and from the reservoir for sampling purposes. A drug also may be introduced into the reservoir for delivery through the catheter to the cerebrospinal fluid in the ventricle.

One problem with delivering drug through an Ommaya reservoir is that the drug must be introduced in fluid form, so that the drug can pass through the catheter and from the openings on the distal tip. Another problem with the Ommaya reservoir is that it is not suited for delivering drug over an extended time period. Instead, the Ommaya reservoir is better suited for delivering bolus doses of drug. Yet another problem with the Ommaya reservoir is that it is not suited for delivering drug directly to the tissue of the brain, as the delivery of fluid drug directly to the brain may disrupt brain function or cause seizure. Instead, the Ommaya reservoir is better suited for delivering drug to the cerebrospinal fluid in the ventricle.

A significant need therefore exists for new systems and methods for local drug delivery and controlled release to the brain over an extended period, preferably without the need for additional frequent interventions, such as refilling of an implanted device.

Moreover, it would be desirable to be able to be able to target specific tissues or regions within the brain.

Summary

In one aspect, methods of treatment of cerebral edema are provided. The method may include implanting within a cranial cavity of a patient, who is in need treatment or prophylaxis of cerebral edema, a drug delivery device for the local controlled release of at least one drug, which may be a steroid, such as a corticosteroid, which is effective for treating cerebral edema; and then releasing an effective amount of the drug from the reservoir into the cranial cavity at a controlled rate. The drug delivery device has a housing that defines at least one reservoir in which the drug is stored. The drug may be provided in the reservoir in a solid drug formulation, which becomes solubilized by a liquid vehicle, such as CSF, after the device has been implanted into the cranial cavity. The drug may be selected from

methylprednisolone, dexamethasone, and analogs and combinations thereof.

In another aspect, an implantable device is provided for local intracranial drug delivery. The device may include an implantable housing defining at least one reservoir; a solid drug formulation which comprises a water-soluble drug and which is disposed in the at least one reservoir, the housing comprising an aperture or valve configured to receiving a liquid vehicle to solubilize the water-soluble drug when the device is implanted in a patient; and a tissue interfacing member operably connected to the at least one reservoir for conducting the solubilized drug to an intracranial site and configured to provide controlled release of the solubilized drug to the intracranial site. The reservoir, the tissue interfacing member, or both, may be filled by the solid drug formulation. The housing of the device may include an aperture configured to permit a physiological fluid in vivo to diffuse into the at least one reservoir, or the housing may include a septum configured to receive a hypodermic needle for injection of a liquid vehicle into the reservoir. The tissue interfacing member may include a flexible catheter, which has a proximal end attached to the housing and an opposed distal end through which solubilized drug can be released. Brief Description of the Drawings

FIGS. 1A and IB are schematic illustrations of embodiments of implantable drug delivery devices having a reservoir potion and a tissue interfacing portion for intracranial drug delivery.

FIG. 2 is an exploded view of a schematic illustration of an embodiment of an implantable drug delivery device having a reservoir potion and a tissue interfacing potion for intracranial drug delivery.

FIGS. 3A-3D are schematic illustrations of the distal end of the tissue interfacing portion of the implantable drug delivery devices according to different embodiments. FIG. 3C also includes a cross-sectional view of the distal end of the tissue interfacing portion and a magnified view of the surface of the tissue interfacing portion according to an embodiment. FIG. 3D includes a schematic illustration and cross-sectional view of the distal end of a tissue interfacing portion having an expandable balloon at the distal tip before injection of a drug formulation and a schematic illustration of the distal end of the tissue interfacing potion after injection of the drug formulation according to an embodiment.

FIG. 4 is a perspective view of an embodiment of an implantable drug delivery device.

FIG. 5 is a flowchart of a method for treatment of a patient in need of treatment or prophylaxis for cerebral edema according to an embodiment.

FIGS. 6A and 6B are cross-sectional views of a drug delivery device at least partially implanted in a tumor bed (6A) or the ventricle (6B) according to embodiments.

FIG. 7 is an illustration of a perspective view of an embodiment of an implantable drug delivery device used in the examples and a photograph showing the relative size of the device.

FIG. 8 is a graph comparing the in vitro release profiles of dexamethasone sodium phosphate in phosphate buffered saline (IxPBS) or artificial cerebral spinal fluid (a-CSF) from the implantable drug delivery device illustrated in FIG. 7.

FIG. 9 is a graph comparing the in vitro release profiles of dexamethasone sodium phosphate (DSP) in phosphate buffered saline (IxPBS) and artificial cerebral spinal fluid (a- CSF) of FIG. 8 to the amount of DSP remaining in implantable drug delivery devices after being implanted intracranially in normal mice.

FIG. 10 is a graph illustrating the in vitro release profile of dexamethasone sodium phosphate in a-CSF from silicone tubing. FIG. 11 is a graph showing MRI volumetric analysis was performed to determine the edema to tumor ratio in a mouse model comparing corticosteroids treated, untreated and sham procedures, suggesting that local delivery of corticosteroids can reduce brain tumor associated edema. Detailed Description

Drug delivery systems and methods have been developed to address the above- described needs by providing a means for the localized delivery of drug to the brain. In one particular embodiment, the system includes an implantable medical device designed for local release of one or more drugs to a local treatment site within the body of patient, particularly in the patient's brain. In a particular embodiment, the drug is effective for treating cerebral edema, such as cerebral edema associated with a tumor.

Embodiments of the devices desirably are implantable devices with a self-contained drug payload that is deployed at least partially or wholly within the brain or cerebrospinal fluid to provide local, sustained delivery of at least one drug formulation locally to the brain or surrounding fluid. Following deployment of the device, at least a portion of the payload may be released from the device over an extended period in a predefined manner to the brain and or nearby tissues or surrounding fluids. For example, embodiments of the devices permit substantially continuous release of a relatively lower level of drug (as compared to levels of drug required for systemic drug delivery) directly to the targeted site over an extended period. In a preferred embodiment, the device is configured to release the drug formulation over a predetermined period, such as 1 to 30 days, 1 to 4 weeks, 1 to 3 months, 3 to 12 months, or more.

Thus, the systems and methods provided herein advantageously provide a means for delivering therapeutically effective amounts of drug locally to a patient's brain, particularly in the treatment of cerebral edema, while preventing the undesirable side effects often associated with systemic delivery of drugs such as steroids. That is, the local treatment achieved by the implantable drug delivery devices embodied herein can reduce or even eliminate unwanted side effects of therapeutic agents, while delivering therapeutically effective concentrations of the drugs locally to the tissues where it is needed.

I. Implantable Drug Delivery Device

Embodiments of drug delivery devices provided herein generally comprise a reservoir portion and a tissue interfacing portion configured for intracranial drug delivery. The reservoir portion of the device desirably comprises a housing defining the reservoir and has drug formulation disposed in the reservoir. The housing also may be referred to herein as the "device body" or the "wall." The housing houses (e.g., contains) the drug formulation and may be sized and shaped for implantation wholly or partially within the cranial cavity or subcutaneously (e.g., positioned between the scalp and skull). Thus, the device desirably is relatively small in size.

An exemplary embodiment of such a drug delivery device is illustrated in FIGS. 1 A- B. Generally described, the device 10 includes an implantable housing 12 defining at least one reservoir 14, a solid drug formulation 11 disposed in the at least one reservoir 14, and a tissue interfacing member 18 operably connected at its proximal end to the at least one reservoir 14 via a lumenal connector 16. The tissue interfacing member 18 may be a catheter designed for controlling the release of the drug formulation from the reservoir to the target intracranial delivery site. The tissue interfacing member 18 of the device 10 may, for example, be in the form of a catheter having a proximal end attached to the housing 12 and an opposed distal end. As shown in FIG. IB, the solid drug formulation may also be loaded into a lumen in the tissue interfacing member. The housing 12 may comprise one or more apertures or valve means, such as septum (not shown) configured to receive a liquid vehicle to solubilize the solid drug formulation 11 when the device 10 is implanted in a patient.

The length of the tissue interfacing member 18 can vary depending on the target local tissue or the approach taken during surgery. For example, in some embodiments, the tissue interfacing member 18 is cut to a desired length and is sutured to the reservoir 12 to form a assembled device for drug delivery. Unlike a conventional Ommaya reservoir, however, the tissue interfacing member 18 may not have holes or openings on its distal tip.

FIG. 2 shows another embodiment of the drug delivery device 20. Device 20 includes a housing composed of two parts: a cap portion 22 which mates with a base portion 24. A solid form of a drug 21, e.g., a disk of compacted dry powder form of the drug, is loaded into the housing. A tissue interfacing member 28 which may, for example, be in the form of a catheter having a proximal end attachable to the housing's lumenal connector 26 and an opposed distal end, which has apertures 29.

In certain embodiments, release of the drug is controlled by the tissue interfacing member. For example, the solubilized drug may be released through all or a portion of the tissue interfacing portion. The drug may diffuse through apertures or thin regions provided at selected areas of the catheter wall. These selected areas may be provided at the distal end portion of the catheter, for example, as illustrated in FIG. 3. Several alternative embodiments of the distal tip of the tissue interfacing member 38 are show in FIG. 3. As shown in FIG. 3A, the distal end of the tissue interfacing member may be closed and the wall of the catheter may be relatively continuous or unperforated.

In FIG. 3B, a plurality of apertures 39 are provided a sidewall of the distal tip portion of the tissue interfacing member 38. Other location for the apertures on the catheter are also envisioned. For example, the catheter may have one or more holes apertures at its proximal end portion to provide a passageway for a physiological fluid (e.g., cerebrospinal fluid) to flow into the catheter and/or into reservoir housing to solubilize a solid drug formulation disposed therein. The same apertures also may provide a passageway for controllably releasing the solubilized drug into the brain.

In FIG. 3C, a plurality of dimples 32 are provided at the distal tip portion of the tissue interfacing member 38. The decreased wall thickness at the dimples 32 permits the drug to diffuse through the distal tip of the tissue interfacing member 18 to the target tissue in the local vicinity of the dimples. Thus, the entire length of the tissue interfacing member 18 may not be needed to achieve the desired dose rate in certain embodiments, since a higher rate can be achieved through the dimpled areas. This design may be an effective compromise, providing a relatively thicker sidewall throughout most of the length of the catheter to provide the necessary mechanical stability of the catheter (e.g., for lumen patency) and a relatively thinner areas arrayed about the distal end portion to provide the needed rates of drug diffusion.

In FIG. 3D, a balloon 34 is provided at the distal tip portion of the tissue interfacing member 38. In operation, upon deployment of the tissue interfacing member into the brain, a drug-containing fluid 31 fills the balloon 34, stretching the balloon 34 and producing a thinner region of the wall through which the drug diffuses across to reach the target site. The unstretched balloon 34 may have a folded structure to decrease the strain induced by drug infusion, thus reducing the possibility of an initial burst of drug due to a burst balloon. The fluid may be injected into the balloon 34 through the tissue interfacing member 38 via a drug reservoir (not shown) connected to the proximal end of the tissue interfacing member 38.

The device may deliver drug directly through a wall of the device, such as via diffusion or using any other suitable drug release mechanism. The drug may diffuse through all or any portion of the device, depending on its configuration. In particular embodiments, the device may deliver drug through a particular portion of the tissue interfacing member for targeted drug delivery to a particular location in the brain. For example, the distal tip of the tissue interfacing member may be configured for delivering drug directly through its wall into the brain. Desirably, the tissue interfacing member may be made from a material that is permeable to the drug so that the drug can diffuse therethrough. For example, silicone has been shown to be permeable to dexamethasone sodium phosphate. Drug may be released throughout the entire length of the tissue interfacing member, or a selected (designed) portion thereof.

In particular, the device may provide extended, continuous, intermittent, or periodic release of a selected quantity of a drug over a period of time that is therapeutically or prophylactically desirable. In one embodiment, the device can deliver the desired dose of drug over an extended period, such as 1 day, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90 days, or more. In one embodiment for treatment of cerebral edema, the drug is dexamethasone, the total payload of the drug loaded in the delivery device weighs from 40 to 60 mg (e.g., about 55 mg), and the device is designed to release the payload over a period of about 30 days. The rate of delivery and dosage of the drug can be selected depending upon the drug being delivered and the disease or condition being treated. The release kinetics of the device can be tailored by varying the number and size of apertures in the device, varying the composition of the drug formulation therein, among other device and drug parameters.

The drug formulation may fill the reservoir, the tissue interfacing member, or both. In certain embodiments, the device is substantially filled with a solid form of the drug. Such configurations may maximize the drug payload on board the device, reducing the size of the device needed to deliver a therapeutically effective dose of the drug over an extended period. For example, the drug formulation desirably is a substantial fraction of the total volume of the entire device at the time of implantation. For example, the drug formulation portion may be more than 50%, more than 75%, more than 90%, e.g., between 75% and 95% inclusive, of the total volume of the drug-loaded device.

The drug delivery device may be sized and shaped for implantation wholly or partially within the cranial cavity. In some embodiments the portion of the device implanted within the cranial cavity may have dimensions that do not exceed 3 mm in width (for example, the diameter of the tissue interfacing member). Because the device is small, the device may permit delivering drug to the brain without further disrupting brain function or further crowding the cranial cavity. The device also may be able to pass through an internal bore of a cannula or needle inserted into the cranial cavity. For pediatric patients, the device may be smaller in size. For example, the device may be proportionally smaller based on differences such as the anatomical difference in size between pediatric and adult patients, the drug dosage difference between pediatric and adult patients, or a combination thereof. The device may be implanted directly in tissue, such as in brain tissue or in a tumor. In other embodiments, the at least a portion of device may be implanted in a fluid-filled space, such as in the cerebrospinal fluid. In such embodiments, at least a portion of the device that is implanted in a fluid-spilled space may have a density that is less than the density of the fluid in which it is implanted, so that the portion of the device implanted in the fluid-spilled space may float. Such floatation, although not required, may facilitate continuous release of the drug into the fluid. For example, the device may be formed from relatively low density materials of construction, or air or other gas may be entrapped in the device. The outer surface of the device, furthermore, may be soft and smooth without sharp edges or tips.

The exact configuration and shape of the device may be selected depending upon a variety of factors including the location, route, and method of implantation, the composition and dosage of the drug formulation, the therapeutic application of the device, or a

combination thereof. The device may be designed to reduce pain and discomfort to the patient, while locally delivering a therapeutically effective dose of the drug to an implantation site, such as the brain.

Another embodiment of a drug delivery device 100 is illustrated in FIG. 4. As shown, the device 100 includes a reservoir portion having a housing 102 that defines a reservoir 104 and a drug formulation 106 positioned within the reservoir 104. The housing 102 is formed from a container 110 and includes at least one side wall 114 and an end face 116. The container 110 is enclosed in a lateral direction by the side wall 114. In a longitudinal direction, the container 110 is enclosed on one end by the end face 116 and is open on the other end to form an opened end 118. Together, the side wall 114 and the end face 116 define the boundary of a hollow interior in the container 110, which forms a reservoir 104. The tissue interfacing member of the device 100 comprises an end cap 112 that is designed to control the release of the drug formulation from the reservoir at a controlled rate. The end cap 112 is configured to mate with the opened end 118 of the container 110 to enclose the hollow reservoir 104. In particular, the end cap 112 has an inner portion 120 that seats within the opened end 118 of the container 110, and a flange 122 that extends over an exposed edge 124 of the side wall 114 at the opened end 118. The end cap 112 is secured to the container 110, such as by forming a snap fitting with the side wall 110, by being secured to the side wall 110 with a medical grade adhesive, or in other manners or combinations thereof. In a particular embodiment, the device 100 releases the drug in vivo at least partially via diffusion from the reservoir through one or more apertures 108 formed through the end cap 112. In some embodiments, the device 100 releases the drug primarily or exclusively via diffusion from the reservoir through one or more apertures. The delivery rate may be affected by the shape, size, number and placement of the apertures. Other factors also may affect the delivery rate, such as the dissolution profile of the drug formulation. In alternative embodiments, release of the drug from the device may involve other mechanisms, such as osmotic pressure or surface erosion. In still other embodiments, the device may operate by a combination of release mechanisms.

Although the housing may have any shape, the illustrated housings 12, 102 are dome- shaped and tubular shaped. The housing 12, 102 may be substantially linear and may have a substantially circular cross-section, or the cross-section may have other shapes. For example, the cross-section may be a square, a triangle, a hexagon, or another polygon, among other shapes. The length, width/diameter, and thickness of the housing may be selected based on the intended site of implantation for the device within the body, the desired mechanical integrity for the device, the desired method or route of insertion into the body, the amount of drug formulation to be contained within the housing, the desired rate of delivery of the drug from the housing, and the desired permeability to water, among others. In the illustrated embodiment in which the device is designed to be implanted wholly in the brain, the housing 102 has a length, an inner diameter, and an outer diameter that are suitable for such implantation.

In some embodiments, the housing defines multiple reservoirs, which facilitates releasing two or more separate drug formulations from a single device, releasing drugs at two or more different release rates, releasing drugs at two or more different times following implantation, or combinations thereof. For example, a first dose of the drug may be preprogrammed to release at a first time and a second dose of the drug may be pre-programmed to release at a second, later time. The term "pre-programming" herein generally refers to designing and building the device to provide the selected release functionality. This different pre-programming can be achieved by using different timing membranes in different apertures for the different reservoirs. In such embodiments, any two reservoirs may be separated by least one partition. The partition may extend across the cross-section of the reservoir or along the longitudinal length of the reservoir. The partition may be formed by molding or by inserting a partition structure into the reservoir. Partitioned reservoirs may prevent an aperture with a faster biodegradable membrane from monopolizing the release of the loaded drug material, potentially leaving little or no drug material for release from apertures with subsequently degrading membranes. Providing a separate reservoir for each release aperture may increase the effect of multiple biodegradable timing membranes.

In a preferred embodiment, the total volume of the reservoir (or combined reservoirs) is sufficient to contain all the drug needed for local delivery over the course of a single therapy. That is, the reservoir desirably contains all of the doses of drug to be delivered.

The housing is made of an biocompatible polymeric material. In some embodiments, the housing includes a material that is permeable to fluid. The permeable material enables selective intake of fluid into the reservoir to solubilize the drug in the reservoir.

Alternatively, one or more apertures in the housing may be configured to enable the selective intake of fluid into the reservoir to solubilize the drug in the reservoir. As used herein, the term "solubilized drug" includes solutions of drug, fine suspensions of drug, or a combination thereof. Any portion of the housing may be permeable to a solubilizing fluid, such as the container, the end cap, or portions or combinations thereof. In various embodiments, the housing is selectively permeable to water but is substantially impermeable to drug, limiting or preventing the drug from exiting the device through the housing wall. Alternatively, the housing may be substantially water impermeable. The housing also may be formed from material that is elastomeric, which may reduce trauma to surrounding tissues upon

implantation.

In embodiments, the housing may be made from a combination of materials. In the illustrated embodiment, for example, one material may be used to form the housing of the reservoir, and another material may be used to form the tissue interfacing member. One or both of the housing and tissue interfacing member can also be formed by combinations of materials, either partially or completely. In embodiments in which the device is configured for implantation in the brain, the material may be suited for neurological applications.

The housing can include a material that is completely or partially resorbable, so that explanation or retrieval of the device is not required following release of the drug

formulation. As used herein, the term "resorbable" means that the housing, or part thereof, degrades in vivo by dissolution, enzymatic hydrolysis, erosion, or a combination thereof. The degradation may occur at a time that does not interfere with the intended kinetics of release of the drug from the housing. For example, substantial resorption of the housing may not occur until after the drug formulation is substantially or completely released. In another embodiment, the housing is resorbable and the release of the drug formulation is controlled at least in part by the degradation characteristics of the resorbable housing. In embodiments in which the housing is resorbable, the housing may include one or more biodegradable or bioerodible polymers. Examples of suitable resorbable materials include synthetic polymers selected from poly(amides), poly(esters), poly(ester amides), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo poly(amino acids), poly(glycerol-sebacate), copolymers thereof, and mixtures thereof. In a preferred

embodiment, the resorbable synthetic polymers are selected from poly(lactic acids), poly(glycolic acids), poly(lactic-co-glycolic acids), poly(caprolactones), and mixtures thereof. Other curable bioresorbable elastomers include poly(caprolactone) (PC) derivatives, amino alcohol-based poly(ester amides) (PEA) and poly (octane-diol citrate) (POC). In one particular embodiment, the housing is formed from a combination of a resorbable polyester, such as poly(lactic acid), and a liquid crystalline polymer (LCP).

Alternatively, the housing may be at least partially non-resorbable. Examples of suitable non-resorbable materials include materials such as medical grade silicone, natural latex, PTFE, ePTFE, PLGA, stainless steel, nitinol, elgiloy (non ferro magnetic metal alloy), polypropylene, polyethylene, polycarbonate, polyester, nylon, or combinations thereof.

Other examples of suitable non-resorbable materials include synthetic polymers selected from poly(ethers), poly(acrylates), poly(methacrylates), polyvinyl pyrolidones), poly(vinyl acetates), poly(urethanes), celluloses, cellulose acetates, poly(siloxanes), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, poly(siloxanes), copolymers thereof, and combinations thereof. Combinations of any of these materials, or these and other materials, may also be employed.

In one embodiment, the material forming the device body may comprise an

"antimicrobial" material, such as a polymer material impregnated with silver or another antimicrobial agent known in the art. In a preferred embodiment, the housing includes at least one radio-opaque portion or structure to facilitate detection or viewing of the device by a medical practitioner, when the device is deployed in vivo and/or as part of the implantation or retrieval procedure. In one embodiment, the housing is constructed of a material that includes a radio-opaque filler material, such as barium sulfate or another radio-opaque material known in the art. Fluoroscopy may be the preferred method of viewing the device during deployment/retrieval of the device, providing accurate real-time imaging of the position and orientation of the device to the practitioner performing the procedure. Other imaging techniques known in the art also may be used.

In one embodiment, the housing further includes at least one retrieval feature. The retrieval feature may be a structure that facilitates removal of the device, for example for removal of a non-resorbable device body following release of the drug formulation. The retrieval feature may, for example, be in the form of a loop on the end of the device, a pair of opposed flattened surface areas or notches that facilitates grasping of the device with forceps or another instrument.

The housing and/or the tissue interfacing member generally include means for receiving a liquid vehicle to effect solubilization of the drug. This means may be in the form of a drug reservoir aperture or valve (e.g., a septum) or other orifice in the housing. For example, in the illustrated embodiment of FIG. 1, a valve or septum can be provided in the cap or dome of the housing, so that a fluid can be injected (e.g., through the scalp) into the reservoir. Alternatively or in addition, the housing base may include an aperture for imbibing CSF or other physiological fluids. In another embodiment, CSF or another liquid vehicle may diffuse into the device, such as through the wall of, and/or through an aperture in, the tissue interfacing member.

Each aperture typically is circular in shape, although other shapes are possible. In embodiments, the shape of the aperture is selected at least in part or primarily based on manufacturing considerations.

The number of apertures and the size of each aperture may be selected to provide a controlled rate of release of the drug. In embodiments in which the device is intended to operate primarily or exclusively via diffusion, the number and size of the apertures may be selected such that the total aperture size is large enough to reduce or avoid the development of osmotic pressure within the reservoir. In embodiments in which the housing is permeable to water, the total aperture size may also be selected to prevent excessive buildup of hydrostatic pressure within the housing, which may increase the volume of fluid in the reservoir causing the housing to swell. For example, an increase in hydrostatic pressure within the reservoir may be prevented by ensuring the size of the aperture is large enough and/or by spacing a number of apertures about the housing as appropriate. Within these constraints on aperture size and number, the size and number of apertures for a given device or reservoir may be varied in order to achieve a selected rate of release.

In some embodiments, a single device may have apertures of two or more different sizes. The device may also include apertures located in two or more discrete positions. The two or more apertures may be in fluid communication with a single reservoir or with different reservoirs. For example, the housing may be subdivided along its length into two reservoirs, each of which is in fluid communication with an aperture formed through one of the ends of the device. Such reservoirs may be created by placing a partition, such as a partition wall or a partition bead, at a discrete position along the length of the housing. As another example, the housing may be subdivided along its cross-section into any number of reservoirs, each of which is in fluid communication with an aperture formed through a side or an end of the device. Such reservoirs may be created by, for example, molding the housing with partition walls extending along the length of the housing.

In embodiments, a degradable membrane is disposed over or in one or more the apertures (e.g., in register with the aperture) to control the initiation of release of the drug formulation from the aperture. In one embodiment, the degradable membrane is in the form of a uniform coating covering the outer surface of the housing. In another embodiment, a discrete degradable membrane may be provided substantially within, i.e., blocking, the aperture. Combinations of two or more degradable membranes may be used to control release from one aperture. The membranes may be formed, for example, of a resorbable synthetic polymer, such as polyester, a poly(anhydride), or a polycaprolactone), or a resorbable biological material, such as cholesterol, other lipids and fats).

The Drug Formulation

The drug can include essentially any therapeutic, prophylactic, or diagnostic agent that would be useful to deliver locally to, for example, the brain. As used herein, the term "drug" with reference to any specific drug described herein includes its alternative forms, such as salt forms, free acid forms, free base forms, and hydrates. In embodiments, the drug in the drug formulation may be a prodrug. In various embodiments, the drug formulation may be in a solid form, semi-solid form (e.g., an emulsion, a suspension, a gel or a paste), or liquid form.

In certain embodiments, the drug is water soluble. As used herein, the term "water soluble" refers to a drug that is more than sparingly soluble. For example, the water soluble drug may have a solubility equal to or greater than about 10 mg/mL water at 37 °C.

In a preferred embodiment, the drug delivery device is used to treat edema, swelling, or inflammation in the brain, including swelling associated with a brain tumor or brain cancer. In such embodiments, the drug formulation preferably includes at least one steroid. In some such embodiments, the steroid is a corticosteroid. In particular embodiments, the corticosteroid may be a glucocorticoid. Representative examples of glucocorticoids include methylprednisolone and dexamethasone. In one particular embodiment, the drug formulation includes methylprednisolone succinate salt. However, a variety of steroids, or combinations thereof, may be used. In a preferred embodiment, the corticosteroid is provided in a solid formulation in the implantable drug delivery device. In various embodiments, the drug formulation may include at least one excipient. Pharmaceutically acceptable excipients are known in the art and may include lubricants, viscosity modifiers, surface active agents, osmotic agents, diluents, and other non-active ingredients of the formulation intended to facilitate handling, stability, dispersibility, wettability, and/or release kinetics of the drug. In a preferred embodiment, however, the excipient is not a matrix material used to modulate or control the rate of release of the drug from the reservoir.

In various embodiments, the drug formulation is in a substantially solid form, such as in the form of a drug rod, a drug tablet, a drug pellet, a number of rods, tablets, or pellets, a compact powder (for example in a disk shape) or a combination thereof, although other configurations are possible. In a preferred embodiment, the drug formulation is in a solid form in order to reduce the overall volume of the drug formulation and thereby reduce the size of the device, which is especially advantageous for devices that are implanted in tight spaces like the cranial cavity. Desirably, in embodiments the drug formulation includes a reduced quantity of excipients, substantially no excipients, or no excipients.

In other embodiments, the drug delivery device is used to treat a tumor directly. In such embodiments, the drug formulation includes a drug that is used to treat cancerous tumors, such as an antiproliferative agent, a cytotoxic agent, a chemotherapeutic agent, or a combination thereof. The drug formulation may also include a biologic, such as a monoclonal antibody, a TNF inhibitor, an anti-leukin, or the like. The drug treatment may be coupled with a conventional radiation or surgical therapy targeted to the cancerous tissue.

In still another embodiment, the drug delivery device may be used to treat infections involving the brain. In such embodiments, the drug formulation may include an antibiotic, antibacterial, antifungal, antiprotozoal, antiviral and other antiinfective agent, which can be administered for treatment of such infections. Representative examples of drugs for the treatment of infections include mitomycin, ciprofloxacin, norfloxacin, ofloxacin,

methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, sulfonamides trimethoprimsulfamethoxazole, erythromycin, doxycycline, metronidazole, tetracycline, kanamycin, penicillins, cephalosporins, and aminoglycosides.

In yet other embodiments, the drug delivery device is used for other purposes, such as to manage pain. Other drugs and excipients may be used for other therapies and at sites other than the brain. Combinations of two or more drugs are also envisioned. In such cases, the different drugs may be stored in and released from the same or separate compartments. The drug formulation may provide a temporally modulated release profile or a more continuous or consistent release profile. Pulsatile release can be achieved from a plurality of reservoirs. For example, different degradable membrane can be used to by temporally stagger the release from each of several reservoirs.

Π. Applications and Use

In another aspect, a method of treating a patient with a drug delivery device is provided. As used herein, the term "patient" may include a human or other mammal. The drug delivery device may be implanted in the patient to release drug locally to essentially any implantation site in the patient and may be particularly useful for delivering drugs that cause undesirable side effects or result in insufficient bioavailability when delivered systemically. In a preferred embodiment, the implantation site is the brain of a male or female human patient in need of treatment or prophylaxis, whether adult or a child.

FIG. 5 is a block diagram illustrating an embodiment of a method 200 of reducing swelling or inflammation within the cranial cavity of a patient. Generally described, the method comprises implanting a drug delivery device at least partially within a cranial cavity of a patient and thereafter releasing the drug from the drug delivery device into the cranial cavity. In some embodiments, the method is implemented with reference to a patient that presents with cerebral edema, swelling in the brain, or inflammation in the brain. These conditions may be attributed to the presence of a tumor in the brain, brain surgery, radiation therapy, or chemotherapy, or trauma to the brain or head area in general, among other conditions.

The step of implantation of the drug delivery device 202 may comprises a minimally invasive procedure or an open surgical procedure. The implantation may be guided using imaging and positioning techniques and navigation systems known in the art.

In one embodiment in which the drug delivery device is preloaded with drug and preassembled (such as with the embodiment of FIG. 4), the implantation may include loading the drug delivery device into a delivery instrument and thereafter deploying the drug delivery device from the delivery instrument into an implantation site at least partially within the cranial cavity into the brain tissue, a brain tumor, or the cerebrospinal fluid of a patient's brain. The delivery instrument may include a large bore needle, a cannula, or a catheter, having suitably sized internal bore. In some embodiments, injection of the device to the target tissue site is guided using imaging and positioning systems and techniques known in the art. The drug delivery device also can be implanted in association with various procedures. In some embodiments, the drug delivery device is implanted in block 202 in a non-surgical procedure, which may be performed primarily or exclusively for the purpose of implanting the drug delivery device, or for other purposes, such as a diagnostic purposes. For example, the drug delivery device may be implanted in association with a procedure that entails injecting a diagnostic or contrast agent into or about the brain of the patient, such as for the purpose of taking an MRI. In other embodiments, the drug delivery device is implanted in block 202 during a surgical procedure, such as a brain tumor de-bulking procedure.

The drug delivery device can be implanted in various locations such that it is at least partially disposed within the cranial cavity. In certain embodiments, a portion of the device is implanted subcutaneously (e.g., the reservoir portion) while the remainder of the device is implanted in the cranial cavity (e.g., the tissue interfacing portion). For example, when the drug delivery device is in one of the forms illustrated in FIGS. 1-3, the implantation 202 may include deploying the distal end of the tissue interfacing member (e.g., the catheter or tubular conduit member) to a particular intracranial site, depending on the indication. For example, as shown in FIG. 6, the site may be a tumor bed (Fig. 6a) or a ventrical (Fig. 6b). In other embodiments, the device may be wholly deployed intracranially. For example, when the drug delivery device is the form illustrated in FIG. 4, the implantation 202 may include implanting the drug delivery device in or adjacent a brain tumor of the patient. In other embodiments, embedding the drug delivery device in brain tissue located in the brain of the patient, or suspending the drug delivery device in cerebrospinal fluid about the brain of the patient. Implanting the drug delivery device in block 202 may include implanting the drug delivery device in combinations of these and other locations.

In embodiments in which the patient has a brain tumor, the implantation site will depend at least in part on the site of the tumor. For example, if a tumor is situated deep within healthy brain tissue, or in other words, is deemed inoperable, then an intraventricular site may be preferred. If the tumor site were near the cerebral cortex (i.e. outer surfaces of the brain), then an intracranial site may be more appropriate. In certain embodiments of intracranial implantation, an intracranial device will be implanted after a tumor is resected, such that the implant can be at least partially implanted within the resected space.

Once the device is implanted, the drug formulation is released from the drug delivery device into the cranial cavity in block 204. In embodiments, the drug may be released for an extended time period. For example, the drug may be released over a period of about one day to about six months. In some embodiments, the drug may be released at a relatively continuous rate.

In embodiments in which the drug delivery device houses a drug in solid form, releasing the drug in block 204 further includes solubilizing the drug. For example, the drug may be solubilized with a physiological fluid passing into the housing from the implantation environment. The physiological fluid may pass through an aperture in the drug delivery device. The fluid may also pass through the housing of the drug delivery device, which may be permeable to fluid. Alternatively, an aqueous fluid may be injected into the reservoir to solubilize the drug. In other embodiments, the drug is stored in the device in semi-solid, gel, slurry, or liquid form, in which case the drug may or may not need to be solubilized prior to release.

In particular, the drug may be released in block 204 from the tissue interfacing portion of the drug delivery device. Release of the drug may be driven at least in part by diffusion. In some embodiments, the release may be driven primarily or exclusively by diffusion. In other embodiments, the release may be driven by diffusion in combination with another release mechanism, in whole or in part. For example, in certain embodiments the release rate may be determined at least in part based on the size of one or more apertures. In some cases, the release rate may be determined primarily or exclusively by the size of the aperture or apertures. In still other cases, the release rate may be further influenced by the location of the aperture, the shape of the apertures, other characteristics of the aperture or device in general, or combinations thereof. In other embodiments, the release of the drug may be driven by the permeability of the catheter wall or reservoir housing.

In block 204, the drug is released into the implantation site and surrounding areas. For example, the drug may be released into one or more of the following: brain tissue, a brain tumor, and cerebrospinal fluid.

In some embodiments, in which the reservoir may be positioned between the scalp and the skull, the reservoir position may enable it to be refilled with drug, such as drug solution, slurry, or colloid suspension, via injection. Thus, in certain embodiments the method of treating a patient may further comprise refilling the device with a drug

formulation. For example, the device may be refilled with a drug in slurry or liquid form once the original drug payload has been at least partially released. The refilled drug may be injected into the reservoir and may flow through the catheter and out of its wall into the body. In certain embodiments, the device may be implanted and refilled much like a conventional Ommaya reservoir. Thus, a medical professional who is implanting the device advantageously may not need to learn entirely new deployment techniques and procedures.

In some embodiments, the drug delivery device is resorbable. In particular, the housing may be resorbable material, such as a resorbable polyester and a liquid crystalline polymer. In such embodiments, the device may degrade by surface erosion into

biocompatible monomers. The device may begin degrading upon implantation and may degrade while the drug is released. After the drug is released, the device may continue degrading to the point of loss of mechanical integrity. For example, the device may degrade over a suitable time period. Thus, the method 200 may further include permitting any remaining portions of the device, such as the housing, to degrade in vivo, which may avoid the need for removing or retrieving the device after the drug has been released.

In other embodiments, the drug delivery device is non-resorbable. In such

embodiments, the device may be removed following implantation. In one such a case, the method 200 further includes removing the drug delivery device following release of the drug. In still other embodiments, the device may not be removed even though the device is not resorbable.

ΠΙ. Methods of Manufacture

In another aspect, a method of making an implantable drug delivery device is provided. Generally, the method includes forming a drug formulation, forming a housing, and loading the drug formulation into the housing.

In embodiments, forming a drug formulation entails forming a drug formulation that includes one or more steroids, and optionally, one or more excipients. The one or more steroids may include a corticosteroid, and particularly may include a glucocorticoid, such as methylprednisolone or dexamethasone. In one particular embodiment, the drug formulation includes methylprednisolone succinate salt and at least one excipient. In some embodiments, the drug formulation includes a limited amount of excipient or is substantially free of excipient, so that a relatively higher percentage of the volume of the drug formulation is steroid, permitting the delivery of a relatively larger amount of steroid with a relatively smaller volume of drug formulation. Also in embodiments, forming the drug formulation may include forming a solid drug formulation, as a solid drug formulation may require relatively less space in the housing, permitting the delivery of a relatively larger amount of drug formulation from a reservoir of a given size. Methods of forming solid drug

formulations generally are known in the art, and include granulating the drug formulation to produce a high concentration drug formulation with specific physicochemical properties (e.g., solubility, dissolution rate, etc.) and, thereafter, compacting the drug formulation using a tablet press. Desirably, the compacted solid drug formulation has dimensions and a shape that are substantially similar to that of the reservoir so that it may be easily encapsulated in the reservoir.

In one embodiment, forming a housing includes forming a reservoir housing and a tissue interfacing member. The housing and the tissue interfacing member may be formed using a variety of methods, such as injection molding, compression molding, extrusion molding, transfer molding, insert molding, thermoforming, casting, or a combination thereof. In one particular embodiment, the housing is formed using precision injection molding. The housing is formed with a hollow interior, defining a reservoir for holding the drug

formulation. The tissue interfacing member is formed to mate with an open end of the housing.

Forming a housing also may include forming one or more apertures through the housing. In particular embodiments, the aperture is formed through the housing and/or through a wall of the tissue interfacing member, such as by mechanically punching, mechanical drilling, or laser drilling one or more holes, or such as by injection molding, forming, or casting the housing or tubular body with a hole formed therein. Forming an aperture generally includes sizing and positioning the aperture to achieve a selected release rate for the drug formulation once the device is implanted. In embodiments, the step of forming the housing may also include forming multiple different drug reservoirs in a single housing, such as by forming one or more partitioning structures in the housing or by inserting one or more partition structures into the housing once formed.

In an embodiment, loading the housing with the drug formulation includes placing the drug formulation in the reservoir in the housing and sealing the housing to contain the drug formulation therein. In embodiments in which the drug formulation is a solid drug formulation, loading the housing may include placing one or more drug rods, pellets, or tablets in the housing. Alternatively, the drug formulation may be in a fluidized form (e.g., melted, in solution with a solvent liquid, or in suspension with a non-solvent liquid) for reservoir loading and then subsequently solidified (e.g., by cooling or volatilization of the liquid). Loading the housing may include substantially filling the reservoir with the drug formulation, maximizing the amount of drug that can be delivered from a device of a given size. Sealing the housing may include placing the tissue interfacing member onto the housing, such as by fitting the tissue interfacing member into/onto an open end of the housing. In some embodiments, the tissue interfacing member may be further sealed to the housing, such as with a medical-grade adhesive. Loading the housing may also include associating one or more release controlling structures with the housing, such as a sheath or coating placed over at least a portion of the housing to modulate the passage of water into the housing, or a degradable membrane positioned over or in one or more of the apertures to control the initial time of release of the drug there through.

In embodiments, the device is assembled using sterile techniques, for example, assembly in a clean room environment and sterilization using ethylene oxide gas, irradiation, or high intensity pulsed light. The sterilization technique will depend upon the sensitivity of the components used, such as the tendency for polymers and drugs to degrade after exposure to radiation. The device then may be vacuum-sealed in a polymeric package prior to distribution to reduce the amount of moisture or air that could potentially cause any one of the components to become contaminated or prematurely decompose during its shelf life.

The present invention may be further understood with reference to the following non- limiting examples.

Example 1: In vitro release of TMZ from reservoir device

Mini reservoir devices were injection molded from polylactic acid and a liquid crystalline polymer. The devices were substantially shaped as shown in FIG. 4 with an outer diameter of about 3 mm, an inner diameter of about 2.5 mm, and a height of about 3 mm (the relative size of the device is shown in the photograph on the left side of FIG. 7). Ten milligrams of temozolomide (TMZ) was loaded inside each of the devices and then the caps were sealed with a UV-cured epoxy. The caps were laser drilled to obtain an orifice having a diameter of about 890 microns.

The TMZ-loaded devices were then placed in water and the TMZ release was measured periodically over 80+ hours. The measured release agreed well with the predicted release. The predicted release was calculated from the measured solubility of TMZ in water (8 mg mL) and the assumption that the solution inside the reservoir was saturated with drug and that the rate limiting diffusion step is simply diffusion through the orifice. TMZ is a prodrug, with a measured half-life of 40 hours in water. The measured release showed 70% of the payload being delivered as TMZ over 80 hours.

Example 2: In vitro release of DSP from reservoir device

Mini reservoir devices were injection molded from an opaque liquid crystalline polymer. The devices were substantially shaped as shown in FIG. 4 with an outer diameter of about 2 mm, an inner diameter of about 1.5 mm, and a height of about 3 mm. Dexamethasone sodium phosphate (DSP) was loaded inside each of the devices and then the caps, each having an orifice of about 100 microns, were joined to the reservoir by

biocompatible medical epoxy or welding.

The DSP-loaded devices were then placed in artificial cerebral spinal fluid (a-CSF) or lxPBS at 37°C for about a week and the first order release profiles were compared in FIG. 8.

Example 3: In vivo release of DSP from reservoir device

DSP-loaded mini reservoir devices as described in Example 2 were implanted intracranially in normal mice and retrieved after 7 days. There was no brain damage inflicted by the surgery or the devices.

The amount of drug remaining in the devices was quantified and compared to the first order in vitro release profiles (FIG. 9). Results suggested that in vivo release may be comparable to in vitro release in a-CSF.

Example 4: In vitro release of DSP from silicone tubing

Silicone tubing was filled with a saturated solution of DSP and submerged in a-CSF at 37°C for about 10 days to characterize the release profile of the DSP (shown in FIG. 10). The graph illustrates the cumulative release of DSP from the inside of the silicone tube to the a-CSF over a period of about 213 hours (approximately 9 days). The average release for 10 days was calculated to be 0.00267 mg h-1.

The drug release increased at a decreasing rate, suggesting that it exhibits first order kinetics. Its decreasing rate can be explained by the fact that the drug concentration inside the silicone tube decreases with drug release, thereby decreasing the driving force for diffusion.

The gathered permeability data was then used to determine whether the preliminary device design was feasible. Approximate calculations of DSP's permeability were performed based on the desired local drug delivery rate (76.7 μg/l hour) needed to provide a desired therapeutic effect. This was assumed to be a constant hourly rate, as opposed to the variable dosage regimen used in clinical practice. Assuming the rate-limiting step is permeation to the surrounding CSF or tissue (i.e., convective fluid flow is unaccounted for) and steady-state diffusion, Fick's First Law could be used to first calculate the permeability of DSP through silicone. Using the calculated value of D and the required local drug delivery rate, the length, inner diameter and outer diameter of the device were calculated. It was found that if the thickness, inner and outer diameter were similar to the silicone tube used in the experiment, then its length would need to be greater than 6 cm. However, because the device is expected to be implanted in the lateral ventricle or directly in the brain tissue, its dimensions must be constrained to the space available at that site. Not wishing to be bound by any theory, a preliminary study suggested that the optimal length of a ventricular catheter should extend no deeper than 6 cm, which is the distance between the scalp and the occipital horn of the lateral ventricle. In order to reduce the length of the silicone tube required, the flux of the drug that crosses the silicone membrane could be increased, which may be achieved for example by reducing the thickness of the silicone tube in some or all areas of the tube wall where drug diffusion is desired.

Example 5: In vivo release of GBM mouse model

A Charest transgenic GBM mouse model was used to evaluate the responsiveness of cerebral edema to localized delivery of dexamethasone sodium phosphate. The tumor was initiated with a drug, the device was implanted, and the mice were sacrificed after 7 days of treatment. The mini reservoir devices were described in Example 2. The in vivo release profile was estimated to be similar to that as in in vitro release. Tumors in mice were monitiored by bioluminescence imaging. Twenty-one (21) days after tumor induction, the tumor bearing mice were implanted with either drug-filled or sham devices for a week and imaged at the end of the study. MRI volumetric analysis was performed to determine the edema to tumor ratio. The extent of edema to tumor burden was found to be less in mice treated with DSP-loaded devices compared to mice implanted with the sham devices. DSP was not detected in the plasma samples of the treated animals, thereby indicating limited systemic drug exposure. These results suggest that local delivery of corticosteroids can reduce brain tumor associated edema and avoid the systemic side effects.

As illustrated in FIG. 11, local delivery of steroids to the brain markedly reduced cerebral edema.

Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.

Claims

We claim:
1. A method of treatment of cerebral edema comprising:
implanting within a cranial cavity of a patient in need treatment or prophylaxis of cerebral edema a drug delivery device for the local controlled release of at least one drug for treating cerebral edema, wherein the drug delivery device comprises a housing which defines at least one reservoir in which the at least one drug is stored; and
releasing an effective amount of the at least one drug from the reservoir into the cranial cavity at a controlled rate.
2. The method of claim 1, wherein the at least one drug is provided in the reservoir in a solid drug formulation.
3. The method of claim 2, wherein the solid drug formulation is substantially free of excipients.
4. The method of claim 2, wherein the at least one drug is a water-soluble drug.
5. The method of any one of claims 1 to 4, wherein the at least one drug is a steroid.
6. The method of any one of claims 1 to 4, wherein the at least one drug is a
corticosteroid.
7. The method of any one of claims 1 to 4, wherein the at least one drug is
methylprednisolone, dexamethasone, analogs thereof, or a combination thereof.
8. The method of claim 1, wherein the implanting comprises injecting the drug delivery device through an internal bore of a cannula or needle inserted into the cranial cavity.
9. The method of claim 1, wherein the device is implanted directly in brain tissue, a tumor, or cerebrospinal fluid.
10. The method of claim 1, wherein the releasing of the at least one drug comprises diffusion of the at least one drug from the reservoir through at least one aperture housing.
11. The method of claim 1, wherein the releasing of the at least one drug comprises
diffusion of the at least one drug from a catheter in fluid communication with the reservoir.
12. The method of claim 1, wherein releasing an effective amount of the at least one drug into the cranial cavity at a controlled rate is extended over a period of at least one month.
13. The method of claim 2, wherein the solid drug formulation is solubilized by a
physiological fluid after at least partially implanting the device into the cranial cavity.
14. The method of claim 2, wherein the solid drug formulation is solubilized by an
aqueous fluid injected into the reservoir after at least partially implanting the device into the cranial cavity.
15. The method of claim 1, wherein the patient is a human who has been diagnosed with a head injury, stroke, or brain tumor.
16. An implantable device for local intracranial drug delivery comprising:
an implantable housing defining at least one reservoir;
a solid drug formulation which comprises a water-soluble drug and which is disposed in the at least one reservoir, the housing comprising an aperture or valve configured to receiving a liquid vehicle to solubilize the water-soluble drug when the device is implanted in a patient; and
a tissue interfacing member operably connected to the at least one reservoir for conducting the solubilized drug to an intracranial site and configured to provide controlled release of the solubilized drug to the intracranial site.
17. The device of claim 16, wherein the housing comprises an aperture configured to permit a physiological fluid in vivo to diffuse into the at least one reservoir.
18. The device of claim 20, wherein the housing comprises a septum configured to receive a hypodermic needle for injection of a liquid vehicle into the reservoir.
19. The device of claim 20, wherein the tissue interfacing member comprises a flexible catheter, which has a proximal end attached to the housing and an opposed distal end through which solubilized drug can be released.
20. The device of claim 19, wherein the distal end of the tube is closed.
21. The device of claim 20, wherein the distal end of the tube comprises a plurality of dimples, the dimpled areas having a wall thickness less than the wall thickness of non-dimpled areas of the tube.
22. The device of claim 20, wherein the distal end of the tube comprises an inflatable balloon.
23. The device of claim 16, wherein the reservoir, the tissue interfacing member, or both, are filled by the solid drug formulation.
24. The device of claim 16, wherein the housing is sized and shaped for implantation wholly within the brain.
25. The device of any one of claims 16 to 24, wherein the drug comprises a steroid.
26. The device of any one of claims 16 to 24, wherein the drug comprises a
corticosteroid.
27. The device of any one of claims 16 to 24, wherein the drug comprises a
glucocorticoid.
28. The device of claim 27, wherein the glucocorticoid comprises methylprednisolone, dexamethasone, analogs thereof, or a combination thereof.
PCT/US2011/054818 2010-10-04 2011-10-04 Device for local drug delivery and treatment of cerebral edema and other brain-related diseases WO2012047931A1 (en)

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WO2014159757A3 (en) * 2013-03-14 2015-01-29 Incube Labs, Llc Apparatus, systems and methods for delivery of medication to the brain to treat neurological condidtions
CN105377354A (en) * 2013-03-14 2016-03-02 因库博实验室有限责任公司 Apparatus, systems and methods for delivery of medication to the brain to treat neurological condidtions
JP2016515866A (en) * 2013-03-14 2016-06-02 インキューブ ラブズ, エルエルシー Device for delivery of drugs to the brain to treat neurological conditions, system and method
EP2968881A4 (en) * 2013-03-14 2016-12-14 Incube Labs Llc Apparatus, systems and methods for delivery of medication to the brain to treat neurological condidtions
AU2014244437B2 (en) * 2013-03-14 2018-11-08 Incube Labs, Llc Apparatus, systems and methods for delivery of medication to the brain to treat neurological conditions
AU2014244437B9 (en) * 2013-03-14 2019-05-02 Incube Labs, Llc Apparatus, systems and methods for delivery of medication to the brain to treat neurological conditions

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