U.S. patent application number 11/949751 was filed with the patent office on 2008-05-15 for ocular therapy using alpha-2 adrenergic receptor anterior compounds having enhanced clearance rates.
This patent application is currently assigned to ALLERGAN, INC. Invention is credited to James A. Burke, Joan-En Chang-Lin, Patrick M. HUGHES.
Application Number | 20080112923 11/949751 |
Document ID | / |
Family ID | 37397258 |
Filed Date | 2008-05-15 |
United States Patent
Application |
20080112923 |
Kind Code |
A1 |
HUGHES; Patrick M. ; et
al. |
May 15, 2008 |
OCULAR THERAPY USING ALPHA-2 ADRENERGIC RECEPTOR ANTERIOR COMPOUNDS
HAVING ENHANCED CLEARANCE RATES
Abstract
Ophthalmically therapeutic materials, such as liquid-containing
compositions and polymeric drug delivery systems, include a
therapeutic component which includes an alpha 2 adrenergic receptor
agonist that is cleared from the anterior segment of an
individual's eye to which the material is administered. The alpha 2
adrenergic receptor agonist may have a vitreal half-life greater
than about three hours. The present materials are effective in
treating an ocular condition(s) that affect the anterior segment of
an eye, or the anterior and posterior segment of the eye. The
materials are suitable for intravitreal or periocular
administration and can provide prolonged drug delivery and
therapeutic benefits to patients to which the materials have been
administered. The alpha 2 adrenergic receptor agonists can be
provided in liquid-containing formulations and/or bioerodible
and/or non-bioerodible polymeric implants and microparticles.
Methods of making and using the present materials are also
described.
Inventors: |
HUGHES; Patrick M.; (Aliso
Viejo, CA) ; Burke; James A.; (Santa Ana, CA)
; Chang-Lin; Joan-En; (Tustin, CA) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
ALLERGAN, INC
Irvine
CA
92612
|
Family ID: |
37397258 |
Appl. No.: |
11/949751 |
Filed: |
December 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11416929 |
May 2, 2006 |
|
|
|
11949751 |
Dec 3, 2007 |
|
|
|
60679771 |
May 10, 2005 |
|
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|
Current U.S.
Class: |
424/78.37 |
Current CPC
Class: |
A61P 27/06 20180101;
A61P 27/02 20180101; A61P 27/10 20180101; A61P 25/00 20180101; A61K
9/1647 20130101; A61P 43/00 20180101; A61K 9/0048 20130101; A61K
9/0051 20130101 |
Class at
Publication: |
424/078.37 |
International
Class: |
A61K 31/765 20060101
A61K031/765 |
Claims
1-24. (canceled)
25. A method of improving or maintaining vision of an eye of a
patient, comprising the step of administering an ophthalmically
therapeutic material to an eye of an individual, wherein said
ophthalmically therapeutic material comprises: a therapeutic
component comprising a therapeutically effective amount of an alpha
2 adrenergic receptor agonist having a structure effective in
providing elimination of the agonist from the anterior chamber of
an eye to which the agonist is administered.
26. The method of claim 25, wherein the method is effective to
treat an ocular condition selected from the group consisting of
anterior ocular condition, posterior ocular conditions, and
combinations thereof.
27. The method of claim 25, wherein the method is effective to
provide neuroprotection to ocular neuronal cells and to reduce
elevated intraocular pressure.
28. The method of claim 25, wherein the method is effective in
treating glaucoma.
29. The method of claim 25, wherein the material is administered by
a step selected from the group consisting of intraocular
administration, periocular administration, and combinations
thereof.
30. The method of claim 25, wherein the material is administered by
intravitreal injection of the material into the eye.
31. The method of claim 25, wherein the administering comprises
subconjunctival administration or periocular administration to
deliver the alpha 2 adrenergic receptor agonist to a posterior
structure of the eye selected from the group consisting of: the
uveal tract, the vitreous, the retina, the choroid, the retinal
pigment epithelium, and combinations thereof.
32. The method of claim 25, wherein the administering comprises
administering the material to a location in the eye selected from
the group consisting of the anterior chamber, the posterior
chamber, and combinations thereof.
33. The method of claim 25, wherein the administering comprises
using a syringe or a trocar to administer the material to the
eye.
34. The method of claim 25, wherein said ophthalmically therapeutic
material further comprises a polymeric component associated with a
therapeutic component in the form of a polymeric drug delivery
system suitable for administration to a patient by at least one of
intravitreal administration and periocular administration.
35. The method of claim 34, wherein the polymeric drug delivery
system is selected from the group consisting of biodegradable
polymeric implants, non-biodegradable polymeric implants,
biodegradable polymeric microparticles, and combinations
thereof.
36. The method of claim 34, wherein the polymeric component
comprises a poly(lactide-co-glycolide) polymer.
37. The method of claim 34, wherein the polymeric component
comprises a polymer selected from the group consisting of
poly-lactic acid (PLA), poly-glycolic acid (PGA),
poly-lactide-co-glycolide (PLGA), polyesters, poly(ortho ester),
poly(phosphazine), poly(phosphate ester), polycaprolactones,
gelatin, collagen, derivatives thereof, and combinations
thereof.
38. The method of claim 34, wherein the therapeutic component and
the polymeric component are associated in the form of an implant
selected from the group consisting of solid implants, semisolid
implants, and viscoelastic implants.
39. The method of claim 25, wherein the alpha 2 adrenergic receptor
agonist is provided in an amount to provide a therapeutic effect
selected from the group consisting of neuroprotection, reduction in
intraocular pressure, and combinations thereof.
40. The method of claim 25, wherein the alpha 2 adrenergic receptor
agonist is coupled to a polyethylene glycol.
41. The method of claim 25, wherein the alpha 2 adrenergic receptor
agonist has a structure effective in providing substantially equal
elimination rates from the anterior chamber of the eye and the
posterior segment of the eye.
42. The method of claim 25, wherein the alpha 2 adrenergic receptor
agonist has a structure effective in providing a greater enhanced
anterior elimination rate relative to a posterior elimination rate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Application No. 60/679,771, filed May 10, 2004, the content of
which in its entirety is hereby incorporated by reference.
BACKGROUND
[0002] The present invention generally relates to the use of
alpha-2 adrenergic receptor agents that are cleared from the
anterior of an eye to treat an eye of a patient, and more
specifically to ophthalmic compositions and drug delivery systems
that provide extended release of the alpha-2 adrenergic receptor
agents to an eye to which the agents are administered; and to
methods of making and using such compositions and systems, for
example, to treat or reduce one or more symptoms of an ocular
condition to improve or maintain vision of a patient.
[0003] In ocular therapies, alpha agonists (e.g., agonists of alpha
adrenergic receptors) are used to reduce aqueous humor production
and increase aqueous humor outflow through the trabecular meshwork.
The outflow through the trabecular meshwork accounts for about 90%
of the eye's fluid drainage capability, and the remaining
approximately 10% is provided by the uveoscleral outflow where
fluid flows into the ciliar muscle beneath the trabecular meshwork.
Two examples of alpha agonists used for ocular therapy include
apraclonidine (IOPIDINE) and brimonidine-P (ALPHAGAN-P).
[0004] Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino)
quinoxaline, is an alpha-2-selective adrenergic receptor agonist
that is effective in the treatment of open-angle glaucoma by
decreasing aqueous humor production and increasing uveoscleral
outflow. Apraclonidine generally has a mixed alpha-1 and alpha-2
stimulatory activity. Brimonidine is available in two chemical
forms, brimonidine tartrate and brimonidine free base. Brimonidine
tartrate (Alphagan.RTM. P) is publicly available by Allergan for
treating glaucoma. Topical ocular brimonidine formulation, 0.15%
Alphagan.RTM. P (Allergan, Irvine, Calif.), is currently
commercially available for treatment of open-angle glaucoma. The
solubility of brimonidine tartrate in water is, 34 mg/mL in water
and 2.4 mg/mL in a pH 7.0 phosphate buffer while the solubility of
brimonidine freebase is negligible in water.
[0005] Recent studies have suggested that brimonidine can promote
survival of injured retinal ganglion nerve cells by activation of
the alpha-2-adrenoceptor in the retina and/or optic nerve. For
example, brimonidine can protect injured neurons from further
damage in several models of ischemia and glaucoma.
[0006] Glaucoma-induced ganglion cell degeneration is one of the
leading causes of blindness. This indicates that brimonidine can be
utilized in a new therapeutic approach to glaucoma management in
which neuroprotection and intraocular pressure reduction are valued
outcomes of the therapeutic regimen. For brimonidine to protect the
optic nerve, however, it must have access to the posterior segment
of the eye at therapeutic levels. Currently available techniques
for administering brimonidine to the posterior chamber of the eye
are not sufficient to address this issue.
[0007] Agents that are administered to the vitreous of an eye of a
patient can be eliminated from the vitreous by diffusion to the
retro-zonular space (anterior clearance) with clearance via the
aqueous humor, such as through the trabecular meshwork outflow and
the uveoscleral outflow, or by trans-retinal elimination (posterior
clearance). Most compounds that are relatively hydrophilic to
moderately lipophilic utilize the former (anterior clearance)
pathway unless a facilitated or active transport mechanism exists
for these while extremely lipophilic compounds and those with
trans-retinal transport mechanisms will utilize the latter (i.e.,
will go out through the retina). For example, macromolecules and
peptides, including antibiotics, are often eliminated via the
anterior route. In comparison, existing alpha 2 adrenergic receptor
agonists are eliminated via the posterior route. This is most
likely the result of an organic cationic transport mechanism in the
outer blood retinal barrier, the RPE. Unfortunately, compounds that
are eliminated across the retina have extremely short intravitreal
half-lives. Additionally, these compounds tend to have extremely
small aqueous humor/vitreous humor concentration ratios at
steady-state. This dramatically impacts the treatment of anterior
tissues from posterior administration of such compounds.
[0008] Intravitreal delivery of therapeutic agents can be achieved
by injecting a liquid-containing composition into the vitreous, or
by placing polymeric drug delivery systems, such as implants and
microparticles, into the vitreous. Examples of biocompatible
implants for placement in the eye have been disclosed in a number
of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652;
5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079;
6,074,661; 6,331,313; 6,369,116; and 6,699,493.
[0009] Other ocular therapies may include periocular delivery of
drugs to a patient. Penetration of drugs directly into the
posterior segment of the eye is restricted by the blood-retinal
barriers. The blood-retinal barrier is anatomically separated into
inner and outer blood barriers. Movement of solutes or drugs into
the internal ocular structures from the periocular space is
restricted by the retinal pigment epithelium (RPE), the outer
blood-retinal barrier. The cells of this structure are joined by
zonulae oclludentae intercellular junctions. The RPE is a tight ion
transporting barrier that restricts paracellular transport of
solutes across the RPE. The permeability of most compounds across
the blood-retinal barriers is very low. Extremely lipophilic
compounds, however, such as chloramphenical and benzyl penicillin,
can penetrate the blood-retinal barrier achieving appreciable
concentrations in the vitreous humor after systemic administration.
The lipophilicity of the compound correlates with its rate of
penetration and is consistent with passive cellular diffusion. The
blood retinal barrier, however, is impermeable to polar or charged
compounds in the absence of a transport mechanism. Hydrophilic to
moderately lipophilic drugs can diffuse into the iris-ciliary body
achieving very low posterior chamber or iris root concentrations.
Anterior bulk flow of aqueous humor competes with the posterior
elimination of drugs. For compounds that cannot passively penetrate
the RPE, but are eliminated across the retina, it is
extraordinarily difficult to achieve therapeutic concentrations of
drugs at reasonable doses due to the differential rate processes
involved.
[0010] Thus, there remains a need for new agents that can be used
to treat ocular conditions, and that have different pharmacokinetic
properties than existing agents.
SUMMARY
[0011] Ophthalmically therapeutic materials, such as
liquid-containing compositions and polymeric drug delivery systems,
include a therapeutic component which includes an alpha 2
adrenergic receptor agonist that is cleared from the anterior
segment of an individual's eye to which the material is
administered. The alpha 2 adrenergic receptor agonist may have a
vitreal half-life greater than about three hours. The present
materials are effective in treating an ocular condition(s) that
affect the anterior segment of an eye, or the anterior and
posterior segment of the eye. The materials are suitable for
intravitreal or periocular administration and can provide prolonged
drug delivery and therapeutic benefits to patients to which the
materials have been administered. The alpha 2 adrenergic receptor
agonists can be provided in liquid-containing formulations and/or
bioerodible and/or non-bioerodible polymeric implants and
microparticles. Methods of making and using the present materials
are also described.
[0012] Ophthalmically therapeutic materials in accordance with the
disclosure herein comprise a therapeutic component that comprises a
therapeutically effective amount of an alpha 2 adrenergic receptor
agonist having a structure effective in providing elimination of
the agonist from the anterior chamber of an eye to which the
agonist is administered.
[0013] The anteriorly cleared alpha-2 adrenergic receptor agonists
of the present materials may be an agonist or agent that
selectively activates alpha-2 adrenergic receptors, for example by
binding to an alpha-2 adrenergic receptor, relative to other types
of adrenergic receptors, such as alpha-1 adrenergic receptors. The
selective activation can be achieved under different conditions,
but preferably, the selective activation is determined under
physiological conditions, such as conditions associated with an eye
of a human or animal patient.
[0014] A method of producing the present ophthalmically therapeutic
materials may comprise selecting an alpha 2 adrenergic receptor
agonist that has a vitreous half-life greater than about 3 hours;
and combining the selected alpha 2 adrenergic receptor agonist with
a liquid carrier component or a polymeric component to form a
material suitable for administration to an eye.
[0015] Methods of treating one or more ocular conditions comprise a
step of administering the present materials to an eye of a patient.
The materials can be intravitreally administered and/or
periocularly administered. When drug delivery systems are used to
deliver the anteriorly cleared alpha 2 adrenergic receptor
agonists, sustained delivery and prolonged therapeutic benefits can
be obtained.
[0016] Kits in accordance with the present invention may comprise
one or more of the present materials, and instructions for using
the materials. For example, the instructions may explain how to
administer the materials to a patient, and types of conditions that
may be treated with the materials.
[0017] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent. In addition,
any feature or combination of features may be specifically excluded
from any embodiment of the present invention.
[0018] Additional aspects and advantages of the present invention
are set forth in the following description, examples, and claims,
particularly when considered in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a graph of the vitreal concentration of
brimonidine as a function of time after a single intravitreal
administration of 928 ng of brimonidine into the vitreous of rabbit
eyes (n=4).
DESCRIPTION
[0020] Ophthalmically therapeutic materials and methods have been
invented which provide effective treatment of ocular conditions,
such as disorders or diseases of the anterior and/or posterior
segment of an eye of an individual, such as a human or animal. The
present ophthalmically therapeutic materials comprise a therapeutic
component which comprises an alpha 2 adrenergic receptor agonist.
The alpha 2 adrenergic receptor agonists of the present materials
have structures that are effective in providing anterior clearance
or elimination of the agonist from the eye. For example, the alpha
2 adrenergic receptor agonists of the present materials have
structures that are effective in permitting the agonists to be
cleared via the anterior route or the anterior chamber, as compared
to the posterior route or via the retina of an eye to which the
materials are administered. Thus, the present materials can provide
one or more therapeutic effects for treating anterior ocular
conditions, posterior ocular conditions, and combinations of
anterior and posterior ocular conditions. For example, the present
materials can reduce elevated intraocular pressure in an eye, can
provide neuroprotection, and treat glaucoma, and/or can reduce
intraocular pressure and provide neuroprotection.
DEFINITIONS
[0021] For the purposes of this description, we use the following
terms as defined in this section, unless the context of the word
indicates a different meaning.
[0022] As used herein, an "intraocular drug delivery system" refers
to a device or element that is structured, sized, or otherwise
configured to be placed in an eye. The present drug delivery
systems are generally biocompatible with physiological conditions
of an eye and do not cause unacceptable or undesirable adverse side
effects. The present drug delivery systems may be placed in an eye
without disrupting vision of the eye. The present drug delivery
systems may be in the form of a plurality of particles, such as
microparticles, or may be in the form of implants, which are larger
in size than the present particles. Intraocular drug delivery
systems described herein include a polymeric component.
[0023] As used herein, a "composition" refers to a material
suitable for administration to an eye of an individual.
Compositions may include a polymeric drug delivery systems if
desired. Compositions may comprise a liquid carrier, and
compositions refers to material such as solutions, suspensions,
emulsions, and the like.
[0024] As used herein, a "therapeutic component" refers to a
portion of a drug delivery system or composition comprising one or
more therapeutic agents, active ingredients, or substances used to
treat a medical condition of the eye. The therapeutic component may
be a discrete region of an intraocular implant, or it may be
homogenously distributed throughout the implant or particles or
composition. The therapeutic agents of the therapeutic component
are typically ophthalmically acceptable, and are provided in a form
that does not cause adverse reactions when the ophthalmically
therapeutic material is placed in an eye.
[0025] As used herein, "associated with" means mixed with,
dispersed within, coupled to, covalently bonded, covering, or
surrounding.
[0026] As used herein, an "ocular region" or "ocular site" refers
generally to any area of the eyeball, including the anterior and
posterior segment of the eye, and which generally includes, but is
not limited to, any functional (e.g., for vision) or structural
tissues found in the eyeball, or tissues or cellular layers that
partly or completely line the interior or exterior of the eyeball.
Specific examples of areas of the eyeball in an ocular region
include the anterior chamber, the posterior chamber, the vitreous
cavity, the choroid, the suprachoroidal space, the subretinal
space, the conjunctiva, the subconjunctival space, the episcleral
space, the intracorneal space, the epicorneal space, the sclera,
the pars plana, surgically-induced avascular regions, the macula,
and the retina.
[0027] As used herein, an "ocular condition" is a disease, ailment
or condition which affects or involves the eye or one of the parts
or regions of the eye. Broadly speaking the eye includes the
eyeball and the tissues and fluids which constitute the eyeball,
the periocular muscles (such as the oblique and rectus muscles) and
the portion of the optic nerve which is within or adjacent to the
eyeball.
[0028] An anterior ocular condition is a disease, ailment or
condition which affects or which involves an anterior (i.e. front
of the eye) ocular region or site, such as a periocular muscle, an
eye lid or an eye ball tissue or fluid which is located anterior to
the posterior wall of the lens capsule or ciliary muscles. Thus, an
anterior ocular condition primarily affects or involves the
conjunctiva, the cornea, the anterior chamber, the iris, the
posterior chamber (behind the iris but in front of the posterior
wall of the lens capsule), the lens or the lens capsule and blood
vessels and nerve which vascularize or innervate an anterior ocular
region or site.
[0029] Thus, an anterior ocular condition can include a disease,
ailment or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
[0030] A posterior ocular condition is a disease, ailment or
condition which primarily affects or involves a posterior ocular
region or site such as choroid or sclera (in a position posterior
to a plane through the posterior wall of the lens capsule),
vitreous, vitreous chamber, retina, retinal pigmented epithelium,
Bruch's membrane, optic nerve (i.e. the optic disc), and blood
vessels and nerves which vascularize or innervate a posterior
ocular region or site.
[0031] Thus, a posterior ocular condition can include a disease,
ailment or condition, such as for example, acute macular
neuroretinopathy; Behcet's disease; choroidal neovascularization;
diabetic uveitis; histoplasmosis; infections, such as fungal or
viral-caused infections; macular degeneration, such as acute
macular degeneration, non-exudative age related macular
degeneration and exudative age related macular degeneration; edema,
such as macular edema, cystoid macular edema and diabetic macular
edema; multifocal choroiditis; ocular trauma which affects a
posterior ocular site or location; ocular tumors; retinal
disorders, such as central retinal vein occlusion, diabetic
retinopathy (including proliferative diabetic retinopathy),
proliferative vitreoretinopathy (PVR), retinal arterial occlusive
disease, retinal detachment, uveitic retinal disease; sympathetic
opthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a
posterior ocular condition caused by or influenced by an ocular
laser treatment; posterior ocular conditions caused by or
influenced by a photodynamic therapy, photocoagulation, radiation
retinopathy, epiretinal membrane disorders, branch retinal vein
occlusion, anterior ischemic optic neuropathy, non-retinopathy
diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma.
Glaucoma can be considered a posterior ocular condition because the
therapeutic goal is to prevent the loss of or reduce the occurrence
of loss of vision due to damage to or loss of retinal cells or
optic nerve cells (i.e. neuroprotection).
[0032] The term "biodegradable polymer" refers to a polymer or
polymers which degrade in vivo, and wherein erosion of the polymer
or polymers over time occurs concurrent with or subsequent to
release of the therapeutic agent. The terms "biodegradable" and
"bioerodible" are equivalent and are used interchangeably herein. A
biodegradable polymer may be a homopolymer, a copolymer, or a
polymer comprising more than two different polymeric units.
[0033] The term "treat", "treating", or "treatment" as used herein,
refers to reduction or resolution or prevention of an ocular
condition, ocular injury or damage, or to promote healing of
injured or damaged ocular tissue.
[0034] The term "therapeutically effective amount" as used herein,
refers to the level or amount of agent needed to treat an ocular
condition, or reduce or prevent ocular injury or damage without
causing significant negative or adverse side effects to the eye or
a region of the eye.
[0035] The present materials described herein include, without
limitation, liquid-containing compositions, such as formulations,
and polymeric drug delivery systems. The present compositions may
be understood to include solutions, suspensions, emulsions, and the
like, such as other liquid-containing compositions used in
ophthalmic therapies. Polymeric drug delivery systems comprise a
polymeric component, and may be understood to include biodegradable
implants, nonbiodegradable implants, biodegradable microparticles,
such as biodegradable microspheres, and the like. The present drug
delivery systems may also be understood to encompass elements in
the form of tablets, wafers, rods, sheets, and the like. The
polymeric drug delivery systems may be solid, semisolid, or
viscoelastic.
[0036] The agonists of the present materials refer to agents that
bind or interact with a target receptor, such as a receptor
expressed on a cell surface, and activate that target receptor. As
used herein, the alpha 2 adrenergic receptor agonist is an agent
that selectively interacts with alpha 2 adrenergic receptors. For
example, an alpha 2 adrenergic receptor agonist of the present
material is typically an agent that selectively activates alpha-2
adrenergic receptors relative to alpha-1 adrenergic receptors. In
certain materials, the alpha-2 adrenergic receptor agonist
selectively activates or stimulates a subtype of the alpha-2
adrenergic receptors. For example, the agonist may selectively
activate one or more of the alpha-2a, the alpha-2b, or the alpha-2c
receptors, under certain conditions, such as physiological
conditions. The present agonists may partially activate or fully
activate alpha 2 adrenergic receptors. The present agonists may
also be understood to encompass modified or engineered alpha 2
adrenergic receptor agonists, such as a conventional or publicly
known alpha 2 adrenergic receptor agonist that has been modified or
engineered to have the desired anterior clearance described herein.
Modified or engineered alpha 2 adrenergic receptor agonists
interact with alpha 2 adrenergic receptors to activate the
receptors, but differ from other alpha 2 adrenergic receptor
agonists at least by the clearance of such agonists from the eye.
For purposes of convenience, the alpha 2 adrenergic receptor
agonists of the present materials may also be referred to as
"anteriorly cleared alpha 2 adrenergic receptor agonists".
[0037] Certain embodiments of the present materials comprise a
therapeutic component that comprises an alpha 2 adrenergic receptor
agonist that is preferentially cleared via the anterior segment of
an eye relative to the posterior segment of the eye. Or, stated
differently, the alpha 2 adrenergic receptor agonist is cleared
from the eye by mixing with the aqueous humor present in the
anterior and/or posterior chambers of an eye or through the
iris-ciliary body, as opposed to being cleared via the retina of
the eye. In certain embodiments, the alpha 2 adrenergic receptor
agonist has an anterior clearance rate that is at least 30% greater
than a posterior clearance rate. For example, the alpha 2
adrenergic receptor agonist may have an anterior clearance rate
that is at least about 40% greater, or 50% greater, or 60% greater,
or 70% greater, or 90% greater than the posterior clearance rate.
Thus the alpha 2 adrenergic receptor agonists have a greater
anterior clearance rate/posterior clearance rate ratio than other
alpha 2 adrenergic receptor agonists that are cleared via the
retina. In addition, the alpha 2 adrenergic receptor agonists may
have a high aqueous humor/vitreous humor concentration ratio. The
enhanced anterior clearance can be observed when the alpha 2
adrenergic receptor agonist is administered intraocularly, such as
into the posterior segment of an eye, such as into the vitreous of
an eye, and can be observed when the alpha 2 adrenergic receptor
agonist is administered periocularly, such as when the agent is
administered into one or more of the following regions: retrobulbar
regions, subconjunctival regions, subtenon regions, suprachoroidal
regions, and intrascleral regions. In many situations, the alpha 2
adrenergic receptor agonist will be cleared from the eye by passing
from the anterior chamber through the trabecular meshwork at the
angle or the filtration angle.
[0038] In other embodiments, the alpha 2 adrenergic receptor
agonist has a substantially equal anterior and posterior clearance
rate. Importantly, the present materials comprise an alpha 2
adrenergic receptor agonist that has a measurable anterior
clearance. For example, when administered to the vitreous of an
eye, a sample of the aqueous humor obtained from an individual will
contain a measurable amount of the alpha 2 adrenergic receptor
agonist after a certain time period. In comparison, existing alpha
2 adrenergic receptor agonists, such as brimonidine, are not
detected or are not calculable in the aqueous humor when
administered intravitreally or periocularly, as discussed
herein.
[0039] As discussed above, the therapeutic component of the present
materials may comprise a modified or engineered alpha-2 adrenergic
agonist. For example, the modified or engineered alpha-2 adrenergic
agonist may comprise a base structure effective in interacting with
or activating an alpha-2 adrenergic receptor, and a bulking agent
or modifier component associated with the base structure to provide
an enhanced anterior clearance relative to an identical base
structure without the bulking agent or modifier component. The
bulking agent or modifier component may be coupled to or covalently
bonded with the base structure. For example, the bulking agent or
modifier component may be directly covalently bonded to the base
structure, or it may be indirectly coupled to the base structure
via one or more linking agents. The bulking agent or modifier
component can alter the hydrophilicity or lipophilicity of the base
structure to achieve the desired anterior clearance. Preferably,
the bulking agent or modifier component does not substantially
interfere with the base structure's interaction with an alpha-2
adrenergic receptor.
[0040] Some modified or engineered alpha-2 adrenergic receptor
agonists may comprise a bulking agent or modifier component
associated with the base structure in a manner which permits the
bulking agent or modifier component to disassociate from the base
structure under certain conditions. For example, a bulking agent
may be temporarily bonded with the base structure, and after a
certain amount of time, the bond degrades and the base structure is
released from the bulking agent. The bond may be sensitive to light
passing through the eye, or it may be sensitive to one or more
chemical agents that can be topically applied to the eye. Or, the
base structure may be complexed with the bulking agent or modifier
component, and the complex dissociates over time in the vitreous of
an eye.
[0041] One non-limiting example of a modified or engineered alpha-2
adrenergic receptor agonist that has a relatively long vitreal
half-life is an alpha-2 adrenergic receptor agonist coupled to a
polyethylene glycol (PEG). For example, a PEG agent may be
covalently bonded to an amino or sulfhydryl group present on the
alpha-2 adrenergic receptor agonist via a chemically reactive group
on the PEG agent. The resulting modified or engineered alpha-2
adrenergic receptor agonist can be linear or branched in structure.
In certain embodiments, the PEG agent has a molecular weight from
about 30 kDa to about 60 kDa, for example about 40 kDa or about 50
kDa.
[0042] A second non-limiting example of a modified or engineered
alpha-2 adrenergic receptor agonist that has a relatively long
vitreal half-life is an alpha-2 adrenergic receptor agonist that
includes one or more lipophilic components. For example, the
alpha-2 adrenergic receptor agonist may be coupled to a hydrophobic
hydrocarbon including one or more hydrophilic groups. One example
of such an agent includes hydroxy-containing hydrocarbons. Such
agents can be effective to provide both hydrophobic and hydrophilic
groups and thereby alter the vitreal-half life of the alpha-2
adrenergic agonist. One specific example of a modified or
engineered alpha-2 adrenergic receptor agonist includes
alkylpropanediol coupled to an alpha-2 adrenergic receptor agonist.
Additional examples include alkylpropanediols other than
1-O-hexadecylpropanediol. 1-O-hexadecylpropanediol has been shown
to be effective in slowing the release of ganciclovir into the
vitreous of rabbit eyes (Cheng et al., "Treatment or prevention of
herpes simplex virus retinitis with intravitreally injectable
crystalline 1-O-Hexadecylpropanediol-3-phospho-ganciclovir", (2002)
Investigative Opthalmology & Visual Science,
43(2):515-521).
[0043] Additional examples of suitable bulking agents or modifier
components can be identified and obtained using routine methods
known to persons of ordinary skill in the art. Thus, the alpha 2
adrenergic receptor agonists of the present therapeutic components
can be identified by screening the agents for the desired
pharmacokinetic properties, such as vitreal half-life, aqueous
humor/vitreous humor concentration ratios, and the like, using the
methods described above. The screened or selected alpha 2
adrenergic receptor agonists can then be combined with one or more
components or component precursors of the present compositions and
drug delivery systems.
[0044] The bulking agent or modifier component may be effective in
increasing the molecular weight of the alpha 2 adrenergic receptor
agonists. With the increased molecular weight, the alpha 2
adrenergic receptor agonists may exhibit a reduced posterior
clearance rate from an eye, and/or may exhibit an enhanced anterior
clearance from the eye. One example of a modified alpha 2
adrenergic receptor agonist includes a brimonidine base structure
coupled or associated with a polyethylene glycol. The alpha-2
adrenergic agonist of the therapeutic component may have a greater
aqueous humor/vitreous humor concentration ratio and greater
vitreal half-life relative to other alpha-2 adrenergic receptor
agonists, such as brimonidine.
[0045] Another example of a modified or engineered alpha-2
adrenergic receptor agonist that has a relatively long vitreal
half-life is an alpha-2 adrenergic receptor agonist that prevents
trans RPE transport by the organic cation transporters. At
physiologic pH many of the alpha 2 adrenergic receptor agonists are
positively charged. Transport of organic cations can be mediated by
substrate-specific, sodium-dependent transporters and by less
specific sodium-independent transporters. Two major families of
organic cation transporters have been identified: organic cation
transporters (OCT) and organic cation/carnitine transporters
(OCTN). The OCT transporters have been identified in the retinal
pigmented epithelium (the outer blood-retinal barrier).
Additionally, a novel organic cation transporter, distinct from the
known OCT family, has been identified in the RPE.
[0046] Brimonidine is a substrate for the organic cation
transporter present in the conjunctiva. It is possible that
elimination of brimonidine across the retina/RPE may be a result of
an organic cation transporter. The pKa of the imidazole nitrogen on
brimonidine is 7.78.
[0047] Thus, the present alpha 2 adrenergic receptor agonists may
be effective agents in activating alpha 2 adrenergic receptors
without being a substrate for organic cation transporters. Such
agonists may not necessarily include a bulking agent, as described
above. For example, generating an N-Mannich base prodrug may create
a compound that is not a substrate for the organic cation
transporters. Another example of the present alpha-2 adrenergic
receptor agonists that could possess a decreased organic cation
transport is a sulfonyl prodrug of brimonidine. These compounds
would be expected to have a decreased transretinal elimination and
prolonged vitreous half-life. Synthesis of these compounds is
straight forward by those skilled in the art.
[0048] Thus, certain embodiments of the present alpha 2 adrenergic
receptor agonists may be non-cationic at a physiological pH, such
as at the pH of the interior of an eye. In other words, the present
agonists can be present as neutrally charged or anionic molecules
in the interior of an eye. In certain embodiments, the present
agonists are non-cationic at a pH from about 6.0 to about 7.8. For
example, the present agonists are non-cationic at a pH from about
7.0 to about 7.4. In certain embodiments, the agonists are
non-cationic at a pH of about 7.2, or at a pH of about 7.3, or at a
pH of about 7.4. In certain embodiments, a major portion of the
present agonists in the compositions and/or drug delivery systems
are non-cationic at the recited pHs or pH ranges. For example,
about 90%, or about 80%, or about 70%, or about 60%, or about 50%
of the agonists may be non-cationic at the recited pHs or pH
ranges.
[0049] When the present alpha 2 adrenergic receptor agonists are
organic cations (e.g., organic molecules having a transient or
permanent positive net charge), the agonists may have a basic
functionality with a pKa of less than about 7. Certain agonists may
have a pKa of about 6.5, or about 6, or about 5.5, or about 5.
[0050] Additional alpha 2 adrenergic receptor agonists in
accordance with the present disclosure include alpha 2 adrenergic
receptor agonists that have no ionizable groups. Other additional
alpha 2 adrenergic receptor agonists may have only acidic
functionalities, as compared to basic functionalities. Acidic
functionalities may be provided by coupling or associating one or
more acidic moieties with an alpha 2 adrenergic receptor agonist
base structure.
[0051] One example of an N-Mannich base prodrug is provided below
as compound A. ##STR1##
[0052] This N-Mannich base prodrug will have a pKa of 6.9, thus
having a much higher fraction of uncharged species. Chemical
decomposition back to brimonidine can occur. Optimizing the rate of
decomposition back to brimonidine may result in an appropriate
vitreous half-life.
[0053] An example of a sulfonyl prodrug is provided below as
compound B: ##STR2##
[0054] The rate of chemical hydrolysis of the sulfonyl prodrugs
back to brimonidine can be optimized by judicious selection of
sulfonyl moiety. The sulfonyl prodrug will have a pKa of 5 and will
be uncharged at physiologic pH.
[0055] Another example of the present alpha 2 adrenergic receptor
agonists include agents that activate alpha 2 adrenergic receptors
and that are neutral at a physiological pH. For example, the alpha
2 adrenergic receptor agonist is not a cation at a physiological
pH, such as at the pH of the interior of an eye of a human. One
example of such an agonist is provided below as compound C.
##STR3##
[0056] Another example of such an alpha 2 adrenergic receptor
agonist is provided below as compound D ##STR4##
[0057] Another example of such an alpha 2 adrenergic receptor
agonist is provided below as compound E ##STR5##
[0058] Anteriorly cleared alpha 2 adrenergic receptor agonists can
be identified and obtained using standard pharmacokinetic
experiments and conventional methods that are routine to persons of
ordinary skill in the art. For example, potential anteriorly
cleared alpha 2 adrenergic receptor agonists can be produced using
conventional chemical synthesis techniques, such as techniques
suitable for producing conventional alpha 2 adrenergic receptor
agonists, such as brimonidine, xylazine, medetomidine, ketamine,
clonidine, apraclonidine, and the like. If desired, the alpha 2
adrenergic receptor agonist can be modified or engineered, as
described above. The alpha 2 adrenergic receptor agonist activity
can be examined using conventional screening assays for testing
conventional alpha 2 adrenergic receptor agonists. Such screening
assays are routine to persons of ordinary skill in the art.
[0059] Potential anteriorly cleared alpha 2 adrenergic receptor
agonists can be screened by injecting the potential agonist into a
rabbit vitreous. The vitreous humor and aqueous humor can be
sampled as a function of time, and the amount of the potential
agonist in the vitreous and aqueous humor can be measured. The
vitreous concentration of the potential agonist can be plotted as a
function of time, and using standard pharmacokinetic techniques,
the vitreous half-life for the potential agonist and clearance of
the potential agonist can be calculated. Similarly, the aqueous
concentration of the potential agonist can be plotted as a function
of time, and standard pharmacokinetic techniques can be used to
determine the anterior clearance of the potential agonists. Agents
with desired vitreal half-lives and/or that are measurable in the
aqueous humor may be used in the present materials. For example,
agents that have vitreous half-lives greater than about three hours
can be selected for the present ophthalmically therapeutic
materials.
[0060] Compounds that have a short vitreal half-life (e.g., less
than about three hours), are likely eliminated from the eye via a
posterior route across the retina (Cunha-Vaz et al., "The active
transport of fluoroscein by the retinal vessels and the retina", J.
Physiol., 191:467-486 (1967); Barza et al., "The effects of
infection and probenecid on the transport of carbenicillin from the
rabbit vitreous humor", Invest Opthalmol Vis. Sci., 22:720-726
(1982); Miller et al., "Fleroxacin pharmacokinetics in aqueous and
vitreous humors determination by using complete concentration-time
data from individual rabbits", Antimicrob. Agents. Chemother.,
36:32-38 (1992); Cunha-Vaz, "The blood-ocular barriers", Surv.
Opthalmol., 5:279-296 (1979); Maurice et al., "Handbook of
Experimental Pharmacology: Pharmacology of the Eye", Sears, Eds.,
Vol. 69, (Springer-Verlag, Berlin-Heidelberg), 19-116 (1986); and
Lesar et al., "Antimicrobial drug delivery to the eye", Drug Intell
Clin. Pharm., 19:642-654 (1985)).
[0061] Because of the large surface are of the retina available for
exchanges between the vitreous and plasma, strict anterior
diffusion of molecules does not occur for compounds able to cross
the retina and the retinal pigment epithelium (RPE). Instead, the
compounds will radially diffuse from an initial concentration
distribution followed by elimination from the vitreous across the
retina (e.g., the trans-retinal or posterior elimination route).
Additionally, a low aqueous humor/vitreous humor concentration
ratio for the compound is further evidence of a trans-retinal
mechanism of elimination for such compounds (Maurice, "The exchange
of sodium between the vitreous body and the blood and aqueous
humor", J. Physiol, 137:119-125 (1957); and Maurice, "Protein
dynamics in the eye studied with labelled proteins", Am J
Opthalmol, 49:361-367 (1959)).
[0062] In comparison, compounds eliminated by the anterior chamber
route will develop an aqueous humor/vitreous humor concentration
ratio that correlates well with their molecular weight (Maurice et
al., "Handbook of Experimental Pharmacology: Pharmacology of the
Eye", Sears, Eds., Vol. 69, (Springer-Verlag, Berlin-Heidelberg),
19-116 (1986)). Examples of compounds that are cleared by the
anterior route include albumin, gentamicin, streptomycin,
sulfacetamide tobramycin, kanamycin, as well as other
macromolecules and peptides. It is important to note that such
compounds are not alpha 2 adrenergic receptor compounds.
[0063] In view of the above, one embodiment of the present
invention, relates to an ophthalmically therapeutic material that
comprises a therapeutic component which comprises a therapeutically
effective amount of an alpha 2 adrenergic receptor agonist having a
structure effective in providing elimination of the agonist from
the anterior chamber of an eye to which the agonist is
administered. For example, the ophthalmically therapeutic material
comprises an alpha 2 adrenergic receptor agonist that is cleared
via the anterior route (e.g., through the trabecular meshwork
outflow and/or the uveoscleral outflow) compared to being cleared
solely through the posterior route (e.g., through the retina).
[0064] The alpha 2 adrenergic receptor agonist of the present
materials is provided in an amount effective in providing one or
more therapeutic effects. For example, a material may comprise an
amount of an anteriorly cleared alpha 2 adrenergic receptor agonist
that provides neuroprotection to the neurons in an eye, a reduction
in elevated intraocular pressure, and combinations thereof. As
another example, the anteriorly cleared alpha 2 adrenergic receptor
agonists may be provided in amounts that are effective in treating
glaucoma. In certain materials, such as the polymeric drug delivery
systems described herein, the anteriorly cleared alpha 2 adrenergic
receptor agonist may be released from the drug delivery system in
such therapeutically effective amounts.
[0065] Some of the present materials comprise an alpha 2 adrenergic
receptor agonist that has an intravitreal half-life after solution
dosing greater than about three hours. For example, certain
materials comprises an anteriorly cleared alpha 2 adrenergic
receptor agonist that has an intravitreal half life of 4 hours, or
5 hours, or 10 hours, or 15 hours, or more. Half-life determination
of such agonists can be determined as described herein.
[0066] The alpha 2 adrenergic receptor agonist of the present
materials may be associated with a bulking agent, as described
herein. For example, an alpha 2 adrenergic receptor agonist may be
coupled to a polyethylene glycol (PEG). In certain embodiments, the
alpha 2 adrenergic receptor agonist has a molecular weight greater
than the molecular weight of a different alpha 2 adrenergic
receptor agonist that is eliminated from the posterior segment of
an eye (e.g., via the trans-retinal route).
[0067] As discussed herein, the alpha 2 adrenergic receptor
agonists of the present materials may have substantially equal
anterior and posterior clearance rates, or may have an enhanced
anterior clearance rate relative to the posterior clearance rate.
In some materials, the anterior clearance rate is less than the
posterior clearance rate, but the alpha 2 adrenergic receptor
agonist has an anterior clearance rate that is effective in
permitting the alpha 2 adrenergic receptor agonist to be measured
above a quantitation limit in the aqueous humor of an eye to which
it has been administered.
[0068] The present materials are ophthalmically acceptable. Thus,
the present materials can be administered to an eye of an
individual without substantial negative or adverse side effects. In
certain materials, the alpha 2 adrenergic receptor agonist is
delivered to the anterior chamber, the posterior chamber, or a
combination of the anterior chamber and posterior chamber when the
material is administered to the eye.
[0069] As discussed herein, the present materials can be produced
by a variety of methods. In one embodiment, the ophthalmically
therapeutic material comprises a therapeutic component produced by
a process comprising a step of selecting an alpha 2 adrenergic
receptor agonist that has a vitreous half-life greater than about
three hours. Methods of determining the vitreous half-life of such
agonists are described herein. Other embodiments may comprise
selecting an agonist that has a vitreous half-life of about 4
hours, or 5 hours, or 10 hours, or 15 hours, or more.
[0070] In certain embodiments, the present materials comprise a
therapeutic component produced by a process comprising
administering an alpha-2 adrenergic receptor agonist to an eye of a
subject; determining the concentration of the alpha-2 adrenergic
receptor agonist in the vitreous body or vitreous humor and/or
aqueous humor as a function of time; determining the vitreous
half-life and/or clearance of the alpha-2 adrenergic receptor
agonist; and combining the alpha-2 adrenergic receptor agonist with
at least one other component useful in the present materials if the
half-life of the alpha-2 adrenergic receptor agonist is greater
than about three hours. In situations where modeling methods may be
used, some of the foregoing steps used to produce the therapeutic
component may be changed or omitted. Thus, the therapeutic
component may be produced by a process comprising determining
whether the half-life of the alpha-2 adrenergic receptor agonist is
greater than about three hours, and if so, combining the alpha-2
adrenergic receptor agonist with one or more components or
component precursors of the compositions or polymeric drug delivery
systems. The half-life may specifically be understood to be the
intravitreal half-life after solution dosing of the alpha-2
adrenergic receptor agonist.
[0071] The present materials may also include salts of the
anteriorly cleared alpha 2 adrenergic receptor agonist or other
therapeutic agents when appropriate. Pharmaceutically acceptable
acid addition salts are those formed from acids which form
non-toxic addition salts containing pharmaceutically acceptable
anions, such as the hydrochloride, hydrobromide, hydroiodide,
sulfate, or bisulfate, phosphate or acid phosphate, acetate,
maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate,
saccharate and p-toluene sulphonate salts.
[0072] As discussed herein, the present materials may be understood
to be liquid-containing compositions. Thus, certain of the present
materials may comprise a liquid carrier component associated with
the therapeutic component in the form of a composition suitable for
administration to a patient by intravitreal administration and/or
periocular administration. As used herein, periocular
administration refers to delivery of the therapeutic component to a
retrobulbar region, a subconjunctival region, a subtenon region, a
suprachoroidal region or space, and/or an intrascleral region or
space. For example, an anteriorly cleared alpha 2 adrenergic
receptor agonist may be associated with water, saline, phosphate
buffer, or other ophthalmically acceptable liquid carrier. The
present liquid-containing compositions are preferably in an
injectable form. In other words, the compositions may be
intraocularly administered, such as by intravitreal injection,
using a syringe and needle or other similar device (e.g., see U.S.
Patent Publication No. 2003/0060763), or the compositions can be
periocularly administered using an injection device.
[0073] The therapeutic component of the present compositions may be
present in an amount in the range of about 1% or less to about 5%
or about 10% or about 20% or about 30% or more (w/v or w/w) of the
composition. For intravitreally administered compositions,
providing relatively high concentrations or amounts of the
therapeutic component in the present compositions may be beneficial
in that reduced amounts of the composition may be required to be
placed or injected into the posterior segment of the eye in order
to provide the same amount or more of the therapeutic component in
the posterior segment of the eye relative to other
compositions.
[0074] In certain embodiments, the material further comprises an
excipient component. The excipient component may be understood to
include solubilizing agents, viscosity inducing agents, buffer
agents, tonicity agents, preservative agents, and the like.
[0075] In some embodiments of the present compositions, a
solubilizing agent may be a cyclodextrin. In other words, the
present materials may comprise a cyclodextrin component provided in
an amount from about 0.1% (w/v) to about 5% (w/v) of the
composition. In further embodiments, the cyclodextrin comprises up
to about 10% (w/v) of certain cyclodextrins, as discussed herein.
In further embodiments, the cyclodextrin comprises up to about 60%
(w/v) of certain cyclodextrins, as discussed herein. The excipient
component of the present compositions may comprise one or more
types of cyclodextrins or cyclodextrin derivatives, such as
alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, and
derivatives thereof. As understood by persons of ordinary skill in
the art, cyclodextrin derivatives refer to any substituted or
otherwise modified compound that has the characteristic chemical
structure of a cyclodextrin sufficiently to function as a
cyclodextrin, for example, to enhance the solubility and/or
stability of therapeutic agents and/or reduce unwanted side effects
of the therapeutic agents and/or to form inclusive complexes with
the therapeutic agents.
[0076] Viscosity inducing agents of the present materials, include
without limitation, polymers that are effective in stabilizing the
therapeutic component in the composition. The viscosity inducing
component is present in an effective amount in increasing,
advantageously substantially increasing, the viscosity of the
composition. Increased viscosities of the present compositions may
enhance the ability of the present compositions to maintain the
therapeutic component, including therapeutic component particles,
in substantially uniform suspension in the compositions for
prolonged periods of time, for example, for at least about one
week, without requiring resuspension processing. The relatively
high viscosity of the present compositions may also have an
additional benefit of at least assisting the compositions to have
the ability to have an increased amount or concentration of the
therapeutic component, as discussed elsewhere herein, for example,
while maintaining such therapeutic component in substantially
uniform suspension for prolonged periods of time.
[0077] Any suitable viscosity inducing component, for example,
ophthalmically acceptable viscosity inducing component, may be
employed in the present compositions. Many such viscosity inducing
components have been proposed and/or used in ophthalmic
compositions used on or in the eye. The viscosity inducing
component is present in an amount effective in providing the
desired viscosity to the composition. Advantageously, the viscosity
inducing component is present in an amount in a range of about 0.5%
or about 1.0% to about 5% or about 10% or about 20% (w/v or w/w) of
the composition. The specific amount of the viscosity inducing
component employed depends upon a number of factors including, for
example and without limitation, the specific viscosity inducing
component being employed, the molecular weight of the viscosity
inducing component being employed, the viscosity desired for the
present composition being produced and/or used and the like
factors.
[0078] The viscosity inducing component preferably comprises a
polymeric component and/or at least one viscoelastic agent, such as
those materials which are useful in ophthalmic surgical procedures.
Examples of useful viscosity inducing components include, but are
not limited to, hyaluronic acid, carbomers, polyacrylic acid,
cellulosic derivatives, polycarbophil, polyvinylpyrrolidone,
gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl
alcohol, polyvinyl acetate, derivatives thereof and mixtures
thereof.
[0079] The molecular weight of the presently useful viscosity
inducing components may be in a range of about 10,000 Daltons or
less to about 2 million Daltons or more. In one particularly useful
embodiment, the molecular weight of the viscosity inducing
component is in a range of about 100,000 Daltons or about 200,000
Daltons to about 1 million Daltons or about 1.5 million Daltons.
Again, the molecular weight of the viscosity inducing component
useful in accordance with the present invention, may vary over a
substantial range based on the type of viscosity inducing component
employed, and the desired final viscosity of the present
composition in question, as well as, possibly one or more other
factors.
[0080] If desired, buffering agents may be provided in an amount
effective to control the pH of the composition. Tonicity agents may
be provided in an amount effective to control the tonicity or
osmolality of the compositions. Certain of the present compositions
include both a buffer component and a tonicity component, which may
include one or more sugar alcohols, such as manitol, or salts, such
as sodium chloride, as discussed herein. The buffer component and
tonicity component may be chosen from those which are conventional
and well known in the ophthalmic art. Examples of such buffer
components include, but are not limited to, acetate buffers,
citrate buffers, phosphate buffers, borate buffers and the like and
mixtures thereof. Phosphate buffers are particularly useful. Useful
tonicity components include, but are not limited to, salts,
particularly sodium chloride, potassium chloride, any other
suitable ophthalmically acceptably tonicity component and mixtures
thereof.
[0081] The amount of buffer component employed preferably is
sufficient to maintain the pH of the composition in a range of
about 6 to about 8, more preferably about 7 to about 7.5. The
amount of tonicity component employed preferably is sufficient to
provide an osmolality to the present compositions in a range of
about 200 to about 400, more preferably about 250 to about 350,
mOsmol/kg respectively. Advantageously, the present compositions
are substantially isotonic.
[0082] Preservative agents that may be used in the present
materials include benzyl alcohol, benzalkonium chloride, methyl and
ethyl parabens, hexetidine, chlorite components, such as stabilized
chlorine dioxide, metal chlorites and the like, other
ophthalmically acceptable preservatives and the like and mixtures
thereof. The concentration of the preservative component, if any,
in the present compositions is a concentration effective to
preserve the composition, and is often in a range of about 0.00001%
to about 0.05% or about 0.1% (w/v) of the composition.
[0083] The present compositions can be produced using conventional
techniques routinely known by persons of ordinary skill in the art.
For example, a therapeutic component can be combined with a liquid
carrier. The composition can be sterilized. In certain embodiments,
such as preservative-free embodiments, the compositions can be
sterilized and packaged in single-dose amounts. The compositions
may be prepackaged in intraocular dispensers which can be disposed
of after a single administration of the unit dose of the
compositions.
[0084] The present compositions can be prepared using suitable
blending/processing techniques, for example, one or more
conventional blending techniques. The preparation processing should
be chosen to provide the present compositions in forms which are
useful for intravitreal or periocular placement or injection into
eyes of humans or animals. In one useful embodiment a concentrated
therapeutic component dispersion is made by combining the
therapeutic component with water, and the excipients (other than
the viscosity inducing component) to be included in the final
composition. The ingredients are mixed to disperse the therapeutic
component and then autoclaved. The viscosity inducing component may
be purchased sterile or sterilized by conventional processing, for
example, by filtering a dilute solution followed by lyophylization
to yield a sterile powder. The sterile viscosity inducing component
is combined with water to make an aqueous concentrate. The
concentrated therapeutic component dispersion is mixed and added as
a slurry to the viscosity inducing component concentrate. Water is
added in a quantity sufficient (q.s.) to provide the desired
composition and the composition is mixed until homogenous.
[0085] In one embodiment, a sterile, viscous, suspension suitable
for administration is made using an anteriorly cleared alpha 2
adrenergic receptor agonist. A process for producing such a
composition may comprise sterile suspension bulk compounding and
asceptic filling.
[0086] Other embodiments of the present materials are in the form
of a polymeric drug delivery system that is capable of providing
sustained drug delivery for extended periods of time after a single
administration. For example, the present drug delivery systems can
release the anteriorly cleared alpha 2 adrenergic receptor agonist
for at least about 1 month, or about 3 months, or about 6 months,
or about 1 year, or about 5 years or more. Thus, such embodiments
of the present materials may comprise a polymeric component
associated with the therapeutic component in the form of a
polymeric drug delivery system suitable for administration to a
patient by at least one of intravitreal administration and
periocular administration.
[0087] The polymeric drug delivery system may be in the form of
biodegradable polymeric implants, non-biodegradable polymeric
implants, biodegradable polymeric microparticles, and combinations
thereof. Implants may be in the form of rods, wafers, sheets,
filaments, spheres, and the like. Particles are smaller than the
implants disclosed herein, and may vary in shape. For example,
certain embodiments of the present invention utilize substantially
spherical particles. These particles may be understood to be
microspheres. Other embodiments may utilize randomly configured
particles, such as particles that have one or more flat or planar
surfaces. The drug delivery system may comprise a population of
such particles with a predetermined size distribution. For example,
a major portion of the population may comprise, particles having a
desired diameter measurement.
[0088] As discussed herein, the polymeric component of the present
drug delivery systems can comprise a polymer selected from the
group consisting of biodegradable polymers, non-biodegradable
polymers, biodegradable copolymers, non-biodegradable copolymers,
and combinations thereof. In certain embodiments, the polymeric
component comprises a poly(lactide-co-glycolide) polymer (PLGA). In
other embodiments, the polymeric component comprises a polymer
selected from the group consisting of poly-lactic acid (PLA),
poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA),
polyesters, poly(ortho ester), poly(phosphazine), poly(phosphate
ester), polycaprolactones, gelatin, collagen, derivatives thereof,
and combinations thereof. The polymeric component may be associated
with the therapeutic component to form an implant selected from the
group consisting of solid implants, semisolid implants, and
viscoelastic implants.
[0089] The anteriorly cleared alpha 2 adrenergic receptor agonist
may be in a particulate or powder form and entrapped by a
biodegradable polymer matrix. Usually, anteriorly cleared alpha 2
adrenergic receptor agonist particles in intraocular implants will
have an effective average size less than about 3000 nanometers.
However, in other embodiments, the particles may have an average
maximum size greater than about 3000 nanometers. In certain
implants, the particles may have an effective average particle size
about an order of magnitude smaller than 3000 nanometers. For
example, the particles may have an effective average particle size
of less than about 500 nanometers. In additional implants, the
particles may have an effective average particle size of less than
about 400 nanometers, and in still further embodiments, a size less
than about 200 nanometers. In addition, when such particles are
combined with a polymeric component, the resulting polymeric
intraocular particles may be used to provide a desired therapeutic
effect.
[0090] The anteriorly cleared alpha 2 adrenergic receptor agonist
of the present systems is preferably from about 1% to 90% by weight
of the drug delivery system. More preferably, the anteriorly
cleared alpha 2 adrenergic receptor agonist is from about 20% to
about 80% by weight of the system. In a preferred embodiment, the
anteriorly cleared alpha 2 adrenergic receptor agonist comprises
about 40% by weight of the system (e.g., 30%-50%). In another
embodiment, the anteriorly cleared alpha 2 adrenergic receptor
agonist comprises about 60% by weight of the system.
[0091] Suitable polymeric materials or compositions for use in the
drug delivery systems include those materials which are compatible,
that is biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
materials preferably include polymers that are at least partially
and more preferably substantially completely biodegradable or
bioerodible.
[0092] In addition to the foregoing, examples of useful polymeric
materials include, without limitation, such materials derived from
and/or including organic esters and organic ethers, which when
degraded result in physiologically acceptable degradation products,
including the monomers. Also, polymeric materials derived from
and/or including, anhydrides, amides, orthoesters and the like, by
themselves or in combination with other monomers, may also find
use. The polymeric materials may be addition or condensation
polymers, advantageously condensation polymers. The polymeric
materials may be cross-linked or non-cross-linked, for example not
more than lightly cross-linked, such as less than about 5%, or less
than about 1% of the polymeric material being cross-linked. For the
most part, besides carbon and hydrogen, the polymers will include
at least one of oxygen and nitrogen, advantageously oxygen. The
oxygen may be present as oxy, e.g. hydroxy or ether, carbonyl, e.g.
non-oxo-carbonyl, such as carboxylic acid ester, and the like. The
nitrogen may be present as amide, cyano and amino. The polymers set
forth in Heller, Biodegradable Polymers in Controlled Drug
Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier
Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which
describes encapsulation for controlled drug delivery, may find use
in the present drug delivery systems.
[0093] Of additional interest are polymers of hydroxyaliphatic
carboxylic acids, either homopolymers or copolymers, and
polysaccharides. Polyesters of interest include polymers of
D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. Generally, by employing
the L-lactate or D-lactate, a slowly eroding polymer or polymeric
material is achieved, while erosion is substantially enhanced with
the lactate racemate.
[0094] Among the useful polysaccharides are, without limitation,
calcium alginate, and functionalized celluloses, particularly
carboxymethylcellulose esters characterized by being water
insoluble, a molecular weight of about 5 kD to 500 kD, for
example.
[0095] Other polymers of interest include, without limitation,
polyesters, polyethers and combinations thereof which are
biocompatible and may be biodegradable and/or bioerodible.
[0096] Some preferred characteristics of the polymers or polymeric
materials for use in the present systems may include
biocompatibility, compatibility with the therapeutic component,
ease of use of the polymer in making the drug delivery systems of
the present invention, a half-life in the physiological environment
of at least about 6 hours, preferably greater than about one day,
not significantly increasing the viscosity of the vitreous, and
water insolubility.
[0097] The biodegradable polymeric materials which are included to
form the matrix are desirably subject to enzymatic or hydrolytic
instability. Water soluble polymers may be cross-linked with
hydrolytic or biodegradable unstable cross-links to provide useful
water insoluble polymers. The degree of stability can be varied
widely, depending upon the choice of monomer, whether a homopolymer
or copolymer is employed, employing mixtures of polymers, and
whether the polymer includes terminal acid groups.
[0098] Also important to controlling the biodegradation of the
polymer and hence the extended release profile of the drug delivery
systems is the relative average molecular weight of the polymeric
composition employed in the present systems. Different molecular
weights of the same or different polymeric compositions may be
included in the systems to modulate the release profile. In certain
systems, the relative average molecular weight of the polymer will
range from about 9 to about 64 kD, usually from about 10 to about
54 kD, and more usually from about 12 to about 45 kD.
[0099] In some drug delivery systems, copolymers of glycolic acid
and lactic acid are used, where the rate of biodegradation is
controlled by the ratio of glycolic acid to lactic acid. The most
rapidly degraded copolymer has roughly equal amounts of glycolic
acid and lactic acid. Homopolymers, or copolymers having ratios
other than equal, are more resistant to degradation. The ratio of
glycolic acid to lactic acid will also affect the brittleness of
the system, where a more flexible system or implant is desirable
for larger geometries. The % of polylactic acid in the polylactic
acid polyglycolic acid (PLGA) copolymer can be 0-100%, preferably
about 15-85%, more preferably about 35-65%. In some systems, a
50/50 PLGA copolymer is used.
[0100] The biodegradable polymer matrix of the present systems may
comprise a mixture of two or more biodegradable polymers. For
example, the system may comprise a mixture of a first biodegradable
polymer and a different second biodegradable polymer. One or more
of the biodegradable polymers may have terminal acid groups.
[0101] Release of a drug from an erodible polymer is the
consequence of several mechanisms or combinations of mechanisms.
Some of these mechanisms include desorption from the implants
surface, dissolution, diffusion through porous channels of the
hydrated polymer and erosion. Erosion can be bulk or surface or a
combination of both. It may be understood that the polymeric
component of the present systems is associated with the therapeutic
component so that the release of the therapeutic component into the
eye is by one or more of diffusion, erosion, dissolution, and
osmosis. As discussed herein, the matrix of an intraocular drug
delivery system may release drug at a rate effective to sustain
release of an amount of the anteriorly cleared alpha 2 adrenergic
receptor agonist for more than one week after implantation into an
eye. In certain systems, therapeutic amounts of the anteriorly
cleared alpha 2 adrenergic receptor agonist are released for more
than about one month, and even for about twelve months or more. For
example, the therapeutic component can be released into the eye for
a time period from about ninety days to about one year after the
system is placed in the interior of an eye.
[0102] The release of the anteriorly cleared alpha 2 adrenergic
receptor agonist from the drug delivery systems comprising a
biodegradable polymer matrix may include an initial burst of
release followed by a gradual increase in the amount of the
anteriorly cleared alpha 2 adrenergic receptor agonist released, or
the release may include an initial delay in release of the
anteriorly cleared alpha 2 adrenergic receptor agonist followed by
an increase in release. When the system is substantially completely
degraded, the percent of the anteriorly cleared alpha 2 adrenergic
receptor agonist that has been released is about one hundred.
[0103] It may be desirable to provide a relatively constant rate of
release of the therapeutic agent from the drug delivery system over
the life of the system. For example, it may be desirable for the
anteriorly cleared alpha 2 adrenergic receptor agonist to be
released in amounts from about 0.01 .mu.g to about 2 .mu.g per day
for the life of the system. However, the release rate may change to
either increase or decrease depending on the formulation of the
biodegradable polymer matrix. In addition, the release profile of
the anteriorly cleared alpha 2 adrenergic receptor agonist may
include one or more linear portions and/or one or more non-linear
portions. Preferably, the release rate is greater than zero once
the system has begun to degrade or erode.
[0104] The drug delivery systems, such as the intraocular implants,
may be monolithic, i.e. having the active agent or agents
homogenously distributed through the polymeric matrix, or
encapsulated, where a reservoir of active agent is encapsulated by
the polymeric matrix. Due to ease of manufacture, monolithic
implants are usually preferred over encapsulated forms. However,
the greater control afforded by the encapsulated, reservoir-type
implant may be of benefit in some circumstances, where the
therapeutic level of the anteriorly cleared alpha 2 adrenergic
receptor agonist falls within a narrow window. In addition, the
therapeutic component, including the therapeutic agent(s) described
herein, may be distributed in a non-homogenous pattern in the
matrix. For example, the drug delivery system may include a portion
that has a greater concentration of the anteriorly cleared alpha 2
adrenergic receptor agonist relative to a second portion of the
system.
[0105] The polymeric implants disclosed herein may have a size of
between about 5 .mu.m and about 2 mm, or between about 10 .mu.m and
about 1 mm for administration with a needle, greater than 1 mm, or
greater than 2 mm, such as 3 mm or up to 10 mm, for administration
by surgical implantation. The vitreous chamber in humans is able to
accommodate relatively large implants of varying geometries, having
lengths of, for example, 1 to 10 mm. The implant may be a
cylindrical pellet (e.g., rod) with dimensions of about 2
mm.times.0.75 mm diameter. Or the implant may be a cylindrical
pellet with a length of about 7 mm to about 10 mm, and a diameter
of about 0.75 mm to about 1.5 mm.
[0106] The implants may also be at least somewhat flexible so as to
facilitate both insertion of the implant in the eye, such as in the
vitreous, and accommodation of the implant. The total weight of the
implant is usually about 250-5000 .mu.g, more preferably about
500-1000 .mu.g. For example, an implant may be about 500 .mu.g, or
about 1000 .mu.g. However, larger implants may also be formed and
further processed before administration to an eye. In addition,
larger implants may be desirable where relatively greater amounts
of the anteriorly cleared alpha 2 adrenergic receptor agonist are
provided in the implant. For non-human individuals, the dimensions
and total weight of the implant(s) may be larger or smaller,
depending on the type of individual. For example, humans have a
vitreous volume of approximately 3.8 ml, compared with
approximately 30 ml for horses, and approximately 60-100 ml for
elephants. An implant sized for use in a human may be scaled up or
down accordingly for other animals, for example, about 8 times
larger for an implant for a horse, or about, for example, 26 times
larger for an implant for an elephant.
[0107] Drug delivery systems can be prepared where the center may
be of one material and the surface may have one or more layers of
the same or a different composition, where the layers may be
cross-linked, or of a different molecular weight, different density
or porosity, or the like. For example, where it is desirable to
quickly release an initial bolus of anteriorly cleared alpha 2
adrenergic receptor agonist, the center may be a polylactate coated
with a polylactate-polyglycolate copolymer, so as to enhance the
rate of initial degradation. Alternatively, the center may be
polyvinyl alcohol coated with polylactate, so that upon degradation
of the polylactate exterior the center would dissolve and be
rapidly washed out of the eye.
[0108] The drug delivery systems may be of any geometry including
fibers, sheets, films, microspheres, spheres, circular discs,
plaques and the like. The upper limit for the system size will be
determined by factors such as toleration for the system, size
limitations on insertion, ease of handling, etc. Where sheets or
films are employed, the sheets or films will be in the range of at
least about 0.5 mm.times.0.5 mm, usually about 3-10 mm.times.5-10
mm with a thickness of about 0.1-1.0 mm for ease of handling. Where
fibers are employed, the fiber diameter will generally be in the
range of about 0.05 to 3 mm and the fiber length will generally be
in the range of about 0.5-10 mm. Spheres may be in the range of
about 0.5 .mu.m to 4 mm in diameter, with comparable volumes for
other shaped particles.
[0109] The size and form of the system can also be used to control
the rate of release, period of treatment, and drug concentration at
the site of implantation. For example, larger implants will deliver
a proportionately larger dose, but depending on the surface to mass
ratio, may have a slower release rate. The particular size and
geometry of the system are chosen to suit the site of
implantation.
[0110] The proportions of therapeutic agent, polymer, and any other
modifiers may be empirically determined by formulating several
implants, for example, with varying proportions of such
ingredients. A USP approved method for dissolution or release test
can be used to measure the rate of release (USP 23; NF 18 (1995)
pp. 1790-1798). For example, using the infinite sink method, a
weighed sample of the implant is added to a measured volume of a
solution containing 0.9% NaCl in water, where the solution volume
will be such that the drug concentration is after release is less
than 5% of saturation. The mixture is maintained at 37.degree. C.
and stirred slowly to maintain the implants in suspension. The
appearance of the dissolved drug as a function of time may be
followed by various methods known in the art, such as
spectrophotometrically, HPLC, mass spectroscopy, etc. until the
absorbance becomes constant or until greater than 90% of the drug
has been released.
[0111] In addition to the therapeutic component, and similar to the
compositions described herein, the polymeric drug delivery systems
disclosed herein may include an excipient component. The excipient
component may be understood to include solubilizing agents,
viscosity inducing agents, buffer agents, tonicity agents,
preservative agents, and the like.
[0112] Additionally, release modulators such as those described in
U.S. Pat. No. 5,869,079 may be included in the drug delivery
systems. The amount of release modulator employed will be dependent
on the desired release profile, the activity of the modulator, and
on the release profile of the therapeutic agent in the absence of
modulator. Electrolytes such as sodium chloride and potassium
chloride may also be included in the systems. Where the buffering
agent or enhancer is hydrophilic, it may also act as a release
accelerator. Hydrophilic additives act to increase the release
rates through faster dissolution of the material surrounding the
drug particles, which increases the surface area of the drug
exposed, thereby increasing the rate of drug bioerosion. Similarly,
a hydrophobic buffering agent or enhancer dissolve more slowly,
slowing the exposure of drug particles, and thereby slowing the
rate of drug bioerosion.
[0113] Various techniques may be employed to produce the drug
delivery systems described herein. Useful techniques include, but
are not necessarily limited to, solvent evaporation methods, phase
separation methods, interfacial methods, molding methods, injection
molding methods, extrusion methods, co-extrusion methods, carver
press method, die cutting methods, heat compression, combinations
thereof and the like.
[0114] Specific methods are discussed in U.S. Pat. No. 4,997,652.
Extrusion methods may be used to avoid the need for solvents in
manufacturing. When using extrusion methods, the polymer and drug
are chosen so as to be stable at the temperatures required for
manufacturing, usually at least about 85 degrees Celsius. Extrusion
methods use temperatures of about 25 degrees C. to about 150
degrees C., more preferably about 65 degrees C. to about 130
degrees C. An implant may be produced by bringing the temperature
to about 60 degrees C. to about 150 degrees C. for drug/polymer
mixing, such as about 130 degrees C., for a time period of about 0
to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, a time
period may be about 10 minutes, preferably about 0 to 5 min. The
implants are then extruded at a temperature of about 60 degrees C.
to about 130 degrees C., such as about 75 degrees C.
[0115] In addition, the implant may be coextruded so that a coating
is formed over a core region during the manufacture of the
implant.
[0116] Compression methods may be used to make the drug delivery
systems, and typically yield elements with faster release rates
than extrusion methods. Compression methods may use pressures of
about 50-150 psi, more preferably about 70-80 psi, even more
preferably about 76 psi, and use temperatures of about 0 degrees C.
to about 115 degrees C., more preferably about 25 degrees C.
[0117] In certain embodiments of the present invention, a method of
producing a sustained-release intraocular drug delivery system,
comprises combining an anteriorly cleared alpha 2 adrenergic
receptor agonist and a polymeric material to form a drug delivery
system suitable for placement in an eye of an individual. The
resulting drug delivery system is effective in releasing the
anteriorly cleared alpha 2 adrenergic receptor agonist into the eye
for extended periods of time. The method may comprise a step of
extruding a particulate mixture of the anteriorly cleared alpha 2
adrenergic receptor agonist and the polymeric material to form an
extruded composition, such as a filament, sheet, and the like.
[0118] When polymeric particles are desired, the method may
comprise forming the extruded composition into a population of
polymeric particles or a population of implants, as described
herein. Such methods may include one or more steps of cutting the
extruded composition, milling the extruded composition, and the
like.
[0119] As discussed herein, the polymeric material may comprise a
biodegradable polymer, a non-biodegradable polymer, or a
combination thereof. Examples of polymers include each and every
one of the polymers and agents identified above.
[0120] Embodiments of the present invention also relate to
compositions comprising the present drug delivery systems. For
example, and in one embodiment, a composition may comprise the
present drug delivery system and an ophthalmically acceptable
carrier component. Such a carrier component may be an aqueous
composition, for example saline or a phosphate buffered liquid.
[0121] Another embodiment of the invention relates to anteriorly
cleared alpha 2 adrenergic receptor agonists. Such agonists have
chemical or physical structures that are effective in providing an
anterior clearance of the agonist from the eye to which they are
administered. Such agonists can be administered to the eye by
intravitreal or periocular administration. Such agonists can be
used in the manufacture of a medicament to treat one or more ocular
conditions, such as glaucoma. In certain embodiments, the agonists
can be used in a medicament to treat a condition affecting the
anterior segment of the eye and the posterior segment of the
eye.
[0122] Another embodiment relates to a method of producing an
ophthalmically therapeutic material which comprises an anteriorly
cleared alpha 2 adrenergic receptor agonist. In a broad aspect, the
method comprises the steps of selecting an alpha 2 adrenergic
receptor agonist that has a vitreous half-life greater than about 3
hours; and combining the selected alpha 2 adrenergic receptor
agonist with a liquid carrier component or a polymeric component to
form a material suitable for administration to an eye. Or stated
differently, a method of producing the present materials may
comprise a step of selecting alpha 2 adrenergic receptor agonists
having a high aqueous humor/vitreous humor concentration ratio and
long intravitreal half-lifes.
[0123] The method may further comprise one or more of the following
steps, which will typically be used to select the anteriorly
cleared alpha 2 adrenergic receptor agonist: administering an alpha
2 adrenergic receptor agonist to an eye of a subject and
determining the concentration of the alpha 2 adrenergic receptor
agonist in at least one of the vitreous humor and aqueous humor as
a function of time; and administering an alpha 2 adrenergic
receptor agonist to an eye of a subject and determining at least
one of the vitreous half-life and clearance of the alpha 2
adrenergic receptor agonist from the eye.
[0124] The material formed in the method may be a liquid-containing
composition, a biodegradable polymeric implant, a non-biodegradable
polymeric implant, polymeric microparticles, or combinations
thereof. As discussed herein, the material may be in the form of
solid implants, semisolid implants, and viscoelastic implants. In
certain embodiments, the anteriorly cleared alpha 2 adrenergic
receptor agonist is combined with a polymeric component to form a
mixture, and the method further comprises extruding the
mixture.
[0125] Additional embodiments of the present invention related to
methods of improving or maintaining vision of an eye of a patient.
In general, the methods comprise a step of administering the
present ophthalmically therapeutic material to an eye of an
individual in need thereof. Administration, such as intravitreal or
periocular administration of the present materials can be effective
in treating anterior ocular conditions, posterior ocular
conditions, or combinations thereof. For example, certain of the
present materials can be administered to a patient to provide
neuroprotection to ocular neuronal cells and to reduce elevated
intraocular pressure. The present materials may be particularly
useful in treating glaucoma. Administration of the present
materials are effective in delivering the alpha 2 adrenergic
receptor agonist to one or more posterior structures of the eye
including the uveal tract, the vitreous, the retina, the choroid,
the retinal pigment epithelium.
[0126] The present compositions and drug delivery systems can
effectively treat anterior ocular conditions, such as conditions or
diseases affecting the anterior segment of an eye (including the
anterior chamber and posterior chamber of the eye) when
administered intraocularly into the posterior segment of an eye, or
periocularly, as described above. In addition, the present
compositions and drug delivery systems may also effectively treat
posterior ocular conditions, such as conditions or diseases
affecting the posterior segment of an eye (including the retina of
the eye).
[0127] In additional embodiments, the present compositions and drug
delivery systems may be administered to a patient in combination
with one or more topical ophthalmic compositions. For example, the
present compositions and drug delivery systems may be administered
in combination with a composition effective in lowering intraocular
pressure (IOP) of an eye of a patient. The present combination
therapies may enhance the anterior clearance of the therapeutic
agents of the present compositions and drug delivery systems. For
example, by lowering the IOP of a patient, for example by about 5
mmHg, enhanced movement of the therapeutic agent towards the
anterior segment of the eye can be obtained. It has been proposed
that the movement of FITC-dextran from the vitreous into the
aqueous was enhanced when IOP was lowered with a topical bunazosin
solution applied to rabbit eyes (Sugiura et al., "Effects of
intraocular pressure change on movement of FITC-dextran across
vitreous-aqueous interface", (1989), Jpn J. Opthalmol,
33(4):441-450).
[0128] Other combination therapies may include the administration
of the present compositions and/or drug delivery systems in
combination with surgical procedures which attempt to decrease IOP.
For example, the present compositions and/or drug delivery systems
can be administered in patients who have received or will be
receiving trabecular meshwork surgery using a laser or mechanical
surgical techniques.
[0129] Organic cations can be understood to be organic molecules
having a transient or permanent positive net charge, for example at
a physiological pH. Examples of organic cations include
anticholinergics, adrenergics, antineoplastics, sympathomimetics,
antihistamines, xenobiotics, some vitamins, and a variety of
endogenous amines, such as choline, epinephrine, dopamine, and
guanidine. Such organic cations can be transported across barriers
or membranes by organic cation transporters. Inhibition, including
competitive inhibition and non-competitive inhibition, can reduce
the transport of organic cations using organic cation
transporters.
[0130] Thus, additional combination therapies may include
administration of the present compositions and/or drug delivery
systems in combination with administration of an RPE organic cation
transporter inhibitor. For example, administration of an RPE
organic cation transporter inhibitor may decrease the posterior
transport rate of the present alpha 2 adrenergic receptor agonists
and thereby cause an increase in intravitreal half-life of the
alpha 2 adrenergic receptor agonists and an associated increase or
enhancement in anterior clearance rate. Examples of suitable RPE
organic cation transporter inhibitors include metabolic inhibitors
and organic cations. Examples of metabolic inhibitors include,
without limitation,
carbonylcyanide-p-(trifluoromethoxy)phenylhydrazone,
2,4-dinitrophenol, NaN.sub.3, rotenone, and HgCl.sub.2. Competitive
inhibition can occur with organic cations. Examples of organic
cations include, without limitation, quinacrine, pyrilamine,
quinidine, valinomycin, diprivefrine, carbachol, diphenylhydramine,
diltiazem, timolol, propanolol, and verapamil. Such inhibitors are
useful in inhibiting transport of verapamil in human RPE cell lines
(Han et al., "Characterization of a Novel Cationic Drug Transporter
in Human Retinal Pigment Epithelial Cells", Journal of Pharmacology
and Experimental Therapeutics, 296(2): 450-457, 2001). Other
inhibitors include cimetidine, which is a high affinity inhibitor
of organic cation transporter 2 (OCT2), and tyrosine, which is a
high affinity inhibitor of OCT1. In certain embodiments, the
present alpha 2 adrenergic receptor agonists can be administered to
an eye of a patient in combination with an alpha 2 adrenergic
receptor agonist that is present as a cation at physiological pHs.
For example, the present alpha 2 adrenergic receptor agonists can
be administered in conjunction with brimonidine. Such cationic
alpha 2 adrenergic receptor agonists can competitively inhibit
organic cation transport of the present alpha 2 adrenergic receptor
agonists.
[0131] The RPE organic cation transporter inhibitors can be
administered separately from the present alpha 2 adrenergic
receptor agonists, or can be administered in combination with the
present agonists. Thus, the combination therapy may include
administration of a single composition or polymeric drug delivery
system comprising the present alpha 2 adrenergic receptor agonists
and one or more RPE organic cation transporter inhibitors.
[0132] When a syringe apparatus is used to administer the present
materials, the apparatus can include an appropriately sized needle,
for example, a 27 gauge needle or a 30 gauge needle. Such apparatus
can be effectively used to inject the materials into the posterior
segment or a periocular region of an eye of a human or animal. The
needles may be sufficiently small to provide an opening that self
seals after removal of the needle.
[0133] The present methods may comprise a single injection into the
posterior segment of an eye or may involve repeated injections, for
example over periods of time ranging from about one week or about 1
month or about 3 months to about 6 months or about 1 year or
longer.
[0134] The present materials are preferably administered to
patients in a sterile form. For example, the present materials may
be sterile when stored. Any routine suitable method of
sterilization may be employed to sterilize the materials. For
example, the present materials may be sterilized using radiation.
Preferably, the sterilization method does not reduce the activity
or biological or therapeutic activity of the therapeutic agents of
the present systems.
[0135] The materials can be sterilized by gamma irradiation. As an
example, the drug delivery systems can be sterilized by 2.5 to 4.0
mrad of gamma irradiation. The drug delivery systems can be
terminally sterilized in their final primary packaging system
including administration device e.g. syringe applicator.
Alternatively, the drug delivery systems can be sterilized alone
and then aseptically packaged into an applicator system. In this
case the applicator system can be sterilized by gamma irradiation,
ethylene oxide (ETO), heat or other means. The drug delivery
systems can be sterilized by gamma irradiation at low temperatures
to improve stability or blanketed with argon, nitrogen or other
means to remove oxygen. Beta irradiation or e-beam may also be used
to sterilize the implants as well as UV irradiation. The dose of
irradiation from any source can be lowered depending on the initial
bioburden of the drug delivery systems such that it may be much
less than 2.5 to 4.0 mrad. The drug delivery systems may be
manufactured under aseptic conditions from sterile starting
components. The starting components may be sterilized by heat,
irradiation (gamma, beta, UV), ETO or sterile filtration.
Semi-solid polymers or solutions of polymers may be sterilized
prior to drug delivery system fabrication and anteriorly cleared
alpha 2 adrenergic receptor agonist incorporation by sterile
filtration of heat. The sterilized polymers can then be used to
aseptically produce sterile drug delivery systems.
[0136] In addition to the anteriorly cleared alpha 2 adrenergic
receptor agonist included in the present ophthalmically therapeutic
materials disclosed hereinabove, the materials may also include one
or more additional ophthalmically acceptable therapeutic agents.
For example, an ophthalmically therapeutic material may include one
or more antihistamines, one or more antibiotics, one or more beta
blockers, one or more steroids, one or more antineoplastic agents,
one or more immunosuppressive agents, one or more antiviral agents,
one or more antioxidant agents, and mixtures thereof.
[0137] Examples of additional pharmacologic or therapeutic agents
which may find use in the present materials, include, without
limitation, those disclosed in U.S. Pat. Nos. 4,474,451, columns
4-6 and 4,327,725, columns 7-8.
[0138] Examples of antihistamines include, and are not limited to,
loradatine, hydroxyzine, diphenhydramine, chlorpheniramine,
brompheniramine, cyproheptadine, terfenadine, clemastine,
triprolidine, carbinoxamine, diphenylpyraline, phenindamine,
azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine,
methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine,
chiorcyclizine, thonzylamine, and derivatives thereof.
[0139] Examples of antibiotics include without limitation,
cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime,
cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil,
ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin,
cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine,
cefuroxime, cyclosporine, ampicillin, amoxicillin, cyclacillin,
ampicillin, penicillin G, penicillin V potassium, piperacillin,
oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin,
carbenicillin, methicillin, nafcillin, erythromycin, tetracycline,
doxycycline, minocycline, aztreonam, chloramphenicol, ciprofloxacin
hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin,
tobramycin, vancomycin, polymyxin B sulfate, colistimethate,
colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim,
gatifloxacin, ofloxacin, and derivatives thereof.
[0140] Examples of beta blockers include acebutolol, atenolol,
labetalol, metoprolol, propranolol, timolol, and derivatives
thereof.
[0141] Examples of steroids include corticosteroids, such as
cortisone, prednisolone, fluorometholone, dexamethasone, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,
prednisone, methylprednisolone, riamcinolone hexacatonide,
paramethasone acetate, diflorasone, fluocinonide, fluocinolone,
triamcinolone, triamcinolone acetonide, derivatives thereof, and
mixtures thereof.
[0142] Examples of antineoplastic agents include adriamycin,
cyclophosphamide, actinomycin, bleomycin, duanorubicin,
doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil,
carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide,
interferons, camptothecin and derivatives thereof, phenesterine,
taxol and derivatives thereof, taxotere and derivatives thereof,
vinblastine, vincristine, tamoxifen, etoposide, piposulfan,
cyclophosphamide, and flutamide, and derivatives thereof.
[0143] Examples of immunosuppresive agents include cyclosporine,
azathioprine, tacrolimus, and derivatives thereof.
[0144] Examples of antiviral agents include interferon gamma,
zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir and
derivatives thereof.
[0145] Examples of antioxidant agents include ascorbate,
alpha-tocopherol, mannitol, reduced glutathione, various
carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide
dismutase, lutein, zeaxanthin, cryotpxanthin, astazanthin,
lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine,
quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba
extract, tea catechins, bilberry extract, vitamins E or esters of
vitamin E, retinyl palmitate, and derivatives thereof.
[0146] Other therapeutic agents include squalamine, carbonic
anhydrase inhibitors, alpha agonists, prostamides, prostaglandins,
antiparasitics, antifungals, and derivatives thereof.
[0147] The present materials are configured to release an amount of
the anteriorly cleared alpha 2 adrenergic receptor agonist
effective to treat or reduce a symptom of an ocular condition, such
as an ocular condition such as glaucoma.
[0148] The materials disclosed herein may also be configured to
deliver additional therapeutic agents, as described above, which to
prevent diseases or conditions, such as the following:
[0149] MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age
Related Macular Degeneration (ARMD), Exudative Age Related Macular
Degeneration (ARMD), Choroidal Neovascularization, Diabetic
Retinopathy, Acute Macular Neuroretinopathy, Central Serous
Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular
Edema.
[0150] UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid
Pigment Epitheliopathy, Behcet's Disease, Birdshot
Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis,
Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal
Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular
Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis,
Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada
Syndrome.
[0151] VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease,
Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch
Angitis, Sickle Cell Retinopathy and other Hemoglobinopathies,
Angioid Streaks, Familial Exudative Vitreoretinopathy.
[0152] TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal
Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,
Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow
Transplant Retinopathy.
[0153] PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy
and Epiretinal Membranes, Proliferative Diabetic Retinopathy,
Retinopathy of Prematurity (retrolental fibroplastic).
[0154] INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular
Toxocariasis, Presumed Ocular Histoplasmosis Syndrome (POHS),
Endophthalmitis, Toxoplasmosis, Retinal Diseases Associated with
HIV Infection, Choroidal Disease Associated with HIV Infection,
Uveitic Disease Associated with HIV Infection, Viral Retinitis,
Acute Retinal Necrosis, Progressive Outer Retinal Necrosis, Fungal
Retinal Diseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse
Unilateral Subacute Neuroretinitis, Myiasis.
[0155] GENETIC DISORDERS: Systemic Disorders with Accosiated
Retinal Dystrophies, Congenital Stationary Night Blindness, Cone
Dystrophies, Fundus Flavimaculatus, Best's Disease, Pattern
Dystrophy of the Retinal Pigmented Epithelium, X-Linked
Retinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric
Maculopathy, Bietti's Crystalline Dystrophy, pseudoxanthoma
elasticum, Osler Weber syndrome.
[0156] RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant
Retinal Tear.
[0157] TUMORS: Retinal Disease Associated with Tumors, Solid
Tumors, Tumor Metastasis, Benign Tumors, for example, hemangiomas,
neurofibromas, trachomas, and pyogenic granulomas, Congenital
Hypertrophy of the RPE, Posterior Uveal Melanoma, Choroidal
Hemangioma, Choroidal Osteoma, Choroidal Metastasis, Combined
Hamartoma of the Retina and Retinal Pigmented Epithelium,
Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus,
Retinal Astrocytoma, Intraocular Lymphoid Tumors.
[0158] MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior
Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal
Degeneration, Acute Retinal Pigment Epithelitis, Ocular
inflammatory and immune disorders, ocular vascular malfunctions,
Corneal Graft Rejection, Neovascular Glaucoma and the like.
[0159] In another aspect of the invention, kits for treating an
ocular condition of the eye are provided, comprising: a) a
container, such as a syringe or other applicator, comprising an
anteriorly cleared alpha 2 adrenergic receptor agonist as herein
described; and b) instructions for use. Instructions may include
steps of how to handle the material, how to insert the material
into an ocular region, and what to expect from using the material.
The container may contain a single dose of the anteriorly cleared
alpha 2 adrenergic receptor agonist.
EXAMPLES
[0160] The following non-limiting examples provide those of
ordinary skill in the art with specific preferred drug delivery
systems, methods of making such systems, and methods to treat
conditions within the scope of the present invention. The following
examples are not intended to limit the scope of the invention.
Example 1
Intravitreal Clearance of Brimonidine
[0161] Intravitreal clearance of brimonidine was examined in albino
rabbits. Rabbits were dosed bilaterally via a 50 microliter
intravitreal injection of a solution containing 928 nanograms of
brimonidine. Vitreous humor samples were collected at different
time points and the brimonidine concentration in the vitreous humor
was determined.
[0162] As shown in FIG. 1, the vitreal concentration of brimonidine
declined exponentially from 608.+-.116 ng/mL at 0.5 hours post dose
to 9.68.+-.6.48 ng/mL at 10 hours post dose. The estimated vitreous
half-life (t.sub.1/2) of brimonidine was determined to be 1.45
hours. The vitreal clearance rate was estimated to be 0.487
mL/hour.
[0163] Based on these results, it was concluded that brimonidine is
eliminated from the vitreous by a trans-retinal route. These
results demonstrate that hydrophilic to moderately lipophilic alpha
2 adrenergic receptor agonists having a trans-retinal route of
clearance from the posterior segment of the eye, cannot be
effectively delivered to the anterior and/or posterior chambers of
the eye via intravitreal administration.
Example 2
Pharmacokinetic Properties of Brimonidine Intravitreal Implants
[0164] Biodegradable polymeric implants containing brimonidine were
prepared in accordance with the methods described herein. The
implants were made from polylactic acid (PLA) and included 200
micrograms of brimonidine. These brimonidine implants were
administered to the vitreous of rabbit eyes. Vitreous humor and
aqueous humor samples were obtained at various time points, and the
amount of brimonidine was determined in the samples, as shown in
Table 1 below TABLE-US-00001 TABLE 1 Brimonidine Concentration
Aqueous Iris-ciliary Vitreous Humor body Lens Retina humor Day
(ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) 8 NC 942 (3010).sup.d 45.1
.+-. 13.4 3630 .+-. 47.2 .+-. 2111 13.1 31 NC 25.9 .+-. 9.11 17.0
.+-. 3.92 35.3 .+-. 9.35 .+-. 15.5 6.25.sup.b 58 NC 69.4 .+-. 55.3
.sup. 17.9 .+-. 12.5.sup.b 122 .+-. 5.6 .+-. 57.3.sup.a 3.24.sup.b
91 NC .sup. 42.9 .+-. 18.7.sup.c 50.1 .+-. 14.8 488 .+-. 59.3 .+-.
471.sup.b 43.2 136 NC 107 .+-. 41.5 .sup. 16.2 .+-. 12.3.sup.a 22.6
.+-. NC 5.9 184 NC NC .sup. 1.18 .+-. 0.71.sup.b 59.8 .+-. NC
35.0.sup.b
[0165] In Table 1, NC means "not calculable" because greater than
50% of concentrations contributing to the mean were BLQ (below the
limit of quantitation). The data are expressed as the mean .+-.SEM
(N=4 eyes and N=2 plasma per sampling time). In addition, the
letters a, b, c, and d are defined as follows:
[0166] a N=4. One sample was BLQ (included in the mean calculation
as 0).
[0167] b N=4. Two samples were BLQ (included in the mean
calculation as 0).
[0168] c N=3. One sample was not detectable (ND).
[0169] d N=2. Two samples were above the limit of quantitation
(estimated mean value in parentheses).
[0170] The EC.sub.50 for brimonidine to activate the alpha 2
adrenergic receptor in isolated assay systems is about 2 nM. Based
on doubling this as a target concentration (C.sub.ss) and the
vitreal clearance (Cl) a constant delivery of 2.5 .mu.g of
brimonidine at 0.57 ng/hour (R.sub.o) is desirable for intravitreal
implant devices to maintain the desired steady state drug level
for, a duration of six months using the following equation:
R.sub.o=C.sub.ss*Cl.
[0171] Unexpectedly, as shown in Table 1, when the brimonidine
implants were implanted in the vitreous, the implants released
brimonidine to provide high vitreous and retinal concentrations of
brimonidine that were maintained over a long period of time but
only provided low or undetectable amounts of brimonidine in the
aqueous humor. Thus, the brimonidine implants resulted in
therapeutic levels of brimonidine at the retina for
neuroprotection, but not in the anterior chamber. Thus, it was
concluded that brimonidine when administered intravitreally can
provide a neuroprotective effect, but may not provide a reduction
in intraocular pressure associated with effects in the anterior
segment of the eye.
Example 3
Pharmacokinetic Properties of Brimonidine Subconjunctival
Administered to an Eye
[0172] Brimonidine was administered to the subconjunctiva of New
Zealand White rabbits by implantation of a polylactic acid (PLA)
wafer containing 250 .mu.g of brimonidine, a poly-ortho-ester (POE)
rod containing 200 .mu.g of brimonidine, or a single 100 .mu.L
injection containing 20 .mu.g or 200 .mu.g of brimonidine PLA
microspheres. A 100 .mu.L injection of 10 mg/mL of microspheres (20
.mu.g brimonidine) contained 98% (w/w) of PLA polymer having an
inherent viscosity of 0.6 dl/g (i.e., 980 .mu.g of PLA) and 2%
(w/w) of brimonidine free base (i.e., 20 .mu.g). A less than or
equal to 100 .mu.L or 200 .mu.L injection of 100 mg/mL or 200 mg/mL
microspheres, respectively (200 .mu.g brimonidine) contained 98%
(w/w) of PLA polymer having an inherent viscosity of 0.6 dL/g (i.e.
9.8 mg of PLA), and 2% (w/w) of brimonidine free base (i.e., 200
.mu.g). A 1 mg waver containing 250 .mu.g brimonidine contained 75%
(w/w) PLA (R206) polymer (750 .mu.g), and 25% (w/w) of brimonidine
tartrate (250 .mu.g). A 1 mg rod containing 250 .mu.g of
brimonidine contained 80% (w/w) of APF 255 POE (APF94) polymer (800
.mu.g) and 20% (w/w) of brimonidine (200 .mu.g). A 1 mg rod
containing 200 .mu.g of brimonidine contained 80% (w/w) of APF 260
POE (APF99) polymer (800 .mu.g) and 20% (w/w) of brimonidine (200
.mu.g). A 1 mg rod containing 200 .mu.g of brimonidine contained
80% (w/w) of APF 423 POE (APF162) polymer (800 .mu.g) and 20% (w/w)
of brimonidine (200 .mu.g).
[0173] Thirty groups of rabbits (2 rabbits per group) were used.
The groups were divided into 6 sections of 5 groups. One section
received 10 mg/mL of microspheres containing 20 .mu.g of
brimonidine, one section received 100 mg/mL of microspheres
containing 200 .mu.g of brimonidine, one section received 1 mg
POE-AP94 implants containing 200 .mu.g of brimonidine, one section
received 1 mg POE-AP99 implants containing 200 .mu.g of
brimonidine, one section received 1 mg POE-AP162 implants
containing 200 .mu.g of brimonidine, and one section received 1 mg
PLA wafers containing 250 .mu.g of brimonidine. In each section,
one group underwent ophthalmic observation at 5 days after dosing
(DAD) and were euthanized at 8 DAD, one group underwent ophthalmic
observation at 5 and 29 DAD and were euthanized at 31 DAD, one
group underwent ophthalmic observation at 5, 29, and 54 DAD and
were euthanized at 60 DAD, and two groups underwent ophthalmic
observation at 5, 29, 54, and 86 DAD and were euthanized at 93 DAD.
The drug delivery systems were formulated to provide a 10-20 nM
(3-6 ng/mL) brimonidine target concentration since the at least 2
nM of brimonidine are required to provide optic
neuroprotection.
[0174] The dose of brimonidine was based on a vitreal clearance
rate of 0.487 ml/day and a target therapeutic concentration for
brimonidine. Based on the relationship C.sub.ss=R.sub.o/Cl, where
R.sub.o=delivery rate, C.sub.ss=steady-state concentration, and
Cl=vitreal clearance, the release rate over a 3 month period of
time was calculated to be about 1.46-2.92 ng/day. The 10 mg/mL and
100 mg/mL microspheres provided release rates of 1.4 and 14
.mu.g/day for 60 days. The APF255, APF260, and APF423 provided
release rates of about 2.2, 2.6, and 2.5 .mu.g/day, respectively.
The PLA wafer provided a release rate of about 5 .mu.g/day over 30
days and 1.25 .mu.g/day out to 90 days. A single implant was
sufficient, and conventional methods were used to determine
intraocular and systemic pharmacokinetics.
[0175] Eyes were prepared for surgery by topical application of two
drops of 1% tropicamide and two drops of phenylephrine
hydrochloride 2.5%. Betadine was applied and washed from the eyes,
and 1-2 drops of 0.5% proparacaine hydrochloride were delivered to
each eye. After a 3 mm conjunctival incision was made extending
from the limbus and lateral to the dorsal rectus muscle, a single
subconjunctival injection or implantation of a brimonidine drug
delivery system was made. Rods and wafers were administered using
forceps. Conjunctivae were sutured closed and received a ocular
lubricant. Subconjunctival injections were performed by elevating
the bulbar conjunctiva in the dorsotemporal quadrant using forceps.
An injection was made into the subconjunctival space.
[0176] Gross ocular examinations were performed once weekly and
during the first week, more thorough ophthalmic examinations (slit
lamp and indirect opthalmoscopy) were performed instead. The
examinations included observations of the eyelids, conjunctiva,
cornea, anterior chamber, iris, lens, vitreous, and retina.
Intraocular pressure (IOP) was recorded at 8 am, 12 noon and 4 pm
using a Medtronic Solan, Model 30 classic pneumatonometer on
conditioned rabbits. Tear tissue, aqueous humor tissue, and
remaining tissues were collected and stored.
[0177] Based on gross ocular examinations, no conjunctival
congestion, swelling, or discharge was observed.
[0178] Based on slit lamp and indirect opthalmoscopy, an
insignificant number of eyes exhibited conjunctival congestion. A
minor number of eyes were observed to have cataracts that were
concluded to not be drug-related. Conjunctival pigmentation was
observed in some eyes, and was not considered to be of
toxicological significance. Similarly, some eyes exhibited
increased vascularization which was not considered to be
toxicocologically significant.
[0179] At day 14, the mean IOP fore eyes treated with APF 423 POE
implants (200 .mu.g brimonidine) were significantly higher than the
mean IOP at baseline at 8:00 am. Higher IOP was also observed at
days 7, 14, 56, and 89/90 at 4:00 pm for eyes treated with APF
423.
[0180] At day 30, mean IOP for eyes treated with APF 255 POE
implants (200 .mu.g brimonidine) was significantly lower than the
mean IOP at baseline for placebo treated eyes at 8:00 am and noon.
At day 56, mean IOP for eyes treated with APF 255 was significantly
lower than the mean IOP for base at 8:00 am and noon.
[0181] At day 30, mean IOP for eyes treated with APF 260 POE
implants (200 .mu.g brimonidine) was significantly lower than the
mean IOP for baseline at 8:00 am and lower than the mean IOP for
baseline and placebo-treated eyes at noon.
[0182] At day 56, the mean IOP at 8:00 am, noon, and 4:00 pm for
eyes treated with PLGA1206.sub.--01 microspheres (20 .mu.g
brimonidine) was significantly lower than the mean IOP for
baseline.
[0183] Following a single bilateral subconjunctival implantation of
APF 255 POE, APF 260 POE or APF 423 POE rod, brimonidine was
detected at below the limit of quantitation levels in all ocular
tissues at every time point up to day 91 post implant, except for
the lens tissue at day 8 with the APF 255 POE implant. Following a
single subconjunctival implantation of BF9 waver, brimonidine was
detected at BLQ levels in all ocular tissues. Following a single
subconjunctival injection of 100 .mu.L microspheres, brimonidine
was detected at BLQ levels in all tissues at all time points up to
day 91 post implant, except for the iris-ciliary body at day 8 and
day 33, and the lens at day 8 and day 33.
[0184] Plasma brimonidine concentrations were below the lower limit
of quantitation in all samples. The concentrations of brimonidine
observed are described in Tables 2-7 below TABLE-US-00002 TABLE 2
brimonidine concentration following subconjunctival injection of
100 .mu.L microspheres containing 20 .mu.g brimonidine Brimonidine
Concentration Aqueous Iris-ciliary Vitreous Humor body Lens Retina
Humor Plasma Day (ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC
4.36 .+-. 3.04.sup.a NC NC NC NC 33 NC 18.1 .+-. 3.0.sup.a 1.40
.+-. NC NC 0.040.sup.c 0.73.sup.b (BLQ, 0.079) 57 NC NC NC NC NC NC
91 NC NC NC NC NC NC
[0185] In Table 2, NC=not calculable, a means N=4 and one sample is
BLQ, b means N=4 and two samples are BLQ, and c means N=2, and one
sample is BLQ. TABLE-US-00003 TABLE 3 brimonidine concentrations
following subconjunctival injection of 100 .mu.L microspheres
containing 200 .mu.g brimonidine Brimonidine Concentration Aqueous
Iris-ciliary Vitreous Humor body Lens Retina Humor Plasma Day
(ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC 26.9 .+-. 10.8
10.4 .+-. NC NC NC 9.7.sup.a 33 NC NC 0.703 .+-. NC NC NC
0.352.sup.b 57 NC NC NC NC NC NC 91 NC NC NC NC NC NC
[0186] In Table 3, NC=not calculable, a means N=4 and one sample is
BLQ, and b means N=4 and two samples are BLQ. TABLE-US-00004 TABLE
4 brimonidine concentrations following subconjunctival implantation
of APF 255 POE containing 200 .mu.g brimonidine Brimonidine
Concentration Aqueous Iris-ciliary Vitreous Humor body Lens Retina
Humor Plasma Day (ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC
NC 0.463 .+-. NC NC NC 0.463.sup.a 33 NC NC NC NC NC NC 57 NC NC NC
NC NC NC 91 NC NC NC NC NC NC
[0187] In Table 4, NC=not calculable, and a means N=4 and two
samples are BLQ. TABLE-US-00005 TABLE 5 brimonidine concentrations
following subconjunctival implantation of APF 260 POE containing
200 .mu.g brimonidine Brimonidine Concentration Aqueous
Iris-ciliary Vitreous Humor body Lens Retina Humor Plasma Day
(ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC NC NC NC NC NC 33
NC NC NC NC NC 0.064.sup.a (BLQ, 0.127) 57 NC NC NC NC NC NC 91 NC
NC NC NC NC 0.59.sup.a (BLQ, 1.17
[0188] In Table 5, NC=not calculable, and a means N=2 and one
sample is BLQ. TABLE-US-00006 TABLE 6 brimonidine concentrations
following subconjunctival implantation of APF 423 POE implant
containing 200 .mu.g brimonidine Brimonidine Concentration Aqueous
Iris-ciliary Vitreous Humor body Lens Retina Humor Plasma Day
(ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC NC NC NC NC NC 33
NC NC NC NC NC NC 57 NC NC NC NC NC 0.267.sup.a (0.267, BLQ) 91 NC
NC NC NC NC 0.084.sup.a (BLQ, 0.167)
[0189] In Table 6, NC not calculable, and a means N=2 and one
sample is BLQ. TABLE-US-00007 TABLE 7 brimonidine concentrations
following subconjunctival implantation of a wafer containing 250
.mu.g brimonidine Brimonidine Concentration Aqueous Iris-ciliary
Vitreous Humor body Lens Retina Humor Plasma Day (ng/mL) (ng/g)
(ng/g) (ng/g) (ng/mL) (ng/mL 8 NC NC NC NC NC NC 33 NC NC NC NC NC
NC 57 NC NC NC NC NC NC 91 NC NC NC NC NC 0.032.sup.a (BLQ,
0.063)
[0190] In Table 7, NC=not calculable, and a means N=2 and one
sample is BLQ.
[0191] In the above, the samples were quantified using LC-MS/MS
methods with quantitation limits of 10 ng/mL for aqueous and
vitreous humor samples, 0.05 ng/mL for plasma samples, 0.5 ng for
iris-ciliary body samples, lens samples, and retina samples.
[0192] In summary, subconjunctival administration of polymeric drug
delivery systems containing 20-250 .mu.g of brimonidine was unable
to deliver sufficient amounts of brimonidine to the aqueous humor
to reduce IOP. Using these drug delivery systems and methods of
delivery, therapeutic intraocular concentrations of brimonidine
were not observed.
Example 4
Manufacture and Testing of Drug Delivery Systems Containing an
Anteriorly Cleared Alpha 2 Adrenergic Receptor Agonist and a
Biodegradable Polymer Matrix
[0193] Biodegradable drug delivery systems are made by combining a
anteriorly cleared alpha 2 adrenergic receptor agonist with a
biodegradable polymer composition in a stainless steel mortar. The
combination is mixed via a Turbula shaker set at 96 RPM for 15
minutes. The powder blend is scraped off the wall of the mortar and
then remixed for an additional 15 minutes. The mixed powder blend
is heated to a semi-molten state at specified temperature for a
total of 30 minutes, forming a polymer/drug melt.
[0194] Rods are manufactured by pelletizing the polymer/drug melt
using a 9 gauge polytetrafluoroethylene (PTFE) tubing, loading the
pellet into the barrel and extruding the material at the specified
core extrusion temperature into filaments. The filaments are then
cut into about 1 mg size implants or drug delivery systems. The
rods have dimensions of about 2 mm long.times.0.72 mm diameter. The
rod implants weigh between about 900 .mu.g and 1100 .mu.g.
[0195] Wafers are formed by flattening the polymer melt with a
Carver press at a specified temperature and cutting the flattened
material into wafers, each weighing about 1 mg. The wafers have a
diameter of about 2.5 mm and a thickness of about 0.13 mm. The
wafer implants weigh between about 900 .mu.g and 1100 .mu.g.
[0196] In-vitro release testing can be performed on each lot of
implant (rod or wafer). Each implant may be placed into a 24 mL
screw cap vial with 10 mL of Phosphate Buffered Saline solution at
37.degree. C. and 1 mL aliquots are removed and replaced with equal
volume of fresh medium on day 1, 4, 7, 14, 28, and every two weeks
thereafter.
[0197] Drug assays may be performed by HPLC, which consists of a
Waters 2690 Separation Module (or 2696), and a Waters 2996
Photodiode Array Detector. An Ultrasphere, C-18 (2), 5 .mu.m;
4.6.times.150 mm column heated at 30.degree. C. can be used for
separation and the detector can be set at 264 nm. The mobile phase
can be (10:90) MeOH-buffered mobile phase with a flow rate of 1
mL/min and a total run time of 12 min per sample. The buffered
mobile phase may comprise (68:0.75:0.25:31) 13 mM 1-Heptane
Sulfonic Acid, sodium salt-glacial acetic
acid-triethylamine-Methanol. The release rates can be determined by
calculating the amount of drug being released in a given volume of
medium over time in .mu.g/day.
[0198] The polymers chosen for the implants can be obtained from
Boehringer Ingelheim or Purac America, for example. Examples of
polymers include: RG502, RG752, R202H, R203 and R206, and Purac
PDLG (50/50). RG502 is (50:50) poly(D,L-lactide-co-glycolide),
RG752 is (75:25) poly(D,L-lactide-co-glycolide), R202H is 100%
poly(D, L-lactide) with acid end group or terminal acid groups,
R203 and R206 are both 100% poly(D, L-lactide). Purac PDLG (50/50)
is (50:50) poly(D,L-lactide-co-glycolide). The inherent viscosity
of RG502, RG752, R202H, R203, R206, and Purac PDLG are 0.2, 0.2,
0.2, 0.3, 1.0, and 0.2 dL/g, respectively. The average molecular
weight of RG502, RG752, R202H, R203, R206, and Purac PDLG are,
11700, 11200, 6500, 14000, 63300, and 9700 daltons,
respectively.
Example 5
Treatment of Glaucoma with an Anteriorly Cleared Alpha 2 Adrenergic
Receptor Agonist Implant
[0199] A 58 year old man diagnosed with glaucoma is treated by
administration of a biodegradable drug delivery system administered
to each eye of the patient. A 1 mg intravitreal implant containing
about 500 .mu.g of PLGA and about 500 .mu.g of an anteriorly
cleared alpha 2 adrenergic receptor agonist is placed in his left
eye at a location that does not interfere with the man's vision. A
similar implant is administered subconjunctivally to the patient's
right eye. A more rapid reduction in intraocular pressure in the
right eye appears to be due to the location of the implant. After
about 3 months from the surgery, the man's intraocular pressure
remains steady at acceptable levels, and degeneration of the optic
nerve appears to be reduced.
Example 6
Treatment of Glaucoma with an Anteriorly Cleared Alpha 2 Adrenergic
Receptor Agonist Composition
[0200] A 62 year old woman with glaucoma is treated with an
intravitreal injection of a solution containing about 20 .mu.g of
an anteriorly cleared alpha 2 adrenergic receptor agonist. The
patient exhibits an acceptable reduction in elevated intraocular
pressure and a decrease in nerve degeneration. The patient reports
an overall improvement in quality of life.
[0201] All references, articles, publications and patents and
patent applications cited herein are incorporated by reference in
their entireties.
[0202] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced within the scope of the following claims.
* * * * *