U.S. patent application number 11/273131 was filed with the patent office on 2006-03-23 for process for the production of sustained release drug delivery devices.
Invention is credited to Michael J. Brubaker, Ramesh Krishnamoorthy, Pavlos Papadopoulos.
Application Number | 20060062826 11/273131 |
Document ID | / |
Family ID | 23006089 |
Filed Date | 2006-03-23 |
United States Patent
Application |
20060062826 |
Kind Code |
A1 |
Brubaker; Michael J. ; et
al. |
March 23, 2006 |
Process for the production of sustained release drug delivery
devices
Abstract
Disclosed is an improved sustained release drug delivery device
and method of producing such device. The device comprises a drug
core in an impermeable cup or impermeable coating layer that is
adhered to an uncured suture tab and covered with a permeable
polymer coating layer that is similar to the makeup of the suture
tab. The permeable polymer coating layer that covers the device,
covering the impermeable coating layer and at least a portion of
the drug core, is cured (after drying) along with the uncured
suture tab. The "cocuring" or one step curing process forms a very
strong bond between the outer coating layer to the suture tab
preventing leaks.
Inventors: |
Brubaker; Michael J.; (Ft.
Worth, TX) ; Papadopoulos; Pavlos; (Antioch, IL)
; Krishnamoorthy; Ramesh; (Apex, NC) |
Correspondence
Address: |
Bausch & Lomb Incorporated
One Bausch & Lomb Place
Rochester
NY
14604-2701
US
|
Family ID: |
23006089 |
Appl. No.: |
11/273131 |
Filed: |
November 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10055584 |
Jan 23, 2002 |
6991808 |
|
|
11273131 |
Nov 14, 2005 |
|
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60264441 |
Jan 26, 2001 |
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Current U.S.
Class: |
424/424 |
Current CPC
Class: |
A61K 9/0051
20130101 |
Class at
Publication: |
424/424 |
International
Class: |
A61F 2/00 20060101
A61F002/00 |
Claims
1-23. (canceled)
24. A method for providing controlled and sustained administration
of an agent effective in obtaining a desired local or systemic
physiological or pharmacological effect comprising inserting in a
desired location in the body of a mammalian organism a sustained
release drug delivery device comprising; a) a drug core comprising
a therapeutically effective amount of at least one agent effective
in obtaining a diagnostic effect or effective in obtaining a
desired local or systemic physiological or pharmacological effect;
b) a unitary cup essentially impermeable to the passage of said
agent that surrounds and defines an internal compartment to accept
said drug core, said unitary cup comprising an open top end with at
least one recessed groove around at least some portion of said open
top end of said unitary cup; and c) a permeable plug which is
permeable to the passage of said agent positioned at said open top
end of said unitary cup wherein said groove interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
25. The method according to claim 24, wherein said inserting step
comprises inserting said sustained release drug device in a
location selected from a group consisting of the vitreous of the
eye, under the retina, and onto the sclera.
26. The method according to claim 24, wherein said drug core
comprises a plurality of agents.
27. The method according to claim 24, wherein said inserting step
comprises injecting said sustained release drug delivery device at
the desired location.
28. A method for providing controlled and sustained administration
of an agent effective in obtaining a desired local or systemic
physiological or pharmacological effect comprising inserting at a
desired location in the body of a mammalian organism a sustained
release drug delivery device comprising; a) a drug core comprising
at least one agent effective in obtaining a diagnostic effect or
effective in obtaining a desired local or systemic physiological or
pharmacological effect; b) a unitary cup essentially impermeable to
the passage of said agent that surrounds and defines an internal
compartment to accept said drug core, said unitary cup comprising
an open top end and at least one lip around at least a portion of
said open top end of said unitary cup; and c) a permeable plug
permeable to the passage of said agent positioned at said open top
end of said unitary cup wherein said lip interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
29. The method according to claim 28, wherein said inserting step
comprises inserting said sustained release drug delivery device in
a location selected from a group consisting of the vitreous of the
eye, under the retina, and onto the sclera.
30. The method according to claim 28, wherein said drug core
contains a plurality of said agents.
31. The method according to claim 28, wherein said inserting step
comprises injecting said sustained release drug delivery device at
the desired location.
32. A method of manufacturing a sustained release drug delivery
device comprising: a) manufacturing a drug core comprising at least
one agent effective in obtaining a diagnostic effect or effective
in obtaining a desired local or systemic physiological or
pharmacological effect; b) providing a unitary cup essentially
impermeable to the passage of said agent that surrounds and defines
an internal compartment to accept said drug core, said unitary cup
comprising an open top end with at least one recessed groove around
at least some portion of said open top end of said unitary cup; c)
inserting said drug core into said unitary cup; and d) filling a
material which is permeable to the passage of said agent into said
open top end of said unitary cup, allowing said material to
solidify thereby forming a permeable plug wherein said groove
interacts with said permeable plug holding it in position and
closing said open top end, said permeable plug allowing passage of
said agent out of said drug core, through said permeable plug, and
out said open top end of said unitary cup.
33. The method of manufacturing a sustained release drug delivery
device according to claim 32, wherein said drug core is
manufactured as a solid dose form.
34. The method of manufacturing a sustained release drug delivery
device according to claim 32, wherein said drug core is
manufactured as a solid dispersion.
35. The method of manufacturing a sustained release drug delivery
device according to claim 32, comprising the further step of curing
the assembled sustained release drug delivery device.
36. A method of manufacturing a sustained release drug delivery
device comprising: a) manufacturing a drug core comprising at least
one agent effective in obtaining a diagnostic effect or effective
in obtaining a desired local or systemic physiological or
pharmacological effect; b) providing a unitary cup essentially
impermeable to the passage of said agent that surrounds and defines
an internal compartment to accept said drug core, said unitary cup
comprising an open top end with at least one lip extending around
at least a portion of the said open top end of said unitary cup; c)
inserting said drug core into said unitary cup; and d) filling a
material which is permeable to the passage of said agent into said
open top end of said unitary cup, allowing said material to
solidify thereby forming a permeable plug wherein said lip
interacts with said permeable plug holding it in position and
closing said open top end, said permeable plug allowing passage of
said agent out of said drug core, through said permeable plug, and
out said open top end of said unitary cup.
37. The method of manufacturing a sustained release drug delivery
device according to claim 36, wherein said drug core is
manufactured as a solid dose form.
38. The method of manufacturing a sustained release drug delivery
device according to claim 36, wherein said drug core is
manufactured as a solid dispersion.
39. The method of manufacturing a sustained release drug delivery
device according to claim 36, comprising the further step of curing
the assembled sustained release drug delivery device.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an improved process for
producing a device for delivering drug directly to the interior
portions of the body of a mammalian organism, such as to the eye.
The drug delivery method includes administration of an agent
effective in obtaining a desired diagnostic effect or local or
systemic physiological or pharmacological effect by inserting in a
desired location in the body of a mammalian organism a sustained
release drug delivery device.
BACKGROUND
[0002] Over the years, various drugs have been developed to assist
in the treatment of a wide variety of ailments and diseases.
However, in many instances such drugs are not capable of being
administered either orally or intravenously without the risk of
various detrimental side effects.
[0003] CMV retinitis is a disease that is characterized by
inflammation of the retina caused by infection with
cytomegalovirus. CMV retinitis is one of the most common causes of
sight-threatening infections among people with HIV. The symptoms
include loss of visual acuity, blind spots, and the loss of
peripheral vision. Left untreated, CMV retinitis can lead to
blindness.
[0004] Intravenous ganciclovir (GCV) is effective in the treatment
of CMV retinitis in AIDS patients, but bone marrow toxicity limits
its usefulness. Continuous maintenance GCV therapy is necessary to
prevent progression or recrudescence of the disease, but despite
maintenance therapy a significant number of patients experience a
relapse during treatment. Additionally, there are other risks and
problems associated with systemic GCV administration.
[0005] Intravitreal GCV injections administered once or twice
weekly have resulted in temporary remission of CMV retinitis in
AIDS patients. Intravitreal GCV injections may provide a higher
intraocular drug concentration than systemic therapy and reduce the
incidence of neutropenia. However, current treatment of CMV
retinitis in AIDS patients is clearly suboptimal. Ganciclovir is
virustatic and thus disease inhibition requires maintenance drug
administration.
[0006] A more detailed explanation of the use of intravenous GCV
and intravitreal injections of GCV can be found in U.S. Pat. No.
5,902,598, herein incorporated in its entirety by reference. A
discussion of the difficulties associated with the systemic therapy
of cyclosporine A in the treatment of uveitis can be found in U.S.
Pat. Nos. 5,773,019 and 6,001,386, herein incorporated in their
entirety by reference.
[0007] Accordingly, there exists a strong need for the elimination
of the undesirable physiological problems associated with GCV
treatment of CMV retinitis, while maintaining the advantageous
properties of this treatment. Although delivering the drug locally
with injections may minimize the systemic toxicity of GCV, repeated
injection is not a practical mode of administration.
[0008] Due to the risks that certain drugs impose, researchers have
developed systems for administering such drugs to aid in the
treatment of these ailments and diseases. A general discussion of
drug delivery control systems is provided in Controlled Drug
Delivery (Part I), Xue Shen Wu, Ph.D. pp 32, 33, 44-46, 63, 66, and
67 (Technomic Publishing Co. Inc., 1996), the entire contents of
which are incorporated herein by reference. The systems have been
designed largely to reduce and to control the release rate of
incorporated drugs. However, these systems failed to achieve many
of the advantages solved by later devices.
[0009] For example, U.S. Pat. No. 4,014,335 to Arnold, relates to
various ocular inserts that act as a deposit or drug reservoir for
slowly releasing a drug into the tear film for prolonged periods of
time. These inserts are fabricated as a three-layer laminate of
flexible polymeric materials that are biologically inert,
non-allergenic, and insoluble in tear fluid. To initiate the
therapeutic programs of these devices, the ocular inserts are
placed in the cul-de-sac between the sclera of the eyeball and the
eyelid for administering the drug to the eye. Multiple layer
laminate systems can present a challenge to reproducibly
manufacture and are more difficult to produce by large-scale or
commercial manufacturing procedures.
[0010] The device of U.S. Pat. No. 3,416,530 is manufactured with a
plurality of capillary openings that communicate between the
exterior of the device and the interior chamber generally defined
from a polymeric membrane. While the capillary openings in this
construction are effective for releasing certain drugs to the eye,
they add considerable complexity to the manufacture of the device
because it is difficult to control the size of these openings in
commercial manufacturing using various polymers.
[0011] U.S. Pat. No. 3,618,604 describes a device that does not
involve such capillary openings, but instead provides for the
release of the drug by diffusion through a polymeric membrane. The
device, as disclosed in a preferred embodiment, comprises a sealed
container with the drug contained in an interior chamber.
Nonetheless, as described in U.S. Pat. No. 4,014,335, certain
problems have been identified with such devices such as the
difficult task of sealing the margins of the membrane to form the
container. In addition, stresses and strains introduced into the
membrane walls from deformation during manufacturing of those
devices may cause the reservoir to rupture and leak.
[0012] U.S. Pat. No. 6,001,386 to Ashton, et al. relates to an
implantable sustained release drug delivery device with an inner
core containing an effective amount of a low solubility agent
covered by a non-bioerodible polymer coating layer that is
permeable to the low solubility agent disclosed.
[0013] The above described systems and devices are intended to
provide sustained release of drugs effective in treating patients
at a desired local or systemic level for obtaining certain
physiological or pharmacological effects. However, there are many
disadvantages associated with their use, including the fact that it
is often difficult to obtain the desired release rate of the drug
(either too much or too little drug is released into the body).
Further, it is difficult to adhere the device to the tab that is
used to suture the device inside of the organ, such as an eye.
Great effort is expended to ensure a strong bond of the device to
this "suture tab." Even if the device is strongly adhered to the
suture tab, it is a difficult task to completely seal all of the
margins and prevent rupture and leaking of drug into the body.
[0014] The need for a better release system is especially
significant in the treatment of CMV retinitis. Thus, there remains
a long-felt need in the art for an improved device for providing
sustained release of a drug to a patient to obtain a desired local
or systemic physiological or pharmacological effect.
[0015] Prior to the development of the present invention, there was
a drug delivery device developed that ameliorated many of the
problems associated with sustained release drug delivery. The
device, which is disclosed in U.S. Pat. No. 5,378,475 (incorporated
herein by reference in its entirety), included a first coating
essentially impermeable to the passage of the effective agent and a
second coating permeable to the passage of the effective agent. In
the device, the first coating covered at least a portion of the
inner core; however, at least a small portion of the inner core is
not coated with the first coating layer. The second coating layer
essentially completely covers the first coating layer and the
uncoated portion of the inner core. The portion of the inner core
which is not coated with the first coating layer allows passage of
the agent into the second coating layer thus allowing controlled
release.
[0016] While the devices described in U.S. Pat. No. 5,378,475 solve
many of the aforementioned problems pertaining to drug delivery,
the devices and the method of making the devices are not without
some problems. In particular, polymers suitable for the second
coating of the inner core are frequently relatively soft and
technical difficulties can arise in production of uniform films
that do not rupture and leak. This is especially true when
attempting to coat non-spherical bodies with edges (such as a
cylindrical shape or edges of a suture tab). In such cases,
relatively thick films must be applied to achieve uninterrupted and
uniform coatings, which adds significant bulk to the device. Thus,
the devices tend to be larger than necessary as a result of the
thickness needed to seal the ends of the inner core and seal it to
the suture tab. In addition to adding bulk, multiple layer devices
are more difficult to manufacture reproducibly and are more
difficult to produce by commercial manufacturing procedures. Also,
the various layers can be made of materials that are relatively
incompatible with one another adding to the difficulties in
coating. Often devices such as these require a plurality of manual
assembly steps that is time consuming, limits available supply, and
adds variability.
[0017] U.S. Pat. No. 5,902,598 also presents solutions to some of
the problems associated with manufacturing small devices. The
device in U.S. Pat. No. 5,902,598 includes a third permeable
coating layer that essentially completely covers the device. While
the third coating layer improves the structural integrity of the
device and helps to prevent potential leakage, some manufacturing
difficulties can limit scaled up manufacturing. For example,
consistent application of the outermost coating layer and
reproducibility in manufacturing can be problems with designs which
require manual assembly, a significant number of steps in the
assembly process, or outer dip coatings.
[0018] The problem of device size is extremely important in the
design of devices for implantation into the limited anatomical
spaces such as small organs like the eye. Larger devices require
more complex surgery to both implant and remove. The increased
complexity can result in complication, longer healing or recovery
periods, and potential side effects (e.g. increased chance of
astigmatism). Further, the extra polymer required to achieve a
uniform coating reduces the potential internal volume of the
implant and hence limits the amount of drug that can be delivered,
potentially limiting both efficacy and duration.
[0019] Also, failure of some of these devices in use can lead to a
dumping of the agent, which can cause harm to the mammalian
organism being treated.
[0020] It would, therefore, be desirable to have a structurally
stable device that can be reproducibly manufactured and
manufactured by commercial techniques. As a result of all of the
above, there remains a long felt need in the art for an improved
device and an improved process of producing such a device for
providing sustained release of a drug to a mammalian organism to
obtain a desired local or systemic physiological or pharmacological
effect, especially for ocular use.
SUMMARY OF THE INVENTION
[0021] The sustained release drug delivery device according to the
present invention comprises: [0022] a) a drug core comprising at
least one agent effective in obtaining a diagnostic effect or
effective in obtaining a desired local or systemic physiological or
pharmacological effect; [0023] b) an impermeable coating layer
impermeable to the passage of said agent that surrounds a portion
of said drug core; [0024] c) a suture tab adhered to and extending
from said drug delivery device that is used during surgery to
adhere said device to the body of a mammalian organism; and [0025]
d) a permeable polymer coating layer, permeable to the passage of
said agent that essentially completely covers the impermeable
coating layer b) and the uncoated portion of the drug core a) that
is not coated with said impermeable coating layer: wherein the
polymer coating layer d) is of a similar polymer material as said
suture tab c) and both polymer coating layer and suture tab have
been cured at the same time, bonding both together.
[0026] This invention is also directed to a method for providing
controlled and sustained administration of an agent effective in
obtaining a desired local or systemic physiological or
pharmacological effect comprising inserting in a desired location
in the body of a mammalian organism the sustained release drug
delivery device above.
[0027] The method of manufacturing a sustained release drug
delivery device according to the present invention comprises:
[0028] A) providing a drug core comprising at least one agent
effective in obtaining a diagnostic effect or effective in
obtaining a desired local or systemic physiological or
pharmacological effect; [0029] B) coating a portion of said drug
core with an impermeable coating layer impermeable to the passage
of said agent; [0030] C) coating the resulting coated core of B)
with an outer coating of a permeable polymer coating layer,
permeable to the passage of said agent that essentially completely
covers the impermeable coating layer of B) and the uncoated portion
of the drug core of A) that is not coated with said impermeable
coating layer; and [0031] D) curing the resulting device of C) at a
temperature of about 130.degree. C. to about 160.degree. C. for
about 1 to about 5 hours: wherein an uncured solid polymer suture
tab has been adhered to the device prior to step D) such that a
portion of said suture tab extends away from said device and the
curing of step D) jointly cures the uncured solid polymer suture
tab and the permeable polymer coating layer of C) and wherein the
permeable polymer coating layer applied in C) is of a similar
polymer material as said solid polymer suture tab.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is a schematic perspective view of a sustained drug
delivery device according to various embodiments of this
invention.
[0033] FIG. 2 is a schematic view illustrating the device of FIG. 1
attached to the eye.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The drawings, which are not drawn to scale, are set forth to
generally illustrate the sustained release drug delivery device of
the present invention.
[0035] FIGS. 1 and 2 show an embodiment of the present invention
with a coated drug core 1 that is coated with coating 2. This
coating 2 is preferolly composed of an inner impermeable coating
layer adjacent the drug core and an outer permeable polymer coating
layer on the exterior of the device. The device includes a suture
tab 3. The permeable polymer coating layer and suture tab
preferolly appear as an integral single unit made of the same
material.
[0036] According to this aspect of the present invention, once the
device has been constructed with the uncured outer coating layer
attached to the uncured suture tab, it is cured. This forms a
strong destructible bond between the suture tab and permeable
polymer.
[0037] FIG. 2 also illustrates how the suture tab 3 is used to
attach the device to a structure of the mammalian body, inside an
organ such as the eye 4 with suture 5, where eye wall 6 separates
inside eye 7 and outside eye 8.
[0038] The inventors have unexpectedly discovered a sustained
release drug delivery device design and manufacture method that
provides a structurally stable, safe device that can be more easily
and reproducibly manufactured than current designs that are known
in the art. The inventors have unexpectedly discovered that the
suture tab can be assembled with the device uncured and then cured
when the outer permeable coating layer is cured. This unexpectedly
provides a device that has a much stronger "destructive" bond
between the suture tab and the outer polymer coating.
[0039] In one preferred embodiment, the device includes an
impermeable cup made of silicone with an attached polyvinyl alcohol
(PVA) suture tab, the cup acts as a reservoir for a drug core
containing an agent such as fluocinolone acetonide. A hole through
the proximal end of the suture tab enables a suture to be used for
securing the device. The open end of the cup permits drug to
diffuse out of the core, through the PVA suture tab, and out of the
outer permeable polymer coating layer. An inner core is formed of a
pellet of fluocinolone acetonide. The device is formed by coating
the cup holding the pellet and the attached suture tab with a
permeable polymer solution of 10% PVA. The PVA coating is allowed
to dry. The device is then cured at 135-145.degree. C. The dry
uncured suture tab is cured as the outer coating layer is also
cured.
[0040] According to the process of the present invention, the
curing time and temperature can vary, depending upon the extent of
curing desired. Generally this curing is done at a particular
temperature (such as between about 130.degree. C. and about
160.degree. C.) for a time until a color change from clear to amber
is seen. The darker the amber the more the polymer like PVA is
cured. The cure time can be fairly long or short depending upon the
cure temperature and the desired extent of curing and is preferably
between about 1 and about 5 hours.
[0041] The suture tab and the outer permeable polymer coating layer
need to be made of compatible materials such that, upon curing a
strong bond is formed between the two. The strength of the bond is
a result of the curing of like polymer coatings, which upon heating
or curing form a continuous crystalline lattice framework. This
bond is generally so strong that it is a destructive bond.
[0042] By "destructive" bond, it is meant such a bond that when the
suture tab is attempted to be pulled away and separated from the
rest of the device, the bond is so strong that either the device or
the suture tab is destroyed at separation.
[0043] Alternatively, another aspect of the present invention
entails a sustained release drug delivery device comprising: [0044]
1) a coated drug core comprising an inner core comprising at least
one agent effective in obtaining a diagnostic effect or effective
in obtaining a desired local or systemic physiological or
pharmacological effect and a permeable polymer coating layer, the
polymer being permeable to the passage of said agent, wherein the
permeable polymer coating layer covers at least a portion of the
inner core; [0045] 2) an impermeable coating layer impermeable to
the passage of said agent that surrounds only a portion of said
coated drug core; and [0046] 3) a suture tab adhered to and
extending from said drug delivery device that is used during
surgery to adhere said device to the body of a mammalian organism:
wherein the permeable polymer coating layer covering at least a
portion of the inner core in 1) is of a similar polymer material as
said suture tab 3) and both polymer coating layer and suture tab
have been cured at the same time and wherein said inner core is
completely covered by a combination of permeable polymer coating
layer, impermeable coating layer, and suture tab such that the
agent is able to diffuse out of the inner core through the
permeable polymer coating layer or permeable suture tab.
[0047] The sustained drug delivery device according to the above
alternate aspect of the present invention alternatively can have
said impermeable coating layer of 2) essentially covering the
entire drug core of 1). In this aspect at least one passageway must
then be made through said impermeable layer allowing passage of
said agent out of said inner core, through said polymer coating
layer, and out of said passageway.
[0048] The expression "agent" as used herein broadly includes any
compound, composition of matter, or mixture thereof that can be
delivered from the device to produce a beneficial and useful
result.
[0049] The term "impermeable" refers to a material that is
sufficiently impermeable to environmental fluids as well as
ingredients contained within the delivery device, such that the
migration of such fluids and ingredients into or out of the device
through the impermeable material is so low as to have substantially
no adverse impact on the function of the device.
[0050] The term "permeable" refers to a material that is capable of
being passed through or permeated. Permeating includes passing
through openings, holes, pores, or intersections.
[0051] The term "drug core" refers to any drug supply, drug depot,
drug in suspension, reservoir or drug matrix. It includes one or
more agents necessary to obtain the desired diagnostic effect or
local or systemic physiological or pharmacological effect. It
includes any excipients, suspending agents, or binders. Reference
may be made to any standard pharmaceutical textbook such as
Remington's Pharmaceutical Sciences. The drug core can be in liquid
form, solid form, in dispersion, or any other form known in the
art. Solid dose includes all conventional solid dose forms known in
the art including the preferred tablets and pellets. Dispersions
include all conventional forms known in the art, such as liquid in
liquid dispersions and solid in liquid dispersions.
[0052] The expression "passageway" as used herein comprises means
and methods suitable for releasing the agent from the device. The
expression includes an aperture, orifice, or bore through the
device. The passageway can be formed by mechanical procedures such
as erosion, laser, or molding; and chemical procedures.
[0053] The device according to the present invention functions by
delivering active drug agent out of the device into a structure of
the mammalian body. The agent diffuses out of the drug core, out
the open end of the impermeable coating layer or cup, and through
the permeable polymer coating layer. Glue, polymers, or other
adhesion means can be employed to further bond the drug core to the
cup. However, by curing both the suture tab and the outer permeable
polymer coating layer together, the bond is generally sufficient
without the use of an adhesive.
[0054] The device has an attached suture tab with a hole through
the proximal end through which a suture can be placed to anchor the
device to a structure of the organism requiring treatment.
Providing a suture hole at the proximal end of the suture tab of
the device enables the surgeon to attach the device without
additional steps. The proximal end of the suture tab is at the
point of attachment, i.e. the point where the suture is used to
attach the device to the body. The preferred point of attachment is
at the end of the suture tab opposite the cup/reservoir/drug
core.
[0055] The location of the suture and the structure the device is
sutured to can be any that meet with current surgical techniques
known in the art, such as the sclera of the eye.
[0056] By curing both the suture tab and the outer permeable
polymer coating layer together, the bond is generally sufficient
without the use of an adhesive and provides structural integrity to
the device, and facilitates manufacturing and handling as a solid
structure. In addition, by eliminating the suture tab curing step,
prior to it being attached onto the cup, the process and design
decreases the number of steps and reduces the chance for
variability in the size and shape of the device.
[0057] The invention further relates to a method for treating a
mammalian organism to obtain a desired local or systemic
physiological or pharmacological effect. The method includes
administering the sustained release drug delivery device to the
mammalian organism and allowing the agent effective in obtaining
the desired local or systemic physiological or pharmacological
effect to pass out of the inner core, out the open end of the
impermeable coating or cup, and through the permeable polymer
layer. The term "administering", as used herein, means positioning,
inserting, implanting, or any other means for exposing the device
to a mammalian organism. The route of administration depends on a
variety of factors including type of response or treatment, type of
agent, and the preferred site of administration. However, the
preferred method is to insert the device into the target organ and
suture it into place. In ocular applications, more preferably
through a surgical procedure into the vitreous of the eye followed
by suturing the device in place.
[0058] In combination with the examples above, a variety of methods
may also be utilized to provide adhesion of the drug core to the
cup portion of the device. These methods include the use of
adhesives, polymers such as PVA, or any other procedure known in
the art to provide adhesion at the points of contact between the
drug core, the cup, and/or the suture tab. The methods of co-curing
to improve adhesion will vary depending on the materials that the
components are manufactured from, so long as the suture tab and the
outer permeable polymer coating layer are compatible.
[0059] For example, the drug cores or the cups of the present
invention can also be treated before or after assembly with an
adhesive, which would serve to further secure the drug core in the
device. The sealant must be permeable to the agent or agents in the
device. For example, a few drops of a permeable polymer could be
placed in the unitary cup before inserting the drug core into the
cup device and prior to attaching the suture tab to the open end of
the cup. Alternative points of attachment of the suture tab is also
permitted.
[0060] The drug core contains an agent effective in obtaining a
desired local or systemic physiological or pharmacological effect.
The following classes of agents could be incorporated into the
devices of the present invention: anesthetics and pain killing
agents such as lidocaine and related compounds and benzodiazepam
and related compounds; anti-cancer agents such as 5-fluorouracil,
adriamycin and related compounds; anti-fungal agents such as
fluconazole and related compounds; anti-viral agents such as
trisodium phosphomonoformate, trifluorothymidine, acyclovir,
ganciclovir, DDI and AZT; cell transnort/mobility impending agents
such as colchicine, vincristine, cytochalasin B and related
compounds; antiglaucoma drugs such as beta-blockers: timolol,
betaxolol, atenalol, etc; antihypertensives; decongestants such as
phenylephrine, naphazoline, and tetrahydrazoline; immunological
response modifiers such as muramyl dipeptide and related compounds;
peptides and proteins such as cyclosporin, insulin, growth
hormones, insulin related growth factor, heat shock proteins and
related compounds; steroidal compounds such as dexamethasone,
prednisolone and related compounds; low solubility steroids such as
fluocinolone acetonide and related compounds; carbonic anhydrize
inhibitors; diagnostic agents; antiapoptosis agents; gene therapy
agents; sequestering agents; reductants such as glutathione;
antipermeability agents; antisense compounds; antiproliferative
agents; antibody conjugates; antidepressants; bloodflow enhancers;
antiasthmatic drugs; antiparasiticagents; non-steroidal anti
inflammatory agents such as ibuprofen; nutrients and vitamins;
enzyme inhibitors: antioxidants; anticataract drugs; aldose
reductase inhibitors; cytoprotectants; cytokines, cytokine
inhibitors, and cytokin protectants; uv blockers; mast cell
stabilizers; and anti neovascular agents such as antiangiogenic
agents like matrix metalloprotease inhibitors.
[0061] Examples of such agents also include neuroprotectants such
as nimodipine and related compounds; antibiotics such as
tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,
gramicidin, oxytetracycline, chloramphenicol, gentamycin, and
erythromycin; antiinfectives; antibacterials such as sulfonamides,
sulfacetamide, sulfamethizole, sulfisoxazole; nitrofurazone, and
sodium propionate; antiallergenics such as antazoline,
methapyriline, chlorpheniramine, pyrilamine and prophenpyridamine;
anti-inflammatories such as hydrocortisone, hydrocortisone acetate,
dexamethasone 21-phosphate, fluocinolone, medrysone,
methylprednisolone, prednisolone 21-phosphate, prednisolone
acetate, fluoromethalone, betamethasone and triminolone; miotics
and anti-cholinesterase such as pilocarpine, eserine salicylate,
carbachol, di-isopropyl fluorophosphate, phospholine iodine, and
demecarium bromide; mydriatics such as atropine sulfate,
cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,
and hydroxyamphetamine; sympathomimetics such as epinephrine; and
prodrugs such as those described in Design of Prodrugs, edited by
Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam,
1985. In addition to the above agents, other agents suitable for
treating, managing, or diagnosing conditions in a mammalian
organism may be placed in the drug core and administered using the
sustained release drug delivery devices of the current invention.
Once again, reference may be made to any standard pharmaceutical
textbook such as Remington's Pharmaceutical Sciences for the
identity of other agents.
[0062] Any pharmaceutically acceptable form of such a compound can
be employed in the practice of the present invention, i.e., the
free base or a pharmaceutically acceptable salt or ester thereof.
Pharmaceutically acceptable salts, for instance, include sulfate,
lactate, acetate, stearate, hydrochloride, tartrate, maleate and
the like.
[0063] A large number of polymers can be used to construct the
devices of the present invention. The only requirements are that
they are inert, non-immunogenic and of the desired permeability.
Materials that may be suitable for fabricating the device include
naturally occurring or synthetic materials that are biologically
compatible with body fluids and body tissues, and essentially
insoluble in the body fluids with which the material will come in
contact. The use of rapidly dissolving materials or materials
highly soluble in body fluids are to be avoided since dissolution
of the wall would affect the constancy of the drug release, as well
as the capability of the device to remain in place for a prolonged
period of time.
[0064] Naturally occurring or synthetic materials that are
biologically compatible with body fluids and eye tissues and
essentially insoluble in body fluids which the material will come
in contact include, but are not limited to, glass, metal, ceramics,
polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked
polyvinyl butyrate, ethylene ethylacrylate copolymer, polyethyl
hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized
ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl
acetate, ethylene vinylchloride copolymer, polyvinyl esters,
polyvinylbutyrate, polyvinylformal, polyamides,
polymethylmethacrylate, polybutylmethacrylate, plasticized
polyvinyl chloride, plasticized nylon, plasticized soft nylon,
plasticized polyethylene terephthalate, natural rubber,
polyisoprene, polyisobutylene, polybutadiene, polyethylene,
polytetrafluoroethylene, polyvinylidene chloride,
polyacrylonitrile, cross-linked polyvinylpyrrolidone,
polytrifluorochloroethylene, chlorinated polyethylene,
poly(1,4'-isopropylidene diphenylene carbonate), vinylidene
chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumerale
copolymer, butadiene/styrene copolymers, silicone rubbers,
especially the medical grade polydimethylsiloxanes,
ethylene-propylene rubber, silicone-carbonate copolymers,
vinylidene chloride-vinyl chloride copolymer, vinyl
chloride-acrylonitrile copolymer and vinylidene
chloride-acrylonitride copolymer.
[0065] In the preferred embodiment of the present invention the
drug core is a solid tablet; the impermeable coating layer is made
of a prefabricated silicone cup; the suture tab is a prefabricated
tab of dried uncured PVA; and the outer permeably polymer coating
layer is PVA, coated in liquid form over the cup and a portion of
the suture tab. This assembly is then allowed to set while the PVA
outer coating dries. The entire device is then cured at about
130.degree. C. to about 150.degree. C. for about 1 to about 5
hours.
[0066] The device can be formulated in any convenient shape. For
example, the device can be 5 of any geometric shape dimensionally
suitable for insertion in the eye. Thus, the device can be
ellipsoid, rectangular, round, etc.
[0067] The dimensions of the device can vary with the size of the
device, the size of the core or reservoir, and the membrane that
surrounds the core or reservoir. The physical size of the device
should be selected so that it does not interfere with physiological
functions at the implantation site of the mammalian organism. The
targeted disease state, type of mammalian organism, location of
administration, and agents or agent administered are among the
factors which would effect the desired size of the sustained
release drug delivery device.
[0068] The devices according to the present invention may be made
in a variety of ways. For example, if the cup or reservoir is going
to be made entirely of polymer, then the polymer can be injection
molded or die cast into a desired shape and size. The drug core can
be made as any solid dose form such as a tablet or pellet. The drug
core can also be coated with permeable polymer using any coating
means currently known in the art. The drug core could also be
formed with an inner core that is a drug in liquid form or
suspension that is encapsulated in a permeable polymer.
[0069] The reservoir can be made in one piece, such as by
encapsulating the drug core then boring out the desired
passageway(s) and then coating with the outer permeable polymer
coating layer. The size or number of passageways can be selected to
achieve the desired release rate. The reservoir can also be formed
using a unitary cup and inserting a plug of impermeable material.
The assembled device having at least one passageway to permit the
active drug to diffuse out through the outer permeable polymer
coating layer. The unitary cup can have lip(s) or groove(s) around
the open top end which interact with the impermeable plug holding
it in place and closing the open top end of the cup. Due to the
elastic nature of some polymers, such as silicone, the same result
could also be achieved by essentially molding the reservoir as one
piece and stretching the passageway wide enough to insert the drug
core through the passageway.
[0070] The preceding descriptions of how to make the devices of the
present invention is merely illustrative and should not be
considered as limiting the scope of the invention in any way. In
particular, the methods of making the device depend on the identity
of the agent.
[0071] The devices can be surgically implanted at or near the site
of action. This is the case for devices of the present invention
used in treatment of ocular conditions, primary tumors, rheumatic
and arthritic conditions, and chronic pain. The devices can also be
implanted subcutaneously, intramusclarly, intraarterially, or
intraperitoneally. This is the case when devices are to give
sustained systematic levels and avoid premature metabolism.
[0072] Once in place, the device functions as a drug reservoir
gradually releasing drug to the organ such as the eye and
surrounding tissue. This device is particularly useful for treating
ocular conditions such as glaucoma, proliferative
vitreoretimopathy, diabetic retinopathy, uveitis, and keratitis.
The device is also particularly useful as an ocular device in
treating mammalian organisms suffering from cytomegalovirus
retinitis wherein the device is surgically implanted within the
vitreous of the eye.
[0073] As would be readily understood by one skilled in the art,
the preferred amounts, materials, and dimensions depend on the
method of administration, the effective agent used, the polymers
used, the desired release rate and the like. Likewise, actual
release rates and release duration depend on a variety of factors
in addition to the above, such as the disease state being treated,
the age and condition of the patient, the route of administration,
as well as other factors which would be readily apparent to those
skilled in the art. All of the forgoing U.S. patents and other
publications are expressly incorporated by reference herein in each
of their entities.
[0074] Thus, the devices of the present invention provide many
important advantages over previously known sustained release drug
delivery devices. The co-curing of the suture tab and the outer
permeable polymer coating layer design of the present invention
provide an improved device that maintains its physical and chemical
integrity in both the environments of use and in the presence of
agent during the controlled and continuous dispensing of agent over
a prolonged period of time.
[0075] Due to the structural integrity of the present design, the
need for multiple outer layers can be minimized, i.e. a plurality
of dip coating steps are not generally needed to prevent device
failure and "dumping" of the agent. The ease of making the devices
of the present invention minimizes stresses, strains, and
deformations during manufacture, which may cause the reservoir to
rupture and leak. The leaking of agent can result in harm to the
patient and is a significant concern in the manufacture of
implantable devices.
[0076] The co-cured device design of the present invention results
in a device that is more easily and reproducibly manufactured then
current designs known in the art and minimizes the number of steps
and decreases potential variability in assembly. The present design
also allows for mechanized manufacture. Eliminating all or part of
manual assembly greatly decreases the potential variability in the
finished product. In addition, the co-curing design and method
eliminates the difficulties of sealing the margins faced by other
devices in the prior art. This permits the therapeutic program to
be precisely controlled and the release of drug to be constant and
predicted with accuracy.
[0077] Another advantage of the devices of the present invention is
the ease of construction by more standard manufacturing techniques
into devices with different release rates. The number and size of
the passageways in the reservoir embodiment of the present
invention can be used to control diffusion properties to achieve a
desired release rate. Varying the composition of the drug core can
also be used to achieve a desired release rate. The same reservoir
can be used for implants with different release rates making it
possible to use a single manufacturing line or type of
equipment.
[0078] The following specific examples demonstrate the sustained
release drug delivery device design of the present invention.
However, it is to be understood that these examples are for
illustrative purposes only and do not purport to be wholly
definitive as to the conditions and scope.
EXAMPLE 1
[0079] A device according to the present invention is prepared. The
cup is made of silicone. The suture tab is dried uncured PVA. A
drug core is formed as a pellet composed of 2.5 mg of fluocinolone
acetonide. The drug core pellet is then inserted into the cup. The
suture tab is glued to the drug core/cup assembly with a 10%
solution of PVA. The assembly is coated with a 10% solution of PVA.
The PVA coated assembly is dried and then cured for 5 hours at
135-145.degree. C. A hole is then made at the end of the tab
opposite the end that is glued to the cup.
EXAMPLE 2
[0080] The device of example 1 above is placed in a vial with 2.0
mL of a release media of 0.1 Sodium Acetate, pH 4.2. The vial is
maintained in a 37.degree. C. bath for 24 hours. After 24 hours,
the vial is inverted to ensure homogeneity and the device is
removed to a new vial with fresh media. This process is repeated
for each day. The media is tested to determine the amount of the
drug and verifies that it is being released from the device. From
the data that is collected, the release rate of the device can be
determined.
[0081] From the foregoing description, one of ordinary skill in the
art can easily ascertain the essential characteristics of the
instant invention, and without departing from the spirit and scope
thereof, can make various changes and/or modifications of the
inventions to adapt it to various usages and conditions. As such,
these changes and/or modifications are properly, equitably, and
intended to be, within the full range of equivalence of the
following claims.
* * * * *