U.S. patent application number 12/903837 was filed with the patent office on 2011-03-31 for intraocular iontophoretic device and associated methods.
Invention is credited to John W. Higuchi, Anthony L. Tuitupou.
Application Number | 20110077582 12/903837 |
Document ID | / |
Family ID | 40523906 |
Filed Date | 2011-03-31 |
United States Patent
Application |
20110077582 |
Kind Code |
A1 |
Tuitupou; Anthony L. ; et
al. |
March 31, 2011 |
INTRAOCULAR IONTOPHORETIC DEVICE AND ASSOCIATED METHODS
Abstract
The present invention includes methods and devices for
non-invasively delivering an active agent to the eye of a subject.
In one aspect, for example, a device for delivering an active agent
to an eye of a subject may include an ocular lens-shaped housing
configured to contact a surface of the eye, and a reservoir coupled
to the housing and configured to deliver an active agent to the
eye, wherein the reservoir is located entirely within a 180 degree
section of the housing. In another aspect, the reservoir is located
entirely within a 150 degree section of the housing.
Inventors: |
Tuitupou; Anthony L.; (Salt
Lake City, UT) ; Higuchi; John W.; (Salt Lake City,
UT) |
Family ID: |
40523906 |
Appl. No.: |
12/903837 |
Filed: |
October 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11867503 |
Oct 4, 2007 |
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12903837 |
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Current U.S.
Class: |
604/20 ;
604/300 |
Current CPC
Class: |
A61P 27/02 20180101;
A61M 2210/0612 20130101; A61N 1/30 20130101; A61K 9/0009 20130101;
A61M 35/003 20130101; A61F 9/0017 20130101 |
Class at
Publication: |
604/20 ;
604/300 |
International
Class: |
A61N 1/30 20060101
A61N001/30; A61F 9/00 20060101 A61F009/00 |
Claims
1. A device for delivering an active agent to an eye of a subject,
comprising: an ocular lens-shaped housing operable to contact a
surface of the eye; a reservoir coupled to the housing and operable
to deliver an active agent into the eye, wherein the reservoir
surface area configured to face the eye is less than about 50% of
the surface area of the housing configured to face the eye; and a
vacuum device coupled to the housing and operable to create
negative pressure between the housing and the surface of the
eye.
2. The device of claim 1, wherein the reservoir surface area
configured to face the eye is less than about 25% of the surface
area of the housing configured to face the eye.
3. The device of claim 1, wherein the reservoir surface area
configured to face the eye is less than about 10% of the surface
area of the housing configured to face the eye.
4. The device of claim 1, wherein the reservoir includes an
electrode operable to provide an electrical current capable of
iontophoresing an active agent.
5. The device of claim 1, wherein the vacuum device is a vacuum
bulb.
6. The device of claim 1, wherein the vacuum device is removably
coupled to the housing.
7. The device of claim 1, wherein the housing is configured in size
and shape to allow the subject's eyelids to close substantially
thereover when positioned on the eye.
8. The device of claim 1, wherein the reservoir is a plurality of
reservoirs.
9. The device of claim 8, wherein the plurality of reservoirs has a
combined surface area configured to face the eye that is less than
about 50% of the surface area of the housing configured to face the
eye.
10. The device of claim 1, wherein a portion of the housing is
configured to extended into a cul-de-sac under an eyelid of the eye
of the subject.
11. The device of claim 1, wherein the housing is configured as a
scleral lens.
12. The device of claim 1, wherein the housing is configured to
position at least a portion of the reservoir in a lower cul-de-sac
of the eye.
13. A method for enhancing ocular delivery of an active agent to
the eye of a subject, comprising: contacting an ocular lens-shaped
housing having a reservoir containing the active agent against an
eye surface such that the reservoir contacts a delivery region of
the eye, wherein the reservoir surface area configured to face the
eye is less than about 50% of the surface area of the housing
configured to face the eye; applying a vacuum between the housing
and the eye surface sufficient to maintain the reservoir
substantially in alignment with the delivery region during delivery
of the active agent; delivering the active agent from the reservoir
into the eye; and removing the housing from the eye.
14. The method of claim 13, wherein delivering the active agent
from the reservoir further includes actively delivering the active
agent.
15. The method of claim 14, wherein actively delivering the active
agent from the reservoir further includes iontophoretically
delivering the active agent.
16. The method of claim 13, wherein delivering the active agent
from the reservoir further includes passively delivering the active
agent.
17. The method of claim 13, wherein removing the housing from the
eye further includes releasing the vacuum between the housing and
the eye surface sufficient to release the housing from the eye.
18. The method of claim 13, further comprising delivering a
vasoconstrictor agent into the eye.
19. A method of iontophoretically delivering an active agent to an
eye of a subject, comprising: positioning the device of claim 1 on
the surface of the eye of the subject; applying negative pressure
between the device and the eye; and delivering the active agent
into the eye.
20. The method of claim 19, wherein the negative pressure is
applied via a vacuum bulb.
Description
PRIORITY DATA
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/867,503, filed Oct. 4, 2007, which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to systems, methods, and
devices for the ocular delivery of an active agent into a subject's
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.
Additionally, 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.
[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, and the
return electrode is typically placed remote from the eye, for
example on the earlobe. The compound of interest is transported at
the active electrode across the tissue when a current is applied to
the electrodes. 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] One potential problem with present ocular iontophoretic
methods and devices concerns the actual delivery, or rather, the
non-delivery of the drug into the eye tissue. Because the return
electrode is located remote from the eye, various conductive
pathways may be formed. Such divergence of the electric current
will decrease the efficiency of drug delivery to the target sites
in the eye, and as a result, much of the drug may be delivered into
the tissues surrounding the eye rather than into the eye per
se.
[0009] Additionally, despite its apparent advantages, iontophoresis
is really just a method of limiting the invasiveness of drug
delivery into the eye'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.
[0010] The problem of patient compliance may be compounded by the
need to receive daily treatment in a medical facility with high
healthcare costs and limited resources and practitioners for
treating retinal diseases. Existing ocular iontophoresis systems
are not patient-friendly, require multiple parts and assembly to
practice, and include clumsy and/or complicated procedures. As
such, they require the involvement of experienced healthcare
professionals to perform the treatments. Paraprofessional and/or
in-home self administration use of such devices are precluded by
the technical complexity of many existing iontophoretic devices, as
well as the costs of expensive dose-controlling equipment.
Individuals have a greater tendency to deviate from a medication
regimen when required to leave home for medical treatment,
particularly when such treatment is frequent.
SUMMARY OF THE INVENTION
[0011] Accordingly, the present invention provides methods and
devices for non-invasively delivering an active agent to the eye of
a subject. In one aspect, for example, a device for delivering an
active agent to an eye of a subject may include an ocular
lens-shaped housing configured to contact a surface of the eye, and
a reservoir coupled to the housing and configured to deliver an
active agent to the eye, wherein the reservoir is located entirely
within a 180 degree section of the housing. In another aspect, the
reservoir is located entirely within a 150 degree section of the
housing.
[0012] A variety of mechanisms are contemplated to deliver an
active agent from the reservoir and into the eye. For example, in
one aspect the active agent may be delivered by passive mechanisms.
In another aspect, the reservoir may further include an electrode
configured to provide an electrical current capable of
iontophoresing an active agent.
[0013] Additional elements may be included in the device for
enhancing delivery of the active agent. For example, in one aspect
a vacuum port may be coupled to the housing and configured to
create negative pressure between the housing and the surface of the
eye. One specific example of such a vacuum port may include a
vacuum bulb. Furthermore, the housing of the device may be
configured in size and shape to allow the subject's eyelids to
close substantially thereover when positioned on the eye.
[0014] The reservoir may be configured in a variety of ways,
depending on the overall design and intended functionality of the
device. For example, in one aspect the reservoir may be a plurality
of reservoirs located entirely within a 180 degree section of the
housing. Numerous configurations for a plurality of reservoirs are
contemplated. For example, in one specific aspect the plurality of
reservoirs may be configured in a side-by-side arrangement. In
another aspect, the plurality of reservoirs may be configured in a
nested arrangement with respect to the center of the housing.
[0015] Various configurations for the lens-shaped housing are also
contemplated. In one aspect, for example, the housing may be
configured as a corneal lens. In another aspect, the housing may be
configured as a scleral lens. In yet another aspect, a portion of
the housing may be configured to extended into a cul-de-sac under
an eyelid of the eye of the subject such that electrical current
flow is hindered between the eye and the eyelid. In a further
aspect, the housing may be configured to position the reservoir in
a lower cul-de-sac of the eye.
[0016] The present invention additionally provides methods for
ocularly delivering an active agent into the eye of a subject. For
example, in one aspect a method for a method for enhancing ocular
delivery of an active agent to the eye of a subject may include
contacting an ocular lens-shaped housing having a reservoir
containing the active agent against an eye surface such that the
reservoir contacts a delivery region of the eye, wherein said
reservoir is located entirely within a 180 degree section of the
housing, and delivering the active agent from the reservoir into
the eye while substantially maintaining alignment between the
reservoir and the delivery region. In another aspect, substantially
maintaining alignment may further include applying a vacuum between
the housing and the eye surface sufficient to maintain the
reservoir substantially in alignment with the delivery region
during delivery of the active agent.
[0017] The delivery of the active agent from the reservoir and into
the eye may be by a variety of passive or active mechanisms. For
example, in one aspect the active agent is delivered from the
reservoir into the eye by an active mechanism such as
iontophoresis. In another aspect, the active agent is delivered
from the reservoir into the eye by a passive mechanism such as
passive diffusion.
[0018] In yet another aspect of the present invention, a method is
provided for iontophoretically delivering an active agent to an eye
of a subject. Such a method may include positioning a device
according to aspects of the present invention on the surface of the
eye of the subject, and activating the device to deliver the active
agent into the eye. Additionally, in another aspect positioning the
device further includes applying negative pressure between the
device and the eye.
[0019] In a further aspect of the present invention, a device for
delivering an active agent to an eye of a subject is provided. Such
a device may include an ocular lens-shaped housing configured to
contact a surface of the eye, and a reservoir coupled to the
housing and configured to deliver an active agent to the eye,
wherein the reservoir surface area configured to face the eye is
less than about 50% of the surface area of the housing configured
to face the eye. Additionally, in one aspect the reservoir may be a
plurality of reservoirs. In another aspect, each of the plurality
of reservoirs has a surface area configured to face the eye that is
less than about 50% of the surface area of the housing configured
to face the eye. In a further aspect, the plurality of reservoirs
is a plurality of annular reservoirs.
[0020] A variety of exemplary techniques are contemplated for
maintaining the alignment between the reservoir contact surface and
the delivery region. In one aspect, substantially maintaining
alignment may further include applying a vacuum between the housing
and the eye surface sufficient to maintain the reservoir
substantially in alignment with the delivery region during delivery
of the active agent. In another aspect, substantially maintaining
alignment may further include applying a tackifier between the
housing and the eye surface sufficient to maintain the reservoir
substantially in alignment with the delivery region during delivery
of the active agent. In a further aspect, substantially maintaining
alignment may be achieved by configuring the shape of the housing
such that the housing resists movement in the eye.
[0021] 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, and sustained release formulations, as required
in order to provide convenient and effective non-invasive delivery.
Exemplary active agents are enumerated further herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a side view of a scleral lens device in accordance
with an aspect of the present invention.
[0023] FIG. 2 is a side view of a scleral lens device in accordance
with another aspect of the present invention.
[0024] FIG. 3 is a top view of a scleral lens device in accordance
with yet another aspect of the present invention.
[0025] FIG. 4 is a top view of a scleral lens device in accordance
with a further aspect of the present invention.
[0026] FIG. 5 is a top view of a scleral lens device in accordance
with another aspect of the present invention.
[0027] FIG. 6 is a top view of a scleral lens device in accordance
with another aspect of the present invention.
[0028] FIG. 7 is an MRI image of a rabbit eye in accordance with
yet another aspect of the present invention.
[0029] FIG. 8 is an MRI image of a rabbit eye in accordance with a
further aspect of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Before the present systems and methods for 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.
[0031] 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.
DEFINITIONS
[0032] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set forth below.
[0033] 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, depot formation, etc.
[0034] 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, antifungals, 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.
[0035] 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 a prodrug of dexamethasone, and
triamcinolone acetonide phosphate can be classified as a prodrug of
triamcinolone acetonide.
[0036] As used herein, "tackifier" refers to a substance that
increases the adherence of an ocular lens device to an eye surface
as compared to the ocular device in the absence of a tackifier.
[0037] 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.
[0038] 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.
[0039] As used herein, "subject" refers to a mammal that may
benefit from the administration of a composition or method as
recited herein. Examples of subjects include humans, and may also
include other animals such as horses, pigs, cattle, dogs, cats,
rabbits, aquatic mammals, etc.
[0040] 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.
[0041] 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.
[0042] As used herein, the term "reservoir" and refer to a body or
a mass that may contain an active agent, a depot forming agent, or
other pharmaceutically useful compound or composition. As such, a
reservoir may include any structure that may contain a liquid, a
gelatin, a semi-solid, a solid or any other form of active agent or
secondary compound known to one of ordinary skill in the art. In
some cases, an electrode may be considered to be a reservoir. The
reservoir may be made of a number of suitable materials. However,
in one aspect, such a material may be an electrically
non-conductive, or semi-conductive material. In yet another aspect,
the reservoir may also include a barrier element configured to
attach at a distal portion of the reservoir housing and therefore
rest between the reservoir housing and the skin surface or tissue
of a subject when the reservoir assembly is in use. Such barrier
element can be made of an electrically non-conductive material, and
in some aspects, such material will be different from the material
of the lens housing. Examples of such materials include without
limitation, polymeric materials, such as adhesives or resins,
rubbers, etc. In some aspects it is intended that a reservoir
deliver an active agent through passive diffusion. In other aspects
a reservoir may include an electrode configured to introduce an
electrical current into the reservoir, and thus deliver an active
agent actively, functioning as either an anode or a cathode.
[0043] As used herein, the terms "anode" and "cathode" refer to the
electrical polarity of an electrode. The terms "anode" and
"cathode" are well known in the art. It should be noted, however,
that in some aspects these descriptive terms may be transitory.
When using alternating current, for example, two electrodes will
alternate between anode and cathode as the current alternates in
electrical polarity.
[0044] As used herein, the term "corneal lens" refers to a lens
sized to fit approximately over the cornea of the eye.
[0045] As used herein, the term "scleral lens" refers to a lens
sized to cover and extend beyond the cornea across at least a
portion of the sclera of the eye.
[0046] As used herein, the term "active electrode" refers to an
electrode utilized to iontophoretically deliver an active
agent.
[0047] As used herein, the term "passive electrode" refers to an
electrode that is used to complete an electrical circuit without
delivering a compound or substance to a subject.
[0048] As used herein, the term "return electrode" refers to an
electrode utilized to complete an electrical circuit for active
electrode. In one aspect, a return electrode may be an active
electrode used to deliver a secondary compound, such as an active
agent, a depot forming agent, etc. In another aspect, a return
electrode may be a passive electrode.
[0049] As used herein, the term "self-contained" refers to a device
that contains therein, or substantially therein, all the components
required for use. For example, a self-contained iontophoretic
device may contain active agents, reservoirs, electrodes, power
supplies, etc., within a single housing.
[0050] 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.
[0051] 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.
[0052] As used herein, the term "substantially" refers to the
complete or nearly complete extent or degree of an action,
characteristic, property, state, structure, item, or result. For
example, an object that is "substantially" enclosed would mean that
the object is either completely enclosed or nearly completely
enclosed. The exact allowable degree of deviation from absolute
completeness may in some cases depend on the specific context.
However, generally speaking the nearness of completion will be so
as to have the same overall result as if absolute and total
completion were obtained. The use of "substantially" is equally
applicable when used in a negative connotation to refer to the
complete or near complete lack of an action, characteristic,
property, state, structure, item, or result. For example, a
composition that is "substantially free of" particles would either
completely lack particles, or so nearly completely lack particles
that the effect would be the same as if it completely lacked
particles. In other words, a composition that is "substantially
free of" an ingredient or element may still actually contain such
item as long as there is no measurable effect thereof.
[0053] As used herein, the term "about" is used to provide
flexibility to a numerical range endpoint by providing that a given
value may be "a little above" or "a little below" the endpoint.
[0054] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0055] Concentrations, amounts, 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. 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.
[0056] 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.
THE INVENTION
[0057] The present invention provides devices and associated
methods for delivering an active agent into the eye of a subject.
In many circumstances, it is desirable to deliver an active agent
through a relatively small area tissue on the surface of the eye in
order to more effectively target a specific ocular tissue. In this
case, the delivery region on the periphery of the eye through which
drug is delivered is established by the contact surface area of a
reservoir containing the active agent. Thus there is a spatial
correspondence between the reservoir and the delivery region of the
eye. When this delivery region of the eye is small, it may be
difficult to maintain this spatial correspondence with the
reservoir, particularly for delivery devices that are large, bulky,
and/or handheld. In such cases, movements by the subject and/or the
individual holding the device may cause spatial misalignment
between the delivery region and the reservoir. Such a misalignment
may affect the efficiency of delivery of the active agent. For
example, in many cases tissues through which an active agent has
been passing may be "primed" and thus may more readily pass
additional active agent as compared to tissue that has not been so
primed. If the reservoir is shifted because of movement to a
non-primed area, the efficiency of active agent delivery may, at
least temporarily, decease. In another example, the location of the
delivery area on the surface of the eye may be facilitating
formation of a drug depot within deeper ocular tissues at a
specific location. If the reservoir is shifted in this case, a
second drug depot may be formed in a region distinct from the first
drug depot. Accordingly, active agent may be more quickly released
from two drug depots having an increased surface area as compared
to one more concentrated depot, thus reducing the effectiveness of
this sustained release mechanism.
[0058] It has thus been discovered that administration of an active
agent into the eye of a subject can be improved or maximized by
maintaining a spatial correspondence between the reservoir
delivering an active agent and the tissue region through which the
agent is passing. In one aspect, such a spatial correspondence may
be maintained by reducing the size and bulkiness of the delivery
device. In another aspect, the spatial correspondence may be
maintained by increasing the adherence of the delivery device to
the surface of the eye to minimize movement thereof. It should be
noted, however, that any technique of maintaining such a spatial
correspondence is considered to be within the scope of the present
invention.
[0059] Accordingly, in one aspect a method for enhancing ocular
delivery of an active agent to the eye of a subject is provided.
Such a method may include contacting an ocular lens-shaped housing
having a reservoir containing the active agent against an eye
surface such that the reservoir contacts a delivery region of the
eye, wherein said reservoir is located entirely within a 180 degree
section of the housing. The method may also include delivering the
active agent from the reservoir into the eye while substantially
maintaining alignment between the reservoir and the delivery
region.
[0060] The reservoir surface area facing the eye may be understood
to be the proportion of the surface area of an ocular lens housing
associated with the reservoir through which through which an active
agent is capable of passing, as compared to the total surface area
of the ocular lens that is contacting or is facing and in close
proximity with the surface of the eye. In the case of multiple
reservoir assemblies in a single ocular lens device, the area of
contact for the reservoir would include the combined surface area
of all of the reservoir assemblies. As has been described, in one
aspect the reservoir surface area may be less than or equal to
about 50% of lens area facing the eye. In another aspect, the
reservoir surface area may be less than or equal to about 25% of
lens area facing the eye. In yet another aspect, the reservoir
surface area is less than or equal to about 10% of lens area facing
the eye.
[0061] In addition to surface area, in one aspect the reservoir is
located entirely within a 180 degree section of the lens housing.
In another aspect, the aspect the reservoir is located entirely
within a 150 degree section of the lens housing. In those aspects
including a plurality of reservoirs, all reservoirs are located
within the same 180 degree section of the device. In some aspects
the plurality of reservoirs are arranged in a side-by-side
configuration. In other aspect, the plurality of reservoirs may be
arranged in a nested pattern with respect to the center of the
housing.
[0062] A variety of techniques are contemplated for maintaining the
alignment between the reservoir and the delivery region. As has
been described, maintaining such an alignment may facilitate more
effective delivery of an active agent into deeper ocular tissues.
In one aspect, for example, alignment may be maintained due to the
shape configuration of the lens housing. For example, a scleral
lens has a somewhat oval shape to match the shape of the eye. This
somewhat oval shape helps to prevent rotation of the housing in the
eye. Additionally, because the curvature of an ocular lens-shaped
housing closely matches the curvature of the eye, capillary forces
between the housing and the eye may cause greater adhesion
therebetween as compared to a housing with a mismatched shape.
[0063] Additionally, maintaining the alignment between the
reservoir and the delivery region may be further enhanced by
applying a vacuum between the lens device and the eye surface
sufficient to maintain the reservoir contact surface area
substantially in alignment with the delivery region during delivery
of the active agent. Such a suction mechanism may even hold the
device in place during blinking in some aspects. Following delivery
of the active agent, the device can be pressurized at the interface
surface between the eye and the lens device to allow release and
subsequent removal. The vacuum may be applied by any technique
known to one of ordinary skill in the art. In one aspect, as is
shown in FIG. 1, a vacuum port 12 may be incorporated into an
ocular lens device 14 to allow attachment of external device to
draw the vacuum. Such an external device may include a variety of
devices, including pumps, syringes, etc. In another aspect, as is
shown in FIG. 2, a vacuum bulb 16 may be coupled to an ocular lens
device 14. The vacuum bulb 16 is operated by squeezing the bulb
prior to positioning the ocular device 14 on the eye of a subject,
and releasing the bulb following such positioning to provide a
vacuum between the ocular device 14 and the eye of the subject. In
one aspect, the vacuum bulb 16 is coupled to the ocular device 14
by an intermediate structure such as a vacuum port 12. In another
aspect, the vacuum port 16 may be coupled directly to the ocular
device 14 (not shown). In another aspect, the vacuum may be
accomplished by the shape of the device housing alone. For example,
a device housing conforming to the surface of the eye may be
depressurized by merely applying pressure to the device. Removal of
such a device may, however, be more problematic that a device
having a means to control pressurization, such as a valve
element.
[0064] In another aspect, maintaining alignment between the
reservoir and the delivery region may be accomplished by applying a
tackifier between the lens device and the eye surface sufficient to
maintain the reservoir assembly substantially in alignment with the
delivery region during delivery of the active agent. A tackifier
should be chosen to allow the ocular lens device to be held in
place during delivery of the active agent, and to be easily removed
following such delivery. Non-limiting examples of tackifiers may
include waxes, petroleum jellies, impermeable polymeric or resinous
materials, oils, etc.
[0065] 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.
[0066] Accordingly, 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, any agent that may be beneficial to a
subject when administered ocularly 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.
[0067] 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.
[0068] 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.
[0069] Under a number of circumstances, the active agent used may
be a prodrug, or in prodrug form. 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
beneficial. In this case, 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.
[0070] Though any prodrug 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, etc. 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.
[0071] Active agents may be delivered by a variety of mechanisms
into an eye of the subject. In one aspect, for example, the active
agent may be iontophoretically administered. In such a case, an
electrical current delivered from an electrode is utilized to drive
the active agent from the reservoir and into the eye. Such an
active delivery mechanism is used to drive an active agent having a
charge of the same polarity as the electrical current into the eye.
Iontophoretic techniques are well known in the art, and any such
technique should be considered to be within the scope of the
present invention.
[0072] In one aspect, an ocular iontophoretic device may include at
least two electrodes having opposite charge characteristics, such
as an anode and a cathode. Depending on the configuration of the
ocular device, both electrodes may be placed on the eye surface, or
one electrode may be placed on the eye surface and the other may be
located remote from the eye in a location such as an earlobe. The
anode and cathode are intended to pass current due to a potential
difference established therebetween by a power source. The current
acts to move an active agent iontophoretically in a direction that
is dependent on the charge characteristics of the active agent and
the charge orientation of the potential difference between the
anode and the cathode. An active electrode, whether it is an anode
or a cathode, is designed to deliver electrical current across an
associated reservoir to iontophoretically deliver the active agent
located therein. In one aspect, one electrode may be an active
electrode and the other electrode may be a return electrode for
merely completing the electrical circuit. For example, the active
electrode may be an anode and the return electrode may be a
cathode, or vice versa. In another aspect, one both the anode and
the cathode may each have an associated reservoir for the delivery
of compounds, as is described more fully herein. The compounds may
be the same or different, depending on the intended use and/or
configuration of the device. The anode and the cathode can be of
the same or different size relative to each other. Also, the
surface area of one or both electrodes can be configured to modify
their respective current densities when in use.
[0073] The anode and cathode can be of any material or manufacture
known to one skilled in the art. Various examples include metal
electrodes, conductive glass electrodes, conductive fluids or gels,
etc. A single electrode may be coupled to a single reservoir or to
multiple reservoirs depending on the particular configuration of a
given reservoir assembly. Conversely, multiple electrodes having
the same polarity may be coupled to a single reservoir in certain
aspects.
[0074] As has been described, in some aspects a return electrode is
located remote from the eye. Such configurations are inconvenient
and allow various conductive pathways to be formed across the
tissues surrounding the eye rather than focused only in the eye per
se. Placing both the anode assembly and the cathode assembly on the
surface of the eye may facilitate the passage of electrical current
transsclerally into the eye under the anode and cathode,
particularly when current movement across the surface of the eye is
limited. In one aspect, the anode assembly and the cathode assembly
may be respectively configured on the surface of the eye such that
the anode and the cathode complete an electrical circuit
substantially within the eye of the subject. In other words, the
current between the anode and the cathode may pass predominantly
through the eye tissues rather than into or through the connective
tissues surrounding the eye. In one aspect, both the anode and the
cathode may be oriented within the anode and cathode assemblies to
face the surface of the eye. The anode and the cathode may directly
contact the surface of the eye, or they may contact the surface of
the eye through an intermediate material or reservoir that is part
of the device. In either case, such a "direct" contact between the
electrodes and the eye surface may facilitate the focusing of
electrical current within the eye.
[0075] The relative spacing or the inter-electrode distance between
the anode and the cathode may play an important role in determining
where an active agent is localized in the eye upon delivery. As
such, in accordance with one aspect of the present invention, the
anode and the cathode may be spaced at an inter-electrode distance
which controls the depth and extent of penetration of the active
agent within the eye. Such a spacing may focus the electric field
more effectively within the eye, thus more effectively delivering
the active agent. Increasing the inter-electrode distance will
generally cause current to flow deeper into the eye, thus
iontophoretically delivering the active agent deeper. Small
inter-electrode distances will cause a more superficial delivery of
active agent into the eye. Thus, by altering the physical locations
of each of the electrode assemblies, and thus the inter-electrode
distance between them, the active agent can be delivered to
particular regions of the eye at specific depths. As such, the
inter-electrode distance may vary depending on the intended
delivery location. In one aspect of the present invention, however,
the inter-electrode distance may be less than about 40.0 mm. In yet
another aspect, the inter-electrode distance may be from about 1 mm
to about 10 mm. In a further aspect, the inter-electrode distance
may be from about 0.3 mm to about 4 mm.
[0076] In another aspect of the present invention, devices
utilizing iontophoretic delivery mechanisms may include an
electrically insulating barrier located between the anode and the
cathode to preclude or reduce electrical current flow across the
surface of the eye. By preventing current flow across the eye
surface between the anode and the cathode, current is focused, or
forced transsclerally into the eye to complete an electrical
circuit. In one aspect, the barrier element located on the device
between the anode and the cathode and configured to contact the
surface of the eye. As such, the barrier element is configured to
electrically isolate the anode from the cathode at the surface of
the eye. In another aspect, the barrier element may surround each
of the anode assembly and the cathode assembly at the surface of
the eye to preclude the passage of fluid and minimize current flow
between the anode and the cathode. The barrier element may be
constructed of any electrically inert material known that is
capable of forming a barrier. The barrier element material may be
the same material as the reservoir and/or the device housing, or it
may be a different material selected for its dielectric properties.
The barrier element may also be physically coupled to the reservoir
assembly, or it may be a protruding portion of the device housing,
and thus be continuous with the housing or reservoir. In those
aspects where the barrier element is not continuous with the
housing or reservoir, the barrier element may be comprised of a
material that is either the same or different from either the
device housing or the reservoir material. Non-limiting examples of
barrier element materials may include plastics, composites, nylons,
polyesters, polyurethanes, polyethylenes, polycarbonates, etc.
Barrier element materials may also include conductive materials
such as metals provided the material is rendered non-conductive by
coating or other means.
[0077] The power sources of the present invention may be any
component known to one of ordinary skill in the art that is capable
of powering an iontophoretic device. Powering the iontophoretic
device includes providing an electrical current or an electrical
potential facilitating the delivery of an active agent. In those
aspects having power sources self-contained within the device
housing, it may be beneficial for the power source to be a flexible
battery or the like. Conductive subcomponents may be utilized to
electrically couple the power source to the anode and to the
cathode. These conductive subcomponents may include wires, traces,
microelectronics, or other conductive materials such as conductive
fluids within insulated tubing or channels. Such microelectronics
may be useful in controlling the delivery of the active agent,
and/or for safety purposes.
[0078] The reservoirs according to aspects of the present invention
are designed to hold an active agent or other secondary substance
to be delivered prior to administration through the eye tissues of
a subject. Reservoirs may be configured to passively or actively
deliver an active agent into the eye. Active reservoirs, for
example, are configured to receive electrical current from an
electrode to thus iontophoretically deliver an active agent or
other compound therefrom. In one aspect, a reservoir may be a
distinct compartment, having a lumen for holding an active agent or
other secondary compound to be delivered. Additionally, such 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. In another
aspect, a reservoir may be filled during manufacture of the device
with an active agent or other secondary compound to be delivered,
particularly in those aspects where the device is intended for a
single use. 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. Additionally, the active agent or
secondary substance may be included in the reservoir in any form,
including, without limitation, a liquid, gelatinous, semi-solid, or
solid form. In another aspect the reservoir may consist of a
portion of the active electrode, such that an active agent or
secondary substance is delivered from the electrode when electrical
current is introduced.
[0079] For optimal iontophoretic delivery of active agents and
other compounds 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 thus may
increase the transference efficiency of the active agent or other
compound of interest during iontophoresis. As a result, the active
agent may 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 an active electrode
(e.g., Ag/AgCl) between the electrode and a reservoir 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
at the interface between the surface of the eye and the device. As
such, the permselective material may be located between the eye
surface and the reservoir to prevent the migration of the active
agent and endogenous ions into a reservoir containing a secondary
substance of opposite charge, or vice versa the secondary substance
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 an active 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. Additionally, in one aspect a permselective
material may be functionally coupled to an electrode delivering an
active agent or secondary compound, and/or to an electrode merely
completing the electrical circuit.
[0080] In addition to active delivery techniques, aspects of the
present invention also provide ocular delivery devices and
associated methods that utilize passive techniques to delivery the
active agent into the eye. Thus an ocular lens device may be
positioned on the eye for a sufficient period of time to allow an
active agent located therein to diffuse from the device and into
the eye. The various techniques for maintaining alignment between
the reservoir surface contact area and the delivery area may thus
facilitate the immobilization of the ocular lens device with
respect to the eye surface for the longer durations that may be
required to passively deliver an active agent to the eye.
[0081] It is also contemplated that reservoirs containing
additional compounds or substances may be incorporated into both
passive and active delivery devices according to aspects of the
present invention. In one aspect, for example, a secondary
reservoir assembly may be contacted against the eye surface so that
the secondary reservoir contacts a secondary delivery region of the
eye. A secondary substance may be delivered from the secondary
reservoir into the eye while substantially maintaining alignment
between the secondary reservoir and the secondary delivery
region.
[0082] The secondary substance may be delivered in a similar or in
a different manner compared to the active agent. For example, in
one aspect both the active agent and the secondary substance may be
iontophoretically administered. In another aspect, the active agent
may be iontophoretically administered and the secondary substance
may be passively delivered. In another aspect, the active agent may
be passively delivered and the secondary substance may be
iontophoretically delivered.
[0083] As with the reservoir contact surface area, secondary
reservoir surface area facing the eye may be understood to be the
proportion of the surface area of an ocular lens housing associated
with the secondary reservoir through which a secondary substance is
capable of passing, as compared to the total surface area of the
ocular lens that is contacting or is facing and in close proximity
with the surface of the eye. In the case of multiple secondary
reservoirs in a single ocular lens device, the secondary reservoir
surface contact area would include the combined surface area of all
of the secondary reservoir assemblies. As has been described, in
one aspect the secondary reservoir assembly contact surface area is
less than or equal to about 50% of lens area contacting the eye. In
another aspect, the secondary reservoir assembly contact surface
area is less than or equal to about 25% of lens area contacting the
eye. In yet another aspect, the secondary reservoir assembly
contact surface area is less than or equal to about 10% of lens
area contacting the eye.
[0084] A variety of secondary substances may be included in a
secondary reservoir. For example, in one aspect the secondary
substance may include a secondary active agent, a depot forming
agent, a vasoconstrictor agent, or a combination thereof. As has
been described, a secondary substance may be delivered by an active
mechanism such as iontophoresis, or by a passive mechanism such as
diffusion.
[0085] In some cases, for example, ocular treatment may be hampered
by the in-vivo movement/clearance of the active agent in the eye.
It is therefore contemplated that various means for restricting or
slowing such movement may improve the effectiveness of the active
agent therapy. In one aspect, the in-vivo movement may be
restricted by constriction of the blood vessels exiting an area in
which the active agent is being delivered or precipitated. Such
constriction may be induced by the administration of a secondary
substance such as 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,
oxymetazoline, phentermine, fenfluramine, propylhexedrine,
diethylpropion, phenmetrazine, and phendimetrazine. In one specific
aspect, the vasoconstricting agent is oxymetazoline.
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 opposite
polarity as active agent, and thus be administered from a return
electrode assembly.
[0086] Various treatment regimens according to aspects of the
present invention are contemplated. In one aspect, the administered
active agent may provide an immediate therapeutic effect. In
another aspect, the active agent may provide a sustained
therapeutic effect. In yet another aspect, the active agent may
provide an immediate therapeutic effect and a sustained therapeutic
effect. In many cases, some form of sustained release may be
beneficial in order to reduce the frequency of administration. Such
a reduction in administration may increase patient compliance and
reduce the frequency of eye infections and other related issues due
to the decreased physical contact with the eye.
[0087] Various methods of providing sustained release, and
therefore sustained therapeutic effect, are contemplated, some of
which have been discussed herein. Such a sustained release may be
due to a property of the active agent, the use of a prodrug, the
use of a sustained release depot, etc. In one aspect, a sustained
release depot may be formed in the eye tissue by the reaction of an
active agent with a secondary substance such as a depot forming
agent following delivery of the active agent to the subject. The
depot forming agent may be delivered to the subject as a secondary
substance, 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 or
a derivative 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.
[0088] 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. Further details on such depot
administration and depot agents can be found in U.S. patent
application Ser. Nos. 11/238,144 and 11/238,104, both filed on Sep.
27, 2005, both of which are incorporated herein by reference.
[0089] Numerous configurations for the ocular lens devices of the
present invention are contemplated, for both single-use and
multiple-use devices. FIG. 3, for example, shows an ocular
lens-shaped housing 32 having a reservoir 34 configured to contain
an active agent. The reservoir 34 is located entirely within a
180.degree. section of the housing 32, as is indicated by 36. FIG.
4 shows one aspect having multiple reservoirs 34 located
side-by-side entirely within a 180.degree. section of the housing
32. Additionally, a vacuum port 38 may optionally be coupled to the
ocular lens housing 32 in order to generate a vacuum between the
device and the surface of the eye during delivery of the active
agent. Although FIG. 4 shows three reservoirs 34 in the housing, it
should be understood that this is merely exemplary, and any number
of such reservoirs can be incorporated into an ocular device. As
has been described, in one aspect it is also contemplated that a
single reservoir assembly be included in the ocular lens
housing.
[0090] FIG. 5 shows one aspect having a housing 32 with a reservoir
34, a vacuum port 38, and two secondary reservoirs 40. The number
of secondary reservoirs will vary depending on the configuration of
a particular device, and should not be considered as limiting.
Additionally, the secondary reservoirs 40 may be located proximal
to a reservoir 34 as shown, or they may be positioned at a more
distal location.
[0091] FIG. 6 shows one aspect having a housing 32 with two
reservoirs 34, where the reservoirs are configured in a nested
arrangement with respect to the center of the housing. In this
aspect, both of the reservoirs 34 are located entirely within the
same 180.degree. section 36 of the housing 32.
[0092] It is also contemplated that the ocular lens housing may be
of any shape that conforms to fit the surface of the eye. In one
aspect, for example, the ocular lens housing may be a corneal lens
housing, and thus be shaped to fit at least substantially over the
cornea. In another aspect, the ocular lens housing may be a scleral
lens housing, and thus be shaped to fit at least substantially over
the scleral tissues of the eyes. In such an example, the ocular
lens housing would be configured to extended into a cul-de-sac
under an eyelid of the eye of the subject. Such a configuration may
hinder electrical current flow between the eye and the eyelid. In
one aspect, the ocular lens housing may be configured such that the
reservoir or reservoirs associated therewith are positioned within
the lower cul-de-sac of the eye during use. As the lower eyelid
generally exhibits less movement during blinking, such a
configuration may assist in maintaining the position of the ocular
housing during use.
[0093] Various materials are contemplated for use as the ocular
lens housing that may securely hold the various components of the
device. It may be additionally beneficial to utilize materials that
provide some level of flexibility to avoid damage or irritation to
the eye surface. Any material having properties beneficial to the
construction of such a device would be considered to be within the
scope of the present invention. For example, the housing material
may include, without limitation, plastics, metals, composites,
Teflon, nylons, polyesters, polyurethanes, polyethylenes,
polycarbonates, etc. Materials such as metals may be utilized that
are conductive, and thus would need have dielectric materials
incorporated therein in order to maintain electrical isolation
between various components of the device through the housing in
those aspects utilizing iontophoretic delivery techniques.
EXAMPLES
Example 1
[0094] A handheld ocular iontophoretic device is constructed from a
plastic tube, wherein one end is shaped to conform to the eye of a
rabbit. An electroplated AgAgCl electrode is positioned in one end
of the plastic tube and a hydrogel is inserted into the tube so
that one side of the hydrogel contacts the electrode, while the
opposite side is configured to contact the eye. The hydrogel has
been previously loaded with 1.0M Mn.sup.++. The iontophoretic
device is coupled to a power source and placed against the surface
of an eye of a rabbit, partially within the cul-de-sac in a dorsal
location. A return electrode is attached to the ear of the rabbit,
and finger pressure is used to seal the device against the eye. 2
mA of current is applied to the iontophoretic device for 20 minutes
to deliver the Mn.sup.++ from the hydrogel and into the eye.
Distribution of the Mn.sup.++ within the eye of the rabbit is
analyzed using a 3 Tesla Siemens MRI system as is shown in FIG. 7.
As can be seen in this figure, Mn.sup.++ ions (white contrast) were
delivered primarily to the eyelid and surrounding tissues with
relatively little delivery into the eye itself.
Example 2
[0095] An iontophoretic scleral lens device is configured to
conform to the eye of a rabbit. An electroplated AgAgCl electrode
coupled to a 1.0M Mn.sup.++ filled hydrogel is located within a
reservoir structure along the contact surface of the scleral lens.
The iontophoretic device is coupled to a power source and
positioned on an eye of a rabbit, such that the reservoir is
located partially within the cul-de-sac in a dorsal region of the
eye. A return electrode is attached to the ear of the rabbit, and
suction is applied to the scleral lens to preclude movement of the
lens relative to the eye surface. 3 mA of current is applied to the
scleral lens device for 20 minutes to deliver the Mn.sup.++ from
the hydrogel and into the eye. Distribution of the Mn.sup.++ within
the eye of the rabbit is analyzed using a 3 Tesla Siemens MRI
system as is shown in FIG. 8. As can be seen in this figure,
Mn.sup.++ ions (white contrast) were delivered primarily into the
eye tissues. Additionally, the black region along the dorsal region
of the eye represents the formation of a depot of concentrated
Mn.sup.++. Diffusion from this region can be seen in the white band
extending toward the posterior eye tissues.
[0096] 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.
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