U.S. patent application number 10/836880 was filed with the patent office on 2005-11-03 for sustained release intraocular implants and methods for treating ocular neuropathies.
This patent application is currently assigned to Allergan, Inc.. Invention is credited to Huang, Glenn T., Nivaggioli, Thierry.
Application Number | 20050244458 10/836880 |
Document ID | / |
Family ID | 34967183 |
Filed Date | 2005-11-03 |
United States Patent
Application |
20050244458 |
Kind Code |
A1 |
Huang, Glenn T. ; et
al. |
November 3, 2005 |
Sustained release intraocular implants and methods for treating
ocular neuropathies
Abstract
Biocompatible intraocular implants include a beta adrenergic
receptor antagonist and a polymer associated with the beta
adrenergic receptor antagonist to facilitate release of the beta
adrenergic receptor antagonist into an eye for an extended period
of time. The beta adrenergic receptor antagonist may be associated
with a biodegradable polymer matrix, such as a matrix of a two
biodegradable polymers. The implants may be placed in an eye to
treat one or more ocular conditions, such as an ocular
neuropathies, for example, various forms of glaucoma.
Inventors: |
Huang, Glenn T.; (Fremont,
CA) ; Nivaggioli, Thierry; (Los Altos Hills,
CA) |
Correspondence
Address: |
STOUT, UXA, BUYAN & MULLINS LLP
4 VENTURE, SUITE 300
IRVINE
CA
92618
US
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
34967183 |
Appl. No.: |
10/836880 |
Filed: |
April 30, 2004 |
Current U.S.
Class: |
424/426 ;
514/237.5; 514/651 |
Current CPC
Class: |
A61K 9/0051 20130101;
A61P 27/06 20180101; A61P 27/02 20180101; A61P 43/00 20180101; A61K
31/5377 20130101 |
Class at
Publication: |
424/426 ;
514/237.5; 514/651 |
International
Class: |
A61K 031/537; A61K
031/138 |
Claims
We claim:
1. A biodegradable drug delivery implant comprising: a beta
adrenergic receptor antagonist associated with a biodegradable
polymer matrix that releases drug at a rate effective to sustain
release of an amount of the beta adrenergic receptor antagonist
from the implant for a time effective to reduce intraocular
pressure in an eye in which the implant is placed, the time being
at least about one week after the implant is placed in the eye.
2. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is selected from the group consisting of timolol,
betaxol, levobunolol, carteolol, metipranolol, derivatives thereof
and mixtures thereof.
3. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is a beta non-specific adrenergic antagonist.
4. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is selected from the group consisting of timolol, salts
thereof, and mixtures thereof.
5. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is timolol maleate.
6. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is dispersed within the biodegradable polymer
matrix.
7. The implant of claim 1, wherein the matrix comprises a mixture
of a first biodegradable polymer, and a different second
biodegradable polymer.
8. The implant of claim 1 wherein the beta adrenergic receptor
antagonist is provided in an amount of up to about 50% by weight of
the implant.
9. The implant of claim 1 wherein the beta adrenergic receptor
antagonist is provided in an amount of up to about 30% by weight of
the implant.
10. The implant of claim 1 wherein the beta adrenergic receptor
antagonist is provided in an amount of about 10% by weight of the
implant.
11. The implant of claim 1 wherein the beta adrenergic receptor
antagonist is timolol maleate and is provided in an amount of about
26% by weight of the implant.
12. The implant of claim 1, wherein the matrix releases drug at a
rate effective to sustain release of an amount of the beta
adrenergic receptor antagonist from the implant for at least about
one week from the time the implant is placed in the eye.
13. The implant of claim 1, wherein the matrix releases drug at a
rate effective to sustain release of an amount of the beta
adrenergic receptor antagonist from the implant for at least about
one month from the time the implant is placed in the eye.
14. The implant of claim 1, wherein the matrix releases drug at a
rate effective to sustain release of an amount of the beta
adrenergic receptor antagonist from the implant for at least about
3 months from the time the implant is placed in the eye.
15. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is timolol and the matrix releases drug at a rate
effective to sustain release of a therapeutically effective amount
of timolol for about three months.
16. The implant of claim 1, wherein the implant is structured to be
placed in the anterior chamber of the eye.
17. The implant of claim 1, wherein the beta adrenergic receptor
antagonist is a timolol maleate provided in an amount of about 20%
by weight of the implant, and the biodegradable polymer matrix
comprises a combination of two different polylactide polymers.
18. The implant of claim 1 which is a filament in form.
19. A method of reducing intraocular pressure in an eye of a
patient, comprising the step of placing the implant of claim 1 in
an eye of the patient to provide a therapeutically effective amount
of the beta adrenergic receptor antagonist to the patient for at
least about one week.
20. A method of reducing intraocular pressure in an eye of a
patient, comprising the step of placing the implant of claim 3 in
an eye of the patient to provide a therapeutically effective amount
of the beta adrenergic receptor antagonist to the patient for at
least about one week.
21. A method of reducing intraocular pressure in an eye of a
patient, comprising the step of placing the implant of claim 6 in
an eye of the patient to provide a therapeutically effective amount
of the beta adrenergic receptor antagonist to the patient for at
least about one week.
22. A method of reducing intraocular pressure in an eye of a
patient, comprising the step of placing the implant of claim 11 in
an eye of the patient to provide a therapeutically effective amount
of the beta adrenergic receptor antagonist to the patient for at
least about one week.
23. A method of making a biodegradable intraocular implant,
comprising the step of: extruding a mixture of a beta adrenergic
receptor antagonist and a biodegradable polymer component to form a
biodegradable material that degrades at a rate effective to sustain
release of an amount of the beta adrenergic receptor antagonist
from the implant for a time effective to reduce ocular intraocular
pressure in an eye in which the implant is placed, the time being
at least about one week after the implant is placed in the eye.
24. The method of claim 23, wherein the beta adrenergic receptor
antagonist is selected from the group consisting of timolol,
betaxol, levobunolol, carteolol, metipranolol, derivatives thereof
and mixtures thereof.
25. The method of claim 23, wherein the beta adrenergic receptor
antagonist is selected from the group consisting of timolol, salts
thereof, and mixtures thereof.
26. The method of claim 23, wherein the polymer component comprises
a mixture of different biodegradable polymers.
27. The method of claim 23, wherein the implant is placed in the
anterior chamber of the eye.
28. The method of claim 23, wherein the implant is placed in the
posterior segment of the eye.
29. The method of claim 23, further comprising a step of
administering a therapeutic agent in addition to the beta
adrenergic receptor antagonist to the patient.
30. A method of treating glaucoma, comprising the step of placing
the implant of claim 1 into an ocular region of a patient to
provide a therapeutically effective amount of the beta adrenergic
receptor antagonist to the eye of the patient for a period of at
least one week, thereby treating the glaucoma.
Description
BACKGROUND
[0001] The present invention generally relates to devices and
methods to treat an eye of a patient, and more specifically to
intraocular implants that provide extended release of a therapeutic
agent to an eye in which the implant is placed, and to methods of
making and using such implants, for example, to treat ocular
neuropathies.
[0002] Glaucoma is a progressive optic neuropathy characterized by
excavation of the optic nerve head and visual field loss in the
mid-periphery. Retinal ganglion cell death and consequent axon loss
on the retinal nerve fiber layer result in cupping of the optic
disc and visual field defects typical for glaucoma.
[0003] A major risk factor in glaucoma is thought to be elevation
of the intraocular pressure (IOP) beyond the statistical norm, i.e.
21 mm Hg. The high IOP originates from an increased resistance to
drainage of aqueous humor through the trabecular meshwork.
[0004] Although different forms of glaucoma are known, the most
common form is adult onset open chamber angle glaucoma (OAG), which
is age related and characterized by an open angle, IOPs over 21 mm
Hg, a visual field defect typical for glaucoma, and a
pathologically excavated optic disc.
[0005] Beta adrenergic receptor antagonists, also known as
beta-blockers, are a mainstay and a first therapy choice for
glaucoma.
[0006] The available beta-blockers are typically categorized as
being either nonselective (also referred to as "nonspecific"),
inhibiting both .beta..sub.1 and .beta..sub.2-adrenoceptors, or
.beta..sub.1 selective, which means that .beta..sub.1-adrenoceptors
are preferably inhibited.
[0007] Timolol maleate,
(-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thi-
adiazo-3-yl)oxy]-2-propanol maleate, (1:1) salt, is a non-selective
beta-adrenergic (beta.sub.1, and beta.sub.2) receptor blocking
agent that does not have sympathomimetic or myocardial depressant
activity. Timolol maleate, when applied topically, is effective in
reducing elevated intraocular pressure in most forms of glaucoma,
including acute angle-closure and secondary glaucomas.
[0008] Timolol maleate has been used clinically to lower
intraocular pressure for treatment of chronic OAG for approximately
30 years. It does it by inhibiting aqueous humor production, and
not by increasing outflow facility. However, as with many types of
eye drops, it is believed that only about one percent of the daily
regiment of either one drop (Timoptic XE.RTM. 0.5% q.d., Merck and
Co., Inc., Whitehouse Station, N.J.) or two drops (Timoptic.RTM.
0.5% b.i.d. Merck and Co., Inc., Whitehouse Station, N.J.) actually
gets absorbed inside the eyes to provide the therapeutic level.
Research studies have shown that the bioavailability of timolol
maleate can be improved by increasing its residence time in the
precorneal area by adding a thickening agent to the drop
formulation which tends to enhance the therapeutic effect of the
drops.
[0009] The following patents and additional publications include
disclosure which is relevant to and/or helpful in understanding the
present invention: 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. David L. Epstein,
Chandler and Grant's Glaucoma, Lea & Febiger, (1986) pp
129-181; Physician's Desk Reference for Ophthalmic Medicines, 30
Edition, (2002) p 285; Chiao-His Chiang, Jing-Ing Ho, and Jiin-Long
Chen, Journal of Ocular Pharmacology and Therapeutics, Volume 12,
Number 4, 471, (1996). Calbert I. Phillips, R. Shayle Bartholomew,
Anthony M. Levy, Jeffrey Grove, and Roger Vegel, British Journal of
Ophthalmology, Volume 69, 217, (1985). The entire disclosure of
each of these documents is incorporated herein by this
reference.
[0010] There is still a need for more effective formulations and
techniques for administering therapeutic agents, for example, beta
adengergic receptor antagonists, for example, timolol maleate, to
an eye in order to enhance bioavailability of the therapeutic agent
to the eye.
[0011] It would be advantageous to provide eye implantable drug
delivery systems, such as intraocular implants, and methods of
using such systems, that are capable of releasing a therapeutic
agent at a sustained or controlled rate for extended periods of
time and in amounts with few or no negative side effects.
SUMMARY
[0012] The present invention provides new drug delivery systems,
and methods of making and using such systems, for extended or
sustained drug release into an eye, for example, to achieve one or
more desired therapeutic effects. The drug delivery systems are in
the form of implants or implant elements that may be placed in an
eye. The present systems and methods advantageously provide for
extended release times of one or more therapeutic agents. Thus, the
patient in whose eye the implant has been placed receives a
therapeutic amount of an agent for a long or extended time period
without requiring additional administrations of the agent. For
example, the patient has a substantially consistent level of
therapeutically active agent available for consistent treatment of
the eye over a relatively long period of time, for example, on the
order of at least about one week, such as between about two and
about six months after receiving an implant. Such extended release
times facilitate obtaining successful treatment results.
[0013] Intraocular implants in accordance with the disclosure
herein comprise a therapeutic component and a drug release
sustaining component associated with the therapeutic component. In
accordance with a preferred embodiment of the present invention,
the therapeutic component comprises, consists essentially of, or
consists of, a beta adrenergic receptor antagonist. The drug
release sustaining component is associated with the therapeutic
component to sustain release of an amount of the beta adrenergic
receptor antagonist into an eye in which the implant is placed. The
amount of the beta adrenergic receptor antagonist is released into
the eye for a period of time greater than about one week after the
implant is placed in the eye and is effective in preventing or
reducing ocular vasculopathies, such as vascular occlusions.
[0014] In one embodiment, the intraocular implants comprise a beta
adrenergic receptor antagonist and a biodegradable polymer matrix.
The beta adrenergic receptor antagonist is associated with a
biodegradable polymer matrix that degrades at a rate effective to
sustain release of an amount of the antagonist from the implant for
a time sufficient to reduce or prevent an ocular vascular
occlusion. The intraocular implant is biodegradable or bioerodible
and provides a sustained release of the beta adrenergic receptor
antagonist in an eye for extended periods of time, such as for more
than one week, for example for about three months or more and up to
about six months or more. In certain implants, the beta adrenergic
receptor antagonist is released for about 30-35 days or less. In
other implants, the beta adrenergic receptor antagonist is released
for 40 days or more.
[0015] The biodegradable polymer component of the foregoing
implants may be a mixture of biodegradable polymers, wherein at
least one of the biodegradable polymers is a polylactic acid
polymer having a molecular weight less than 64 kiloDaltons (kD).
Additionally or alternatively, the foregoing implants may comprise
a first biodegradable polymer of a polylactic acid, and a different
second biodegradable polymer of a polylactic acid. Furthermore, the
foregoing implants may comprise a mixture of different
biodegradable polymers, each biodegradable polymer having an
inherent viscosity in a range of about 0.3 deciliters/gram (dl/g)
to about 1.0 dl/g.
[0016] The beta adrenergic receptor antagonist of the implants
disclosed herein may include a .beta. non specific antagonist, a
.beta..sub.1, selective antagonist, a .beta..sub.2 selective
antagonist, or other antagonists that are effective in treating
ocular conditions. Examples of suitable .beta. non specific
antagonist include timolol, propranolol, nadolol, pindolol and
derivatives thereof. Examples of .beta..sub.1 selective antagonists
include metoprolol acebutolol, alprenolol, atenolol, esmolol, and
derivatives thereof. An example of a .beta..sub.2 selective is
butoxamine. In addition, the therapeutic component of the present
implants may include one or more additional and different
therapeutic agents that may be effective in treating an ocular
condition.
[0017] A method of making the present implants involves combining
or mixing the beta adrenergic receptor antagonist with a
biodegradable polymer or polymers. The mixture may then be extruded
or compressed to form a single composition. The single composition
may then be processed to form individual implants suitable for
placement in an eye of a patient.
[0018] The implants may be placed in an ocular region to treat a
variety of ocular conditions, including conditions such as ocular
neuropathies that affect an anterior region or posterior region of
an eye. For example, the implants may be used to treat many
conditions of they eye, including, without limitation, conditions
associated with glaucoma.
[0019] Kits in accordance with the present invention may comprise
one or more of the present implants, and instructions for using the
implants. For example, the instructions may explain how to
administer the implants to a patient, and types of conditions that
may be treated with the implants.
[0020] 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.
[0021] Additional aspects and advantages of the present invention
are set forth in the following description and claims, particularly
when considered in conjunction with the accompanying drawings.
DRAWINGS
[0022] FIG. 1 is a graph of timolol maleate release profiles of
drug delivery systems in accordance with the invention, comprising
timolol maleate and a polymer, the systems each having 50% drug
load.
[0023] FIG. 2 is a graph of timolol maleate release profiles of
drug delivery systems in accordance with the invention, comprising
timolol maleate and a polymer, the systems each having 50% drug
load.
[0024] FIG. 3 is a graph of timolol maleate release profiles of
drug delivery systems in accordance with the invention, comprising
timolol maleate and a polymer, the systems each having 10% drug
load.
[0025] FIG. 4 is a graph of timolol maleate release profiles of
drug delivery systems in accordance with the invention, the graph
comparing two different sized filaments of timolol maleate and a
polymer.
[0026] FIG. 5A, 5B and 5C are graphs of timolol maleate release
profiles of drug delivery systems in accordance with the invention,
the graphs comparing release profiles of such systems comprising
various drug loads and various polymer matrices.
[0027] FIG. 6 is a graph of timolol maleate release profiles of
drug delivery systems in accordance with the invention, comprising
timolol maleate and a polymer, in which formulations were prepared
with drug content based on the weight of timolol, rather than on
the weight of timolol maleate.
[0028] FIG. 7 is a graph showing timolol maleate in-vivo release
based on total content of drug in drug delivery system retrieved
after implantation.
[0029] FIG. 8 is a graph showing timolol maleate release profiles
of drug delivery systems in accordance with the invention,
comprising timolol maleate and a polymer, the systems each having
26% drug load.
[0030] FIG. 9A is a graph showing intraocular pressure (IOP)
depressing effect of timolol maleate drug delivery systems, in
accordance with the present invention, placed in the anterior
chamber of an eye.
[0031] FIG. 9B is a graph showing IOP depressing effect of timolol
maleate drug delivery systems, in accordance with the present
invention, placed in the posterior segment of an eye.
[0032] FIG. 9C is a graph showing IOP depressing effect of timolol
maleate drug delivery systems, in accordance with the present
invention, placed under the conjunctiva of an eye.
[0033] FIG. 10 is a graph showing average IOP depressing effect of
timolol maleate drug delivery systems, in accordance with the
present invention, placed in the posterior segment, in the anterior
chamber, and under the conjunctiva of an eye.
[0034] FIG. 11 is a graph showing average IOP depression after
instillation of timolol eye drops (N=3)
DESCRIPTION
[0035] As described herein, controlled and sustained administration
of a therapeutic agent through the use of one or more intraocular
drug delivery systems, or implants, may improve treatment of
undesirable ocular conditions. The implants comprise a
pharmaceutically acceptable polymeric composition and are
formulated to release one or more pharmaceutically active agents,
such as beta adrenergic receptor antagonists, over an extended
period of time. The implants are effective to provide a
therapeutically effective dosage of the agent or agents directly to
a region of the eye to treat or prevent one or more undesirable
ocular conditions. Thus, with a single administration, therapeutic
agents will be made available at the site where they are needed and
will be maintained for an extended period of time, rather than
subjecting the patient to repeated injections or, in the case of
self-administered drops, ineffective treatment with only limited
bursts of exposure to the active agent or agents.
[0036] An intraocular implant in accordance with the disclosure
herein comprises a therapeutic component and a drug release
sustaining component associated with the therapeutic component. In
accordance with a preferred embodiment of the present invention,
the therapeutic component comprises, consists essentially of, or
consists of, a beta adrenergic receptor antagonist. The drug
release sustaining component is associated with the therapeutic
component to sustain release of a therapeutically effective amount
of the beta adrenergic receptor antagonist into an eye in which the
implant is placed. The therapeutic amount of the beta adrenergic
receptor antagonist is released into the eye for a period of time
greater than about one week after the implant is placed in the
eye.
DEFINITIONS
[0037] 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.
[0038] As used herein, an "intraocular implant" refers to a device
or element that is structured, sized, or otherwise configured to be
placed in an eye. Intraocular implants are generally biocompatible
with physiological conditions of an eye and do not cause adverse
side effects. Intraocular implants may be placed in an eye without
disrupting vision of the eye.
[0039] As used herein, a "therapeutic component" refers to a
portion of an intraocular implant comprising one or more
therapeutic agents 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. 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 implant is
placed in an eye.
[0040] As used herein, a "drug release sustaining component" refers
to a portion of the intraocular implant that is effective to
provide a sustained release of the therapeutic agents of the
implant. A drug release sustaining component may be a biodegradable
polymer matrix, or it may be a coating covering a core region of
the implant that comprises a therapeutic component.
[0041] As used herein, "associated with" means mixed with,
dispersed within, coupled to, covering, or surrounding.
[0042] 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 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.
[0043] 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.
[0044] 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 retina 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.
[0045] 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).
[0046] 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, optic nerve (i.e. the optic
disc), and blood vessels and nerves which vascularize or innervate
a posterior ocular region or site.
[0047] 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).
[0048] The present invention is especially useful in the treatment
of the glaucoma, including any of the several different types of
glaucoma, including angle-closure glaucoma, neovascular glaucoma,
open-angle glaucoma and hydrophthalmos.
[0049] The terms "biodegradable" and "bioerodible" are generally
used interchangeably herein.
[0050] 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. Specifically, hydrogels such as
methylcellulose which act to release drug through polymer swelling
are specifically excluded from the term "biodegradable polymer".
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.
[0051] 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.
[0052] 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.
[0053] Intraocular implants have been developed which can release
drug loads over various time periods. These implants, which when
inserted into an eye, such as the vitreous of an eye, provide
therapeutic levels of a beta adrenergic receptor antagonist for
extended periods of time (e.g., for about 1 week or more). The
implants disclosed are effective in treating ocular conditions, for
example ocular neuropathies such as glaucoma.
[0054] In one embodiment of the present invention, an intraocular
implant comprises a biodegradable polymer matrix. The biodegradable
polymer matrix is one type of a drug release sustaining component.
The biodegradable polymer matrix is effective in forming a
biodegradable intraocular implant. The biodegradable intraocular
implant comprises a beta adrenergic receptor antagonist associated
with the biodegradable polymer matrix. Preferably, the matrix
degrades at a rate effective to sustain release of an amount of the
beta adrenergic receptor antagonist for a time greater than about
one week from the time in which the implant is placed in ocular
region or ocular site, such as the vitreous of an eye.
[0055] The beta adrenergic receptor antagonist of the implant may
be beta nonspecific or beta specific. In a preferred embodiment of
the invention, the beta adrenergic receptor antagonist is selected
from the group consisting of timolol, bexatol, levobunolol,
carteolol, metiprenolol, derivatives thereof and mixtures thereof.
For example, the beta adrenergic receptor antagonist comprises
timolol maleate. Generally, the beta adrenergic receptor antagonist
of the implants disclosed herein may include a .beta. non specific
antagonist, a .beta..sub.1, selective antagonist, a .beta..sub.2
selective antagonist, or other antagonists that are effective in
treating ocular conditions. Examples of .beta. non-specific
antagonist include timolol, propranolol, nadolol, pindolol and
derivatives thereof. Examples of .beta..sub.1 selective antagonists
include metoprolol acebutolol, alprenolol, atenolol, esmolol, and
derivatives thereof. An example of a .beta..sub.2 selective is
butoxamine.
[0056] Pharmaceutically acceptable acid addition salts of the
compounds of the invention 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.
[0057] Thus, the implant may comprise a therapeutic component which
comprises, consists essentially of, or consists of a timolol salt,
such as timolol maleate.
[0058] The beta adrenergic receptor antagonist may be in a
particulate or powder form and entrapped by the biodegradable
polymer matrix. Beta adrenergic receptor antagonist particles
commonly have an effective average size less 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.
[0059] The beta adrenergic receptor antagonist of the implant is
preferably from about 10% to 90% by weight of the implant. More
preferably, the beta adrenergic receptor antagonist is from about
20% to about 80% by weight of the implant. In a preferred
embodiment, the beta adrenergic receptor antagonist comprises about
20% by weight of the implant, or about 26% by weight of the
implant. In another embodiment, the beta adrenergic receptor
antagonist comprises up to about 50% by weight of the implant.
[0060] Suitable polymeric materials or compositions for use in the
implant 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 are at least partially and more preferably
substantially completely biodegradable or bioerodible.
[0061] 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 implants.
[0062] 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.
[0063] 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.
[0064] Other polymers of interest include, without limitation,
polyvinyl alcohol, polyesters, polyethers and combinations thereof
which are biocompatible and may be biodegradable and/or
bioerodible.
[0065] Some preferred characteristics of the polymers or polymeric
materials for use in the present invention 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.
[0066] 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.
[0067] Equally important to controlling the biodegradation of the
polymer and hence the extended release profile of the implant is
the relative average molecular weight of the polymeric composition
employed in the implant. Different molecular weights of the same or
different polymeric compositions may be included in the implant to
modulate the release profile. In certain implants, 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.
[0068] In some implants, 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
implant, where a more flexible 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 implants, a 50/50
PLGA copolymer is used.
[0069] The biodegradable polymer matrix of the intraocular implant
may comprise a mixture of two or more biodegradable polymers. For
example, the implant 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.
[0070] Release of a drug from an erodible polymer is the
consequence of several mechanisms or combinations of mechanisms.
Some of these mechanisms include desorption for the surface of the
implant, dissolution, diffusion through porous channels of the
hydrated polymer and erosion. Erosion can be bulk erosion, or
surface erosion, or a combination of both. As discussed herein, the
matrix of the intraocular implant may release drug at a rate
effective to sustain release of an amount of the beta adrenergic
receptor antagonist for more than one week after implantation into
an eye. In certain implants, therapeutic amounts of the beta
adrenergic receptor antagonist are released for more about 30-35
days after implantation. For example, an implant may comprise
timolol maleate, and the matrix of the implant releases drug at a
rate effective to sustain release of a therapeutically effective
amount of timolol maleate for about one month after being placed in
an eye. As another example, the implant may comprise timolol
maleate, and the matrix degrades at a rate effective to sustain
release of a therapeutically effective amount of timolol for more
than forty days, such as for about six months.
[0071] One example of the biodegradable intraocular implant
comprises a beta adrenergic receptor antagonist associated with a
biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers. At least one of the biodegradable
polymers is a polylactide having a molecular weight of about 63.3
kD. A second biodegradable polymer is a polylactide having a
molecular weight of about 14 kD. Such a mixture is effective in
sustaining release of a therapeutically effective amount of the
beta adrenergic receptor antagonist for a time period greater than
about one month from the time the implant is placed in an eye.
[0072] Another example of a biodegradable intraocular implant
comprises a beta adrenergic receptor antagonist associated with a
biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers, each biodegradable polymer having
an inherent viscosity from about 0.16 dl/g to about 1.0 dl/g. For
example, one of the biodegradable polymers may have an inherent
viscosity of about 0.3 dl/g. A second biodegradable polymer may
have an inherent viscosity of about 1.0 dl/g. The inherent
viscosities identified above may be determined in 0.1% chloroform
at 25.degree. C.
[0073] One particular implant comprises timolol maleate associated
with a combination of two different polylactide polymers. The
timolol maleate is present in about 20% by weight of the implant.
One polylactide polymer has a molecular weight of about 14 kD and
an inherent viscosity of about 0.3 dl/g, and the other polylactide
polymer has a molecular weight of about 63.3 kD and an inherent
viscosity of about 1.0 dl/g. The two polylactide polymers are
present in the implant in a 1:1 ratio. Such an implant provides for
release of the timolol for more than two months in vitro, as
described herein. The implant is provided in the form of a rod or a
filament produced by an extrusion process.
[0074] The release of the beta adrenergic receptor antagonist from
the intraocular implant comprising a biodegradable polymer matrix
may include an initial burst of release followed by a gradual
increase in the amount of the beta adrenergic receptor antagonist
released, or the release may include an initial delay in release of
the beta adrenergic receptor antagonist followed by an increase in
release. When the implant is substantially completely degraded, the
percent of the beta adrenergic receptor antagonist that has been
released is about one hundred. Compared to existing implants, the
implants disclosed herein do not completely release, or release
about 100% of the beta adrenergic receptor antagonist, until after
about one week of being placed in an eye.
[0075] It may be desirable to provide a relatively constant rate of
release of the beta adrenergic receptor antagonist from the implant
over the life of the implant. For example, it may be desirable for
the beta adrenergic receptor antagonist to be released in amounts
from about 0.01 .mu.g to about 2 .mu.g per day for the life of the
implant. 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 beta adrenergic
receptor antagonist 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 implant has begun to degrade or
erode.
[0076] The 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 drug falls within a narrow window. In
addition, the therapeutic component, including the beta adrenergic
receptor antagonist, may be distributed in a non-homogenous pattern
in the matrix. For example, the implant may include a portion that
has a greater concentration of the beta adrenergic receptor
antagonist relative to a second portion of the implant.
[0077] The intraocular 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 for example, 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.
[0078] 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. 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.
[0079] Thus, implants 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 drug, 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.
[0080] The implants may be of any geometry including fibers,
sheets, films, microspheres, spheres, circular discs, plaques and
the like. The upper limit for the implant size will be determined
by factors such as toleration for the implant, 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 0.5 .mu.m
to 4 mm in diameter, with comparable volumes for other shaped
particles.
[0081] The size and form of the implant can also be used to control
the rate of release, period of treatment, and drug concentration at
the site of implantation. 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 implant are chosen to suit the site of
implantation.
[0082] The proportions of beta adrenergic receptor antagonist,
polymer, and any other modifiers may be empirically determined by
formulating several implants with varying proportions. 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.
[0083] In addition to the beta adrenergic receptor antagonist or
beta adrenergic receptor antagonists included in the intraocular
implants disclosed herein, the intraocular implants may also
include one or more additional ophthalmically acceptable
therapeutic agents. For example, the implant may include one or
more antihistamines, one or more antibiotics, one or more alpha
adrenergic receptor agonists, 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.
[0084] Pharmacologic or therapeutic agents which may find use in
the present systems, include, without limitation, those disclosed
in U.S. Pat. No. 4,474,451, columns 4-6 and U.S. Pat. No.
4,327,725, columns 7-8.
[0085] 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.
[0086] 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, ampicillin, amoxicillin, cyclacillin, ampicillin,
penicillin G, penicillin V potassium, piperacillin, oxacillin,
bacampicillin, cloxacillin, ticarcillin, aziocillin, 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,
and derivatives thereof.
[0087] Examples of alpha adrenergic receptor agonists include
quinoxalines, (2-imidozolin-2-ylamino) quinoxalines,
5-bromo-6-(2-imidozolin-2-ylamino) quinoxalines, derivatives
thereof and mixtures thereof.
[0088] Examples of steroids include corticosteroids, such as
cortisone, prednisolone, flurometholone, dexamethasone, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,
prednisone, methylprednisolone, riamcinolone hexacatonide,
paramethasone acetate, diflorasone, fluocinonide, fluocinolone,
triamcinolone, derivatives thereof, and mixtures thereof.
[0089] 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.
[0090] Examples of immunosuppresive agents include cyclospqrine,
azathioprine, tacrolimus, and derivatives thereof.
[0091] Examples of antiviral agents include interferon gamma,
zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
valciclovir, dideoxycytidine, phooosphonoformic acid, ganciclovir
and derivatives thereof.
[0092] 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.
[0093] Other therapeutic agents include squalamine, carbonic
anhydrase inhibitors, prostamides, prostaglandins, antiparasitics,
antifungals, and derivatives thereof.
[0094] The amount of active agent or agents employed in the
implant, individually or in combination, will vary widely depending
on the effective dosage required and the desired rate of release
from the implant. Usually the agent will be at least about 1, more
usually at least about 10 weight percent of the implant, and
usually not more than about 80, more usually not more than about 40
weight percent of the implant.
[0095] In addition to the therapeutic component, the intraocular
implants disclosed herein may include effective amounts of
buffering agents, preservatives and the like. Suitable water
soluble buffering agents include, without limitation, alkali and
alkaline earth carbonates, phosphates, bicarbonates, citrates,
borates, acetates, succinates and the like, such as sodium
phosphate, citrate, borate, acetate, bicarbonate, carbonate and the
like. These agents advantageously present in amounts sufficient to
maintain a pH of the system of between about 2 to about 9 and more
preferably about 4 to about 8. As such the buffering agent may be
as much as about 5% by weight of the total implant. Suitable water
soluble preservatives include sodium bisulfite, sodium bisulfate,
sodium thiosulfate, ascorbate, benzalkonium chloride,
chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric
borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl
alcohol, benzyl alcohol, phenylethanol and the like and mixtures
thereof. These agents may be present in amounts of from 0.001 to
about 5% by weight and preferably 0.01 to about 2% by weight. In at
least one of the present implants, a purite preservative is
provided in the implant, such as when the beta adrenergic receptor
antagonist is timolol. Thus, these implants may contain a
therapeutically effective amount of Alphagan-P.RTM..
[0096] In some situations mixtures of implants may be utilized
employing the same or different pharmacological agents. In this
way, a cocktail of release profiles, giving a biphasic or triphasic
release with a single administration is achieved, where the pattern
of release may be greatly varied.
[0097] Additionally, release modulators such as those described in
U. S. Pat. No. 5,869,079 may be included in the implants. 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 beta adrenergic receptor antagonist in the
absence of modulator. Electrolytes such as sodium chloride and
potassium chloride may also be included in the implant. 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.
[0098] In certain implants, an implant comprising timolol or
timolol maleate and a biodegradable polymer matrix is able to
release or deliver an amount of timolol between about 0.1 mg to
about 0.5 mg for about 3-6 months after implantation into the eye.
The implant may be configured as a rod or a wafer. A rod-shaped
implant may be derived from filaments extruded from a 720 .mu.m
nozzle and cut into 1 mg size. A wafer-shaped implant may be a
circular disc having a diameter of about 2.5 mm, a thickness of
about 0.127 mm, and a weight of about 1 mg.
[0099] The proposed 3-month release formulations may be sterile,
and bioerodible in the form of a rod, a wafer or a microsphere
containing timolol maleate within a PLA matrix or POE matrix. The
implants are designed to delay the clearance of the drug and reduce
the need for repeated implantation over 3-month period, thereby
lowering the risk of complications.
[0100] Various techniques may be employed to produce the implants
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.
[0101] Specific techniques and methods are discussed in Wong, 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.
[0102] In addition, the implant may be coextruded so that a coating
is formed over a core region during the manufacture of the
implant.
[0103] Compression methods may be used to make the implants, and
typically yield implants 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.
[0104] The implants of the present invention may be inserted into
the eye, for example the vitreous chamber of the eye, by a variety
of methods, including placement by forceps or by trocar following
making a 2-3 mm incision in the sclera. One example of a device
that may be used to insert the implants into an eye is disclosed in
U.S. patent application Ser. No. 10/246,884, filed on Sep. 18,
2002, which is U.S. patent Publication No. 2004/0054374, the
disclosure of which is incorporated herein in its entirety by this
reference. The method of placement may influence the therapeutic
component or drug release kinetics. For example, delivering the
implant with a trocar may result in placement of the implant deeper
within the vitreous than placement by forceps, which may result in
the implant being closer to the edge of the vitreous. The location
of the implant may influence the concentration gradients of
therapeutic component or drug surrounding the element, and thus
influence the release rates (e.g., an element placed closer to the
edge of the vitreous may result in a slower release rate).
[0105] The present implants are configured to release an amount of
beta adrenergic receptor antagonist in an eye for a period of time
to minimize an ocular neuropathy, such as open angle glaucoma. By
implanting the beta adrenergic receptor antagonist-containing
implants into the vitreous of an eye, it is believed that the
antagonist is effective to reduce IOP of the eye.
EXAMPLE 1
Manufacture of Implants Containing Timolol and a Biodegradable
Polymer Matrix
[0106] Biodegradable drug delivery systems, or implants, in
accordance with the invention, were made by combining timolol
maleate or timolol freebase with a biodegradable polymer
composition.
[0107] More specifically, implants were made in forms of pellets
and wafers. For example, drug delivery system pellet elements,
typically cylindrical in form, were made as pellets having sizes
and weights of 1.8 mm L.times.about 0.72 mm diameter and 900 .mu.g
to 1100 .mu.g by weight, or pellets having sizes and weights of 1.2
mm L.times.0.38 mm diameter and 216 to 264 .mu.g by weight. Drug
delivery system wafer elements were made as generally circular
wafers having a size and weight of 0.13 mm thickness.times.2.5 mm
diameter and 900 .mu.g to 1100 .mu.g weight.
[0108] Different formulations of such pellet elements and wafer
elements were made and tested as described hereinafter. In each
formulation, an active pharmaceutical ingredient (API), timolol
maleate, was combined with a polymer.
[0109] The polymers chosen for the formulation work were obtained
from Boehringer Ingelheim. The polymers were: Resomer RG502,
RG502H, RG503, RG504, RG505, RG506, RG752, RG755, RG756, RG858,
R202H, R203, and R206. Resomer RG502, RG502H, RG503, RG504, RG505,
and RG506 are all 50:50 poly (D, L-lactide-co-glycolide) with
inherent viscosities of 0.2, 0.2, 0.4, 0.5, 0.7 and 0.8 dL/g,
respectively. RG752, RG755, and RG756 are 75:25 poly (D,L
lactide-co-glycolide) with inherent viscosities of 0.2, 0.6, and
0.8 dL/g, respectively. RG858 is 85:15 poly
(D,L-lactide-co-glycolide- ) with inherent viscosity of 1.4 dL/g,
and R203 and R206 are poly (D,L-lactide) with inherent viscosities
of 0.3 and 1.0 dL/g, respectively. Finally, R202H is poly
(D,L-lactide) with inherent viscosity of 0.2 and acid end.
[0110] For each formulation, the drug and polymer were combined in
a stainless steel mortar and mixed by means of a Turbula shaker set
at 96 RPM for 15 minutes. The powder blend was scraped off the wall
of the mortar and then remixed for an additional 15 minutes. The
mixed powder blend was transferred into a Teflon beaker and heated
to a molten state at 95.degree. C. for a total of about 30 to 60
minutes, in ten 3-6 minute intervals, to form a homogeneous
polymer/drug melt.
[0111] The polymer/drug melt was then made into pellets and wafers.
More specifically, the melt was pelletized using a 9 gauge
polytetrafluoroethylene (PTFE) tubing. The pellets were loaded into
the barrel of a piston extruder and extruded at the specified core
extrusion temperature into filaments, then cut into about 1 mg size
pellets. The melt was made into wafers by means of a Carver press
utilized at a appropriate temperature and pressure, and thereafter
pressed polymer/drug sheets were cut into wafers, each weighing
about 1 mg.
Testing of Implants Containing Timolol and a Biodegradable Polymer
Matrix
[0112] The in-vitro drug rate release testing was performed as
follows.
[0113] Each implant, either pellet or wafer, was placed into a 40
mL screw cap vial each filled with 10 mL of 0.9% saline and the
vials were placed into shaken water bath at 37.degree. C./50 rpm.
At specified time points, 8 mL aliquots were removed and replaced
with equal volume of fresh medium. The drug assays-were performed
by HPLC, which generally consists of a Waters HPLC system,
including a 2690 Separation Module (or 2696 Separation Module), and
a 2996 Photodiode Array Detector. A Metachem Inertsil, RP C-18, 5
.mu.m; 4.6.times.250 mm column was used for separation, and
detector was set at 295 nm. The mobile phase was (25:75)
acetonitrile-0.01 M KH.sub.2PO.sub.4, pH=2.8, with flow rate of 1
mL/min and a total run time of 6 min per sample. The release rates
were determined by calculating the amount of drug being released in
a given volume of medium over time in .mu.g/day.
[0114] The drug assays for the in-vivo samples was performed under
the same HPLC condition as those of in-vitro samples except the
mobile phase was (20:80) acetonitrile-0.01 M KH.sub.2PO.sub.4, pH
=2.8.
[0115] Implants containing a 50% drug load and various polymers
were screened. Formulation screening work started out with RG502,
RG503, RG504, R203, RG752, RG755, and R202H with weight average
molecular weight (Mw) of 8,400; 28,300; na; 14,000; 11,200; 40,000;
and 6500 daltons, respectively. Turning to FIG. 1, a graph showing
timolol maleate release rate profiles for the 50% drug load
implants made with these various different polymers, is shown.
[0116] Data revealed that all 50% drug load formulations exhibited
very fast one day release, with half of the formulations reached
release greater than about 90% at day one, while the other half of
the formulations released between 40% to 85% of the timolol maleate
at day one, as shown in FIG. 1.
[0117] This initial high drug release rate resulted in part because
of the high solubility of timolol maleate in aqueous medium.
Although not wishing to be bound by any particular theory of
operation, it is believed that once the implant is in contact with
the dissolution medium, the timolol maleate on the surface of the
implant dissolves quickly and diffuses out of the matrix thereby
leaving channels allowing more dissolution medium to diffuse inside
the implant and dissolve more timolol maleate.
[0118] Timolol freebase, a non-salt form of timolol maleate, is
less soluble in the same dissolution medium. With that in mind,
three different formulations of timolol maleate implants were made
with an equivalent of sodium carbonate added in RG502, and
separately in R203 in an attempt to generate the freebase in-situ
and therefore slow down the release rate of timolol. It was
observed that, the release rates of these implants behaved as if no
timolol freebase was being generated in-situ, as shown in Table
1.
1TABLE 1 Formulations with one equivalent of Na.sub.2CO.sub.3 added
(saline, 37.degree. C., n = 6) Formulation # RT # Lot # Timolol
Polymer Nozzle Size Day 1 9 265-68 241-142 45% RG502 380 um 240 ug
78.70% 10 265-78 241-143 24% RG502 380 um 240 ug 61.30% 11 265-69
241-144 45% R203 380 um 240 ug 94.10%
[0119] As shown, formulations 9, 10, and 11 showed a release of
approximately 79%, 61%, and 94%, respectively. After day one, this
particular release study was stopped.
[0120] Tests were performed in attempt to determine any correlation
between drug load and drug release profile. Implants having drug
loads of 25% and 50% timolol maleate in RG502 and in R206 were
prepared. A graph of the drug release profiles is shown in FIG.
2.
[0121] It was found that by reducing the drug load by half, the
release on day one was reduced by more than two folds. Day one
release for 25% timolol maleate in RG502 was about 13.7%, comparing
to approximately 66% for the 50% drug load samples, and day one
release for 25% timolol maleate in R206 was about 20.0% comparing
to about 88.4% for the 50% drug load samples.
[0122] It was observed that as the release rates dropped with lower
drug load, the duration of release lengthened from one day release
(50% timolol maleate in either RG502 or R206) to 28 days for 25%
timolol maleate in RG502 and up to 60 days for 25% timolol maleate
in R206.
[0123] Implants were made having a 10% drug load to determine if a
desired six-month release could be achieved by reducing the drug
load. The resulting data revealed that for 10% timolol maleate in
RG502, the total release was about 10.7% on day 7 but thereafter
all implants disintegrated such that only an amorphous cloud
remained in the sample vials. The release study was therefore
discontinued. However, the drug release of the formulation
containing 10% timolol maleate in R206 was relatively slower. This
release study was stopped after 98 days with a total release of
about 29.1 percent, as shown in FIG. 3.
[0124] It is noted that FIG. 3 also reflects release profiles of
10% timolol maleate formulation (lot 241-192) in wafer form to
compare the drug release of wafers with the drug release of rods
made from the same formulation. The data showed that the drug
release from the wafer was initially slower than the rod, but then
after day 63, a cross over occurred after which the drug release
from the wafer was faster than the drug release from the rod.
[0125] During the formulation of the 10% timolol maleate in RG502
(lot 241-178) and 10% timolol maleate in R206 (lot 241-792), a 720
.mu.m nozzle was used to extrude the filaments instead of the 380
.mu.m that was used for all earlier formulations. Furthermore, the
implant size for the 10% timolol maleate formulation was 1 mg,
compared to 240 .mu.g in the earlier formulations.
[0126] Another test was conducted to determine how a change in
implant size would affect the rate of drug release. Four
formulations were prepared using a single polymer RG502H and two
different nozzles sizes of 380 .mu.m and 720 .mu.m. The implants
were cut to a weight of 1 mg.+-.10% for the filaments extruded from
the 720 .mu.m nozzle, and 0.24 mg.+-.10% for the filaments extruded
from the 380 .mu.m nozzle. The release profiles of these implants
of different sizes are shown in FIG. 4.
[0127] It was observed that the implants cut from a smaller
diameter filament exhibited a faster drug release than the drug
release from a larger diameter filament (241-185 vs. 241-184, and
241-187 vs. 241-186). However, no substantial difference was
observed between implants of 10% and 25% drug load. Without wishing
to be bound by any particular theory of invention, it is believed
that this lack of any substantial difference in drug release in the
10% and 25% drug load implants may be due to the fact that the
entire release lasted only 12 days, which may be too rapid for any
significant or meaningful differentiation to take place.
Furthermore, it is believed that the use of Resomer RG502H may have
contributed to the apparent lack of differentiation. Drug load and
polymer formulation, or class, are each believed to be significant
parameters for controlling the duration of drug release as well as
controlling the initial burst effect for the drug. In order to test
this theory, a series of formulations were made using Resomer
RG503, RG504, RG505, RG506, RG752, RG755, RG756, RG858, R203, R206,
and R208 each with a 10% drug load to compare the various polymer
matrices. The release profiles are shown in FIGS. 5A, 5B, and 5C,
based on the different classes of polymers.
[0128] As shown in Tables 5A, 5B and 5C, 50:50 poly
(D,L-lactide-co-glycolide) polymers, in general, have approximately
one-month release, 75:25 poly (D,L-lactide-co-glycolide) and 85:15
poly (D,L-lactide-co-glycolide) have approximately two-months
release and the poly (D,L-lactides) have about three-month release
or longer.
[0129] During this release study, it was noticed that certain
formulations appeared to have drug releases higher than 100% of
theory at the end of the study. It is not unusual in these studies
to sometimes obtain an apparent total percent release greater than
100%. This may be explained as follows. Timolol maleate is a salt,
and the actual timolol content by weight is 73.16% of the weight of
salt. The HPLC standards can be prepared based on weight of timolol
maleate salt (Mw 432), or based on the weight of timolol freebase
(Mw 316) and then the weight of timolol maleate can be accordingly
recalculated. Thus, to prepare a 1 .mu.g/mL solution of timolol
maleate, one weighs out 5 mg of timolol maleate which is then
dissolved in 5 liters of medium. However, this 1 .mu.g/mL solution
timolol maleate actually contains only 0.73 .mu.g/mL of timolol
freebase. On the other hand, to prepare a 1 .mu.g/mL solution of
timolol freebase, one would have to weigh out 6.835 mg of timolol
maleate salt, instead of 5 mg, which is then dissolved in 5 liter
of medium.
[0130] Additional release profiles are shown in FIG. 6.
[0131] As shown, timolol maleate formulated with 20% drug load in
R206 (lot 295-13) showed a steady release to 78% on day 106, then a
slightly slower release reaching 89% on day 134, and finally
leveling off gradually to 92% on day 177. Timolol maleate
formulated with 26% drug load in R206 (lot 295-12) showed a steady
release to 91% on day 106, faster than lot 295-13, then a slightly
slower release reaching 92% on day 134, and remained essentially
unchanged to 93% on day 177. In contrast, timolol maleate
formulated with 20% drug load in R203 (lot 295-15) showed a slow
release achieving only 28% on day 106, and reaching 39% by day 134,
but then accelerated to 99% of total release on day 177.
[0132] Because the type of polymer will have an effect on the
release rate of the active agent in the implants in accordance with
the invention, it is contemplated that drug delivery system
implants can be formulated to have a desired release rate by
combining two or more polymers as a matrix material, with the
active agent. The polymers are preferably selected to achieve a
desired release rate of the active component from the implant.
[0133] For example, complimentary release characteristics can be
utilized by combining two different polymers, for example wherein
one polymer has a high release profile representing an upper limit
on a desired release, and another polymer has a low release profile
representing a lower limit on a desired release. For example, both
polymer R203 and R206 with timolol maleate can be used to achieve a
release rate that is more desirable with R203 or R206 alone. In
other words, it can be appreciated that if 20% timolol maleate in
R206 (295-13) is considered the upper limit of what we would like
to achieve, while 20% timolol maleate in R203 is considered the
lower limit, then a more desirable release profile somewhere
between the two can be achieved when combining both polymers
together in various proportions.
EXAMPLE 2
In vivo Testing of Intraocular Implants Containing Timolol and a
Biodegradable Polymer Matrix
[0134] The first in-vivo study conducted on timolol formulation
tested two different types of implants, both having a 10% drug load
and a polymer of R206. The implants were the same implant
formulations having the release profiles shown in FIG. 3. Both
types were formulated with 10% timolol maleate in R206 polymer. A
first type of the implant was in the form or a pellet, or rod, and
the second type was in the form of a wafer.
[0135] The initial study was conducted on two animals. The rods
from lot 241-179 were surgically implanted into the anterior
chamber of the right eye and under conjuntiva of the left eye of
the first animal. The wafers from lot 241-192 were surgically
implanted into the anterior chamber ("AC") of the right eye and
under conjuntiva of the left eye of the second animal. The anterior
chamber sampling days were days 1, 4, 7, 12, 28, and every other
week there after. No detectable levels of timolol were found for
both lots up to day 47. On day 47, the two rods and two wafers were
extracted from the animals and total content analysis performed.
The results are summarized in Table 2.
2TABLE 2 Timolol Maleate Total Content Determination (lot 241-179
& lot 241-192) Sample Wt. Theor. Tim. Tim conc. Timolol
(.sup..mu.g) Percent Rabbit Lot # .sup..mu.g amount, .sup..mu.g
.sup..mu.g/mL Recovered Recovery 7473-OD 241-179 1314 96.05 4.25
106.25 110.62 7473-OS 241-179 1324 96.78 1.87 93.50 96.61 7474-OD
241-192 1312 95.91 1.65 82.50 86.02 7474-OS 241-192 1230 89.91 1.64
82.00 91.20
[0136] The implants were extracted from both animals and total
content analysis of the remnants showed most of timolol maleate was
still in the implants, which meant that only minute quantity of
timolol maleate was released from the implants. This was a stark
contrast to the in-vitro data, which, as described hereinabove with
reference to FIG. 3, showed a release of 20.2% after 35 days for
lot 241-179, and 15.8% after 35 days for lot 24-192. A possible
explanation for the observed no release for these two lots was that
perhaps the rods or wafers were too large in size, especially when
implanted into the anterior chamber, which contains approximately
200-300 .mu.L of aqueous humor, or subconjuntiva. Thus, relatively
smaller implants with relatively higher drug load were used for the
subsequent in-vivo study.
[0137] The second timolol in-vivo study conducted was on lot
241-173 with 25% timolol maleate (w/w) in R206. The study was
conducted on one animal, both eyes were surgically implanted with
implants (240 .mu.g) in the anterior chamber and AC sampling was
scheduled to be done after 1 hr, 6 hr, 48 hr, 7 days, 71 days and
75 days. The in-vivo data is shown in Table 3.
3TABLE 3 Timolol Maleate Levels (.mu.g/mL) in Rabbit (lot #
241-173) Rabbit 1 hr 6 hr 24 hr 48 hr 7 day 7477-D 1.1 0.2 0.19
0.07 0.00 7477-S 4.19 0.37 0.11 0.06 0.00 Average 2.65 0.29 0.15
0.07 0.00 SD 2.18 0.12 0.06 0.01 0.00
[0138] The levels were high initially, at about 2.65 .mu.g/mL,
probably due to the burst effect of the implant formulation, then
the levels steadily dropped off to about 0.29 .mu.g/mL, about 0.15
.mu.g/mL, about 0.07 .mu.g/mL, and about 0.00 .mu.g/mL for 6 hr, 24
hr, 48 hr, and 7 day, respectively. It was not clear if the
implants simply stopped releasing drug on day 7, since the in-vitro
data (FIG. 2.) showed timolol release about 30% by day 7, or
approximately 18 .mu.g. One possible explanation was the rapid
clearance rate of timolol maleate in rabbit eyes. Hypothetically,
if timolol maleate clearance rate in the eye equals the timolol
maleate release rate from the polymer matrix, then the aqueous
humor could yield no level when analyzed. The two implants were
extracted from the animal after 75 days and their total content was
determined. The results are summarized in Table 4. The total
content showed about 89% of timolol maleate was released from the
implant in the right eye and about 88% was released from the
implant in the left eye after 75 days.
4TABLE 4 Timolol Maleate Total Content Determination (lot 241-173)
Sample Wt. Theor. Tim. Tim conc. Timolol (.sup..mu.g) Percent
Rabbit Lot # .sup..mu.g amount, .sup..mu.g .sup..mu.g/mL Recovered
Released 7477-OD 241-173 240 45.6 0.20 5.00 89.00 7477-OS 241-173
240 45.6 0.22 5.50 87.90
[0139] In order to determine whether clearance rate was a possible
explanation, a known quantity of a bolus injection of timolol
maleate solution (1.5 mg in 25 .mu.L) was injected into the eyes of
10 rabbits, five in the anterior chamber and the remaining five in
the posterior segment. Sampling was done from the anterior chamber
for the first five animals after 1 hr, 3 hr, 6 hr, 12 hr, and 24
hr, and from both the anterior chamber and posterior segment of the
remaining five animals after 1 hr, 3 hr, 6 hr, 24 hr, and 48 hr.
One animal was used for each time point. The data for the first
five animals are shown in Table 5A, and the remaining five animals
in Tables 5B and 5C.
5TABLE 5A Timolol Maleate Injection into Anterior Chamber (Levels
in AC, .mu.g/mL) Rabbit 0 hr 1 hr 3 hr 6 hr 12 hr 24 hr 642-D 1500
1191.7 642-S 1500 485.16 628-D 1500 42.82 628-S 1500 56.52 623-D
1500 0.82 623-S 1500 1.49 636-D 1500 0.08 636-S 1500 0.05 643-D
1500 0.02 643-S 1500 0.04 Average 1500 838.43 49.67 1.16 0.07 0.03
SD 499.60 9.69 0.47 0.02 0.01
[0140]
6TABLE 5B Timolol Maleate Injection into Posterior Segment (Levels
in PS, .mu.g/mL) Rabbit 0 hr 1 hr 3 hr 6 hr 24 hr 48 hr 635-D 1500
744.31 635-S 1500 706.34 641-D 1500 395.57 641-S 1500 198.57 640-D
1500 125.69 640-S 1500 104.68 637-D 1500 1.66 637-S 1500 1.4 639-D
1500 0.69 639-S 1500 0.15 Average 1500 725.33 297.07 115.19 1.53
0.42 SD 26.85 139.30 14.86 0.18 0.38
[0141]
7TABLE 5C Timolol Maleate Injection into Posterior Segment (Levels
in AC, .mu.g/mL) Rabbit 0 hr 1 hr 3 hr 6 hr 24 hr 48 hr 635-D 0.75
635-S 0.16 641-D 2.13 641-S 1.6 640-D 0.78 640-S 0.53 637-D 0.39
637-S 0.46 639-D 0.43 639-S 0.16 Average 0.46 1.87 0.66 0.43 0.30
SD 0.42 0.37 0.18 0.05 0.19
[0142] The levels were high initially after the first hour at about
838 .mu.g/mL. However, they dropped off dramatically after 3 hours,
6 hours, 12 hour and 24 hour to about 49.67 .mu.g/mL, about 1.16
.mu.g/mL, about 0.07 .mu.g/mL, and about 0.03 .mu.g/mL,
respectively. The level at the 6 hour time point was only about
0.13% of that at one hour time point. Comparing this result to the
levels at the same two time points for the timolol implant
(295-173, Table 2), it was concluded that the clearance rate of
timolol maleate in the anterior chamber may be a significant factor
in measuring the levels. From this in-vivo study, the clearance
rate of timolol maleate was calculated by taking the difference in
levels between any two time points and divided it by the difference
in time. i.e. between zero hour to the first hour, the clearance
rate was calculated to be about 661 .mu.g/hr, and between first
hour to the third hour, the clearance rate was calculated to be
about 394 .mu.g/hr, and etc. From these, the half-life in rabbit
anterior chamber was calculated to be about 1.43 hour.
[0143] The levels in the posterior segment after same bolus
injection showed relatively slower clearance rate at the 1 hour
time point and even much slower at subsequent time points, as
presented in Table 5B. Detectable levels of timolol maleate were
found in the anterior chamber from the posterior segment bolus
injection, as shown in Table 5C, although the levels were small and
considered insignificant.
[0144] Since it was difficult to determine the levels of timolol in
the rabbit eyes even with bolus injection, we focused our attention
on measuring intra-ocular pressure (IOP) to probe the efficacy of
the implant.
[0145] This led to the fourth in-vivo study, which was designed for
9 animals. They were divided into three groups of three animals
each. The timolol implants were placed into three different areas
in the eyes, anterior chamber, posterior segment, and conjuntiva.
Only the right eye of each animal received an implant, while the
left eye was left alone as control. Intraocular pressure of both
eyes of each rabbit was measured one week prior to the surgery as
background, and days 1, 2, 3, 4, 7, and once a week up to six
months post surgery. The formulation chosen was lot 295-16 (see
FIG. 6), which was 26% timolol maleate in R203. This formulation
was chosen for its seemingly zero order release profile up to 21
day of release. Prior to the surgery, the IOP of all nine animals
were measured to obtain a baseline. The baseline IOP data for the
animals is shown in Table 6.
8TABLE 6 Baseline Intra-Ocular Pressure - Pre-surgery (mm Hg)
Rabbit Day 1 2 3 4 5 8 Average SD Anterior Chamber 1682-OD 23.5
18.5 19.0 18.0 18.5 19.5 19.5 2.0 1682-OS 23.0 18.0 21.0 21.0 20.5
17.5 20.2 2.1 1697-OD 19.0 19.0 18.0 17.5 18.5 15.0 17.8 1.5
1697-OS 16.5 18.0 17.0 18.5 17.5 16.5 17.3 0.8 1689-OD 16.0 18.0
20.0 19.0 19.0 18.5 18.4 1.4 1689-OS 16.5 19.0 17.0 16.5 17.0 17.5
17.3 0.9 Posterior Segment 1696-OD 15.0 19.5 15.0 16.5 15.0 16.0
16.2 1.8 1696-OS 18.0 15.5 17.0 15.0 16.0 15.5 16.2 1.1 1698-OD
19.5 18.5 19.5 20.0 19.5 19.5 19.4 0.5 1698-OS 19.5 17.5 16.0 16.0
17.0 16.5 17.1 1.3 1683-OD 20.5 21.0 20.0 20.5 19.0 20.0 20.2 0.7
1683-OS 16.5 16.0 16.0 17.0 16.5 17.5 16.6 0.6 Conjuntiva 1694-OD
22.5 21.5 21.0 18.5 18.5 17.0 19.8 2.1 1694-OS 16.5 19.0 18.0 19.0
18.0 16.5 17.8 1.1 1693-OD 15.5 15.0 15.0 14.5 15.0 15.0 15.0 0.3
1693-OS 16.0 19.5 16.5 16.5 16.0 17.5 17.0 1.3 1685-OD 18.0 14.5
16.0 18.5 18.0 14.5 16.6 1.8 1685-OS 16.0 16.0 14.5 16.5 16.5 14.5
15.7 0.9
[0146] As expected, the IOP of each animal fluctuated from day to
day but over a period of 8 days it tend to equilibrated around in
the high teens with standard deviation ranging from low of 0.3 to
the high of 2.1. On day 15, one was found to be ill and thus, was
sacrificed on day 17 and the remnant retrieved for total content
analysis. On day 35 animal # 1693 (conjuntiva), animal # 1697
(anterior chamber) and animal # 1698 (posterior segment) were
sacrificed, and on day 69, the remaining five animals were
sacrificed and remnants removed for total content analysis. The
results are presented in Table 7 and the release profiles based on
recovered remnants at each time point is shown in FIG. 7.
9TABLE 7 Timolol Maleate IN-Vivo Total Content Ther. timolol Day
Timolol (.sup..mu.g) Timolol Timolol Animal # Wt. of DDS amount,
(.sup..mu.g) Sacrificed Recovered % Recovery % Released 1696 (PS)
809 150.47 17 105.50 70.11 28.89 1693 (Conj) 791 147.92 35 67.75
45.80 54.20 1697 (AC) 769 143.80 35 55.00 38.25 61.75 1698 (PS) 781
146.05 35 52.50 39.95 64.05 1694 (Conj) 770 143.22 69 36.00 25.14
74.86 1689 (AC) 763 141.92 69 29.00 20.43 79.57 1685 (Conj) 807
150.10 69 33.50 22.32 77.68 1683 (PS) 829 154.19 69 29.25 18.97
81.03 1682 (AC) 765 142.29 69 30.25 21.26 78.74
[0147] As shown in FIG. 7, the data showed similar release profiles
for all three locations, anterior chamber, posterior segment, and
conjuntiva.
[0148] Comparison of the in-vivo profile with the in-vitro profile,
shown in FIG. 8, a good correlation between the release profiles
can be recognized.
[0149] The intra-ocular pressure of both the right and left eyes of
the nine animals was measured on indicated days, as shown in Table
8.
10TABLE 8 Timolol Maleate IOP Schedule Animal # Day 1696 1, 2, 3,
6, 7, 8, 9, 13, 15 1693, 1697, 1698 1, 2, 3, 6, 7, 8, 9, 13, 15,
17, 20, 22, 24, 27, 29, 31, 34 1682, 1683, 1685, 1689, 1, 2, 3, 6,
7, 8, 9, 13, 15, 17, 20, 22, 24, 1695 27, 29, 31, 34, 38, 42, 45,
48, 52, 56, 60, 64
[0150] The data was collected in order to compensate for the IOP
variations from eye to eye of each animal, both presurgery and post
surgery, the IOP changes were calculated as follows:
.DELTA..DELTA.IOP=.DELTA.IOP-.DELTA.IOP.sub.baseline (1)
.DELTA.IOP=.DELTA.IOP.sub.treated-.DELTA.IOP.sub.controlled (2)
[0151] where .DELTA.IOP.sub.treated and .DELTA.IOP.sub.controlled
represent the IOP of treated (right) and controlled (left) eye,
respectively. .DELTA.IOP.sub.baseline is the difference of IOP of
both eyes at time 0. The IOP depressing effect of timolol maleate
in anterior chamber, posterior segment, and conjunctiva are
presented in FIGS. 9A, 9B, and 9C. As a guideline, it is noted that
a relatively more negative value of the IOP change translates to
better therapeutic effect and a value of zero translates to no
measurable therapeutic effect.
[0152] The data showed that when timolol maleate implants, in
accordance with the present invention, were surgically implanted
into the anterior chamber of the eye, the resulting IOP depressing
effect was most pronounced in each of the three locations in the
eye. Additionally, it was concluded that implantation into the
posterior segment seemed to be the second most effective in
reducing IOP, and implantation into the conjunctiva appeared to be
the least effective of the three locations in terms of
effectiveness in depressing IOP. The average IOP depression in the
anterior chamber, posterior segment and conjunctiva was calculated.
This calculation is presented in FIG. 10.
[0153] This study seems to indicate that the most effective
location for the implantation of timolol drug delivery systems or
implants in accordance with the present invention is in the
anterior chamber.
[0154] In order to determine what the average IOP depression would
be for an eye that had the therapeutic levels of timolol, we used
commercially available timolol eye drops and follow the recommended
regiments as described below.
[0155] In the fifth and final in-vivo study, three animals were
used. Each animal's right eye was instilled with two drops of 0.5%
Timolol eye drops in the morning and left eye as control, and IOP
of both eyes were measured at 1 h, 3 h, and 6 h. This was repeated
for two days. Using the same equations (1) and (2) to calculate the
.DELTA.IOP and .DELTA..DELTA.IOP. The average IOP depression of the
three animals is shown in FIG. 11.
[0156] As shown in a marked IOP depression was observed at about 6
hour after instillation on the first day, but such a depression was
not observed on the second day. It seemed the average IOP
depression was localized around -2 mm Hg range, which was similar
to what was observed with the implant formulations of the present
invention which comprised about 26% timolol maleate in R203 polymer
(lot 295-16).
CONCLUSIONS
[0157] Timolol maleate implants in accordance with the present
invention which were formulated with poly (D,L-lactide) Resomer
R206 and/or Resomer R203 (lot 295-15), have provided a in vitro
release profile of about six months. Due to its high water
solubility, timolol maleate exhibits very quick release profiles
using poly (lactide-co-glycolide) of various viscosities. It was
found that drug load was a major contributing factor that
facilitated the rapid release of timolol maleate in aqueous medium.
If the drug load was reduced from 50% down to 10-20% range,
effective sustained release from 3-6 months could be achieved.
[0158] The first timolol formulation selected for the animal study
was 10% timolol maleate in R203 as rods (lot 241-179) and as wafers
(lot 241-192). Unfortunately, timolol were detected and after total
content determination was made, it was found that all timolol
maleate were still in the drug delivery implants and no detectable
levels were released. This was different from the in-vitro release
profiles, which showed about 20.2% release for the rods and about
15.8% release for the wafers after about 35 days. It was reasoned
that perhaps the size of the implants (1300 .mu.g) was too large to
be effective when implanted in the anterior chamber. Using smaller
implants, the next in-vivo study utilized implants of about 26%
timolol maleate in R203 (lot 295-16) and the implant size was
reduced to about 240 .mu.m.
[0159] Further in-vivo studies demonstrated that polymer/timolol
implants in accordance with the invention that were implanted into
the anterior chamber of the eye exhibited better therapeutic levels
than identical implants implanted into either the posterior segment
or the conjuntiva of the eye, as indicated by more negative IOP
depression values. Further, these depression values were similar to
that obtained with implants formulated with 26% timolol maleate in
R203 (lot 295-16). From this, it was inferred that 26% timolol
maleate in R203 (lot 295-16) probably provided therapeutic levels
to effectively depress IOP.
EXAMPLE 3
[0160] A 72 year old woman is diagnosed with age related open angle
glaucoma that is becoming progressively worse. Her intraocular
pressure ranges between about 26 mm Hg and about 28 mm Hg. An
implant containing 15% timolol maleate in a matrix comprising equal
amounts (a 1:1 ratio) of biodegradable polymers (R203 and R206 is
placed into the vitreous of both of the woman's eyes using a
trocar. Over the next several days, the physician measures the
intraocular pressure in the eyes and finds that the intraocular
pressure appears to be decreasing and becomes steady at about 20 mm
Hg. The woman also reports that she notices a decrease in
discomfort in her eyes. The implants continue to provide a
relatively consistent, effective dose of timolol to the eyes over
the next 4 months. At about the fifth month, the physician measures
the intraocular pressure and determines that the implants no longer
seem to be maintaining the desired intraocular pressure in the
woman's eyes. It is presumed that the implants have degraded
completely. The physician repeats the procedure every 5 months for
the remainder of the woman's life. The implants in accordance with
the invention prevent any significant further loss of vision for
the woman.
[0161] The implants disclosed herein may also be configured to
release additional therapeutic agents, as described above, which
may be effective in treating diseases or conditions, such as the
following:
[0162] MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age
Related Macular Degeneration (ARMD), Exudative Age Related Macular
Degeneration (ARM D), Choroidal Neovascularization, Diabetic
Retinopathy, Acute Macular Neuroretinopathy, Central Serous
Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular
Edema.
[0163] 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.
[0164] VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease,
Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch
Angitis, Sickle Cell Retinopathy and other Hemoglobinopathies,
Angioid Streaks, Familial Exudative Vitreoretinopathy.
[0165] TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal
Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,
Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow
Transplant Retinopathy.
[0166] PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy
and Epiretinal Membranes, Proliferative Diabetic Retinopathy.
[0167] 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.
[0168] GENETIC DISORDERS: Retinitis Pigmentosa, Systemic Disorders
with Accosiated Retinal Dystrophies, Congenital Stationary Night
Blindness, Cone Dystrophies, Stargardt's Disease and 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.
[0169] RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant
Retinal Tear.
[0170] TUMORS: Retinal Disease Associated with Tumors, 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.
[0171] MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior
Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal
Degeneration, Acute Retinal Pigment Epithelitis and the like.
[0172] All references, articles, publications and patents and
patent applications cited herein are incorporated by reference in
their entireties.
[0173] 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.
* * * * *