(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0156568 A1
`(43) Pub. Date:
`Jun. 18, 2009
`Hughes et al.
`
`US 20090156568A1
`
`(54) THERAPEUTIC OPHTHALMIC
`COMPOSITIONS CONTAINING RETINAL
`FRIENDLY EXCIPIENTS AND RELATED
`METHODS
`
`(60) Provisional application No. 60/530,062, filed on Dec.
`16, 2003, provisional application No. 60/519,237,
`filed on Nov. 12, 2003.
`Publication Classification
`
`(76)
`
`Inventors:
`
`Partick M. Hughes, Aliso Viejo,
`CA (US); Laurent Delhaye,
`Mougins (FR); Michele Boix,
`Mougins (FR); James N. Chang,
`Newport Beach, CA (US); Robert
`T. Lyons, Laguna Hills, CA (US)
`
`Correspondence Address:
`ALLERGAN, INC.
`2525 DUPONT DRIVE, T2-7H
`IRVINE, CA 92612-1599 (US)
`
`(21) Appl. No.:
`
`12/288,891
`
`(22)
`
`Filed:
`
`Oct. 24, 2008
`
`Related U.S. Application Data
`
`(60) Division of application No. 11/091,977, filed on Mar.
`28, 2005, which is a continuation-in-part of applica-
`tion No. 10/966,764, filed on Oct. 14, 2004.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/58
`(2006.01)
`A61K 47/30
`(2006.01)
`A61K 31/573
`(2006.01)
`A61P 27/02
`(52) U.S. Cl. .................... .. 514/174; 514/772.3; 514/777;
`514/179; 514/180
`
`(57)
`
`ABSTRACT
`
`Pharmaceutical compositions suitable for administration into
`the interior of an eye of a person or animal are described. The
`present compositions include one or more components which
`are effective in providing a reduced toxicity relative to exist-
`ing intraocular ophthalmic compositions. The present com-
`positions include one or more therapeutic agents in amounts
`effective in providing a desired therapeutic effect when
`placed in an eye, and one or more retinal friendly excipients
`that have a reduced toxicity relative to benzyl alcohol or
`polysorbate 80. In certain compositions, the excipient com-
`ponent of the compositions comprises one or more cyclodex-
`trins or cyclodextrin derivatives. Methods of using the com-
`positions to treat ocular conditions are also described.
`
`000001
`
`ARGENTUM PHARM. 1045
`
`ARGENTUM PHARM. 1045
`
`000001
`
`

`

`Patent Application Publication
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`Jun. 18, 2009 Sheet 1 of 23
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`Jun. 18, 2009 Sheet 3 of 23
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 5 of 23
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`Jun. 18, 2009 Sheet 6 of 23
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`Patent Application Publication
`
`Jun. 18, 2009 Sheet 7 of 23
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`US 2009/0156568 A1
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`ARPE-19ResponseIHyaluronicAcid
`
`1.4%
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`

`Patent Application Publication
`
`Jun. 18, 2009 Sheet 8 of 23
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`US 2009/0156568 A1
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`Patent Application Publication
`
`Jun. 18, 2009 Sheet 9 of 23
`
`US 2009/0156568 A1
`
`—O-—24h—I—48h-—A—72h
`
`
`
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`ARPE-19responseIHydroxypropyl7-CD
`
`12%
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`10%
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`
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`
`% Cell Viability
`
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`

`

`Patent Application Publication
`
`Jun. 18, 2009 Sheet 10 of 23
`
`US 2009/0156568 A1
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`Patent Application Publication
`
`Jun. 18, 2009 Sheet 11 of 23
`
`US 2009/0156568 A1
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`-6-24h—~I———48h—-t—72h
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`
`12%
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`

`

`Patent Application Publication
`
`Jun. 18, 2009 Sheet 12 of 23
`
`US 2009/0156568 A1
`
`
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`ARPE-19MorphologyISulfobutytether46-0!)
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`FIG.12
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`
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`

`

`Patent Application Publication
`
`Jun. 18, 2009 Sheet 13 of 23
`
`US 2009/0156568 A1
`
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`Patent Application Publication
`
`Jun. 18, 2009 Sheet 14 of 23
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`US 2009/0156568 A1
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 15 of 23
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`US 2009/0156568 A1
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 16 of 23
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 17 of 23
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 18 of 23
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`Jun. 18, 2009 Sheet 19 of 23
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 22 of 23
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`Patent Application Publication
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`Jun. 18, 2009 Sheet 23 of 23
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`US 2009/0156568 A1
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`

`

`US 2009/0156568 A1
`
`Jun. 18, 2009
`
`THERAPEUTIC OPHTHALMIC
`COMPOSITIONS CONTAINING RETINAL
`FRIENDLY EXCIPIENTS AND RELATED
`METHODS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] The present application is a continuation-in-part of
`U.S. application Ser. No. 10/966,764, filed Oct. 14, 2004,
`which claims the benefit of U.S. Application No. 60/530,062,
`filed Dec. 16, 2003, and U.S. Application No. 60/519,237,
`filed Nov. 12, 2003, the contents of which in their entireties
`are hereby incorporated by reference.
`
`BACKGROUND
`
`invention relates to pharmaceutical
`[0002] The present
`compositions and methods for using such compositions to
`treat diseases or disorders of one or more eyes of an indi-
`vidual. More specifically, the present invention relates to
`ophthalmic compositions useful for administration to the
`interior of an eye of an individual to treat an ocular condition
`without causing substantial toxicity, damage, or injury to
`intraocular tissues.
`
`[0003] The retinal pigmented epithelium (RPE) is made up
`of a monolayer of polarized cells attached on Bri'1ch’s mem-
`brane. The RPE sustains photoreceptor cell integrity and
`function through phagocytosis and regeneration ofvi sual pig-
`ment, active transport of metabolites, light absorption, and
`maintenance of outer blood-retina barrier. Alterations in RPE
`
`cell functions can cause various pathologies of the retina.
`RPE phenotype changes are known to result in dysregulation
`ofextracellular matrix synthesis and degradation. In addition,
`RPE cells play a critical role in the metabolism of the retina.
`RPE cells are responsible for the transport of nutrients to rod
`and cone photoreceptors and removal ofwaste products to the
`blood. RPE cells are part of the outer blood-retinal barrier
`which confers to the eye an immune privilege (Streilein J W
`et al., “Ocular immune privilege: therapeutic opportunities
`from an experiment ofnature”, Nature Reviews Immunology,
`2003, 3:879-89). Therefore, RPE cells are often the targeted
`cells for therapeutics for example to treat proliferative vitreo-
`retinopathy (PVR) or angiogenesis defect-induced patholo-
`gies such as age-related macular degeneration (AMD).
`[0004]
`In certain ocular conditions, the retina can change or
`become damaged and thereby negatively affect vision of an
`individual. For example, in ocular condition, such as dry age
`related macular degeneration (ARMD), lesions form beneath
`the macula due to RPE changes. These lesions, drusen, com-
`prise lipid-rich extracellular matrix components and may
`coalesce overtime resulting in a shallow elevation of the RPE
`cells. The RPE cells begin to clump, aggregate, and atrophy.
`Degeneration ofthe RPE cells leads to a secondary degenera-
`tion of the overlying photoreceptors. Clearly, anything that
`can disrupt the RPE can dramatically affect vision.
`[0005] Many existing therapies for ocular diseases and dis-
`orders utilize topical ophthalmic compositions. These treat-
`ments often require frequent administration of the topical
`ophthalmic compositions. Typically, less than 5% ofa drug or
`therapeutic agent in topical eye drops reach anterior intraocu-
`lar tissues. Reasons for low bioavailability include poor pen-
`etration across the corneal barrier and rapid loss of the
`instilled solution from the precorneal area. Very little drug
`further reaches the posterior segment of the eye; the retina,
`
`RPE, optic nerve head and vitreous. The amount reaching the
`retina from topical ocular dosing typically represents a mil-
`lion fold dilution. Hence, direct intraocular administration is
`required for many drugs targeting the posterior segment ocu-
`lar tissues.
`
`[0006] Cyclodextrins are cyclic oligosaccharides contain-
`ing 6, 7, or 8 glucopyranose units, referred to as alpha-cyclo-
`dextrin, beta-cyclodextrin, or garnma-cyclodextrin, respec-
`tively. Cyclodextrins have been shown to increase aqueous
`solubility and chemical stability of numerous poorly water-
`soluble drugs, reduce local irritation, and often enhance bio-
`availability of the drug to ocular tissues. For example, see
`U.S. Pat. Nos. 4,727,064 (Pitha); 5,324,718 (Loftsson);
`5,332,582 (Babcock et al.); 5,494,901 (Javitt et al.); 6,407,
`079 (Muller et al.); 6,723,353 (Beck et al.); and U.S. Patent
`Publication Nos. 2002/0198174 (Lyons) and 2004/0152664
`(Chang et al.); and Rao et al., “Preparation and evaluation of
`ocular inserts containing norfloxacin”, Tur/(JMed Sci, 2004,
`34:239-246. Thus, cyclodextrins have been used to solubilize
`and/or stabilize therapeutic agents in topical ophthalmic com-
`positions. However, complexes of a cyclodextrin and a drug
`do not appear to permeate the cornea.
`[0007] More recently, intraocular ophthalmic compositions
`have been developed and utilized to treat ocular diseases and
`disorders. By administering a therapeutic agent directly into
`the eye, it is possible to address problems associated with
`topical administration of drugs.
`[0008] As one example, among the therapies currently
`being practiced to treat ocular posterior segment disorders,
`such as uveitis, macular degeneration, macular edema and the
`like, intravitreal injection of a corticosteroid, such as triam-
`cinolone acetonide has been employed. See, for example,
`U.S. Pat. No. 5,770,589 (Billson et al.). However, many com-
`pounds are known to be toxic to the retina, including phar-
`maceutically active agents, such as chloroquine and can-
`thanxanthin.
`In addition to pharmacologically active
`compounds, an overlooked source of drug induced retinal
`toxicity includes drug formulation excipients. The impor-
`tance of understanding retinal toxicity due to therapeutic
`agents and/or excipients present in ophthalmic compositions
`becomes clear when compositions are administered into the
`eye where the components of such compositions can directly
`interact with retinal cells and tissue.
`
`[0009] Triamcinolone acetonide has received a lot of atten-
`tion recently due to its efiicacy in treating macular edema.
`Kenalog®-40 is a commercially available formulation of tri-
`amcinolone acetonide, approved for
`intramuscular and
`intraarticular administration. Kenalog®-40 is reconstituted
`and injected directly into the vitreous of an eye. Each milli-
`liter (ml) of the Kenalog® 40 composition includes 40 milli-
`grams (mg) oftriamcinolone acetonide, sodium chloride as a
`tonicity agent, 10 mg of benzyl alcohol as a preservative, and
`7.5 mg of carboxymethylcellulose and 0.4 mg of polysorbate
`80 as resuspension aids.
`[0010] Although widely used by ophthalmologists, this
`commercially available formulation suffers from several
`important limitations. After intravitreal injection, triamcino-
`lone acetonide and all formulation excipients contact the
`RPE. The retina does not possess intercellular tight junctions
`and poses little resistance to molecules diffusing to the level
`ofthe RPE. Kenalog® -40 injection, when administered intra-
`vitreally, has been implicated in non-bacterial endophthalmi-
`tis.
`
`000025
`
`000025
`
`

`

`US 2009/0156568 A1
`
`Jun. 18, 2009
`
`[0011] The formulation excipients benzyl alcohol (preser-
`vative) and/or polysorbate 80 (surfactant) are thought to be
`the cause of non-bacterial endophthalmitis associated with
`intravitreal injection of Kenalog-40. For example, the pres-
`ence of benzyl alcohol preservative and polysorbate 80 sur-
`factant tends to lead to urmecessary and/or undue cell damage
`or other toxicities in ocular tissues. Even though some clini-
`cians routinely “wash” the triamcinolone acetonide precipi-
`tate several times with saline to reduce the concentration of
`
`these undesirable materials, such washing is inconvenient,
`time consuming, and most importantly, increases the prob-
`ability of microbial or endoxin contamination that could lead
`to intraocular infection and inflammation.
`
`[0012] Moreover, the triamcinolone acetonide in the Kena-
`log® 40 tends to rapidly separate and precipitate from the
`remainder ofthe composition. For example, this composition,
`if left standing for l to 2 hours, results in a substantial sepa-
`ration of a triamcinolone acetonide precipitate from the
`remainder of the composition. Thus, if the composition is to
`be injected into the eye, it must be vigorously shaken and used
`promptly after being so shaken in order to provide a substan-
`tially uniform suspension in the eye. In addition, resuspen-
`sion processing requires the use of the resuspension aids
`noted above, at least one ofwhich is less than totally desirable
`for sensitive ocular tissues, such as the RPE.
`[0013] Thus, there remains a need for new compositions
`and methods which may be used to treat ocular conditions by
`being intraocularly administered to a patient and which have
`little or no adverse reactions to the patient receiving the com-
`positions.
`
`SUMMARY
`
`[0014] The present invention addresses this need and pro-
`vides pharmaceutical compositions and methods that provide
`effective treatment of one or more ocular conditions without
`
`causing substantial damage or injury to oculartissues. Among
`other things, the present compositions may be administered
`into or in the vicinity of an eye of a patient with reduced
`inflammation resulting from administration of the composi-
`tion, but not necessarily caused by the drug itself. The present
`compositions are useful for delivery to the interior ofan eye of
`a individual, such as a person or animal. The compositions
`comprise a therapeutic component and an excipient compo-
`nent.
`
`[0015] The therapeutic component is present in an amount
`effective in providing a desired therapeutic effect when
`administered to the interior of an eye, such as the posterior
`segment of an eye. The therapeutic component may comprise
`one or more agents selected from the group consisting of
`anti-angiogenic agents, anti-inflarnmatory agents, and neuro-
`protective agents, among others.
`[0016] The excipient component of the present composi-
`tions may be present in an amount that is less toxic to RPE
`cells compared to excipients currently used in ophthalmic
`compositions. The excipient component may comprise one or
`more inert substances or agents, such as agents selected from
`the group consisting of viscosing agents (viscosity inducing
`agents),
`solubilizing agents, preservative agents, buffer
`agents, and tensioactive agents, among others. Such agents
`are provided in amounts that are not substantially toxic to
`retinal pigment epithelial cells when administered to an eye.
`[0017]
`In one embodiment, the excipient component of the
`present compositions comprises a cyclodextrin component
`present in an amount that is less toxic to retinal pigment
`
`epithelial cells relative to an equal amount of an excipient
`selected from the group consisting of polysorbate 80 and
`benzyl alcohol. The excipient component comprises substan-
`tially no polysorbate 80 or benzyl alcohol, such as less than
`0.05% (w/v) of benzyl alcohol.
`[0018] The cyclodextrin component can comprise one or
`more cyclodextrins or cyclodextrin derivatives. In a specific
`embodiment, the cyclodextrin component comprises at least
`one cyclodextrin selected from the group consisting of sul-
`fobutyl ether 4-beta-cyclodextrin, hydroxypropyl beta-cyclo-
`dextrin, and hydroxypropyl gamma-cyclodextrin.
`In one
`embodiment, the cyclodextrin component is present in an
`amount from about 0.5% (w/v) to about 5.0% (w/v) of the
`composition. In other embodiments, the cyclodextrin compo-
`nent may be present in an amount from about 0.1% (w/v) to
`about 10% (w/v), for example, 0.1% (w/v) to about 5% (w/v).
`[0019]
`In another embodiment, a method of treating an
`ocular condition of an individual person or animal comprises
`administering the present compositions to the interior of an
`eye of the individual, such as the vitreous or posterior seg-
`ment of the eye.
`[0020] The present invention also provides methods of
`screening potential ophthalmic excipients for toxicity, such as
`RPE cell toxicity. The present methods provide for the ability
`to determine the toxicity of a potential excipient based on
`standardized values and/or in relation to other excipients in
`use. Such methods generally comprise a step of contacting
`cultured retinal pigment epithelial cells with an excipient.
`The cell viability and/or morphology can be determined. By
`exposing cultured RPE cells to different concentrations of an
`excipient or combinations of excipients,
`it is possible to
`evaluate the toxicity of such excipients and determine poten-
`tially useful amounts of such excipients for use in the present
`drug delivery systems.
`[0021] 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 mutu-
`
`ally inconsistent. In addition, any feature or combination of
`features may be specifically excluded from any embodiment
`of the present invention.
`[0022] Additional aspects and advantages of the present
`invention are set forth in the following description, drawings,
`and claims, particularly when considered in conjunction with
`the accompanying examples.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph illustrating cell viability (%) as a
`[0023]
`function of carboxymethyl cellulose (CMC) concentration.
`[0024]
`FIG. 2 is a graph and photographs illustrating cell
`morphology score as a function of CMC concentration at 24
`hour, 48 hour, and 72 hour time points.
`[0025]
`FIG. 3 is a graph illustrating cell viability (%) as a
`function of hydroxypropylmethyl cellulose (HPMC) concen-
`tration.
`
`FIG. 4 is a graph and photographs illustrating cell
`[0026]
`morphology score as a function ofHPMC concentration at 24
`hour, 48 hour, and 72 hour time points.
`[0027]
`FIG. 5 is a graph illustrating cell viability (%) as a
`function of poloxarner 407nf (poloxamer) concentration.
`[0028]
`FIG. 6 is a graph and photographs illustrating cell
`morphology score as a function of poloxarner concentration
`at 24 hour, 48 hour, and 72 hour time points.
`
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`
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`

`US 2009/0156568 A1
`
`Jun. 18, 2009
`
`FIG. 7 is a graph illustrating cell viability (%) as a
`[0029]
`function of hyaluronic acid (HA) concentration.
`[0030]
`FIG. 8 is a graph and photographs illustrating cell
`morphology score as a function of HA concentration at 24
`hour, 48 hour, and 72 hour time points.
`[0031]
`FIG. 9 is a graph illustrating cell viability (%) as a
`function of hydroxypropyl gamma-cyclodextrin (hydrox-
`ypropyl gamma-CD) concentration.
`[0032]
`FIG. 10 is a graph and photographs illustrating cell
`morphology score as a function of hydroxypropyl gamma-
`CD concentration at 24 hour, 48 hour, and 72 hour time
`points.
`FIG. 11 is a graph illustrating cell viability (%) as a
`[0033]
`function of sulfobutyl ether 4 beta-cyclodextrin (sulfobuytyl
`ether 4 beta-CD) concentration.
`[0034]
`FIG. 12 is a graph and photographs illustrating cell
`morphology score as a function of sulfobutyl ether 4 beta-CD
`concentration at 24 hour, 48 hour, and 72 hour time points.
`[0035]
`FIG. 13 is a graph illustrating cell viability (%) as a
`function ofhydroxypropyl beta-cyclodextrin (hydroxypropyl
`beta-CD) concentration.
`[0036]
`FIG. 14 is a graph and photographs illustrating cell
`morphology score as a function of hydroxypropyl beta-CD
`concentration at 24 hour, 48 hour, and 72 hour time points.
`[0037]
`FIG. 15 is a graph and photographs illustrating cell
`viability (%) as a function of benzyl alcohol (benzylOH)
`concentration.
`
`FIG. 16 is a graph and photographs illustrating cell
`[0038]
`morphology score as a function ofbenzylOH concentration at
`24 hour, 48 hour, and 72 hour time points.
`[0039]
`FIG. 17 is a graph illustrating cell viability (%) as a
`function of borate buffer Oi Eur. Ph. Borate Buffer) concen-
`tration.
`
`FIG. 18 is a graph and photographs illustrating cell
`[0040]
`morphology score as a function ofborate buffer concentration
`at 24 hour, 48 hour, and 72 hour time points.
`[0041]
`FIG. 19 is a graph illustrating cell viability (%) as a
`function of phosphate buffer (X phosphate) concentration.
`[0042]
`FIG. 20 is a graph illustrating cell morphology score
`as a function ofphosphate buffer concentration at 24 hour, 48
`hour, and 72 hour time points.
`[0043]
`FIG. 21 is a graph illustrating cell viability (%) as a
`function of polysorbate 80 concentration.
`[0044]
`FIG. 22 is a graph and photographs illustrating cell
`morphology score as a function of polysorbate 80 concentra-
`tion at 24 hour, 48 hour, and 72 hour time points.
`[0045]
`FIG. 23 is a series of photographs illustrating cell
`morphology characteristics used in scoring the RPE cell cul-
`tures.
`
`DESCRIPTION
`
`[0046] Compositions and methods have been invented
`which provide effective treatment of ocular conditions, such
`as disorders or diseases of the posterior segment of an eye of
`an individual, such as a human or animal. The present com-
`positions comprise a therapeutic component and an excipient
`component. The excipient component preferably includes
`one or more agents that are not substantially toxic to retinal
`cells, including retinal epithelial cells. Thus, the present com-
`positions have a reduced toxicity relative to existing intraocu-
`lar compositions used for treating ocular conditions, such as
`Kenalog®-40. The present therapeutic ophthalmic composi-
`tions and methods are effective in alleviating or reducing one
`or more symptoms associated with ocular conditions. Thus,
`
`the present invention relates to new compositions and meth-
`ods employing retinal friendly excipients or excipients that do
`not damage, injure, or otherwise significantly harm retinal
`cells of the individual being administered the compositions.
`[0047] The present therapeutic ophthalmic compositions
`comprise a therapeutic component and an excipient compo-
`nent. The therapeutic component is present in an amount
`effective in providing a desired therapeutic effect to an indi-
`vidual, such as a human or animal patient, when the compo-
`sition is administered to the interior of an eye of the indi-
`vidual. Thus,
`it may be understood that
`the present
`compositions are useful for injection into the interior of an
`eye of the individual. More specifically, the present compo-
`sitions are useful for injection or other administration into the
`posterior segment of the eye.
`[0048] The therapeutic component of the present composi-
`tions comprises one or more therapeutic agents, such as
`chemical compounds, macromolecules, proteins, and the
`like, which are effective in treating an ocular condition, such
`as an ocular condition of the posterior segment of an eye. In
`certain embodiments,
`the therapeutic agents are poorly
`soluble in the composition. For example, the therapeutic
`agents may be present as particles in the composition.
`[0049] Therapeutic agents which may be provided in the
`therapeutic component of the present ophthalmic composi-
`tions may be obtained from public sources or may be synthe-
`sized using routine chemical procedures known to persons of
`ordinary skill in the art. Agents are screened for therapeutic
`efiicacy using conventional assays known to persons of ordi-
`nary skill in the art. For example, agents can be monitored for
`their effects on reducing intraocular pressure, reducing or
`preventing neovascularization in the eye, reducing inflamma-
`tion in the eye, and the like using such conventional assays.
`Thus, the therapeutic component of the present systems can
`comprise a variety of therapeutic agents, including anti-an-
`giogenesis agents, anti-inflammatory agents, neuroprotective
`agents, and the like For example, the therapeutic component
`ofthe present compositions may comprise one or more ofthe
`following: anti-excitotoxic agents, anti-histarnine agents,
`anti-biotic agents, beta blocker agents, one or more steroid
`agents, anti-neoplastic agents, immunosuppressive agents,
`anti-viral agents, anti-oxidant agents, anti-inflammatory
`agents, adrenergic receptor agonists and antagonists, and
`neuroprotective agents.
`[0050] Examples of antihistamines include, and are not
`limited to, loradatine, hydroxyzine, diphenhydramine, chlo-
`rpheniramine, bromphenirarnine, cyproheptadine,
`terfena-
`dine, clemastine, triprolidine, carbinoxamine, diphenylpyra-
`line,
`phenindarnine,
`azatadine,
`tripelennamine,
`dexchlorpheniramine, dexbromphenirarnine, methdilazine,
`and trimprazine doxylamine, phenirarnine, pyrilamine, chior-
`cyclizine, thonzylamine, and derivatives thereof.
`[0051] As used herein, the term “derivative” refers to any
`substance which is sufiiciently structurally similar to the
`material of which it is identified as a derivative so as to have
`
`substantially similar functionality or activity, for example,
`therapeutic effectiveness, as the material when the substance
`is used in place of the material. Useful derivatives of a sub-
`stance can be routinely determined or identified by conduct-
`ing one or more conventional assays using the derivatives
`instead of the sub stance from which the derivative is derived.
`
`[0052] Examples of antibiotics include without limitation,
`cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime,
`cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil,
`
`000027
`
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`

`US 2009/0156568 A1
`
`Jun. 18, 2009
`
`ceftazidime, cephalexin, cephalothin, cefamandole, cefox-
`itin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephra-
`dine, cefuroxime, cyclosporine, ampicillin, arnoxicillin,
`cyclacillin, ampicillin, penicillin G, penicillin V potassium,
`piperacillin, oxacillin, bacarnpicillin, cloxacillin, ticarcillin,
`azlocillin, carbenicillin, methicillin, nafcillin, erythromycin,
`tetracycline, doxycycline, minocycline, aztreonam, chloram-
`phenicol, ciprofloxacin hydrochloride, clindarnycin, metron-
`idazole, gentamicin, lincomycin, tobramycin, vancomycin,
`polymyxin B sulfate, colistimethate, colistin, azithromycin,
`augmentin, sulfamethoxazole,
`trimethoprim, gatifloxacin,
`ofloxacin, and derivatives thereof.
`[0053] Examples of beta blockers include acebutolol,
`atenolol,
`labetalol, metoprolol, propranolol,
`timolol, and
`derivatives thereof.
`
`[0054] Examples of steroids include corticosteroids, such
`as cortisone, prednisolone,
`fluorometholone, dexarnetha-
`sone, medrysone,
`loteprednol, fluazacort, hydrocortisone,
`prednisone, betamethasone, prednisone, methylpredniso-
`lone, triamcinolone hexacatonide, paramethasone acetate,
`diflorasone, fluocinonide, fluocinolone, triamcinolone, tri-
`amcinolone acetonide, derivatives thereof, and mixtures
`thereof.
`
`[0055] Examples of antineoplastic agents include adriamy-
`cin, cyclophosphamide, actinomycin, bleomycin, duanorubi-
`cin, doxorubicin, epirubicin, mitomycin, methotrexate, fluo-
`rouracil, carboplatin, carmustine (BCNU), methyl-CCNU,
`cisplatin, etoposide, interferons, camptothecin and deriva-
`tives thereof, phenesterine,
`taxol and derivatives thereof,
`taxotere and derivatives thereof, vinblastine, vincristine,
`tamoxifen, etoposide, piposulfan, cyclophosphamide, and
`flutamide, and derivatives thereof.
`[0056] Examples of immunosuppresive agents include
`cyclosporine,
`azathioprine,
`tacrolimus,
`and derivatives
`thereof.
`
`[0057] Examples of antiviral agents include interferon
`gamma, zidovudine, arnantadine hydrochloride, ribavirin,
`acyclovir, valciclovir, dideoxycytidine, phosphonoformic
`acid, ganciclovir and derivatives thereof.
`[0058] 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, camosine, gamma-glutamyl-
`cysteine, quercitin, lactoferrin, dihydrolipoic acid, citrate,
`Ginkgo Biloba extract, tea catechins, bilberry extract, vita-
`mins E or esters of vitamin E, retinyl palmitate, and deriva-
`tives thereof.
`
`[0059] Other therapeutic agents include squalarnine, car-
`bonic ar1hydrase inhibitors, brimonidine, prostarnides, pros-
`taglandins, antiparasitics, antifungals, tyrosine kinase inhibi-
`tors, glutamate receptor antagonists,
`including NMDA
`receptor antagonists, and derivatives thereof.
`[0060]
`In view of the foregoing, it can be appreciated that
`therapeutic component of the present compositions can com-
`prise many different types oftherapeutic agents, and that such
`agents are routinely known to persons of ordinary skill in the
`art.
`
`[0061] The excipient component of the present composi-
`tions comprises one or more retinal friendly excipient agents
`or otherwise inert substances. Retinal friendly excipient
`agents contribute to the enhanced compatibility and tolerance
`of the present compositions to the tissues in the posterior
`segment of the eye, for example, the retina of the eye, relative
`
`to compositions previously proposed for intravitreal injection
`into a posterior segment of an eye, for example, the compo-
`sition sold under the trademark Kenalog®-40. Examples of
`excipients which may be present in the compositions include
`retinal friendly or retinal compatible solubilizing agents, sur-
`factant or tensioactive agents, preservative agents, viscosity
`inducing or viscosing agents, tonicity agents, and the like.
`[0062] Viscosing agents
`include, without
`limitation,
`sodium carboxymethylcellulose (CMC), hydroxypropylm-
`ethyl cellulose (HPMC), poloxamer 407nf (Pluronic® F127
`Prill), and hyaluronic acid.
`limitation,
`[0063]
`So