WO2001032068A2 - Time-released substance delivery device - Google Patents

Abstract

An implantable, time-released substance delivery device (9) includes a casing (10) having an exterior surface and a number of pores (13) disposed on the exterior surface of the casing (10). The time-released substance delivery device further has an interior chamber (11) disposed within the casing and a number of excretion tubes (12) disposed within the casing (10). Each of the excretion tubes (12) fluidly connects the interior chamber (11) to one of the pores.

Description

TIME-RELEASED SUBSTANCE DELIVERY DEVICE

5 This application claims the benefit of U.S. Provisional Application No.

60/162,590, filed October 29, 1999 and entitled TIME-RELEASED SUBSTANCE

DELIVERY DEVICE, the contents of which are expressly incorporated herein by

reference.

l o BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical implants and, more

particularly, to medical implants for providing a time-released delivery of drugs.

15 2. Description of Related Art

A medicinal substance can be administered to a patient systemicaliy or locally.

A systemicaliy administered medicinal substance enters into the blood stream, travels

throughout the body, and, hopefully, reaches the part of the patient's body in need of

treatment at an effective dose before being degraded by metabolism and excreted. The

20 systemic administration of medicinal substances can be achieved by oral application

(e.g., syrups, tablets, capsules and the like), needle injection, transdermal delivery (e.g.,

a medicinal substance incorporated into a skin patch), and subdermal delivery (e.g., a

medicinal substance formulation in a matabolizabϊe matrix placed beneath the skin to

release, for example, nicotine or birth control drugs). Systemicaliy delivered medicinal substances can be inefficient, when only a small amount of the administered dose

reaches its site of therapeutic action. Moreover, with systemic delivery a medicinal

substance can enter parts of the body where it can actually do harm or produce a

noxious side effect.

Medicinal substances can be delivered locally by injection (e.g., injection of

anesthetic into a patient's gums) or topically (e.g., creams, ointments, and sprays).

Although the local delivery of medicinal substances can in some instances overcome

the problems of dilution and migration, local medicinal substance delivery can be

difficult in certain cases, leaving systemic administration as the viable alternative. Even

when local delivery of medicinal substances to a target site is possible, an important

consideration still remains of maximizing the therapeutic effectiveness of the local drug

delivery by controlling the proper dose and duration of the local delivery of the

medicinal substance.

SUMMARY OF THE INVENTION

In order to maximize the therapeutic effectiveness of a medicinal substance at a

target site within an organism, which is preferably a human patient, the delivered

substance must be applied to the target site in the proper dose amount and for the proper

duration. As used herein, a dose is defined as an amount of substance delivered per

time, and a duration is defined as a period of time from an initial dose to a final dose.

The present invention relates to improved apparatuses, systems and methods for

achieving delivery of substances in specified doses and durations to target sites. In

particular, a device having a casing with medicinal substances stored in an interior

chamber, which is open to the exterior surface via excretion tubes, is disclosed. Modifications are possible for achieving specific doses and durations of substance

delivery to maximize the therapeutic effectiveness of the substance.

The present invention, together with additional features and advantages thereof,

may best be understood by reference to the following description taken in connection

with the accompanying illustrative drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 A illustrates a time-released substance delivery device formed in the

shape of a plate or panel, in accordance with an embodiment of the present invention;

Figure IB illustrates a time-released substance delivery device formed in the

shape of a block, in accordance with an embodiment of the present invention;

Figure 1 C illustrates a time-released substance delivery device formed in the

shape of a cylinder, in accordance with another embodiment of the present invention;

Figure ID illustrates a time-released substance delivery device formed in the

shape of a screw, in accordance with yet another embodiment of the present invention;

Figure 2 illustrates a time-released substance delivery device having an access

tube that feeds into an internal chamber of the substance delivery device, in accordance

with an embodiment of the present invention; and

Figure 3 illustrates a time-released substance delivery device having a

perforable membrane and an access tube fluidly connected to an internal chamber of the

substance delivery device, in accordance with another embodiment of the present

invention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS Referring more particularly to the drawings, Figure 1 A illustrates a time-

released substance delivery device 9a, which in accordance with the present invention is

implanted at or near a target area to be treated. The substance delivery device 9a

comprises a casing 10a and a plurality of pores 13 a. In the illustrated embodiment, the

shape of the device is defined by the casing 10a. Once implanted, the substance

delivery device 9a delivers medicinal substances X to the target site by releasing

through the pores 13a the medicinal substances X contained within the substance

delivery device 9a in the dose and duration specified. A substance delivery device 9b

defined by a block-shaped casing 10b having pores 13b is shown in Figure IB, and a

substance delivery device 9c defined by a cylinder-shaped casing 10c having pores 13c

is shown in Figure lC. The substance delivery devices of Figures 1A, IB and 1C can

be inserted into or secured to an organ or a deep tissue for local treatment, or can be

implanted under a derma, for example, for systemic treatment.

In accordance with the present invention, the casings forming the substance

delivery devices of the present invention may comprise structures for insertion and

implantation into or on organs or tissue, such as in Figures 1 A, IB and 1C or,

alternatively, may comprise structural or physically functional shapes. For example,

the casing may be formed into a plate, mesh, or other fixation, holding, or containment

member. In the case of a bone plate or mesh, for example, the substance delivery

device can be formed with screw or tack apertures disposed therein. As is known in the

art, screw or tack apertures are typically formed in bone plates and meshes to

accommodate screws or tacks for securing the bone plate or mesh to bone.

Alternatively, the screw or tack apertures may be drilled into the substance deliver)'

device just prior to or during implantation of the substance delivery device. The shape of the plate, mesh, or other fixation, holding, or containment member

may comprise any conventional shape for a such a plate or mesh, with the improvement

being the addition of pores and an optional chamber 11 (Figure 2), in accordance with

the present invention. The plate, mesh, or other fixation, holding, repairing, or

5 containment member may be constmcted for implantation on or in connection with, for

example, muscle, cartilage, tendons, ligaments, connective tissues, blood vessels, bone,

and other tissue and organ sites. In the case of a bone plate or mesh, for example, the

bone plate or mesh may be formed to have slightly larger dimensions to maintain

adequate fixation properties, especially, for example, if the bone plate or mesh is

l o formed of a relatively soft plastic or absorbable material.

In the example of a bone plate or mesh, the bone plate or mesh may be placed

over a defective bone area to provide mechanical, reconstructive, protective and/or

fixation functions, while simultaneously releasing medicinal substances X to facilitate

the bone healing process. The medicinal substances X may comprise, in this example,

15 chemotactic substances for influencing cell-migration, inhibitory substances for

influencing cell-migration, mitogenic growth factors for influencing cell proliferation,

growth factors for influencing cell differentiation (e.g. insulin-like growth factor,

transforming growth factor-beta, fibroblast growth factor, platelet-derived growth

factor), and factors for promoting neoangiogenesis (formation of new blood vessels).

20 A substance delivery device 9d, having a screw-shaped casing lOd with pores

13d, is shown in Figure ID. In the functional-casing embodiment of Figure ID, the

casing lOd can serve as both a fastener and a substance delivery device 9d. For

example, the substance delivery device 9d may be constructed according to the

principles set forth above, in connection with a substance delivery device formed into a bone plate or mesh, and may be used to secure, for example, bone plates or meshes to

bone. Although specific embodiments of functional casings in the form of bone plates,

meshes, and screws have been discussed, other embodiments, which would allow for

the casing to be functional, for example, are also contemplated to be within the scope of

the present invention. For example, substance delivery devices may be formed to

operate, wter alia, as soft tissue tacks or spinal rods.

The casings may be constructed from non-biodegradable or biodegradable

material. For biodegradable casings, a preferred embodiment comprises a

biodegradable casing that degrades only after all of the medicinal substances X

therewithin have been depleted. Alternatively, other embodiments of the casing may

partially or completely degrade before the depletion of the medicinal substances X

contained therein, thereby achieving non-linear releases of the medicinal substances X.

In turn, the aforementioned casings may also be embedded in other implant

devices, for example. These other implant devices can be biodegradable, so that when

they degrade, the time-released substance delivery devices are exposed to the target site

to thereby achieve predetermined releases of the medicinal substances X beginning at a

delayed point in time.

Referring now to Figures 2 and 3, in a preferred embodiment the substance

delivery device 9 comprises a casing 10 and a chamber 11. The substance delivery

device 9 further comprises a set of excretion tubes 12 that fluidly connect the exterior

surface of the casing 10 to the interior chamber 11, resulting in a set of pores 13 and a

set of interior open ends 21, respectively. Preferably, at least one side or portion of the

casing 10 comprises a perforable membrane 15, as shown in Figure 3, so that a needle

17 and syringe 16 can be used to fill the substance delivery device 9 with, for example, medicinal substances X. In accordance with the present invention, the needle 17 can be

used to fill the chamber 11 before and/or after implantation of the substance delivery

device into tissue. For example, the chamber 11 may be filled with a medicinal

substance X before implantation and, subsequently, refilled to maintain an ongoing,

controlled delivery of the medicinal substance X and/or other substances to the target

site.

Operationally, doses and durations are functions of the sizes, shapes and number

of excretion tubes 12 and the concentration of medicinal substance X in the chamber

11. For example, if a low dose is desired, a substance delivery device 9 with narrow

excretion tubes 12 can be selected to physically limit the diffusion rate of the medicinal

substance X from the interior chamber 11 to the exterior pores 13. Since fewer

molecules of medicinal substance X per time reach the exterior pore 13 under this

condition, lower amounts of medicinal substance X are delivered to the targeted site per

time, resulting in lower dosage delivery. Furthermore, the number of individual

excretion tubes 12 in the substance delivery device 9 can directly affect the dosage

delivery. For example, a fewer number of excretion tubes 12 effectively decreases the

number of channels available for the outward diffusion of the medicinal substance X

contained in the chamber 11, thereby decreasing the dosage to the target site. Also, the

concentration of the medicinal substance X in the chamber 11 contributes to the dose.

For example, low concentrations of medicinal substance X in the chamber 11 results in

low gradient pressure, which in turn results in fewer molecules diffusing from inside

the chamber 11 to the exterior pores 13 per time, which ultimately results in a lower

dosage delivery.

The duration of delivery is also a function of the size and number of the excretion tubes 12 and the concentration of medicinal substance X in the chamber 11.

For example, smaller excretion tubes 12 decrease the amount of medicinal substance X

released per time. Because the medicinal substance X is released slowly, it takes longer

to deplete the medicinal substance X in the chamber 11, and therefore, the duration of

the medicinal substance X release is increased. For the same reason, if there is a high

amount of medicinal substance X in the chamber 11 initially, the duration can be

increased.

By applying conventional kinetic models and calculations, the resultant effect of

size, shape, number and distribution of excretion tubes 12 and amount of substance X

in the chamber 11 on dose and duration can be tabulated. Therefore, a system of the

present invention may preferably comprise a lookup table, one or more medicinal

substances X, a needle capped syringe 16 and 17, and a substance delivery device 9.

In practice, a method for using the substance delivery device 9 involving the

following steps may be employed by a physician. First, the physician diagnoses and

determines the appropriate dose and duration for treatment of a certain medical

condition. The physician may then use the lookup table to select the substance delivery

device 9 with the appropriate number and size of excretion tubes 12 and the amount of

medicinal substance X needed in the chamber 11. Subsequently, the physician can use

a syringe 16 and 17 to inject the appropriate medicinal substance X into the chamber

11. After the chamber 11 is loaded, the physician may surgically implant the substance

delivery device 9 into the patient.

After the medicinal substance X is partially or fully depleted from the chamber

11 , the physician may return to the location and surgically retrieve the substance

delivery device 9. Alternatively, if the substance delivery device 9 is constmcted from a biodegradable material, it can be left in the patient's body. If desired, the surgeon

may refill the substance delivery device 9 using, for example, a needle while the

substance delivery device 9 remains in the patient, as shown in Figure 3. This in situ

refill procedure may be accomplished by, for example, reopening the surgical site,

using visual or tactile verification of the location of the substance delivery device, or

implementing an imaging technique to ensure that the refill needle finds its way into the

chamber 11.

In accordance with one embodiment, extended excretion tube lengths are

provided in connection with one or more of the excretion tubes 12. Each increased tube

length delays the time of excretion of medicinal substance X out of the pore from the

time at which the medicinal substance X is placed into the chamber 11. Consequently,

the medicinal substance X can be delayed from being released until after the substance

delivery device 9 is implanted into the patient, with the delay time being a function of

the length and cross-sectional area of the excretion tube, (wherein the excretion tube or

passage does not necessarily have a circular cross-sectional area). Moreover, partial

barriers and/or flow restrictions, enhancers, channelers or directors may be formed and

placed within at least a portion of one or more of the excretion tubes 12. The substance

delivery device 9 with such a delay mechanism, for example, may be used when it is

medically indicated that the medicinal substance X should be released at sometime after

the time-released substance delivery device 9 is implanted. Furthermore, an alternative

system may comprise a substance delivery device 9 with such a delay mechanism and a

substance delivery device 9 (or a set of substance delivery devices) that release

medicinal substance X immediately or shortly after implantation. Such a system when

used can produce certain dosage and duration combinations, such as those specifying immediate and/or delayed releases.

Another embodiment in accordance with the present invention includes an

access tube 14 that feeds directly into the chamber 11. A purpose of this access tube 14

is to allow access into the chamber 11, for example, once the substance delivery device

9 has been implanted. In accordance with one preferred embodiment, the access tube

14 comprises a perforable membrane, disposed at or near its end 14a, and suitable for

being pierced by a needle for delivery of fluids therethrough and into the chamber 11.

The substance delivery device 9 may be constmcted with a needle 17 access

(e.g., a perforable membrane 15) to the chamber 11 and/or with an access tube 14

fluidly connected to the chamber 11. The chamber 11 may initially be filled with a

saline solution and/or other biocompatible fluid (e.g., a medicinal substance X such as

an anesthetic) wherein the user (using, for example, a needle) can introduce a fluid

through a needle 17 access (e.g., a perforable membrane 15) and/or through the access

tube 14 and into the chamber 11 to thereby displace (and/or expedite excretion of),

and/or dilute or modify, the biocompatible fluid in the chamber 11. In modified

embodiments the perforable membrane of the access tube 14 may comprise a locking-

type connector for receiving a corresponding external substance-introducing tube with a

matching or mating connector.

When the substance delivery device 9 is implanted, the end 14a of the access

tube 14 may be positioned to extend out of the dermis for subsequent access. In a

modified embodiment, the end 14a of the access tube 14 may extend below the dermis

of the patient so that the skin is breached only when the user desires to introduce

external fluids (e.g., medicinal substances X) into the access tube 14. If, for example,

the end 14a is just below the dermis, the surgeon can visually or tactilely locate the end 14a beneath the patient's dermis. For example, the substance delivery device 9 may be

implanted deep within an organ with the access tube extending out of the organ and

terminating just beneath the patient's dermis.

For a chemotherapy treatment, for example, a biodegradable substance delivery

device 9 may be implanted within tissue or an organ, such as the brain, with the access

tube extending through the skull and terminating just beneath the patient's dermis.

Imaging techniques, such as Magnetic Resonance Imaging (MRI) can be used to

accurately implant the substance delivery device 9 in close proximity to or within a

target site such as a tumor. In accordance with a preferred embodiment, the substance

delivery device will comprise a biodegradable (e.g., a resorbable polymer based

material) or non-scatterable material for this operation. Once the access device has been

implanted, the surgeon can then access the chamber 11 using an a needle 17/perforable

membrane 15 and, (optionally, using the above-referenced imaging techniques) and/or

an access tube 14, to introduce, for example, chemotherapy medicinal substances X to

the tumor location or target site.

One reason for accessing the chamber 11 is to replenish the chamber 11 with

more of the same medicinal substance X or other medicinal substances X during the

course of treatment. In a modified embodiment, the surgeon can access the chamber 11

to remove medicinal substances X from the chamber with suction. In yet another

modified embodiment, the surgeon can apply suction to the access tube 14 and/or to a

needle 17/perforable membrane 15, to draw body fluids from the extracellular space 22

through the excretion tubes 12 and into the chamber 11 and, subsequently, out of the

chamber 11 through either the needle 17/perforable membrane 15 and/or the access

tube 14. Another reason for accessing the chamber 11 in situ is to introduce reagent that

would activate or deactivate one or more medicinal substances X already contained in

the chamber 11. The access tube 14 and/or needle 17/perforable membrane 15 can

allow for a higher degree of flexibility during the course of treatment. Furthermore,

another system in accordance with the present invention may comprise a substance

delivery device 9 and a plurality of medicinal substances X. With the flexibility of

introducing a different medicinal substance X to the target area once the substance

delivery device 9 is implanted, the system may be employed to treat medical conditions

requiring a series of different medicinal substances X over a course of time. Two or

more chambers 11 may be formed in a single substance delivery device 9, with one or

more of the chambers being engineered to provide a different dose and duration. For

example, a second chamber may be provided with fewer excretion tubes connected

thereto and/or different types of medicinal substances and/or carriers 18 (discussed,

infra) disposed therein.

Yet another embodiment of the present invention includes placement of

medicinal substances X contained within a carrier 18 within the chamber 11. A carrier

comprises a protective exterior coating and an interior empty volume for storage of one

or more medicinal substances X, for example. One or more of these carriers 18 may be

constmcted larger than one or more of the interior open ends 21 for attenuated or

impeded excretion. Thus, in accordance with this embodiment, the medicinal substance

X contained therein may only be released upon the degeneration of the carriers 18. In a

modified embodiment, carriers, which are larger than some or all of the excretion tubes

12, can be placed within the chamber 11 of an absorbable substance delivery device, in

order to attenuate or impede excretion thereof. One effect of these arrangements is to enable a delayed release of medicinal substance X once the substance delivery device 9 is implanted.

Alternatively, the carriers 18 may be constructed sufficiently small so as to enter

into the excretion tube 12 and diffuse out of the pores 13 into the extracellular space 22.

Once in the extracellular space 22, the carriers 18 may further diffuse away from the

substance delivery device 9. One use of this small size carrier is that it can carry (and

protect) the medicinal substance X during the diffusion away from the substance

delivery device 9 and allow for the medicinal substance X to be effective at some

distance away from the substance delivery device 9.

One preferred embodiment of the current invention comprises pores 13 on all

sides of the casing 10. This construction allows for a relatively isotropic dispersion of

medicinal substance X by the substance delivery device 9. However, an alternative

embodiment may restrict the pore surface, for example, to only one side of the casing

10. With the pores 13 present on only one side, it is possible to limit the diffusion of

the medicinal substance X to a particular tissue surface at the implant location for

focused local delivery of the medicinal substance X.

In terms of manufacturing the substance delivery device 9, it is preferable in

accordance with one aspect of the present invention that the chamber 11 remain empty

prior to use. It is only at the time of use, or shortly prior thereto, that the medicinal

substance X is injected into the chamber 11. However, in an alternative embodiment,

the substance delivery device 9 may be filled or impregnated with certain medicinal

substances X during the manufacturing process. For example, in accordance with one

embodiment of the present invention, part or all of the material of the substance

delivery device is impregnated or partially formed with a medicinal substance X, with

15 . the existence of the chamber 11 being optional. The substance delivery device 9 may

be formed of a material that degrades over time after implantation so that degradation

of all or part of the substance delivery device 9 results in the release of the medicinal

substance X. The pores 13 in accordance with this embodiment provide additional

surface area for such degradation and consequential delivery of the medicinal substance

X.

While the foregoing preferred embodiments of the invention have been

described, various alternatives, modifications, and equivalents other than the ones

already discussed may be used. For example, a substance delivery device 9 may have a

set of short and large excretion tubes 12 for immediate release of substance A after the

implantation of the substance delivery device 9. Concurrently, the substance delivery

device 9 may also have substance B contained in large carriers 18 located in the

chamber 11. Because of their sizes, as discussed above, these carriers 18 remain

trapped in the chamber 11 for a period of time and are subsequently released upon

degradation. The overall effect of this particular substance delivery device 9 is that it is

able to release substance A shortly after implantation and delay the release of substance

B. Along this line of constmction of the apparatus and/or systems, it is possible to

engineer an apparatus and/or substance delivery device 9 that is tailored to the

treatment specifications of various medical conditions. For example, a device can be

engineered to release 25% of the chamber 11 contents within three months of

implantation, 50% within the first year, and the remaining contents within the next two

years.

As used herein the term "medicinal substance" includes, but is not limited to,

analgesics, local anesthetics, antibiotics, steroids, anti-tumor agents, hormones, and hormone-like agents. Examples of antibiotics useful with the present invention include,

but are not limited to: ampicillin, chloramphenicol, chlortetracycline, clindamycin,

erythromycin, gramicidin, gentamicin, mupiroicin, neomycin, polymyxin B, bacitracin,

silver sulfadiazine, tetracycline and chlortetracycline. Those of ordinary skill in the art

will appreciate that there are other appropriate topical antibiotics, such as those listed in

U.S.P.D., which may also be used in the present invention. Examples of hormones and

other related dmgs useful with the present invention include, but are not limited to:

human growth hormone (HGH), bone morphogenetic proteins (BMPs) (C. F. Paatsama,

S., et al.) transforming growth factors (TGF-.beta.s), interferons, interleukins,

calcitonin, estrogen and 17-.beta. estradiols. Examples of anti-inflammatory dmgs

include, but are not limited to: cortisone, Nonsteroidal Anti-inflammatory Dmgs

(NSAIDs), and interleukin 3 inhibitors. Many of the antitumor dmgs in current clinical

use are cytotoxic materials, which work by killing the malignant cells faster than the

normal cells.

Although an exemplary embodiment of the invention has been shown and

described, many other changes, modifications and substitutions, in addition to those set

forth in the above paragraphs, may be made by one having ordinary skill in the art

without necessarily departing from the spirit and scope of this invention.

Claims

1. An implantable, time-released substance delivery device, comprising:

5 a casing having an exterior surface;

a plurality of pores disposed on the exterior surface of the casing;

an interior chamber disposed within the casing; and

a plurality of excretion tubes disposed within the casing, each of

the plurality of excretion tubes fluidly connecting the interior chamber to

l o one of the plurality of pores.

2. The time-released substance delivery device as set forth in Claim 1,

wherein the casing comprises an absorbable material.

15 3. The time-released substance delivery device as set forth in Claim 1,

wherein the casing comprises a non-scatterable material that will not

substantially scatter incident imaging beams.

4. The time-released substance delivery device as set forth in Claim 1,

20 wherein the casing has dimensions suitable for being implanted beneath

the skin of a patient.

5. The time-released substance delivery device as set forth in Claim 1,

wherein the casing has dimensions suitable for being implanted within an organ of a patient.

6. The time-released substance delivery device as set forth in Claim 1,

wherein the casing is formed into one of a tack and a screw.

7. The time-released substance delivery device as set forth in Claim 1,

wherein the casing comprises an absorbable material that is formed into

one of a tack and a screw.

8. The time-released substance delivery device as set forth in Claim 1,

wherein the casing is formed into a bone plate.

9. The time-released substance delivery device as set forth in Claim 1 ,

wherein the casing comprises an absorbable material that is formed into

a bone plate.

10. The time-released substance delivery device as set forth in any of Claims

1, 2, 6 and 8, wherein the interior chamber comprises a medicinal

substance.

11. The time-released substance delivery device as set forth in in any of

Claims 1, 2, 6 and 8, wherein the casing is impregnated with a medicinal

substance.

2. The time-released substance delivery device as set forth in any of Claims

1, 2, 6 and 8, wherein the casing comprises a perforable membrane,

which when pimctured by a needle will subsequently re-seal to maintain

a fluid barrier, wherein the perforable membrane is constmcted to

facilitate multiple penetrations by a needle therethrough and into the

interior chamber while maintaining a fluid seal after each penetration.

13. The time-released substance delivery device as set forth in Claim 12,

wherein the interior chamber comprises a medicinal substance.

14. The time-released substance delivery device as set forth in Claim 12,

and further comprising an access tube connected to and extending away

from the exterior surface of the casing.

15. The time-released substance delivery device as set forth in Claim 14,

wherein the interior chamber comprises a medicinal substance.

16. The time-released substance delivery device as set forth in any of Claims

1, 2, 6 and 8 and further comprising an access tube connected to and

extending away from the exterior surface of the casing.

17. The time-released substance delivery device as set forth in Claim 16,

wherein the interior chamber comprises a medicinal substance.

18. The time-released substance delivery device as set forth in Claim 16,

wherein the access tube is in fluid communication with the internal chamber.

19. The time-released substance delivery device as set forth in Claim 18

wherein the access tube comprises a first end and a second end, the first

end being connected to the exterior surface of the casing and the second

end being located opposite the first end.

20. The time-released substance delivery device as set forth in Claim 19,

wherein the interior chamber comprises a medicinal substance.

21. The time-released substance delivery device as set forth in Claim 19,

wherein the second end of the access tube comprises a perforable

membrane fluidly isloating an interior of the access tube from an

exterior surface of the access tube.

22. The time-released substance delivery device as set forth in Claim 19,

wherein a distance between the first end and the second end of the access

tube is greater than a maximum width of the casing.