U.S. patent application number 11/238104 was filed with the patent office on 2006-04-27 for methods and devices for sustained in-vivo release of an active agent.
Invention is credited to Michael Delmage, John Higuchi, William I. Higuchi, Rajan Koehambilli, S. Kevin Li, Daniel Mufson, Anthony Tuitupou.
Application Number | 20060089590 11/238104 |
Document ID | / |
Family ID | 36228523 |
Filed Date | 2006-04-27 |
United States Patent
Application |
20060089590 |
Kind Code |
A1 |
Higuchi; John ; et
al. |
April 27, 2006 |
Methods and devices for sustained in-vivo release of an active
agent
Abstract
The present invention includes methods and devices for providing
sustained in-vivo release of an active agent to a subject. In some
aspects, such release may be achieved by reacting an active agent
in-vivo with a depot forming agent in order to form a sustained
release active agent depot inside the subject. The depot can then
release the active agent over a sustained period of time.
Inventors: |
Higuchi; John; (Salt Lake
City, UT) ; Li; S. Kevin; (Salt Lake City, UT)
; Higuchi; William I.; (Salt Lake City, UT) ;
Mufson; Daniel; (Napa, CA) ; Delmage; Michael;
(Napa, CA) ; Tuitupou; Anthony; (Tooele, UT)
; Koehambilli; Rajan; (Salt Lake City, UT) |
Correspondence
Address: |
THORPE NORTH & WESTERN, LLP.
8180 SOUTH 700 EAST, SUITE 200
SANDY
UT
84070
US
|
Family ID: |
36228523 |
Appl. No.: |
11/238104 |
Filed: |
September 27, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60623150 |
Oct 27, 2004 |
|
|
|
Current U.S.
Class: |
604/20 |
Current CPC
Class: |
A61P 5/38 20180101; A61P
43/00 20180101; A61P 31/04 20180101; A61P 31/10 20180101; A61N
1/0412 20130101; A61N 1/327 20130101; A61P 9/10 20180101; A61N
1/303 20130101; A61K 41/00 20130101; A61P 29/00 20180101; A61K
31/573 20130101; A61P 17/00 20180101; A61P 31/22 20180101; A61P
9/00 20180101; A61K 31/58 20130101; A61K 9/0048 20130101; A61P
27/06 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61P
35/00 20180101; A61P 31/12 20180101; A61K 31/58 20130101; A61K
45/06 20130101; A61N 1/044 20130101; A61F 9/0017 20130101; A61K
9/0009 20130101; A61K 31/573 20130101; A61P 27/02 20180101 |
Class at
Publication: |
604/020 |
International
Class: |
A61N 1/30 20060101
A61N001/30 |
Claims
1. A device for providing sustained in-vivo release of an active
agent in a subject, comprising: a first electrode assembly
configured to contain an active agent; and a second electrode
assembly configured to contain a depot forming agent; said first
and second electrode assemblies having a distance from one another
that controls the location of a sustained release depot formed
in-vivo when used to deliver the active agent and the depot forming
agent to the subject.
2. The device of claim 1, wherein the first electrode assembly and
the second electrode assembly are in an integrated single unit.
3. The device of claim 1, wherein the first electrode assembly and
the second electrode assembly are configured adjacent one another
within the integrated single unit.
4. The device of claim 1, wherein the first and second electrode
assemblies have a shape selected from the group consisting of
annular, circular, elongated, rectangular, triangular, oblong, or
combinations thereof.
5. The device of claim 4, wherein the first and second electrode
assemblies are annular.
6. The device of claim 5, wherein the first annular electrode
assembly has an inner radius and the second annular electrode
assembly is located within the inner radius of the first annular
electrode assembly.
7. The device of claim 5, wherein the first electrode assembly
includes an annular electrode.
8. The device of claim 5, wherein the second electrode assembly
includes an annular electrode.
9. The device of claim 1, wherein the first and second electrode
assemblies are separate devices.
10. The device of claim 1, wherein the first and second electrode
assemblies are configured to be coupled to an electrical current
source.
12. The device of claim 1, wherein the first and second electrode
assemblies are functionally coupled to a permselective
material.
13. The device of claim 12, wherein the permselective material is a
membrane.
14. The device of claim 1, wherein the first electrode assembly is
a plurality of first electrode assemblies and the second electrode
assembly is a plurality of second electrode assemblies.
15. The device of claim 14, wherein the plurality of first
electrode assemblies and the plurality of second electrode
assemblies are configured in a concentric orientation.
16. The device of claim 15, wherein the plurality of first
electrode assemblies and the plurality of second electrode
assemblies are configured to alternate within the concentric
orientation.
17. The device of claim 14, wherein each of the plurality of first
electrode assemblies is electrically coupled to a separate
electrode.
18. The device of claim 14, wherein each of the plurality of second
electrode assemblies is electrically coupled to a separate
electrode.
19. The device of claim 1, further comprising a third electrode
assembly configured to contain the active agent and having an
electrode coupled thereto, the third electrode assembly allowing
administration of a portion of the active agent that does not form
a depot.
20. The device of claim 19, further comprising a return electrode
functionally coupled to the third electrode assembly to facilitate
the administration of the portion of the active agent that does not
form a depot.
21. The device of claim 1, wherein the shape of the device is
configured to conform to an eye surface.
22. The device of claim 21, wherein the first and second electrode
assemblies are in contact with conjunctiva of the eye.
23. The device of claim 21, wherein a part of the device covers the
cornea with the first and second electrode assemblies in contact
with conjunctiva.
24. The device of claim 21, wherein a part of the device is
extended into a cul-de-sac under eyelids of the eye.
25. The device of claim 1, wherein the first and second electrode
assemblies are in contact with skin.
26. The device of claim 1, wherein the first and second electrode
assemblies are separated by one or more barriers positioned on an
eye surface to preclude the passage of fluid and minimize current
flow between the first and second electrode assemblies.
27. The device of claim 26, wherein the one or more barriers forms
a seal around the first and second electrode assemblies.
28. The device of claim 27, wherein the one or more barriers is a
lip-seal.
29. A method of locating a sustained release depot of an active
agent in a subject, comprising: positioning a first reservoir
having a first electrode and containing the active agent on an area
of body surface of the subject; and positioning a second reservoir
having a second electrode and containing a depot forming agent on
an area of body surface of the subject at an inter-electrode
distance from the first electrode that dictates the location of the
depot formation within the subject.
30. The method of claim 29, wherein the active agent and the depot
forming agent are administered simultaneously.
31. The method of claim 29, wherein the active agent is
administered prior to the depot forming agent.
32. The method of claim 29, wherein the active agent is
administered after the depot forming agent.
33. The method of claim 29, wherein the inter-electrode distance
controls the depth and extent of penetration of the depot.
34. The method of claim 29, wherein the inter-electrode distance is
less than about 1 mm.
35. The method of claim 29, wherein the inter-electrode distance is
from about 2 mm to about 4 mm.
36. The method of claim 29, wherein the inter-electrode distance is
from about 1 mm to about 2 mm.
37. The method of claim 29, wherein the inter-electrode distance is
greater than about 4 mm.
38. The method of claim 29, wherein the depot is comprised of the
active agent.
39. The method of claim 29, wherein the depot is comprised of a
derivative of the active agent.
40. The method of claim 29, wherein the second electrode is the
second reservoir.
Description
PRIORITY DATA
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 60/623,150, filed on Oct. 27, 2004,
which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to systems, methods, and
devices for in-vivo sustained release of an active agent following
minimally invasive or noninvasive delivery thereof through a
localized region of an individual's body tissue, particularly the
eye. Accordingly, the present invention involves the fields of
chemistry, pharmaceutical sciences, and medicine, particularly
ophthalmology.
BACKGROUND OF THE INVENTION
[0003] Posterior and intermediate eye diseases that require ocular
drug delivery to prevent blindness include uveitis, bacterial and
fungal endophthalmitis, age-related macular degeneration, viral
retinitis, and diabetic retinopathy, among others. For example, the
reported incidence of posterior uveitis is more than 100,000 people
in the United States. If left untreated, uveitis leads to
blindness. It is responsible for about 10 percent of all visual
impairment in the U.S. and is the third leading cause of blindness
worldwide.
[0004] Treatments of intermediate and posterior uveitis are
complicated by the inaccessibility of the posterior eye to
topically applied medications. Current therapy for intermediate and
posterior uveitis requires repeated periocular injections and/or
high-dose systemic therapy with corticosteroids. Injections are
usually preferred to systemic drug administration because the
blood/retinal barrier impedes the passage of most drugs from the
systemically circulating blood to the interior of the eye.
Therefore large systemic doses are needed to treat intermediate and
posterior uveitis, which often result in systemic toxicities
including immunosuppression, adrenal suppression, ulcerogenesis,
fluid and electrolyte imbalances, fat redistribution and
psychological disorders.
[0005] Endophthalmitis affects approximately 10,000 people in the
United States each year. Endophthalmitis is typically caused by
gram-positive bacteria after ocular surgery or trauma, but it can
also be fungal or viral in nature. The current method of treating
endophthalmitis is direct injection of antimicrobials into the
vitreous. Intravitreal injections are necessary because periocular
injections and systemic administration do not deliver efficacious
amounts of antibiotics to the target sites in the eye. Age-related
macular degeneration (AMD) is the leading cause of irreversible
loss of central vision in patients over the age of 50. AMD affects
more than 15 million people worldwide.
[0006] Treatments of posterior eye diseases require intravitreal
and periocular injections or systemic drug administration. Systemic
administration is usually not preferred because of the resulting
systemic toxicity as discussed above. While intravitreal and
periocular injections are preferable to systemic administration,
the half-life of most injected compounds in the vitreous is
relatively short, usually on the scale of just a few hours.
Therefore, intravitreal injections require frequent administration.
The repeated injections can cause pain, discomfort, intraocular
pressure increases, intraocular bleeding, increased chances for
infection, and the possibility of retinal detachment. The major
complication of periocular injections is accidental perforation of
the globe, which causes pain, retinal detachment, ocular
hypertension, and intraocular hemorrhage. Other possible
complications of periocular injections include pain, central
retinal artery/vein occlusion, and intraocular pressure increases.
Therefore, these methods of ocular drug delivery into the posterior
of the eye have significant limitations and major drawbacks. In
addition, injections are very poorly accepted by patients. These
methods also involve high healthcare cost due to the involvement of
skilled and experienced physicians to perform the injections.
[0007] Ocular iontophoresis is a noninvasive technique used to
deliver compounds of interest into the interior of a patient's eye.
In practice, two iontophoretic electrodes are used in order to
complete an electrical circuit. In traditional, transscleral
iontophoresis, at least one of the electrodes is considered to be
an active iontophoretic electrode, while the other may be
considered as a return, inactive, or indifferent electrode. The
active electrode is typically placed on an eye surface. The
compound of interest is transported at the active electrode across
the tissue when a current is applied to the electrodes through the
tissue. Compound transport may occur as a result of a direct
electrical field effect (e.g., electrophoresis), an indirect
electrical field effect (e.g., electroosmosis), electrically
induced pore or transport pathway formation (electroporation), or a
combination of any of the foregoing. Examples of currently known
iontophoretic devices and methods for ocular drug delivery may be
found in U.S. Pat. Nos. 6,319,240; 6,539,251; 6,579,276; 6,697,668,
and PCT Publication Nos. WO 03/030989 and WO 03/043689, each of
which is incorporated herein by reference.
[0008] Despite its apparent advantages, iontophoresis is really
just a method of limiting the invasiveness of drug transport into
the globe's interior. Once inside the eye, the pharmacokinetics of
water soluble compounds are identical to those following
intravitreal injections i.e. their half-lives are on the order of a
few hours. Therefore, in many cases, traditional iontophoresis must
be repeated as frequently as intravitreal injections, leading to
patient inconvenience, increased costs, and increased possibility
of untoward effects caused by the iontophoretic treatment
itself.
[0009] Various techniques have been proposed to provide sustained
release of a compound in the eye for the treatments of intermediate
and posterior eye diseases. For example, the implantation of
biodegradable polymers within the eye is disclosed and discussed in
U.S. Pat. Nos. 5,443,505; 5,766,242; 5,824,072; 6,331,313; and
6,699,493, each of which is incorporated herein by reference. While
potentially effective, these methods are invasive, and therefore
pose a high degree of risk and discomfort to the patient.
[0010] The issue with respect to dosing frequency is an issue that
not only plagues treatment of occular diseases, but is problematic
for most other pharmacotherapy regimens. Most regimens of oral
dosage formulations must be administered at least one a day, and
often multiple times per day. Most topical dosing regimens also
share this problem and require a daily application of the topical
formulation. While transdermal patches can allow regimens with much
less frequent dosing, transdermal patches suffer from other issues
because of the fact that they are worn on the skin, such as
visibility to others, skin irritation, and delamination issues.
Furthermore, even with their potential to provide long term drug
delivery, because of the skin irritation and delamination issues,
the longest lasting patches currently on the market typically only
last for 7 days and more often only last for 3-4 days before a new
patch must be administered.
[0011] As such, devices, systems, and methods which are capable of
minimally invasively, or non-invasively delivering drugs,
particularly to the interior of the eye, without the need for
frequent administration continue to be sought.
SUMMARY OF THE INVENTION
[0012] Accordingly, the present invention provides systems,
devices, and methods of providing sustained in-vivo release of an
active agent in a subject, with only minimal to noninvasiveness. In
one aspect, such a method may include delivering the active agent
to the subject, reacting the active agent with a depot forming
agent inside the subject to precipitate the active agent and create
an active agent sustained release depot, and allowing the depot to
release the active agent over a sustained period of time. Exemplary
reactions that can be used in order to create the sustained release
depot may include without limitation, ionic associations between
the active agent and the depot forming agent, reactions that cleave
a portion of the active agent and thus lower its aqueous
solubility, and induction of physiological environment influences
that cause formation of a depot, or an effective depot (i.e. create
a sustained release effect) among others. In many cases, the
formation of the sustained release depot may be through in-vivo
precipitation of the active by any of the above-recited mechanisms
or another mechanism.
[0013] One important aspect of the present invention is that the
active agent and depot forming agent are separately administered to
the subject. In other words, they are not in physical contact with
one another when delivered, such as in a mixed solution or
suspension. However, it should be noted, that while the active
agent and depot forming agents are not delivered in physical
contact with one another, they may in some aspects be delivered
from the same device. Furthermore, such agents may be administered
at the same time, through the same route, or at different times and
through different routes, as long as they react in-vivo to form the
sustained release depot.
[0014] In some aspects, the depot forming agent may be an
endogenous substance of the subject's body, and though it can be
administered, in some cases need not be. In this instance, only the
active agent would be delivered.
[0015] The particular active agent to be delivered may be a variety
of substances depending on the particular treatment to be effected.
Such substances may include drugs in various forms, including
prodrugs thereof, as required in order to provide convenient and
effective minimally invasive, or non-invasive delivery, followed by
formation of the sustained release depot in-vivo. Exemplary active
agents are enumerated further herein.
[0016] Likewise, a variety of depot forming agents may be used in
order to facilitate the formation of the in-vivo sustained release
depot. Considerations in selecting a specific depot forming agent
may include without limitation, the particular active agent being
used, the physiologic area and type of administration, and the
other ingredients to be included in the delivery formulation.
Examples of specific depot forming agents that may be used are
further enumerated herein.
[0017] In yet another aspect, the formation of the in-vivo depot
may be aided by immobilizing the active agent in the subject's
body. Immobilization thusly may prevent the active agent from
circulating to other portions of the body before the sustained
release depot is formed. A number of mechanisms for immobilizing
the active agent can be used and will be recognized by those of
ordinary skill in the art, such as the use of vasoconstrictors to
constrict blood vessels in the vicinity of delivery. Similar
mechanisms can be used to immobilize the depot forming agent in the
subject's body.
[0018] In addition to the methods for forming an in-vivo sustained
release depot, the present invention additionally encompasses a
medicinal depot formulation in a subject formed by the methods
articulated herein. In one aspect, such a depot may include a mass
of active agent in precipitated form which becomes solubilized and
releases active agent over a sustained period of time.
[0019] The present invention additionally encompasses devices for
administration of an active agent and a depot forming agent which
can be used to carry out the methods recited herein. In one aspect,
such a device for providing sustained in-vivo release of an active
agent in a subject may include a first electrode assembly
configured to contain an active agent, and a second electrode
assembly configured to contain a depot forming agent, the first and
second electrodes having a distance from one another that controls
the location of a sustained release depot formed in-vivo when used
to deliver the active agent and the depot forming agent to the
subject.
[0020] Additionally, the present invention encompasses methods of
delivering a sustained release depot of an active agent to a
specific location in a subject. In one aspect, such a method may
include positioning a first electrode assembly containing the
active agent on a body surface of the subject, and positioning a
second electrode assembly containing a depot forming agent on an
area of a body surface of the subject at an inter-electrode
distance from the first electrode that dictates the location of the
depot formation within the subject.
[0021] The present invention additionally includes methods of
treating various conditions and diseases using the devices,
systems, and methods recited herein. In one particular aspect, such
a condition or disease may be an ocular condition or disease.
Examples of such conditions include without limitation, macular
edema, age related macular degeneration, anterior, intermediate,
and posterior uveitis, HSV retinitis, diabetic retinopathy,
bacterial, fungal, or viral endophthalmitis, eye cancers,
glioblastomas, glaucoma, and glaucomatous degradation of the optic
nerve.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a front view of an iontophoretic device in
accordance with an aspect of the present invention.
[0023] FIG. 2 is a front view of an iontophoretic device in
accordance with another aspect of the present invention.
[0024] FIG. 3 is a front view of an iontophoretic device in
accordance with yet another aspect of the present invention.
[0025] FIG. 4 is a graphical representation of the dissolution
profiles of three depot formulations in accordance with various
embodiments of the present invention as compared to the dissolution
profile for a control.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Before the present systems and methods for sustained release
ocular drug delivery are disclosed and described, it is to be
understood that this invention is not limited to the particular
process steps and materials disclosed herein, but is extended to
equivalents thereof, as would be recognized by those ordinarily
skilled in the relevant arts. It should also be understood that
terminology employed herein is used for the purpose of describing
particular embodiments only and is not intended to be limiting.
[0027] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and, "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a polymer" includes reference to
one or more of such polymers, and "an excipient" includes reference
to one or more of such excipients.
[0028] Definitions
[0029] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set forth below.
[0030] As used herein, "formulation" and "composition" may be used
interchangeably herein, and refer to a combination of two or more
elements, or substances. In some embodiments a composition may
include an active agent, an excipient, or a carrier to enhance
delivery or depot formation.
[0031] As used herein, "active agent," "bioactive agent,"
"pharmaceutically active agent," and "pharmaceutical," may be used
interchangeably to refer to an agent or substance that has
measurable specified or selected physiologic activity when
administered to a subject in a significant or effective amount. It
is to be understood that the term "drug" is expressly encompassed
by the present definition as many drugs and prodrugs are known to
have specific physiologic activities. These terms of art are
well-known in the pharmaceutical, and medicinal arts. Examples of
drugs useful in the present invention include without limitation,
steroids, antibacterials, antivirals, antifingals, antiprotozoals,
antimetabolites, immunosuppressive agents, VEGF inhibitors, ICAM
inhibitors, antibodies, protein kinase C inhibitors,
chemotherapeutic agents, neuroprotective agents, nucleic acid
derivatives, aptamers, proteins, enzymes, peptides, and
polypeptides.
[0032] As used herein "prodrug" refers to a molecule that will
convert into a drug (its commonly known pharmacological active
form). Prodrugs themselves can also be pharmacologically active,
and therefore are also expressly included within the definition of
an "active agent" as recited above. For example, dexamethasone
phosphate can be classified as the prodrug of dexamethansone, and
triamcinolone acetonide phosphate can be classified as a prodrug of
triamcinolone acetonide.
[0033] As used herein, "effective amount," and "sufficient amount"
may be used interchangeably and refer to an amount of an ingredient
which, when included in a composition, is sufficient to achieve an
intended compositional or physiological effect. Thus, a
"therapeutically effective amount" refers to a non-toxic, but
sufficient amount of an active agent, to achieve therapeutic
results in treating a condition for which the active agent is known
to be effective. It is understood that various biological factors
may affect the ability of a substance to perform its intended task.
Therefore, an "effective amount" or a "therapeutically effective
amount" may be dependent in some instances on such biological
factors. Further, while the achievement of therapeutic effects may
be measured by a physician or other qualified medical personnel
using evaluations known in the art, it is recognized that
individual variation and response to treatments may make the
achievement of therapeutic effects a subjective decision. The
determination of an effective amount is well within the ordinary
skill in the art of pharmaceutical sciences and medicine. See, for
example, Meiner and Tonascia, "Clinical Trials: Design, Conduct,
and Analysis," Monographs in Epidemiology and Biostatistics, Vol. 8
(1986), incorporated herein by reference.
[0034] As used herein, "sclera" refers to the sclera tissue in the
eye or the conjunctiva between the limbus and the fornix on the
surface of the eye, which is the white part of the eye. "Sclera" is
also used in referring to other eye tissues.
[0035] As used herein, "subject" refers to a mammal that may
benefit from the administration of a composition or method as
recited herein. Most often, the subject will be a human but can be
of other animals such as dogs and cats.
[0036] As used herein, "administration," and "administering" refer
to the manner in which an active agent, or composition containing
such, is presented to a subject. As discussed herein, the present
invention is primarily concerned with iontophoretic delivery,
especially with occular delivery.
[0037] As used herein, "noninvasive" refers to a form of
administration that does not rupture or puncture a biological
membrane or structure with a mechanical means across which a drug
or compound of interest is being delivered. A number of noninvasive
delivery mechanisms are well recognized in the transdermal arts
such as patches, and topical formulations. Many of such
formulations may employ a chemical penetration enhancer in order to
facilitate non-invasive delivery of the active agent. Additionally,
other systems or devices that utilize a non-chemical mechanism for
enhancing drug penetration, such as iontophoretic devices are also
known. "Minimally invasive" refers to a form of administration that
punctures a biological membrane or structure but does not cause
excessive discomfort to the subjects and severe adverse effects.
Examples of "minimally invasive" drug delivery are microneedle,
laser, or heat punctuation in transdermal delivery and periocular
injections in ocular delivery.
[0038] As used herein, "depot" refers to a temporary mass inside a
biological tissue or system, which includes a drug that is released
from the mass over a period of time. In some aspects, a depot may
be formed by the interaction of an active agent with a depot
forming agent, such as a complexing ion which will form an active
agent complex that is less soluble than the active agent by itself,
and thus precipitate in-vivo.
[0039] As used herein, the term "body surface" refers to an outer
tissue surface of the subject such as tissue surfaces encountered
in ocular and transdermal delivery, or mucosal tissues lining a
body cavity such as the mouth for buccal delivery or vaginal tract
for vaginal delivery. The term "skin" refers to an outer tissue
surface of the subject. It is therefore intended that skin also
refer to mucosal and epithelial tissues, as well as the outer
surfaces of the eye.
[0040] As used herein, the term "electrode assembly" refers to an
assembly of at least one electrode and at least one reservoir.
[0041] As used herein, the term "reservoir" refers to a body or a
mass that may contain a depot forming agent or an active agent. As
such, a reservoir may include any structure that may contain a
liquid, as well as solid structures made up of the agent to be
delivered. In some cases, an electrode may be considered to be a
reservoir.
[0042] As used herein, the term "reacting" refers to any force,
change in environmental conditions, presence or encounter of other
chemical agent, etc. that alters the active agent. For example,
"reacting" between the active agent and the depot forming agent can
be physical or chemical interactions.
[0043] As used herein, the term "precipitate" refers to anything
less than fully solubilized. As such, a precipitate can include not
only crystals, but also gels, semi-solids, increased molecular
weight, etc.
[0044] Concentrations, amounts, solubilities, and other numerical
data may be expressed or presented herein in a range format. It is
to be understood that such a range format is used merely for
convenience and brevity and thus should be interpreted flexibly to
include not only the numerical values explicitly recited as the
limits of the range, but also to include all the individual
numerical values or sub-ranges encompassed within that range as if
each numerical value and sub-range is explicitly recited.
[0045] As an illustration, a numerical range of "about 1 to about
5" should be interpreted to include not only the explicitly recited
values of about 1 to about 5, but also include individual values
and sub-ranges within the indicated range. Thus, included in this
numerical range are individual values such as 2, 3, and 4 and
sub-ranges such as from 1-3, from 2-4, and from 3-5, etc. This same
principle applies to ranges reciting only one numerical value.
Furthermore, such an interpretation should apply regardless of the
breadth of the range or the characteristics being described.
[0046] The Invention
[0047] The present invention provides methods, devices, and
formulations for forming in-vivo a sustained release depot in a
subject. Such a depot may be created inside the tissue or in an
organ of the subject, from which a therapeutic agent is released on
a sustained basis. One example of an organ where such an
administration method may be beneficial is the eye. It should be
noted, however, that it is intended that the scope of the present
claims cover all tissues where aspects of the present invention may
be effectively carried out.
[0048] In one aspect the sustained release depot may be formed by
the reaction of an active agent with a depot forming agent in a
body tissue, for example an organ such as the eye, following
delivery of the active agent to the subject. The delivery of the
active agent may be by any noninvasive or minimally invasive means
known, and may include active delivery or passive delivery. The
depot forming agent may also be delivered to the subject, or it may
be an endogenous substance that reacts with the active agent. In
either case, the depot forming agent and the active agent do not
interact with one another until the active agent is delivered into
the subject. As such, in most cases the active agent and the depot
forming agent will be separated until both are located in-vivo. If
the depot forming agent is to be delivered to the subject, then
both agents should be delivered separately. Endogenous depot
forming agents will, of course, not come into contact with the
active agent until administration occurs. Thus an in-vivo reaction
between the active agent and the depot forming agent will cause the
active agent or a derivative thereof to form a depot. In one aspect
such a depot forming mechanism may be a change in the solubility of
the active agent, thus causing precipitation and subsequent depot
formation. This depot of active agent complex is then able to
deliver a therapeutic compound to the biological system over time.
Such sustained delivery can include local or systemic delivery of
the active agent to the subject. As such, in one embodiment, a
depot forming agent may be created at a desired location in a
subject, and the active agent may be systemically administered and
may "collect" at the depot forming agent to form a depot as the
active agent circulates through the body. In another aspect, the
depot forming agent may not react directly with the active agent,
but still functions to facilitate the formation of a sustained
release depot. In such a case, the depot forming agent may react
with an area of a local environment to cause an alteration therein.
The active agent would then react with the altered area of the
local environment to form a depot as a result of the changes
facilitated by the depot forming agent.
[0049] As a sustained release mechanism, it will be recognized that
the depot formulation of the present invention generally has an
in-vivo solubility that is lower than that of the active agent by
itself. In this way, as the active agent dissolves out of the depot
over time, a sustained therapeutic effect may be obtained. Further,
since the active agent in the depot is unable to have a therapeutic
effect until released therefrom, the solubility properties of the
depot limit potential toxicity or overdose concerns that would
normally arise when delivering a sufficient amount of drug to last
over a prolonged period.
[0050] In a detailed aspect, one method in accordance with the
present invention may include: a) delivering an active agent to the
subject to a localized physiologic region, for example in an organ
such as the eye, using iontophoresis; b) reacting the active agent
with a depot forming agent inside the subject to precipitate the
active agent and create an active agent sustained release depot;
and c) allowing the depot to release the active agent over a
sustained period of time. The rate of drug release is related to
the solubility of the depot and follows a diffusion-controlled
process. This method is particularly suited for iontophoretic
transport of a therapeutic compound and sustaining its level in the
eye by means of sustained release of the compound in the eye for
the treatment of anterior, intermediate, and posterior eye disease.
In addition to iontophoresis, the active agent may be delivered by
any means known to one of ordinary skill in the art, including
sonophoresis, electroporation, passive diffusion, etc.
[0051] In another aspect, a method of providing non-invasive drug
delivery with subsequent sustained release of the delivered drug to
subject may include forming a depot of an active agent in the
subject by non-invasively administering the active agent and a
depot forming agent to the subject, and allowing release of the
active agent from the depot over a period of time.
[0052] Though numerous conditions would benefit from the methods
and devices of the present invention, they are particularly well
suited for the treatment of ocular diseases such as direct,
combinatory, and adjunctive therapies. This is because of the
relatively high permeability of the eye tissues and the large
aqueous compartments in the eye. Examples of eye diseases include
without limitation, macular edema, age related macular
degeneration, anterior, intermediate, and posterior uveitis, HSV
retinitis, diabetic retinopathy, bacterial, fungal, or viral
endophthalmitis, eye cancers, glioblastomas, glaucoma, and
glaucomatous degradation of the optic nerve. Additionally, skin
diseases such as herpes, cancer, and psoriasis may be effectively
treated by the various aspects described herein. Other conditions
that would benefit from the methods and devices of the present
invention are diseases that can be benefited from local and
systemic transdermal delivery such as in the treatments of pain and
muscle and joint inflammation.
[0053] For effective sustained release in the tissues surrounded by
blood circulation such as the conjunctiva, uvea, and sclera, the
depot should have low aqueous solubility. The aqueous solubility of
the active agent is preferred to be below 10.sup.-4 M or the
solubility product (Ksp) is preferred to be below 10.sup.-8 M.sup.2
for a 1:1 active agent to depot forming agent complex to achieve
sustained release of at least approximately one day. The solubility
of the depot complex should not be too high for long sustained
release of the active agent and not too low to provide a
therapeutic effect. The preferred solubility of the active agent is
in the range from 10.sup.-12 to 10.sup.-4 M depending on the
physicochemical properties and therapeutic actions of the active
agent compound. The solubility of the active agent or the depot
complex is not the only sustained release parameter. The rate of
active agent release is also related to the amount of active agent
deposited in the tissue, which can be controlled by the delivery
method such as iontophoresis, for a desired rate of active agent
release. Other parameters that affect the release of the active
agent compounds are the diffusion coefficient of the active agent
in the tissue, the porosity of the tissue, the tortuosity of the
tissue, and the clearance of the blood vasculature. An external
means such as heat and vibration can also be used to facilitate the
rate of release. In addition, the formation of the depot complex
should occur rapidly to prevent pre-complexation clearance of the
active agent or the depot forming agent. The depot forming agent
and active agent concentrations required for the nucleation of the
depot should be low.
[0054] In use, the depot forming agent may act to lower the aqueous
solubility of the active agent. By altering the solubility
properties thusly, the active agent is caused to precipitate
in-vivo and form a depot of the agent which can then release drug
to the subject over an extended period of time. A variety of
mechanisms for lowering the solubility of the active agent may be
used. In one aspect, the depot forming agent may form a complex
with the active agent that has a solubility that is lower than that
of the active agent by itself.
[0055] A wide range of active agents may be used in the present
invention as will be recognized by those of ordinary skill in the
art. In fact, nearly any agent that can react with a depot forming
agent in-vivo to form a depot may be used. Examples of the active
agents that may be used in the treatment of various conditions
include, without limitation, analeptic agents, analgesic agents,
anesthetic agents, antiasthmatic agents, antiarthritic agents,
anticancer agents, anticholinergic agents, anticonvulsant agents,
antidepressant agents, antidiabetic agents, antidiarrheal agents,
antiemetic agents, antihelminthic agents, antihistamines,
antihyperlipidemic agents, antihypertensive agents, anti-infective
agents, antiinflammatory agents, antimigraine agents,
antineoplastic agents, antiparkinsonism drugs, antipruritic agents,
antipsychotic agents, antipyretic agents, antispasmodic agents,
antitubercular agents, antiulcer agents, antiviral agents,
anxiolytic agents, appetite suppressants, attention deficit
disorder and attention deficit hyperactivity disorder drugs,
cardiovascular agents including calcium channel blockers,
antianginal agents, central nervous system ("CNS") agents,
beta-blockers and antiarrhythmic agents, central nervous system
stimulants, diuretics, genetic materials, hormonolytics, hypnotics,
hypoglycemic agents, immunosuppressive agents, muscle relaxants,
narcotic antagonists, nicotine, nutritional agents,
parasympatholytics, peptide drugs, psychostimulants, sedatives,
steroids, smoking cessation agents, sympathomimetics,
tranquilizers, vasodilators, .beta.-agonists, and tocolytic agents,
and mixtures thereof.
[0056] Additionally, further examples of active agents may include
steroids, aminosteroids, antibacterials, antivirals, antifungals,
antiprotozoals, antimetabolites, VEGF inhibitors, ICAM inhibitors,
antibodies, protein kinase C inhibitors, chemotherapeutic agents,
immunosuppressive agents, neuroprotective agents, analgesic agents,
nucleic acid derivatives, aptamers, proteins, enzymes, peptides,
polypeptides and mixtures thereof. Specific examples of useful
antiviral active agents include acyclovir or derivatives
thereof.
[0057] Specific examples of active agents may also include
hydromorphone, dexamethasone phosphate, amikacin, oligonucleotides,
F.sub.ab peptides, PEG-oligonucleotides, salicylate, tropicamide,
methotrexate, 5-fluorouracil, squalamine, triamcinolone acetonide,
diclofenac, combretastatin A4, mycophenolate mofetil, mycophenolic
acid, and mixtures thereof.
[0058] Under a number of circumstances, the active agent used may
be a prodrug, or in prodrug form. Examples of advantageous use of a
prodrug may include when the drug itself does not properly interact
with the depot forming agent to form a depot, or when an even
lengthier administration period is desired, among others. Prodrugs
for nearly any desired active agent will be readily recognized by
those of ordinary skill in the art. Additionally, prodrugs with
high electromobility which metabolize into drugs with a low aqueous
solubility may be advantageously used as both the drug and the
depot forming agent. In this case, the prodrug may be
iontophoretically delivered and then precipitate into a depot
in-vivo upon the metabolism (e.g. enzymatic cleavage) of the
prodrug into the drug.
[0059] Though any prodrug capable of forming a depot would be
considered to be within the scope of the present invention,
examples may include the derivatives of steroids, antibacterials,
antivirals, antifungals, antiprotozoals, antimetabolites, VEGF
inhibitors, ICAM inhibitors, antibodies, protein kinase C
inhibitors, chemotherapeutic agents, immunosuppressive agents,
neuroprotective agents, analgesic agents, nucleic acid derivatives,
aptamers, proteins, enzymes, peptides, polypeptides, and mixtures
thereof. One specific example of a steroid derivative may include
triamcinolone acetonide phosphate or other derivatives of
triamcinolone acetonide, dexamethasone phosphate. For example, it
may be preferable to label a steroid with one or more phosphate,
sulfate, or carbonate functional groups, so the prodrug can be
effectively delivered into the eye and form a complex with the
precipitating ion.
[0060] In yet another aspect, an electrically mobile prodrug of a
low solubility drug in iontophoresis can be used to create a
sustained release system in the eye. Because the prodrug has high
electromobility, it is effectively delivered into the eye. The
prodrug then converts into the low solubility drug in the eye and
the insoluble drug precipitates in the eye. The drug in solid state
in the eye will be slowly released into the eye and provide an
ocular sustained release condition.
[0061] For a relatively high solubility drug, a prodrug with low
solubility and a pro-prodrug with high electromobility can be used.
The high electromobility pro-prodrug allows the effective
iontophoretic delivery of the pro-prodrug. Once in the eye, the
pro-prodrug is converted into a prodrug which is insoluble and
precipitates in the eye. The conversion of the prodrug to the drug
will slowly release the drug from the precipitate and provide a
sustained release condition.
[0062] Various reactions are contemplated that result in a
sustained release depot being formed. The reaction between the
active agent and the depot forming agent may include an ionic
association. Accordingly, in one aspect the depot forming agent can
have at least one opposite charge to at least one of the charged
groups on the active agent. In another aspect, the depot forming
agent can have more than one charge and will be capable of being
juxtaposed with more than one charge on the active agent. In yet
another aspect, the charges on the depot forming agent can be
polyvalent, allowing more than one active agent ion to enter the
depot complex. This allows stronger associations between complexing
depot forming agents, thereby lowering the solubility constant of
the depot complex, Ksp, thus increasing the duration of therapy. In
one aspect, the depot forming agent may be an ion. Examples of
useful depot forming agents include without limitation, Ca.sup.2+,
Sn.sup.2+, Fe.sup.2+, Fe.sup.3+ Mn.sup.2+, Mg.sup.2+, Zn.sup.2+,
NH.sub.4.sup.+, ions of the transition metals in the periodic
tables, PO.sub.4.sup.3-, CO.sub.3.sup.2-, SO.sub.4.sup.2-, organic
cations, organic anions, polyvalent metals, chelation agents, and
ionic pharmaceutical excipients generally used in the
pharmaceutical industry or known to the people skilled in the art.
The depot forming agents preferably have more than one charge for
effective iontophoretic delivery and for effectively precipitating
the active agent. In one aspect, the depot forming agent may have
an adequate ionic charge for both effective iontophoretic delivery
and effectively reacting with the active agent to form the
sustained release depot.
[0063] The ratio of depot forming agent to active agent could be
one to one. However, in the case of polyvalent depot forming
agents, more than one active agent may complex with the same depot
forming agent to form a depot complex. In one aspect, the depot
complex may have a ratio of depot forming agent to active agent of
from about 1:1 to about 1:4. In another aspect, the ratio may be
about 1:1. In a further aspect, the ratio may be about 1:2. In yet
another aspect, the ratio may be about 1:3. In yet a further
aspect, the ratio may be about 1:4. In one more aspect, the ratio
of depot forming agent to active agent may be from about 4:1 to
about 1:4.
[0064] Two or more depot forming agents can be used at the same
time to form the sustained release depot. With multiple depot
forming agents, the concentration of each depot forming agent for
precipitating the same total amount of active agent in the eye can
be reduced. This effectively reduces the concentrations of the
depot forming agent in the eye during and after delivery, so the
depot forming agent concentrations are always below the levels that
may cause adverse effects in the eye. The use of multiple depot
forming agents also provides other advantages. For example,
sustained release can be further controlled by using multiple depot
forming agents that have different depot complex-Ksp values.
[0065] Other examples of depot forming agents may include, without
limitation, catalysts, polymerization initiators, pegylating
agents, solvents, pH, thermal, or ionic strength sensitive
polymers, active agents used in the treatment of eye diseases,
aminosteroids such as squalamine, derivatives of triamcinolone
acetonide, and combinations and mixtures thereof.
[0066] Typically, the depot forming agent is non-toxic in the body
and the eye. The solid depot complex should be non-toxic and should
not cause any side effects in the eye. The formation of the depot
complex should also occur rapidly to prevent pre-complexation
clearance of the active agent or depot forming agent from the
vitreous. Additionally, the depot forming agent and active agent
concentrations required for the nucleation of the depot should be
low. The depot complex has decreased solubility and is not cleared
or has reduced clearance from the eye in its complex form. As such,
the clearance of the depot forming agent and the active agent in
the eye should be relatively slow compared with the precipitation
process to allow the completion of depot formation.
[0067] In another aspect, the reaction process can result in depot
complexes in the form of a gel or aggregation, and may
alternatively be crystalline or amorphous in form. In this case,
the gel should not create any unwanted side effects in the eye. For
example, in one specific aspect the depot may be a gel created by a
complex of an active agent such as triamcinolone acetonide
phosphate and a depot forming agent such as Ca.sup.2+ ion. In some
aspects, the particulate size within the depot may be controlled or
adjusted so as to determine the release rate of the drug.
Additionally, in yet another aspect, the reaction process may be a
result of the cleavage of a portion of the active agent, thus
lowering the aqueous solubility of the active agent. One example of
such a process may include the enzymatic cleavage of the active
agent. As such, the depot forming agent would be the enzyme.
[0068] As has been discussed, in one aspect the depot forming agent
may be an endogenous substance in the subject's body. Examples of
such agents may include without limitation, various enzymes,
ascorbate, lactate, citrate, various amino acids, calcium,
magnesium, zinc, iron, chloride, fluoride, as well as ions found in
the tissues and vitreous of the eye. In such cases, the presence of
such a substance inside the body may be relied upon in order to
form the depot and the active agent only will be delivered.
Alternatively, such substances may be delivered to the body if they
are not thought to be present in sufficient concentration to form a
depot.
[0069] An example of the compound of interest is triamcinolone
acetonide and its derivatives (prodrugs) such as triamcinolone
acetonide phosphate. Triamcinolone acetonide can be obtained from
the metabolism and hydrolysis of triamcinolone acetonide phosphate.
Due to the low aqueous solubility of triamcinolone acetonide, the
precipitation of triamcinolone acetonide in the tissue provides a
sustained release system after the delivery of triamcinolone
acetonide phosphate. However, triamcinolone acetonide phosphate may
be cleared quickly from the delivery site and may not provide long
enough residence in the tissue for the metabolism and hydrolysis of
triamcinolone acetonide phosphate. In one aspect, triamcinolone
acetonide phosphate can first be precipitated by a counterion in
the tissue, which has higher aqueous solubility than that of
triamcinolone acetonide. The triamcinolone acetonide
phosphate-counterion complex has low enough solubility to provide
tissue residence for triamcinolone acetonide
phosphate-to-triamcinolone acetonide conversion. When triamcinolone
acetonide phosphate is released from the precipitate depot,
triamcinolone acetonide phosphate is converted to triamcinolone
acetonide. The solubility of triamcinolone acetonide is low and
will precipitate in the tissue to provide further sustained release
capability. In another aspect, the precipitating process can result
in ion-drug complexes in the form of a gel or aggregation. The gel
or aggregation allows enzyme degradation and conversion to occur
before drug clearance. Gel formation has been observed when
dexamethasone phosphate (a prodrug of dexamethasone) or
triamcinolone acetonide phosphate was mixed with calcium ions.
[0070] In some cases, it is not undesirable to have only a portion,
even a small fraction of the total active agent delivered react
with the depot forming agent during iontophoresis treatment. In
such a case, a relatively high free active agent concentration in
the eye as a result of ocular iontophoretic drug delivery provides
a "burst" therapeutic effect in the first few hours (or days) after
the initial iontophoretic treatment. After this initial "burst"
treatment phase, the depot complex releases the active agent at a
relatively slow rate and sustains a relatively low but therapeutic
effective drug concentration in the eye for up to a few months
after the initial treatment.
[0071] It may be beneficial for the application situs to be sealed
with a sealant following delivery of the active agent and/or the
depot forming agent. This procedure may protect the tissue in which
iontophoretic administration occurred. Sealants may include any
known to one of ordinary skill in the art, including gels, glues
and impermeable polymeric or resinous membranes.
[0072] In some cases, depot formation may be hampered by the
in-vivo movement of either the depot forming agent or the active
agent in the eye. It is therefore contemplated that various means
for restricting or slowing such movement may improve the
effectiveness of depot formation. In one aspect, the in-vivo
movement may be restricted by constriction of the blood vessels
exiting an area in which active agent precipitation or other depot
forming process occurs. Such constriction may be induced by the
administration of a vasoconstricting agent. Such a vasoconstrictor
may be administered actively by iontophoretic or other means, or it
may be delivered passively. Specific non-limiting examples of
vasoconstricting agents may include .alpha.-agonists such as
naphazoline, and tetrahydrozoline, sympathomimetics such as
phenylethylamine, epinephrine, norepinephrine, dopamine,
dobutamine, colterol, ethylnorepinephrine, isoproterenol,
isoetharine, metaproterenol, terbutaline; metearaminol,
phenylephrine, tyramine, hydroxyamphetamine, ritrodrine,
prenalterol, methoxyamine, albuterol, amphetamine, methamphetamine,
benzphetamine, ephedrine, phenylpropanolamine, methentermine,
phentermine, fenfluramine, propylhexedrine, diethylpropion,
phenmetrazine, and phendimetrazine. Vasocontricting agents can be
administered either before or concurrently with the administration
of the active agent. Though administration of the vasoconstrictor
may occur following administration of the active agent, the results
may be less effective than prior or concurrent administration.
Additionally, in some aspects, the vasoconstricting agent may have
the same polarity as the active agent and administered concurrently
with the active agent. Similarly, the vasoconstricting agent may
have the same polarity as the depot forming agent and administered
with the depot forming agent.
[0073] In another aspect of the present invention, in-vivo movement
may be restricted by constriction of blood vessels as a result of
the application of physical force to the blood vessels.
[0074] Various aspects of the present invention are contemplated to
encompass iontophoretic devices that function to form a sustained
release depot. Accordingly, in one aspect a device for providing
sustained in-vivo release of an active agent in a subject is
described. Such a device may include a first electrode assembly
configured to contain an active agent and a second electrode
assembly configured to contain a depot forming agent. Each
electrode assembly is made up of at least one reservoir and at
least one electrode. These electrodes provide electrical current to
the respective reservoirs, and thus iontophoretically drive the
active agent and the depot forming agent into the subject. The
distance between the first and second electrode assemblies may
control the location of the sustained release depot formed in-vivo
when the device is used to deliver the active agent and the depot
forming agent to the subject.
[0075] In another aspect, a method for controlling the location of
depot formation in a subject is described. The method may include
positioning a first electrode assembly containing an active agent,
and positioning a second electrode assembly containing a depot
forming agent, the first and second electrode assemblies being
positioned at an inter-electrode distance that controls a location
of the depot formation.
[0076] Various device configurations are contemplated that allow
the iontophoretic administration of an active agent and a depot
forming agent through the tissue of a subject in order to form such
a depot. For example, devices may be constructed wherein the first
electrode assembly and the second electrode assembly are in an
integrated single unit. In one aspect, the first electrode assembly
and the second electrode assembly may be configured adjacent one
another within the integrated single unit. Alternatively, devices
may be constructed as a collection of separate electrode assemblies
or arrays that function as a single unit. As such, in one aspect of
the present invention, a device may be a single integral unit
containing and delivering both the active agent and the depot
forming agent. Such a device may have separate electrode
assemblies, one to contain the active agent and one to contain the
depot forming agent. Each of these electrode assemblies is placed
in contact with the body surface though which the active agent and
the depot forming agent are to be iontophoretically administered.
In the case of ocular iontophoresis, the shape of the device may be
configured to fit on an eye surface. In such a configuration, the
electrode assemblies and their respective reservoirs may be in
contact with various tissue structures in the eye, such as the
conjunctiva. In one aspect, a portion of the device may cover the
cornea with at least one reservoir being in contact with the
conjunctiva. The portion covering the cornea provides a better fit
of the device onto the eye. In another aspect, the device may
extend into the cul-de-sac under the eyelids for the same purpose.
The portion of the device in the cul-de-sac can also hold an
electrode assembly or electrode assemblies in contact with the
conjunctiva for administering either or both the active agent and
the depot forming agent.
[0077] It may be beneficial to maintain the active agent and the
depot forming agent in isolation from one another to prevent
reaction within the device. Accordingly, the reservoirs of the
electrode assemblies may be separated by a barrier made from an
electrically inert material. This barrier should extend to the
surface of the body surface, such as the eye surface, in order to
minimize current flow between the reservoirs along the body
surface. The barrier may be a lip-seal, and it may form a seal
substantially around the reservoirs. Additionally, the electrically
inert material may be of the same construction as the body of the
reservoirs, or it may be a different material selected for its
dielectric properties. The distance of the separation between the
reservoirs may depend on the dielectric properties of the material
disposed therebetween, and thus may be highly variable. In one
aspect, the separation may be from about 0.05 mm to about 5 mm. In
another aspect, the separation may be from about 0.1 to about 3 mm.
In yet another aspect, the separation may be from about 0.2 to
about 1 mm. In a side-by-side electrode assembly configuration, the
distance of the separation between the reservoirs can also be used
to control the depth of the penetration and the distribution of the
agents in the tissue from the body surface. Depending on the
configuration of the device, the electrode assemblies may also
require electrical isolation from one another at the body surface
in order to direct the electrical current through the tissue rather
than between the reservoirs at the interface with the body surface.
In one aspect, such electrical isolation can be accomplished by
applying a temporary sealant between the electrical assemblies and
the body surface. In addition to directing electrical current
through the tissue, such a sealant may also advantageously function
to temporarily affix and hold the electrode assemblies in place on
the body surface. Sealants may be any useful insulative material
known to one skilled in the art, for example and without
limitation, gels, waxes, adhesives, impermeable polymeric or
resinous materials, etc.
[0078] In another aspect, multiple electrode assemblies may be
utilized to administer the active agent and the depot forming agent
to the subject. As such, each electrode assembly may be coupled to
the subject concurrently or consecutively. When coupled to the
subject concurrently, the active agent and the depot forming agent
can be administered simultaneously or consecutively. Additionally,
one of the agents can be delivered continuously, while the other is
delivered intermittently. Alternatively, when coupled to the
subject consecutively, the first electrode assembly may be coupled
to the subject to administer either the active agent or the depot
forming agent. The first electrode assembly may then be replaced
with the second electrode assembly to administer the remaining
agent in order to cause the formation of the sustained release
depot. The second electrode assembly can be coupled to the same or
a different site as the first electrode assembly. Configurations
having multiple electrode assemblies allow functionality similar to
devices having both electrode assemblies contained therein, but
also allow the ability to dynamically vary the distance between the
electrodes, and thus dynamically vary the location of the in-vivo
formation of the sustained release depot.
[0079] Regardless of whether a single device or multiple devices
are utilized for the iontophoretic administration, various
placement configurations of the electrode assemblies are
contemplated. For example, in many cases side-by-side electrode
assembly configurations may be beneficial. Such a configuration may
allow effective iontophoresis at the target location while
minimizing the extent of the movement of the electrical current in
other parts of the body. This may be particularly beneficial when
administering an active agent to sensitive areas such as the eye,
where potential adverse effects may be caused by excessive
electrical current passing through particularly sensitive tissues
such as the retina in, the back of the eye, the optic nerve, etc.
For administrations involving the eye, in one aspect the electrode
assemblies can be located side-by-side on the conjunctiva and
sclera. In another aspect, one electrode assembly may be located in
the inferior cul-de-sac and the other electrode assembly may be
located in the superior cul-de-sac. The depot may be formed in-vivo
in various tissue regions depending on the relative locations of
the electrode assemblies, such as the sclera, conjunctival,
subconjuctival space, ciliary body, choroids, retina, anterior
chamber, vitreous, etc. The preferred site of the sustained release
depot may depend on the site of drug action in the eye to provide a
pharmacological effect.
[0080] While administration to nearly any portion of the eye may be
suitable, in one aspect, the agents may be delivered to opposite
sides of the eye using separate delivery devices. When electrical
current is applied through the electrodes, the active agent and the
depot forming agent are released and travel in moving fronts
through their respective electrical fields. As such, the fronts
will meet in a substantially central portion of the eye, resulting
in the formation of a sustained release depot near the center of
the globe that is distant from the vascular clearance beds of the
retina and choroid. In such an embodiment, it is possible to
concurrently deliver the active agent and the depot forming agent
at the same time by placing the depot forming agent in the return
electrode and placing both the active and return electrode on the
eye, at the same time albeit separated by some distance such as in
the inferior cul-de-sac and the superior cul-de-sac, respectively,
and conducting iontophoresis. In another embodiment as an example,
when the electrodes are placed on the pars plana next to the
limbus, the site of delivery is preferably in the posterior chamber
under the electrodes and the anterior chamber. When the electrodes
are placed near the fornix, the site of delivery is the conjunctiva
and sclera under the electrodes.
[0081] Various side-by-side configurations for the electrode
assemblies are possible, depending on the desired efficacy of depot
formation, desired depot location, patient comfort, active
agent/depot forming agent configuration, etc. In one aspect, the
electrode assemblies may be placed adjacent to each other, and may
be of various shapes such as, without limitation, circles, ovals,
triangles, squares, rectangles, polygons, trapezoids, etc. Adjacent
may include any relative orientation such as superior to inferior,
lateral to medial, or any diagonal combination thereof.
[0082] In another aspect, the electrode assemblies may be of an
annular configuration, and thus encircle at least a portion of the
eye. Such annular electrode assemblies may be configured to nest
together, and thus administer active agent and depot forming agent
in close proximity within the region defined by the electrodes. For
example, an outer ring electrode and an inner ring electrode may be
positioned on the sclera surrounding the cornea. In one specific
aspect shown in FIG. 1, an iontophoretic device 10 is shown having
a first annular electrode assembly 12 having an inner radius 14. A
second annular electrode assembly 16 may be located within the
inner radius 14 of the first annular electrode assembly 12. In one
aspect, the first and second electrodes associated with the first
and second annular electrode assemblies may be annular in shape. In
this specific embodiment, an outer reservoir associated with the
first annular electrode assembly 12 may be of substantially the
same shape as the first electrode or it may be of a different
shape. Similarly, an inner reservoir associated with the second
annular electrode assembly 16 may be of substantially the same
shape as the second electrode or it may be of a different shape.
The active agent may be contained in the first or outer reservoir
and the depot forming agent may be contained in the second or inner
reservoir, or the active agent may be contained in the inner
reservoir and the depot forming agent may be contained in the outer
reservoir. Such an annular orientation of administered active agent
and depot forming agent may increase the area of interaction
between the two agents while maintaining the same relative distance
between the reservoirs of the two agents, and thus increase the
efficacy of the in-vivo formation of the sustained release
depot.
[0083] In yet another specific aspect, multiple active agent and
depot forming agent electrode assemblies may be utilized to further
increase the area of agent interaction and the efficacy of the
in-vivo formation of the sustained release depot. FIG. 2 shows an
iontophoretic device 20 having multiple electrode assemblies 22, 24
arranged in a concentric "bullseye" pattern. In one aspect, it may
be beneficial for the reservoirs associated with the electrode
assemblies to contain either active agent or depot forming agent in
an alternating configuration. For example, reservoirs associated
with electrode assemblies labeled 22 may contain active agent, and
reservoirs associated with electrode assemblies labeled 24 may
contain depot forming agent, and vice versa. Each electrode
assembly may be couple to a single electrode or to a single
electrical current source, or multiple electrode assemblies can be
coupled to a single electrode or to a single electrical current
source. It should be noted that in other aspects, the arrangement
of multiple electrode assemblies need not be in an alternating
configuration with respect to the active agent and the depot
forming agent, but may be any configuration known to one skilled in
the art. Additionally, numerous configurations including more than
two electrode assemblies are contemplated, all of which are
considered to be within the scope of the present invention. For
example, a single electrode assembly containing an active agent can
be associated with multiple electrode assemblies containing a depot
forming agent or multiple depot forming agents. Similarly, a single
electrode assembly containing a depot forming agent can be
associated with multiple electrode assemblies containing an active
agent or multiple active agents.
[0084] In a further aspect of the present invention, FIG. 3 shows
an example of an ocular iontophoretic device 30 having multiple
non-annular electrode assemblies. The device 30 may include a
substrate 36 having a plurality of electrode assemblies containing
either active agent 32 or depot forming agent 34. Any number or
spatial orientation of electrode assemblies is intended to be
included within the scope of the present invention. FIG. 3 is
merely intended to show that various side-by-side electrode
configurations are possible.
[0085] The reservoirs according to aspects of the present invention
are designed to hold either an active agent or a depot forming
agent prior to administration through the body surface of a
subject. In one aspect, the reservoirs are distinct, having lumens
that are completely separate from one another. Additionally, a
reservoir may contain at least one access port to allow the
reservoir to be filled while in contact with the body surface of
the subject. This configuration may allow the reservoir to be
filled during use as the agent within is depleted. Various
iontophoretic reservoir materials are known to those skilled in the
art, and all are considered to be within the scope of the present
invention.
[0086] Additional electrodes for immediate release of the active
agent without the involvement of the depot forming agent can be
operated concurrently with the side-by-side active-agent and
depot-forming agent electrode. For ocular delivery, this additional
electrode is placed on the eye surface away from the vicinity of
the side-by-side electrodes. The additional electrode will provide
a "burst" of the active agent for an initial high dose treatment of
the disease with iontophoresis. A burst of the depot forming agent
for more effective in-vivo interactions between the active agent
and the depot forming agent can also be provided under this
setting. Another electrode to serve as a return electrode on a body
surface away from the eye, e.g., on the face, can also be used in
conjunction with the side-by-side electrodes and the immediate
release electrodes on the eye. A dose controller as the electrical
current source controlling the electric current applied across the
electrodes can be programmed to provide different dosing intervals
for both the active agent and the depot forming agent from the
side-by-side electrodes and these auxiliary electrodes. This system
allows the switching back and forth of the electric current across
these electrodes to control the delivery of the active agent and
the depot forming agents and reduce the duration of the electric
current passage to minimize possible adverse effects due to the
application of the electric current. Different electric current
protocols can be carried out utilizing these electrodes to provide
effective immediate and sustained release of the active agent.
[0087] The electrodes of the present invention are designed to
deliver electrical current across the associated reservoirs to
iontophoretically deliver the agent located therein. The electrodes
can be of any material or manufacture known to one skilled in the
art. Various examples include metal electrodes, conductive glass
electrodes, etc. A single electrode may be coupled to a single
reservoir or to multiple reservoirs depending on the particular
configuration of a given electrode assembly. Additionally, in some
aspects of the present invention, an electrode may also be a
reservoir, with the depot forming agent being delivered from the
body of the electrode.
[0088] For optimal iontophoretic delivery of active agents,
excipients, and depot forming agents into the eye, a permselective
material may be placed in ion-conducting relation to the eye
surface. An electric current of AC, DC, and AC with superimposed DC
can be used to transport the compound of interest through the
permselective material into the eye. The permselective material is
capable of hindering iontophoretic transport of a competing ion and
increases the transference efficiency of the compound of interest
during iontophoresis. As a result, the invention allows the
compound of interest to be delivered iontophoretically into the eye
more efficiently than iontophoresis without the permselective
material. For example, more efficient iontophoretic transport can
be achieved by placing the permselective material against the
current driving electrode (e.g., Ag/AgCl) between the electrode and
the reservoir chamber to prevent the products of electrochemical
reactions generated at the electrode surface (e.g., Ag or Cl ions)
from moving into the reservoir. Another example is to place the
permselective material between the body surface and the reservoir
to prevent the migration of the active agent and endogenous ions
into depot forming agent reservoir or vice versa the depot forming
agent and endogenous ions into the active agent reservoir during
iontophoresis. Any permselective material capable of hindering
iontophoretic transport of a competing ion during iontophoretic
transport of the compound of interest may be used in conjunction
with the invention. The permselective material may be provided in
any of a number of forms as described in applicant's copending U.S.
patent application Ser. No. 10/371,148 entitled "METHODS AND
SYSTEMS FOR CONTROLLING AND/OR INCREASING IONTOPHORETIC FLUX",
filed on Feb. 21, 2003, which is incorporated herein by reference.
For example, the material may be provided in a liquid, partially
liquid, gelled, partially solid, or fully solid state. In some
instances, the permselective material may be supported by a support
structure such as an additional membrane having sufficient porosity
and chemical inertness so as to avoid interfering with the
performance of the permselective material, yet having sufficient
mechanical integrity for ease in handling. The material can also be
provided in the form of a membrane having a surface sized and/or
shaped for direct contact with the eye or shaped for direct contact
with the current driving electrode (e.g., Ag/AgCl). In other
instances, the permselective material may be comprised of a
polyelectrolyte, which can be a single molecule or an aggregate of
molecules having ions or ionizable groups.
[0089] As will be recognized, the noninvasive delivery mechanism
may be selected from a wide variety of suitable mechanisms known in
the art, such as iontophoretic delivery. In one aspect, the
administration may be to a subject's eye. In other aspects, the
noninvasive delivery mechanism can be related to patches, topical
ointments, sonophoresis, electroporation, such as those used in
either ocular and or transdermal delivery. The specific mechanism
may be selected in part based on suitability for administration to
the target physiological area of a subject's body. Furthermore, it
should be noted that the active agent and depot forming agent may
be administered using a single route, or different routes to arrive
at the site of action. In such cases, either the drug or the depot
forming agent may be delivered through an alternate route as
compared to the other. In the case where a single route is used,
the administration may be made using a single device that properly
accommodates both agents, or may be delivered from separate
devices. In the case of separate or different routes of
administration, nearly always, multiple or separate devices will be
used. Additionally, iontophoretic and sonophoretic methods may be
assisted by perturbing an application situs prior to
administration. Such perturbation may include treatment by
microneedle, heat, laser, etc.
[0090] In addition to the noninvasive iontophoretic mechanisms
discussed above, minimally invasive procedures are also
contemplated for the delivery of the active agent and/or the depot
forming agent into tissues of the subject, including the eye. One
example of a minimally invasive administration method may include
periocular injections
EXAMPLES
[0091] The following examples are intended to be merely
illustrative of the various aspects of the invention disclosed
herein and are not intended in any way to limit the scope of the
claimed invention. Other aspects of the invention that are
considered equivalent by those skilled in the art are also within
the scope of this invention.
Example 1
[0092] Table 1 shows the bench top experiments performed to test
the solubility of dexamethasone phosphate (DexP) and zinc (Zn) ion.
In this example, zinc ion was the depot forming agent and DexP was
the active agent. TABLE-US-00001 TABLE 1 Concentration of Zn ion
DexP 0.1 M 0.05 M 0.01 M 0.005 M 0.001 M 0.05 M Precipitation
Precipitation Precipitates Turbid, settles Slightly on standing
turbid 0.01 M Small amount Turbid, settles Turbid, settles Stays
turbid for Slightly precipitates within few on standing for long
time turbid minutes some time 0.005 M Turbid, settles on Turbid,
settles Turbid but Slight turbidity, Clear standing for several
slowly, very little settles slowly doesn't settle solution minutes
solid material 0.001 M Slightly turbid, no Clear solution Clear
solution Clear solution Clear tendency to settle solution (almost
clear)
[0093] Bench top experiments were also performed with DexP and
ferrous (Fe) ion (Table 2).
Example 2
[0094] In this example, ferrous ion was the depot forming agent and
DexP was the active agent. TABLE-US-00002 TABLE 2 Concentration of
Ferrous Ion DexP 0.1 M 0.05 M 0.01 M 0.005 M 0.001 M 0.05 M
Precipitation Precipitation Very turbid and Turbid, stays Clear, no
turbidity stays turbid for long time appears several minutes
without settling before settling 0.01 M Turbid, but Turbid, settles
on Turbid, do not Stays turbid Clear, no turbidity settles down
standing settle in 30 min. even after 1 hr appears 0.005 M Turbid,
settles Turbid, settles Turbid and Slight turbidity, Clear, no
turbidity on standing for slowly, takes an stays so doesn't settle
appears several minutes hour or more without settling 0.001 M
Slight turbidity, Foggy, not clear Foggy, not a Foggy, not fully
Clear, no turbidity no tendency to solution clear solution clear
solution appears settle
[0095] In yet another example, the solubility of DexP and calcium
(Ca) ion was studied. Calcium ion was the depot forming agent and
DexP was the active agent. It was discovered that mixing a solution
of DexP disodium salt (.gtoreq.0.005 M) and solution of CaCl.sub.2
(.gtoreq.0.005 M) formed a gel.
[0096] In another study, the dissolution of dexamethasone phosphate
(DexP) from different forms of precipitation (ZnDexP, SnDexP, and
CaDexP) as depot was monitored in dialysis membrane systems. FIG. 4
shows the dissolution profiles of these three formulations (depot
forming agents, Zn, Sn, Ca as Formulations 1, 2, and 3,
respectively) and the control (DexP formulation without depot
forming agents; no sustained-release (SR) formulation). The results
in FIG. 4 suggest that the method of precipitation between the
depot forming agents and the active agent can provide slow and
sustained drug delivery for more than a week.
Example 3
[0097] This example provides evidence of non-invasive delivery of a
sustained release system to the eye for ocular drug delivery in
rabbits in-vivo. In this study, an ocular device of side-by-side
active and depot forming agent chambers (similar to that in FIG. 3)
was placed on the eyes of rabbits. The electrode chambers of the
device were positioned on the conjunctiva near the pars plana. The
active and depot forming agents were 0.5 M triamcinolone acetonide
phosphate and 1.0 M dodecyl ammonium, respectively. The delivery of
the sustained release system was achieved by applying a constant
direct electric current of two milliampere across the side-by-side
chambers for 15 minutes, in which the active agent was delivered
from the cathode and the depot forming agent was from the anode.
For comparison, iontophoretic delivery of triamcinolone acetonide
phosphate without the depot forming agent, dodecyl ammonium, was
conducted as the control. Six groups of 2 to 3 rabbits with each
group assigned to the different time point (10-min, 4-hour, or
1-day) and different protocol (conventional iontophoresis control
or sustained release iontophoresis) were used. At 10 minutes, 4
hours, and 1 day after the iontophoresis applications, the animals
were euthanized and the eyes were enucleated for triamcinolone
acetonide and triamcinolone acetonide phosphate assays. The assay
procedure involved extracting these compounds from the conjunctiva,
sclera, and vitreous humor with a pH-adjusted organic solvent and
HPLC analysis. The amounts of the active agent in the eye after the
iontophoresis applications are shown in Table 3. The results in the
table suggest that the present invention provides a sustained
release system compared to that of conventional ocular
iontophoresis. TABLE-US-00003 TABLE 3 Total amounts of
triamcinolone acetonide and triamcinolone acetonide phosphate in
the eye. Sustained release system delivered Conventional by
iontophoresis iontophoresis 10 min 0.7 mg 0.4 mg 4 hours 0.2 mg
0.01 mg 24 hours 0.02 mg 0 mg
[0098] It should be understood that the above-described
arrangements are only illustrative of the application of the
principles of the present invention. Numerous modifications and
alternative arrangements may be devised by those skilled in the art
without departing from the spirit and scope of the present
invention. Thus, while the present invention has been described
above with particularity and detail in connection with what is
presently deemed to be the most practical and preferred embodiments
of the invention, it will be apparent to those of ordinary skill in
the art that numerous modifications, including, but not limited to,
variations in size, materials, shape, form, function and manner of
operation, assembly and use may be made without departing from the
principles and concepts set forth herein.
* * * * *