111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20050244463Al
`
`(19) United States
`(12) Patent Application Publication
`Huang et al.
`
`(10) Pub. No.: US 2005/0244463 Al
`Nov. 3, 2005
`(43) Pub. Date:
`
`(54) SUSTAINED RELEASE INTRAOCULAR
`IMPLANTS AND METHODS FOR TREATING
`OCULAR VASCULOPATHIES
`
`(75)
`
`Inventors: Glenn T. Huang, Fremont, CA (US);
`Brittany Jackson, Huntington Beach,
`CA (US); James A. Burke, Santa Ana,
`CA (US); Ton Lin, Irvine, CA (US);
`Patrick M. Hughes, Aliso Viejo, CA
`(US); Larry A. Wheeler, Irvine, CA
`(US); Rosy Sheng Donn, Saratoga, CA
`(US)
`
`Correspondence Address:
`STOUT, UXA, BUYAN & MULLINS LLP
`4 VENTURE, SUITE 300
`IRVINE, CA 92618 (US)
`
`(73)
`
`Assignee: Allergan, Inc., Irvine, CA
`
`(21)
`
`Appl. No.:
`
`10/836,911
`
`(22) Filed:
`
`Apr. 30, 2004
`
`Publication Classification
`
`(51)
`Int. Cl? .................................................. A61K 31/498
`(52) U.S. Cl. ............................................ 424/427; 514/249
`
`(57)
`
`ABSTRACT
`
`Biocompatible intraocular implants include an alpha-2 adr(cid:173)
`energic receptor agonist and a polymer associated with the
`alpha-2 adrenergic receptor agonist to facilitate release of
`the alpha-2 adrenergic receptor agonist into an eye for an
`extended period of time. The alpha-2 adrenergic receptor
`agonist 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 vasculopathy or glau(cid:173)
`coma, among others.
`
`Page 1 of 23
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`Patent Application Publication Nov. 3, 2005 Sheet 1 of 7
`
`US 2005/0244463 Al
`
`120
`
`100
`
`1 80
`! ~ a:
`i
`~ -c
`
`60
`
`~ 40
`Cl) a.
`
`20
`
`0
`
`0
`
`120
`
`100-
`
`! 80
`J CD a:
`~ 60
`.... -c
`~ 40
`:.
`
`20
`
`0
`
`0
`
`-e- F1 ·50% BT I RG752
`-+- F3 • 50% BT I RG502
`--.!!r- FS - 50% BT I R203
`-e-- F7 ·50% BT I R206
`-a- F29 • 50% BT I R202H
`
`50
`
`60
`
`70
`
`80
`
`10
`
`20
`
`30
`
`40
`Days
`FIG. 1
`
`-+- F2 • 50% BFB I R0752
`-&- F4 • 50% BFB I RQ502
`-6- F6- 50% BFB I R2o:J
`_.__ FB • 50% BFB I R206
`- - F30 ·50% BFB I R202H
`
`50
`
`60
`
`70
`
`80
`
`10
`
`20
`
`30
`
`40
`Days
`FIG. 2
`
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`

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`Patent Application Publication Nov. 3, 2005 Sheet 2 of 7
`
`US 2005/0244463 Al
`
`80
`
`60
`
`Cll
`
`i
`Ill s
`Q) a:
`j
`
`0 .... - 40
`(,) ... Q)
`
`1:
`Q)
`
`Q.
`
`20
`
`0
`
`120
`
`0
`
`14
`
`28
`
`42
`
`56
`
`70
`
`98
`84
`Days
`FIG. 3
`
`--+- F9 • 25% BT I R206
`F10 - 25% BT I R203
`-
`--*"" F16 -15% BT I R206
`_._ F24 - 20% BT I R206
`
`112 126 140 154 168 182
`
`Cll
`.!!!
`
`100 a 80
`Q) a: s 60
`g -1:
`
`~ 40
`I.
`
`20
`
`0
`
`-+-- F17 • 20"kBT I (1:1) R203 • R206
`- - F18- 20%BT I (3:1) R203 • R206
`-.-F25 -17%BT I (1:1) R203· R206
`_._ F53 • 20% BT I (2:1) R203 • R206
`
`0
`
`14
`
`28
`
`42
`
`56
`
`70
`
`84
`
`98 112 126 140 154 168 182 196
`Days
`
`FIG. 4
`
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`

`

`Patent Application Publication Nov. 3, 2005 Sheet 3 of 7
`
`US 2005/0244463 Al
`
`100 . , - - , - - - - - - - - - - - - - - - - - - : - - - - - - y - - - - 1
`
`80
`
`60
`
`{!. - 40
`
`i II)
`j
`Q) a:
`]i
`
`c
`Q) u ... Q)
`a.
`
`. -+---- F26 - 40% BFB I (1 :1) RG752 I RG502
`--- F27 - 40% BFB I (2:1) RG752 I RG502
`-.r.-- F28 - 40% BFB I (1 :1) R203 I RG502
`
`7
`
`14
`
`21
`
`28
`
`35
`Days
`FIG. 5
`
`42
`
`49
`
`56
`
`63
`
`70
`
`20
`
`0
`
`0
`
`100
`
`80
`
`"" 8l as
`Q) a; 60
`a:
`]i
`
`c
`
`0 .... - 40
`~ Q) a.
`
`20
`
`0
`
`0
`
`2
`
`4
`
`6
`
`8
`Days
`
`FIG. 6
`
`-+-- F21·- 25% BT I R206
`....,.__ F22- 20".4 BT I (1:1) R203- R206
`--+- F23 • 20% BT I (3:1) R203 - R206
`
`10
`
`12
`
`14
`
`16
`
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`

`

`Patent Application Publication Nov. 3, 2005 Sheet 4 of 7
`
`US 2005/0244463 Al
`
`100~----------------------------------------------,
`
`,
`CD en
`j
`CD a:
`
`'j .e -c
`i:! :.
`
`CD
`
`80
`
`60
`
`40
`
`-+- F40 - 15% BT I R206
`20 -b--.1.-t~::....;...~~----:JlL-----------1 -
`F47- 15% BT I (1 :1) R203- R206
`---.-. F49 -15% BT I (3:1) R203 • R206
`
`0
`
`14
`
`28
`
`42
`
`56
`Days
`FIG. 7
`
`_.__ F52 • 15% BT I (2:1) R203- R206
`
`70
`
`84
`
`98
`
`112
`
`100 ~r===================~------------------------~
`-+- F46- 10% BT I (1 :1) R203- R206
`
`80
`
`---- F48 -10% BT I (3:1) R2031 R206
`___._. F50 - 1 0% BT I R206
`_.__ F51 -10% BT I (2:1) R203- R206
`
`0 ~--.----,----,----.----~--~----~--~--~--~
`14
`140
`42
`112
`28
`126
`0
`98
`56
`84
`70
`Days
`FIG. 8
`
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`

`Patent Application Publication Nov. 3, 2005 Sheet 5 of 7
`
`US 2005/0244463 Al
`
`100
`
`---+- F41 - 40% BFB I (1 :1) RG752 • RG502
`-II- F42- 40% BFB I (2:1) RG752 • RG502
`-.tr- F43 • 40"/0 BFB I (1:1) R203: RG502
`
`80
`
`60
`
`40
`
`1 Q)
`"i a:
`I
`0 ... -c
`
`·~
`Q) a.
`
`20
`
`0~~---.------~~----~------------~----~
`25
`30
`20
`15
`10
`5
`0
`Days
`FIG. 9
`
`f
`l CD
`
`.E
`~·
`.E
`t
`;!
`
`6
`
`5
`
`4
`
`3
`
`2
`
`0
`
`...,._. Placebo (n=2)
`
`-
`
`Brimonidine (n=2)
`
`Day1
`
`Day3
`
`Day7
`
`Day 14
`
`Day21
`
`Day28
`
`Follow-up
`
`FIG. 10
`
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`Patent Application Publication Nov. 3, 2005 Sheet 6 of 7
`
`US 2005/0244463 Al
`
`1200 ,--------------.--------------~============~~
`-Placebo Group
`E 1000 -1-------------1-----'~---------i-e- Brim onidine Group
`
`::s -m 800 +-------~~-~~---------------------~
`~ :E 600
`
`l-
`ea
`~ 400
`.f
`
`0 +-----~----~------.------.----~------.------.----~
`Day 7 Day 14 Day 21 Day 28
`Day 3
`Baseline Baseline Day 1
`1
`2
`
`FIG. 11
`
`24
`
`22
`
`20
`
`18
`
`-f.
`
`~ 16
`E
`E
`
`14
`
`10
`
`I
`1
`12 ~ T _...... ~ r--
`1
`
`•
`
`---+-
`
`•
`
`•
`
`r • Brim~
`.....-Place
`
`J_ T
`
`J.
`
`' •
`
`~
`
`i
`• l
`
`8
`
`6
`
`4
`
`day 0
`
`day 1
`
`day 3
`
`day 7
`
`day 14 day 21
`
`day 28
`
`day 1
`
`day 3
`
`d~ 7
`
`FIG. 12
`
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`Patent Application Publication Nov. 3, 2005 Sheet 7 of 7
`
`US 2005/0244463 Al
`
`SUperior va lntwlor of BRVO Eyes (OS)
`
`120
`
`----------------~--------------------- --
`
`-----------------
`
`~+-
`
`----------------------------------------------------------------·-
`
`1-:-::.:bol
`
`40+-------r------,-------T-------r------,-------~----~
`Day-28
`Day-21
`Day-3
`Day-7
`Day-14
`Day-1
`Pre
`
`F~
`
`FIG. 13
`
`1100
`1000
`900
`.......
`800
`::)
`~ 700
`~ 600
`li:
`500
`]
`400
`m 300
`200
`100
`0
`
`J.
`/!).
`I \
`I
`\
`\
`I
`I
`I
`rl
`--t_
`.I.
`
`\
`\
`L
`
`.L
`
`I
`r
`
`.............._
`
`T
`
`..
`
`...
`...
`.....
`
`':1:------
`
`.....
`
`Base 1 Base 2 Day 1 Day 3 Day 7 Day 14 Day 21 Day 28
`
`1-+- Brimonidine (N=2) -11- Placebo (N=2) I
`
`FIG. 14
`
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`

`US 2005/0244463 Al
`
`Nov. 3, 2005
`
`1
`
`SUSTAINED RELEASE INTRAOCULAR
`IMPLANTS AND METHODS FOR TREATING
`OCULAR VASCULOPATHIES
`
`BACKGROUND
`
`[0001] The present invention generally relates to devices
`and methods to treat an eye of a patient, and more specifi(cid:173)
`cally 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 vasculopathies, or to generally
`improve vision.
`
`[0002] Brimonidine, 5-bromo-6-(2-imidazolidinylidene(cid:173)
`amino )quinoxaline, is an alpha-2-selective adrenergic recep(cid:173)
`tor agonist that is effective in the treatment of open-angle
`glaucoma by decreasing aqueous humor production and
`increasing uveoscleral outflow. Brimonidine is available in
`two chemical forms, brimonidine tartrate and brimonidine
`free base. Brimonidine tartrate (Alphagan® P) is publicly
`available by Allergan for treating glaucoma. Topical ocular
`brimonidine formulation, 0.15% Alphagan® P (Allergan,
`Irvine, Calif.), is currently commercially available for treat(cid:173)
`ment of open-angle glaucoma. The solubility ofbrimonidine
`tartrate in water is 34 mg/mL, while the solubility of
`brimonidine freebase is negligible in water.
`
`[0003] Recent studies have suggested that brimonidine
`can promote survival of injured retinal ganglion nerve cells
`by activation of the alpha-2-adrenoceptor in the retina and/or
`optic nerve. For example, brimonidine can protect injured
`neurons from further damage in several models of ischemia
`and glaucoma.
`
`[0004] Glaucoma-induced ganglion cell degeneration is
`one of the leading causes of blindness. This indicates that
`brimonidine can be utilized in a new therapeutic approach to
`glaucoma management
`in which neuroprotection and
`intraocular pressure reduction are valued outcomes of the
`therapeutic regimen. For brimonidine to protect the optic
`nerve, however, it must have access to the posterior segment
`of the eye at therapeutic levels. Currently available tech(cid:173)
`niques for administering brimonidine to the posterior cham(cid:173)
`ber of the eye are not sufficient to address this issue.
`
`[0005] Biocompatible implants for placement in the eye
`have been disclosed in a number of patents, such as U.S. Pat.
`Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,
`505; 5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,
`661; 6,331,313; 6,369,116; and 6,699,493.
`
`[0006]
`It would be advantageous to provide eye implant(cid:173)
`able 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
`
`[0007] 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 therapeu(cid:173)
`tic 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 treat(cid:173)
`ment 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.
`[0008]
`Intraocular implants in accordance with the disclo(cid:173)
`sure herein comprise a therapeutic component and a drug
`release sustaining component associated with the therapeu(cid:173)
`tic component. In accordance with the present invention, the
`therapeutic component comprises, consists essentially of, or
`consists of, an alpha-2 adrenergic receptor agonist. The
`alpha-2 adrenergic receptor agonist may be an agonist or
`agent that selectively activates alpha-2 adrenergic receptors,
`for example by binding to an alpha-2 adrenergic receptor,
`relative to other types of adrenergic receptors, such as
`alpha -1 adrenergic receptors. The selective activation can be
`achieved under different conditions, but preferably, the
`selective activation is determined under physiological con(cid:173)
`ditions, such as conditions associated with an eye of a
`human or animal patient. The drug release sustaining com(cid:173)
`ponent is associated with the therapeutic component to
`sustain release of an amount of the alpha-2 adrenergic
`receptor agonist into an eye in which the implant is placed.
`The amount of the alpha-2 adrenergic receptor agonist 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 occular vasculopathies,
`such as vascular occlusions.
`[0009]
`In one embodiment, the intraocular implants com(cid:173)
`prise an alpha-2 adrenergic receptor agonist and a biode(cid:173)
`gradable polymer matrix. The alpha-2 adrenergic receptor
`agonist is associated with a biodegradable polymer matrix
`that degrades at a rate effective to sustain release of an
`amount of the agonist 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 alpha-2 adrenergic recep(cid:173)
`tor agonist 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 alpha-2 adrenergic receptor agonist is released
`for about 30-35 days or less. In other implants, the alpha-2
`adrenergic receptor agonist is released for 40 days or more.
`[0010] The biodegradable polymer component of the fore(cid:173)
`going implants may be a mixture of biodegradable poly(cid:173)
`mers, 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 poly(cid:173)
`mer of a polylactic acid, and a different second biodegrad(cid:173)
`able polymer of a polylactic acid. Furthermore, the forego(cid:173)
`implants may comprise a mixture of different
`ing
`biodegradable polymers, each biodegradable polymer hav(cid:173)
`ing an inherent viscosity in a range of about 0.3 deciliters/
`gram (dl!g) to about 1.0 dl!g.
`[0011] The alpha-2 adrenergic receptor agonist of the
`implants disclosed herein may include quinoxaline deriva-
`
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`

`US 2005/0244463 Al
`
`Nov. 3, 2005
`
`2
`
`tives, or other agonists that are effective in treating ocular
`conditions. One example of a suitable quinoxaline derivative
`is brimonidine or brimonidine tartrate. 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.
`
`[0012] A method of making the present implants involves
`combining or mixing the alpha-2 adrenergic receptor agonist
`with a biodegradable polymer or polymers. The mixture may
`then be extruded or compressed to form a single composi(cid:173)
`tion. The single composition may then be processed to form
`individual implants suitable for placement in an eye of a
`patient.
`
`[0013] The implants may be placed in an ocular region to
`treat a variety of ocular conditions, including conditions
`such as ocular vasculopathies 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 vascular
`occlusion.
`
`[0014] Kits in accordance with the present invention may
`comprise one or more of the present implants, and instruc(cid:173)
`tions 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.
`
`[0015] 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 combina(cid:173)
`tion of features may be specifically excluded from any
`embodiment of the present invention.
`
`[0016] 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
`
`[0017] FIG. 1 is a graph showing the cumulative release
`profiles for biodegradable brimonidine tartrate containing
`implants as determined in 0.9% phosphate buffered saline at
`37 degrees Celsius.
`
`[0018] FIG. 2 is a graph similar to FIG. 1 showing the
`cumulative release profiles for biodegradable brimonidine
`free base containing implants with different combinations of
`biodegradable polymers.
`
`[0019] FIG. 3 is a graph similar to FIG. 1 showing the
`cumulative release profiles for biodegradable brimonidine
`tartrate containing implants having different concentrations
`of brimonidine tartrate.
`
`[0020] FIG. 4 is a graph similar to FIG. 3 showing the
`cumulative release profiles for biodegradable brimonidine
`tartrate containing implants having different concentrations
`of brimonidine tartrate and polymeric blends.
`
`[0021] FIG. 5 is a graph similar to FIG. 4 showing the
`cumulative release profiles for biodegradable brimonidine
`free base containing implants having different concentra(cid:173)
`tions of brimonidine tartrate and polymeric blends.
`
`[0022] FIG. 6 is a graph showing the cumulative release
`profiles
`for brimonidine
`tartrate containing
`implants
`(wafers) having different concentrations of brimonidine tar(cid:173)
`trate and polymeric combinations.
`[0023] FIG. 7 is a graph similar to FIG. 6 showing the
`cumulative release profiles for biodegradable brimonidine
`free base containing implants having a different concentra(cid:173)
`tion of brimonidine tartrate and polymeric blends.
`[0024] FIG. 8 is a graph similar to FIG. 4 showing the
`cumulative release profiles for biodegradable brimonidine
`free base containing implants having a different concentra(cid:173)
`tion of brimonidine tartrate and polymeric blends.
`[0025] FIG. 9 is a graph similar to FIG. 5 showing the
`cumulative release profiles for biodegradable brimonidine
`free base containing wafer implants.
`[0026] FIG. 10 is a graph showing the delay in filling of
`sodium fiuoroscein during angiography following branch
`retinal vein occlusion (BRVO) versus time in monkeys that
`have received brimonidine tartrate containing biodegradable
`implants or placebo implants.
`[0027] FIG. 11 is a graph of foveal thickness as a function
`of time in monkeys that have received brimonidine tartrate
`containing biodegradable implants or placebo implants and
`experienced BRVO.
`[0028] FIG. 12 is a graph of intraocular pressure as a
`function of time in monkeys that have received brimonidine
`tartrate containing biodegradable
`implants or placebo
`implants and experienced BRVO.
`
`[0029] FIG. 13 is a graph of the superior/inferior percent
`response to a multifocal ERG as a function of time in
`monkeys that have received brimonidine tartrate containing
`biodegradable implants or placebo implants and experienced
`BRVO.
`[0030] FIG. 14 is a graph of blood flow as a function of
`time in monkeys that have received brimonidine tartrate
`containing biodegradable implants or placebo implants and
`experienced BRVO.
`
`DESCRIPTION
`
`[0031] As described herein, controlled and sustained
`administration of a therapeutic agent through the use of one
`or more intraocular 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 alpha-2 adrenergic receptor agonists, 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.
`
`[0032] An intraocular implant in accordance with the
`disclosure herein comprises a therapeutic component and a
`drug release sustaining component associated with the thera-
`
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`US 2005/0244463 Al
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`Nov. 3, 2005
`
`3
`
`peutic component. In accordance with the present invention,
`the therapeutic component comprises, consists essentially
`of, or consists of, an alpha-2 adrenergic receptor agonist.
`The drug release sustaining component is associated with
`the therapeutic component to sustain release of a therapeu(cid:173)
`tically effective amount of the alpha-2 adrenergic receptor
`agonist into an eye in which the implant is placed. The
`therapeutic amount of the alpha-2 adrenergic receptor ago(cid:173)
`nist is released into the eye for a period of time greater than
`about one week after the implant is placed in the eye.
`
`[0033] Definitions
`
`[0034] 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.
`
`[0035] 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.
`
`[0036] 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 typi(cid:173)
`cally ophthalmically acceptable, and are provided in a form
`that does not cause adverse reactions when the implant is
`placed in an eye.
`
`[0037] As used herein, a "drug release sustaining compo(cid:173)
`nent" 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.
`
`[0038] As used herein, "associated with" means mixed
`with, dispersed within, coupled to, covering, or surrounding.
`
`[0039] 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 gen(cid:173)
`erally 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 epi(cid:173)
`corneal space, the sciera, the pars plana, surgically-induced
`avascular regions, the macula, and the retina.
`
`[0040] 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 con(cid:173)
`stitute 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.
`
`[0041] 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.
`
`[0042] Thus, an anterior ocular condition can include a
`disease, ailment or condition, such as for example, aphakia;
`pseudophakia; astigmatism; blepharospasm; cataract; con(cid:173)
`junctival diseases; conjunctivitis; corneal diseases;, corneal
`ulcer; dry eye syndromes; eyelid diseases; lacrimal appara(cid:173)
`tus diseases; lacrimal duct obstruction; myopia; presbyopia;
`pupil disorders; refractive disorders and strabismus. Glau(cid:173)
`coma 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).
`
`[0043] 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 vascu(cid:173)
`larize or innervate a posterior ocular region or site.
`
`[0044] 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; infec(cid:173)
`tions, such as fungal or viral-caused infections; macular
`degeneration, such as acute macular degeneration, non(cid:173)
`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 poste(cid:173)
`rior 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 influ(cid:173)
`enced by an ocular laser treatment; posterior ocular condi(cid:173)
`tions caused by or influenced by a photodynamic therapy,
`photocoagulation, radiation retinopathy, epiretinal mem(cid:173)
`brane 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).
`
`[0045] The term "biodegradable polymer" refers to a
`polymer or polymers which degrade in vivo, and wherein
`erosion of the polymer or polymers over time is 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
`
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`
`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.
`
`[0046] 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.
`
`[0047] 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.
`
`Intraocular implants have been developed which
`[0048]
`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 an alpha-2
`adrenergic receptor agonist for extended periods of time
`(e.g., for about 1 week or more). The implants disclosed are
`effective in treating ocular conditions, such as posterior
`ocular conditions.
`
`In one embodiment of the present invention, an
`[0049]
`intraocular implant comprises a biodegradable polymer
`matrix. The biodegradable polymer matrix is one type of a
`drug release sustaining component. The biodegradable poly(cid:173)
`mer matrix is effective in forming a biodegradable intraocu(cid:173)
`lar implant. The biodegradable intraocular implant com(cid:173)
`prises an alpha-2 adrenergic receptor agonist associated with
`the biodegradable polymer matrix. The matrix degrades at a
`rate effective to sustain release of an amount of the alpha-2
`adrenergic receptor agonist 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.
`
`[0050] The alpha-2 adrenergic receptor agonist of the
`implant is typically an agent that selectively activates
`alpha-2 adrenergic receptors relative to alpha-1 adrenergic
`receptors. In certain implants, the alpha-2 adrenergic recep(cid:173)
`tor agonist is selectively activates a subtype of the alpha-2
`adrenergic receptors. For example, the agonist may selec(cid:173)
`tively activate one or more of the alpha-2a, the alpha-2b, or
`the alpha-2c receptors, under certain conditions, such as
`physiological conditions. Under other conditions, the ago(cid:173)
`nist of the implant may not be selective for alpha-2 adren(cid:173)
`ergic receptor subtypes. The agonist may activate the recep(cid:173)
`tors by binding to the receptors, or by any other mechanism.
`
`In certain implants, the alpha-2 adrenergic receptor
`[0051]
`agonist is a quinoxaline derivative. The quinoxaline deriva(cid:173)
`tives useful in the present implants are those quinoxaline
`derivatives having the formula,
`
`[0052] pharmaceutically acceptable acid addition
`salts thereof, and mixtures thereof. R1 and R2 each is
`independently selected from the group consisting of
`H, alkyl radicals containing 1 to 4 carbon atoms and
`alkoxy radicals containing 1 to 4 carbon atoms. R2 is
`preferably a methyl radical. The 2-imidazolin-2-
`ylamino group may be in any of the 5-, 6-, 7- and
`8-positions, preferably in the 6-position, of the qui(cid:173)
`noxaline nucleus. R3 , R4 and R5 each is located in
`one of the remaining 5-, 6-, 7- or 8-positions of the
`quinoxaline nucleus and is independently selected
`from the group consisting of Cl, Br, H and alkyl
`radicals containing 1 to 3 carbon atoms. R3 is pref(cid:173)
`erably in the 5-position of the quinoxaline nucleus,
`and R4 and R5 are preferably both H. In a particularly
`useful embodiment R3 is Br.
`
`In at least one implant, R1 is H and R2 is selected
`[0053]
`from alkyl radicals containing 1 to 4 carbon atoms. R3 may
`advantageously be in the 5-position of the quinoxaline
`nucleus and be selected from Hand alkyl radicals containing
`1 to 3 carbon atoms. All stereoisomers, tautomers and
`mixtures thereof which comply with the constraints of one
`or more of the presently useful compounds are included
`within the scope of the present invention.
`
`[0054] Pharmaceutically acceptable acid addition salts of
`the compounds of the invention are those formed from acids
`which form non-toxic addition salts containing pharmaceu(cid:173)
`tically acceptable anions, such as the hydrochloride, hydro(cid:173)
`bromide, hydroiodide, sulfate, or bisulfate, phosphate or
`acid phosphate, acetate, maleate, fumarate, oxalate, lactate,
`tartrate, citrate, gluconate, saccharate and p-toluene sulpho(cid:173)
`nate salts.
`
`In more specific implants, the quinoxaline deriva(cid:173)
`[0055]
`tive has the formula
`
`In additional implants, the alpha-2 adrenergic
`[0056]
`receptor agonist is provided as a salt having the formula
`
`HO
`\
`CH-COO-
`/
`HO-CH
`\
`COOH
`
`[0057] The foregoing salt is known as brimonidine tartrate
`(AGN 190342-F, 5-bromo-6-(2-imidazolidinylideneamino(cid:173)
`)quinoxaline tartrate), and is publicly available from Aller(cid:173)
`gan, Inc. under the tradename Alphagan®-P. Brimonidine,
`an organic base, is publicly available as either brimonidine
`tartrate salt or as brimonidine freebase. The tartrate salt is
`more soluble than the freebase in various aqueous media.
`
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`Since both the tartrate salt and the freebase are c