(12) United States Patent
`Olejnik et al.
`
`USOO6562873B2
`(10) Patent No.:
`US 6,562,873 B2
`(45) Date of Patent:
`*May 13, 2003
`
`(54) COMPOSITIONS CONTAINING
`THERAPEUTICALLY ACTIVE
`COMPONENTS HAVING ENHANCED
`SOLUBILITY
`
`(75) Inventors: Orest Olejnik, Coto de Coza, CA (US);
`Edward D. S. Kerslake, Charleston,
`MA (US)
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`(*) Notice:
`Subject to any disclaimer, the term of this
`past Sh adjusted under 35
`S.C. 154(b) by 0 days.
`
`4,806,556 A 2/1989 Portoghese
`5,021,416 A 6/1991 Guchowski
`5,202,128 A 4/1993 Morella et al.
`5,352,796 A 10/1994 Hoeger et al.
`5,459,133. A 10/1995 Neufeld
`5,703,077 A 12/1997 Burke et al.
`5,719,197 A * 2/1998 Kanios et al. ........... 514/772.6
`5,725,887 A
`3/1998 Martin et al.
`5,814,638 A 9/1998 Lee et al.
`5,834,502 A 11/1998 Cheng et al.
`5,994,110 A 11/1999 Mosbach et al.
`FOREIGN PATENT DOCUMENTS
`2048315
`2/1992
`O609961
`8/1994
`
`CA
`EP
`
`This patent is Subject to a terminal dis-
`claimer.
`
`-
`
`-
`
`-
`
`-
`
`(21) Appl. No.: 09/903,962
`(22) Filed:
`Jul. 10, 2001
`(65)
`Prior Publication Data
`US 2002/007 1874 A1 Jun. 13, 2002
`Related U.S. Application Data
`(60) Provisional application No. 60/218,206, filed on Jul. 14,
`2000.
`... A61K 47/32; A61K 9/00
`(51) Int. CI.7.
`(52) U.S. Cl. ................................ 514/772.4; 514/772.6;
`424/400
`(58) Field of Search ........................... 514,7724. 726
`424f.400
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3.278.447 A 10/1966 McNicholas
`3,890,319 A 6/1975 Daniewicz et al.
`4530920 A 7/1985 Nestor et al.
`
`4000
`
`
`
`4400
`
`20 O O
`
`WO
`
`WO
`WO
`WO
`WO
`WO
`
`94/16685
`
`98/47878
`99/43299
`99/51273
`OO12137
`OO19981
`
`8/1994
`
`10/1998
`9/1999
`10/1999
`3/2000
`4/2000
`
`* cited by examiner
`
`Primary Examiner Thurman K. Page
`Assistant Examiner Blessing Fubara
`(74) Attorney, Agent, or Firm-Stout, Uxa, Buyan &
`Mullins LLP, Frank J. Uxa
`(57)
`ABSTRACT
`
`Compositions which include therapeutically active
`components, Solubility enhancing components other than
`cyclodextrins, and oxy-chloro components, wherein the
`oxy-chloro components are Substantially effective as preser
`Vatives. In one embodiment, the oxy-chloro components are
`useful for preserving the therapeutically active components.
`In one embodiment, the oxy-chloro components include
`chlorite components. In a useful embodiment, the Solubility
`enhancing components include carboxymethylcellulose.
`
`49 Claims, 1 Drawing Sheet
`
`“
`
`O 0.06224 (MC
`A 0 f7% (WiC
`{O O.4% (WC -
`fa24 (MC
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`SLAYBACK EXHIBIT 1033
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`U.S. Patent
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`May 13, 2003
`
`US 6,562,873 B2
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`3. A. O O
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`3000
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`2 O O O
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`AH 1.
`-\ || ||
`- NIT III
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`1
`COMPOSITIONS CONTAINING
`THERAPEUTICALLY ACTIVE
`COMPONENTS HAVING ENHANCED
`SOLUBILITY
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`This application claims the benefit of U.S. Provisional
`Application No. 60/218,206 filed Jul. 14, 2000.
`BACKGROUND OF THE INVENTION
`The present invention relates to compositions containing
`therapeutically active components having enhanced Solubil
`ity. More particularly, the invention relates to compositions
`which include therapeutically active components (TACs)
`and components effective to enhance the Solubility of the
`TACs at therapeutically effective concentrations.
`TACs in liquid compositions often benefit from being
`Soluble in the liquid carriers of Such compositions. Such
`Solubility promotes uniform and accurate administration.
`Additionally, the dispensed or administered TACs should be
`Soluble in the biological System or environment into which
`they are administered, for example, for effective or enhanced
`in vivo diffusion through cell membranes or lipid bilayers.
`Furthermore, solubilized TACs provide other benefits, for
`example, reduced irritation to tissues that interact with
`TACs.
`It is Sometimes necessary to include Solubilizing agents in
`the compositions to solubilize the TACs. However, the
`inclusion of Solubilizing agents may reduce the effectiveness
`of the preservatives in the compositions.
`For example, cyclodextrins are widely known in the
`literature to increase the solubility of poorly water soluble
`therapeutically active components. However, typical preser
`vatives are rendered relatively ineffective by cyclodextrins
`at normal concentrations in these compositions.
`There continues to be a need to provide new compositions
`containing TACs.
`BRIEF SUMMARY OF THE INVENTION
`New TAC-containing compositions have been discov
`ered. The present compositions provide for enhanced TAC
`solubility substantially without detrimentally affecting the
`effectiveness of the preservative or preservatives being
`employed. Solubility enhancing components (SECs) have
`been found which very effectively increase the solubility of
`the TACS in the present compositions, and preferably in the
`biological Systems or environments into which the compo
`nents are introduced. Also, preferably, Such Solubilization
`allows the provision of more reliable and reproducible
`dosage forms of the drugs. This Solubility enhancement in
`accordance with the present invention is achieved Substan
`tially without degrading preservative effectiveness. In
`addition, TAC-containing compositions have been discov
`ered which include preservatives which provide substantial
`advantages, for example, reduced adverse interactions with
`the TACs and/or with the patients to whom the compositions
`are administered, while maintaining preservative effective
`CSS.
`The present compositions include oxy-chloro components
`which are effective in at least assisting in preserving the
`compositions without detrimentally affecting the TACs and
`substantially without being detrimentally affected by the
`SECs. Moreover, the present oxy-chloro components pro
`vide preservative action with reduced or even Substantially
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`US 6,562,873 B2
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`no harm or irritation to the tissues to which the present
`compositions are administered.
`The present SECs preferably are effective in solubilizing
`the TACs in the environment to which they are introduced,
`for example, a biological environment. Such Solubilization
`preferably facilitates the advantageous transport of TACS
`acroSS lipid membranes.
`Soluble TACs for use in the present compositions include
`those components, e.g., compounds, mixtures of
`compounds, mixtures of other materials, useful to provide a
`therapeutic benefit or effect when administered to a patient,
`e.g. a human patient. The TACs useful in this invention
`include, without limitation, antibacterials, antihistamines,
`decongestants, antiinflammatories, antiparasitics, miotics,
`anticholinergics, adrenergics, antivirals, local anesthetics,
`antifungals, amoebicidals, trichomonocidals, analgesics,
`mydriatics, antiglaucoma drugs, carbonic anhydrase
`inhibitors, ophthalmic diagnostic agents, ophthalmic agents
`used as adjuvants in Surgery, chelating agents,
`antineoplastics, antihypertensives, muscle relaxants, diag
`nostics and the like and mixtures thereof. Specific examples
`of Such TACs are conventional and well known in the art.
`In one embodiment, the TACs include adrenergic
`agonists, precursors thereof, metabolites thereof and com
`binations thereof. Preferably, the TACs include alpha-2-
`adrenergic agonists, for example, imino-imidazolines,
`imidazolines, imidazoles, azepines, thiazines, oxazolines,
`guanidines, catecholamines, biologically compatible Salts
`and esters and mixtures thereof. In one embodiment, the
`TACs include quinoxlaine components. Quinoxaline com
`ponents include quinoxaline, biologically compatible Salts
`thereof, esters thereof, other derivatives thereof and the like,
`and mixtures thereof. Preferably, the quinoxaline
`components, including the quinoxaline derivatives, are
`alpha-2-adrenergic agonists. Non-limiting examples of qui
`noxaline derivatives include (2-imidoZolin-2-ylamino)
`quinoxaline, 5-bromo-6-(2-imido Zolin-2-ylamino)
`quinoxaline, and biologically compatible Salts thereof and
`esters thereof, preferably the tartrate of 5-bromo-6-(2-
`imidoZolin-2-ylamino) quinoxaline, and the like and mix
`tures thereof. Hereinafter, the tartrate of 5-bromo-6-(2-
`imidoZolin-2-ylamino) quinoxaline is referred to as
`“Brimonidine tartrate.”
`In a useful embodiment, the SEC is other than cyclodex
`trin and includes a polyanionic component. AS used herein,
`the term “polyanionic component” refers to a chemical
`entity, for example, an ionically charged Species, Such as an
`ionically charged polymeric material, which includes more
`than one discrete anionic charge, that is multiple discrete
`anionic charges. Preferably, the polyanionic component is
`Selected from polymeric materials having multiple anionic
`charges and mixtures thereof.
`Particularly useful polyanionic components are Selected
`from anionic polymers derived from acrylic acid (meaning
`to include polymers from acrylic acid, acrylates and the like
`and mixtures thereof), anionic polymers derived from meth
`acrylic acid (meaning to include polymers from methacrylic
`acid, methacrylates, and the like and mixtures thereof),
`anionic polymers derived from alginic acid (meaning to
`include alginic acid, alginates, and the like and mixtures
`thereof), anionic polymers of amino acids (meaning to
`include polymers of amino acids, amino acid Salts, and the
`like and mixtures thereof), and the like and mixtures thereof.
`Very useful polyanionic components are those Selected from
`anionic cellulose derivatives and mixtures thereof, espe
`cially carboxymethylcelluloses.
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`3
`The polyanionic component preferably is Sufficiently
`anionic to interact with or otherwise affect, in particular
`increase, the solubility of the TAC. This interaction prefer
`ably is sufficient to render the TAC substantially completely
`Soluble at therapeutically effective concentrations. The
`amount of SEC in the composition preferably is in the range
`of about 0.1% (w/v) to about 30% (w/v), more preferably
`about 0.2% (w/v) to about 10% (w/v), and even more
`preferably about 0.2% (w/v) to about 0.6% (w/v).
`The oxy-chloro components included in the present com
`positions are effective to at least assist in preserving the
`compositions. Any Suitable oxy-chloro component effective
`to at least assist in preserving the compositions may be
`employed. Such oxy-chloro components include, without
`limitation, hypochlorite components, perchlorate
`components, chlorite components and the like and mixtures
`thereof.
`In one useful embodiment, the oxy-chloro component
`includes a chlorite component. Preferably, the chlorite com
`ponent includes Stabilized chlorine dioxides, alkali metal
`chlorites and the like and mixtures thereof. Chlorite com
`ponents are very effective in the present compositions and
`provide preservative effectiveness, often at a relatively
`reduced concentration, with little or no detrimental effect on
`the tissue to which the composition is administered. In
`addition, the oxy-chloro components, e.g., the chlorite
`components, Substantially maintain preservative effective
`neSS in the presence of the SECs, for example, the polyan
`ionic components. Without wishing to limit the invention to
`any particular theory or mechanism of operation, it is
`believed that Such oxy-chloro components are Substantially
`free in the presence of the SECs or do not substantially
`interact the SECs.
`The oxy-chloro components may be effective in the
`compositions in the amount of less than about 1% (w/v) or
`about 0.8% (w/v). In a useful embodiment, the oxy-chloro
`components may be in the compositions in the range of
`about 500 ppm (w/v) or less, preferably about 10 ppm (w/v)
`to about 200 ppm (w/v).
`In one embodiment, additional preservatives other than
`the oxy-chloro components are used in the compositions.
`Any Suitable additional preservative component may be
`employed in accordance with the present invention, pro
`Vided that it is compatible with the oxy-chloro component,
`the TAC and the SEC. Preservative components which are
`well known and/or conventionally used in the pharmaceu
`tical field may be employed. Examples include, without
`limitation, Sorbic acids, benzalkonium chlorides, chlorbutols
`and alkyl esters of p-hydroxybenzoic acids and the like and
`mixtures thereof. If additional preservative component is
`included, it preferably is present in an amount, together with
`the oxy-chloro component, to effectively preserve the com
`position.
`The compositions include a liquid carrier component, for
`example, an aqueous liquid carrier component. Preferably,
`the compositions have pHs of about 7 or greater, more
`preferably about 7 to about 9.
`In one broad aspect of the present invention, compositions
`are provided which comprise a TAC, a SEC, a chlorite
`component and an aqueous liquid carrier. Preferably the
`TAC is Brimonidine tartrate. The SEC is preferably an
`anionic cellulose derivative, more preferably a
`carboxymethylcellulose, for example, in an amount in the
`range of about 0.2% to about 0.6% (w/v).
`In another broad aspect of the present invention, compo
`Sitions are provided which comprise a Brimonidine tartrate,
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`4
`a SEC, a chlorite component and an aqueous liquid carrier
`component. The Brimonidine tartrate is present in an amount
`effective to provide a desired effect to a human or an animal
`after the composition is administered to the human or
`animal, and the SEC is preferably a carboxymethylcellulose.
`In another broad aspect of the present invention, compo
`Sitions are provided which comprise a TAC and a preserva
`tive component in an effective amount to at least aid in
`preserving the compositions. Preferably, the preservative
`components include oxy-chloro components, Such as
`compounds, ions, complexes and the like which are biologi
`cally acceptable, chemically stable and do not Substantially
`or significantly detrimentally affect the TACs in the com
`positions or the patients to whom the compositions are
`administered. Such compositions preferably are Substan
`tially free of cyclodextrin.
`The present compositions preferably are ophthalmically
`acceptable, e.g. the compositions do not have deleterious or
`toxic properties which could harm the eye of the human or
`animal to whom the compositions are administered.
`Any feature or combination of features described herein
`are included within the Scope of the present invention
`provided that the features included in any Such combination
`are not mutually inconsistent as will be apparent from the
`context, this Specification, and the knowledge of one of
`ordinary skill in the art.
`Additional advantages and aspects of the present inven
`tion are apparent in the following detailed description and
`claims.
`
`BRIEF DESCRIPTION OF THE DRAWING
`FIG. 1 is a graph of Soluble Brimonidine tartrate verses
`pH at various carboxymethylcellulose concentrations.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`Compositions comprising TACs, SECs and oxy-chloro
`components are provided. The TACS in the present compo
`Sitions are made more Soluble and may be more effectively
`utilized as therapeutic agents. Suitable SECs for solubilizing
`TACs may be used concurrently with oxy-chloro compo
`nents in the present compositions to increase the Solubility
`of the TACs substantially without detrimentally affecting the
`preservative effectiveness of the oxy-chloro components. In
`other words, SECS employed in the present compositions
`may effectively increase the solubility of TACs without
`Substantially interfering with the functions of other compo
`nents in the compositions. The SECs employed in the
`present compositions may be effective in the Solubilization
`of ionized TACs, unionized TACs or both.
`Oxy-chloro components are included in the present com
`positions to assist in preserving the compositions.
`Particularly, the oxy-chloro components are not Substan
`tially detrimentally affected by the SECs present in the
`compositions. Moreover, the oxy-chloro components in the
`compositions are effective Substantially without causing
`undue harm or irritation to the tissue to which the present
`compositions are administered.
`The present compositions may, and preferably do, include
`liquid carrier components. For example, the components
`often have the characteristics of a liquid, for example, a
`liquid Solution.
`The presently useful TACs preferably are chosen to
`benefit from the presence of the SECs and the oxy-chloro
`components. In general, the TACs are provided with
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`increased apparent Solubility, preferably increased apparent
`water solubility, by the presence of the SECs.
`Preferably, the TACs have increased solubility in the
`present compositions at pHS greater than 7, as compared to
`identical TACs, at comparable concentrations in Similar
`compositions, without the SECs. More preferably, the TACs
`have increased Solubility in the present compositions at pH S
`in the range of about 7 to about 10, as compared to TACs in
`Similar compositions, at comparable concentrations, without
`the SECs.
`Without wishing to be limited by any theory or mecha
`nism of operation, it is believed that solubilized TACs are
`better able to cross the lipid membranes relative to unsolu
`bilized TACs. It is further believed that the Solubilized TACs
`are physically Smaller and are therefore more able to physi
`cally permeate or diffuse through the lipid membranes.
`In one embodiment, the SECs of this invention are
`capable of solubilizing the TACs in the environments into
`which they are introduced at therapeutically effective con
`centrations. Preferably, the biological environments into
`which the present compositions are introduced have pHS
`ranging from about 7 to about 9. For example, a composition
`comprising a SEC and a TAC may be administered to the
`cornea of a human eye, which has a pH of about 7, wherein
`the TAC is substantially solubilized at the administered area.
`Furthermore, in one embodiment, the TACs solubilized by
`SECs at the administered area diffuse through biological
`lipid membranes more readily than TACs which are not
`solubilized by SECs. The solubilization of TACs preferably
`reduces irritation to Sensitive tissues in contact or interacting
`with the TACs.
`Examples of the therapeutically active components which
`may be included in the present compositions include, but are
`not limited to, antibacterial Substances Such as beta-lactam
`antibiotics, Such as cefoXitin, n-formamidoylthienamycin
`and other thie namycin derivatives, tetracyclines,
`chloramphenicol, neomycin, carbenicillin, colistin, penicil
`lin G, polymyxin B, Vancomycin, cefazolin, cephaloridine,
`chibrorifamycin, gramicidin, bacitracin and Sulfonamides,
`aminoglycoside antibiotics Such as gentamycin, kanamycin,
`amikacin, Sisomicin and tobramycin, nalidixic acid and its
`analogS Such as norfloxacin and the antimicrobial combina
`tion fluoroalanine/pentizidone, nitrofurazones and analogs
`thereof; antihistaminics and decongestants Such as
`pyrilamine, chlorpheniramine, tetrahydrazoline, antazoline
`and analogs thereof, mast-cell inhibitors of histamine
`release, Such as cromolyn; anti-inflammatories Such as
`cortisone, hydrocortisone, hydrocortisone acetate,
`betamethasone, dexamethasone, dexamethasone Sodium
`phosphate, prednisone, methylprednisolone, medrySone,
`fluorometholone, prednisolone, prednisolone Sodium
`phosphate, triamcinolone, indainethacin, Sulindac, its Salts
`and its corresponding Sulfides, and analogs thereof, miotics
`and anticholinergicS Such as echothiophate, pilocarpine,
`physostigmine Salicylate, diisopropylfluorophosphate,
`epinephrine, dipivaloylepinephrine, neoStigmine echothio
`pate iodide, demecarim bromide, carbamoyl choline
`chloride, methacholine, bethanechol, and analogs thereof;
`mydriatics Such as atrophine, homatropine, Scopolamine,
`hydroxyamphetamine, ephedrine, cocaine, tropicamide,
`phenylephrine, cyclopentolate, oxyphenonium, eucatropine;
`and the like and mixtures thereof.
`Other TACs are: antiglaucama drugs, for example,
`timalol, and especially its maleic Salt and R-timolol and a
`combination of timolol or R-timolol with pilocarpine; other
`adrenergic agonists and/or antagonists Such as epinephrine
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`and an epinephrine complex, or prodrugs. Such as bitartrate,
`borate, hydrochloride and diplivefrine derivatives; carbonic
`anhydrase inhibitorS Such as aceta Zolamide,
`dichlorphe namide,
`2-(p-hydroxyphenyl)-
`thio thiop he ne Sulfonamide,
`6 - hydroxy-2-
`benzothiazole Sulfonamide, and 6-pivaloyloxy-2-
`benzothiazoleSulfonamide, antiparasitic compounds and/or
`anti-protozoal compounds Such as ivermectin,
`pyrimethamine, trisulfapidimidine, clindamycin and corti
`costeroid preparations, compounds having antiviral activity
`Such as acyclovir, 5-iodo-2'-deoxyuridine (IDU), adenosine
`arabinoside (Ara-A), trifluorothymidine, interferon, and
`interferon-inducing agents Such as poly I.C.; antifungal
`agents Such as amphotericin B, nyStatin, flucytosine, nata
`mycin and miconazole; anesthetic agents Such as etidocaine
`cocaine, benoXinate, dibucaine hydrochloride, dyclonine
`hydrochloride, nae paine, phenacaine hydrochloride,
`piperocaine, proparacaine hydrochloride, tetracaine
`hydrochloride, hexylcaine, bupivacaine, lidocaine, mepiv
`acaine and prilocaine, ophthalmic diagnostic agents, Such
`as: (a) those used to examine the retina Such as Sodium
`fluorescein, (b) those used to examine the conjunctiva,
`cornea and lacrimal apparatus, Such as fluorescein and rose
`bengal and (c) those used to examine abnormal pupillary
`responses Such as methacholine, cocaine, adrenaline,
`atropine, hydroxyamphetamine and pilocarpine, ophthalmic
`agents used as adjuncts in Surgery, Such as alpha
`chymotrypsin and hyaluronidase; chelating agents Such as
`ethylenediaminetetraacetic acid (EDTA) and deferoxamine;
`immunosuppressants and anti-metabolites Such as
`methotrexate, cyclophosphamide, 6-mercaptopurine and
`aZathioprine and combinations of the compounds mentioned
`above, Such as antibioticS/antiinflammatories combinations
`Such as the combination of neomycin Sulfate and dexam
`ethasone Sodium phosphate and combinations concomi
`tantly used for treating glaucoma, for example, a combina
`tion of timolol maleate and aceclidine, and the like and
`mixtures thereof.
`In a preferred embodiment, the useful TACs include
`adrenergic agonists. The adrenergic agonists preferably are
`molecules containing amines. Also, the adrenergic agonists
`preferably are amine-containing molecules with pKa’s of
`greater than 7, preferably about 7 to about 9.
`More preferably, the useful TACs include alpha
`adrenergic agonists. Examples of alpha-adrengergic agonists
`include, but not limited to, adrafinil, adrenolone,
`amidephrine, apraclonidine, budralazine, clonidine,
`cyclopentamine, detomidine, dimetofrine, diplivefrin,
`ephedrine, epinephrine, fenoxazoline, guanaben Z,
`guan facine, hydroxyamphetamine, ibopamine,
`indanazoline, isometheptene, mephentermine, metaraminol,
`methoxamine, methylhexaneamine, metizolene, midodrine,
`naphazoline, norepinephrine, norfenefrine, octodrine,
`Octop a mine, oxy meta Zoline, phenyle phrine,
`phenylpropanolamine, phenylpropylmethylamine,
`pholedrine, propylhexedrine, pseudoephedrine, rillmenidine,
`Synephrine, tetrahydrozoline, tiamenidine, tramaZoline,
`tuaminoheptane, tymazoline, tyramine, Xylometazoline, and
`the like and mixtures thereof.
`In a still more preferred embodiment, the useful TACs
`include alpha-2-adrenergic agonists. AS used herein, the
`term “alpha-2 adrenergic agonist' includes chemical
`entities, Such as compounds, ions, complexes and the like,
`that produces a net Sympatholytic response, resulting in
`increased accommodation, for example, by binding to
`presynaptic alpha-2 receptors on Sympathetic postganglionic
`nerve endings or, for example, to postsynaptic alpha-2
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`receptors on Smooth muscle cells. A Sympatholytic response
`is characterized by the inhibition, diminishment, or preven
`tion of the effects of impulses conveyed by the Sympathetic
`nervous System. The alpha-2 adrenergic agonists of the
`invention bind to the alpha-2 adrenergic receptors
`presynaptically, causing negative feedback to decrease the
`release of neuronal norepinephrine. Additionally, they also
`work on alpha-2 adrenergic receptors postsynaptically,
`inhibiting beta-adrenergic receptor-Stimulated formation of
`cyclic AMP, which contributes to the relaxation of the ciliary
`muscle, in addition to the effects of postsynaptic alpha-2
`adrenergic receptorS on other intracellular pathways. Activ
`ity at either pre- or postsynaptic alpha-2 adrenergic receptors
`will result in a decreased adrenergic influence. Decreased
`adrenergic influence results in increased contraction result
`ing from cholinergic innervations. Alpha-2 adrenergic ago
`nists also include compounds that have neuroprotective
`activity. For example, 5-bromo-6-(2-imidozolin-2-ylamino)
`quinoxaline is an alpha-2-adrenergic agonist which has a
`neuroprotective activity through an unknown mechanism.
`Without limiting the invention to the Specific groups and
`compounds listed, the following is a list of representative
`alpha-2 adrenergic agonists useful in this invention: imino
`imidazolines, including clonidine, apra clonidine,
`imidazolines, including naphazoline, Xymetazoline,
`tetrahydrozoline, and tramaZoline, imidazoles, including
`detomidine, mede tomidine, and deXme detomidine,
`azepines, including B-HT 920 (6-allyl-2-amino-5,6,7,8
`tetrahydro-4H-thiazolo 4,5-d-azepine and B-HT 933;
`thiazines, including Xylazine; oxazolines, including rillmeni
`dine, guanidines, including guanabenZ and guanfacine, cat
`echolamines and the like.
`Particularly useful alpha-2-adrenergic agonists include
`quinoxaline components. In one embodiment, the quinoxa
`line components include quinoxaline, derivatives thereof
`and mixtures thereof. Preferably, the derivatives of quinoxa
`line include (2-imidoZolin-2-ylamino) quinoxaline. More
`preferably, the derivatives of quinoxaline include 5-halide
`6-(2-imidozolin-2-ylamino) quinoxaline. The “halide” of the
`5-halide-6-(2-imidoZolin-2-ylamino) quinoxaline may be a
`fluorine, a chlorine, an iodine, or preferably, a bromine, to
`form 5-bromo-6-(2-imido Zolin-2-ylamino) quinoxaline.
`Even more preferably, the derivatives of quinoxaline to be
`used in accordance with this invention include a tartrate of
`5-bromo-6-(2-imidoZolin-2-ylamino) quinoxaline, or Bri
`monidine tartrate.
`Other useful quinoxaline derivatives are well known. For
`example, useful derivatives of a quinoxaline include the
`ones disclose by Burke et al U.S. Pat. No. 5,703,077. See
`also Danielwicz et al 3,890,319. Each of the disclosures of
`Burke et al and Danielwicz et al is incorporated in its
`entirety by reference herein.
`The quinoxaline and derivatives thereof, for example
`Brimonidine tartrate, are amine-containing and preferably
`have pKa’s of greater than 7, preferably about 7.5 to 9.
`Analogs of the foregoing compounds that function as
`alpha-2 adrenergic agonists also are Specifically intended to
`be embraced by the invention.
`Preferably, the alpha-2-adrenergic agonists, for example
`the ones listed above, are effective toward activating one or
`more of alpha-2A-adrenergic receptors, alpha-2B
`adrenergic receptorS and alpha-2D-adrenergic receptorS.
`Other useful TACS include ocular hypotensive agents
`(Woodward et al U.S. Pat. No. 5,688,819), cyclosporins
`(Ding et al U.S. Pat. No. 5,474,979), androgen tears
`(Sullivan U.S. Pat. No. 5,620.921), pyranoquinolinone
`
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`US 6,562,873 B2
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`derivatives (Cairns et al U.S. Pat. No. 4,474,787), com
`pounds having retinoid-like activities (Chandraratna U.S.
`Pat. No. 5,089,509), ketorolac/pyrrole-1-carboxylic acids
`(Muchowski et al U.S. Pat. No. 4,089,969), ofloxacins/
`benzoxazine derivatives (Hayakawa et al U.S. Pat. No.
`4,382,892), memantines (Lipton et al U.S. Pat. No. 5,922,
`773), RAR antagonists (Klein et al U.S. Pat. No. 5,952,345),
`RAR-alpha agonists (Teng et al U.S. Pat. No. 5,856,490).
`Each of the disclosures referred to in the above patents is
`incorporated in its entirety herein by reference.
`In one embodiment, the TACs, for example Brimonidine
`tartrate, are Substantially unionized in the composition. In
`another embodiment, the TACs are substantially unionized
`in the environment to which they are administered, for
`example the cornea of the human eye. Without wishing to be
`limited by any theory or mechanism of action, it is believed
`that the unionized forms of the TACs facilitate their perme
`ation acroSS membrane lipid bilayers.
`Any suitable SEC, other than cyclodextrin, may be
`employed in accordance with the present invention. In one
`embodiment, the SECS include pyrrolinidone components.
`Example S of pyrrolinid one components are
`polyvinylpyrrolinidones, derivatives thereof and mixtures
`thereof. In a preferred embodiment, the SECs include polya
`nionic components. The useful polyanionic components
`include, but are not limited to, those materials which are
`effective in increasing the apparent Solubility, preferably
`water solubility, of poorly soluble TACs and/or enhance the
`stability of the TACs and/or reduce unwanted side effects of
`the TACs. Furthermore, the polyanionic component is pref
`erably ophthalmically acceptable at the concentrations used.
`Additionally, the polyanionic component preferably
`includes three (3) or more anionic (or negative) charges. In
`the event that the polyanionic component is a polymeric
`material, it is preferred that each of the repeating units of the
`polymeric material include a discrete anionic charge. Par
`ticularly useful anionic components are those which are
`water Soluble, for example, Soluble at the concentrations
`used in the presently useful liquid aqueous media, Such as a
`liquid aqueous medium containing the polyanionic compo
`nent and chlorite component.
`The polyanionic component is preferably Sufficiently
`anionic to interact with the TAC. Such interaction is believed
`to be desirable to Solubilize the TAC and/or to maintain Such
`TAC Soluble in the carrier component, for example a liquid
`medium.
`Polyanionic components also include one or more poly
`meric materials having multiple anionic charges. Examples
`include:
`metal carboxymethylstarchs
`metal carboxymethylhydroxyethylstarchs
`hydrolyzed polyacrylamides and polyacrylonitriles
`heparin
`homopolymers and copolymers of one or more of
`acrylic and methacrylic acids
`metal acrylates and methacrylates
`alginic acid
`metal alginates
`vinylsulfonic acid
`metal vinylsulfonate
`amino acids, Such as aspartic acid, glutamic acid and
`the like
`metal Salts of amino acids
`p-styreneSulfonic acid
`metal p-styreneSulfonate
`2-methacryloyloxyethylsulfonic acids
`
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`9
`metal 2-methacryloyloxethylsulfonates
`3-methacryloyloxy-2-hydroxypropylsulonic acids
`metal 3-methacryloyloxy-2-hydroxypropylsulfonates
`2-acrylamido-2-methylpropanesulfonic acids
`metal 2-acrylamido-2-methylpropanesulfonates
`allylsulfonic acid
`metal allylsulfonate and the like.
`In one embodiment, the polyanionic components include
`anionic polysaccharides, other than cyclodextrins, which
`tend to exist in ionized forms at higher pHs, for example,
`pH's of about 7 or higher. The following are some examples
`of anionic polysaccharides which may be employed in
`accordance with this invention.
`Polydextrose is a randomly bonded condensation polymer
`of dextrose which is only partially metabolized by mam
`15
`mals. The polymer can contain a minor amount of bound
`Sorbitol, citric acid, and glucose.
`Chondroitin Sulfate also known as Sodium chondroitin
`Sulfate is a mucopolysaccharide found in every part of
`human tissue, Specifically cartilage, bones, tendons,
`ligaments, and vascular walls. This polysaccharide has been
`extracted and purified from the cartilage of SharkS.
`Carrageenan is a linear polysaccharide having repeating
`galactose units and 3,6 anhydrogalactose units, both of
`which can be Sulfated or nonsulfated, joined by alternating
`1-3 and beta 1-4 glycosidic linkages. Carrageenan is a
`hydrocolloid which is heat extracted from Several Species of
`red Seaweed and irish moss.
`Maltodextrins are water Soluble glucose polymers which
`are formed by th