(12) United States Patent
`Horn
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,293,742 B2
`Oct. 23, 2012
`
`US008293742B2
`
`( * ) Notice:
`
`(54) PREFERENTIAL VASOCONSTRICTION
`COMPOSITIONS AND METHODS OF USE
`Inventor: Gerald Horn, Deerfield, IL (US)
`(75)
`(73) Assignee: Alpha Synergy Development, Inc.,
`Dana Point, CA (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 385 days.
`(21) Appl. No.: 12/460,941
`Jul. 27, 2009
`(22) Filed:
`Prior Publication Data
`(65)
`US 2010/0029659 A1
`Feb. 4, 2010
`Related U.S. Application Data
`(60) Provisional application No. 61/137,714, filed on Aug.
`1, 2008, provisional application No. 61/192,777, filed
`on Sep. 22, 2008, provisional application No.
`61/203,120, filed on Dec. 18, 2008, provisional
`application No. 61/207,481, filed on Feb. 12, 2009.
`Int. Cl.
`A61K 31/498
`(2006.01)
`A61P 27/02
`(2006.01)
`(52) U.S. Cl.
`....................................................... 514/249
`(58) Field of Classification Search ................... 514/249
`See application file for complete search history.
`
`(51)
`
`(56)
`
`References Cited
`
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`OTHER PUBLICATIONS
`
`Lee, “Efficacy of brimonidine tartrate 0.2% ophthalmic solution in
`reducing halos after laser in situ keratomileusis”, J Cataract Refract
`Surg 2008, (34), pp. 963-967.*
`Mechanism of decongestant activity of x2-adrenoceptor agnosits,
`Corboz M.R. et al., Pulmonary Pharmacology & Therapeutics 21
`(2008) 449-454.
`
`Alpha-adrenoceptor agonistic activity of oxymetazoline and
`xylometazoline, Haenisch B. et al., Fundam Clin Pharmacol. Dec. 17,
`2009.
`An Evaluation of Nasal Response Following Different Treatment
`Regimes of . . . , Morris S. et al.,American Journal Rhinology, vol. 11,
`No. 2, Mar.-Apr. 1997, pp. 109-115(7).
`Pharmacological Characterization of Postjunctional a-Adrenocep-
`tors in . . . , Corboz M.R. et al., American Jour of Rhinology, vol. 19,
`No. 5, Sep.-Oct. 2005, pp. 495-502(8).
`Postjuntional a2-adrenoceptors in blood ve3ssels of human nasal
`mucosa, Ichimura K. et al., Arch Otorhinolaryngol (1988) 245:127-
`131.
`Long-term use of oxy- and xylometazoline nasal sprays induces
`rebound swelling, tolerance, and nasal hyperreactivity, Graf P.,
`Rhinology 1996, 34(1):9-13.
`Alpha 1-receptors at pre-capillary resistance vessels of the human
`nasal mucosa, Johannssen V et al., Rhinology 1997; 35(4):161-65.
`Correspondence A Propos De L’article: <<Traitement Des
`Glaucomes Par La Brimonidine>>, M. Detry-Morel Et C. Dutrieux<
`J Fr Ophtalmo1.2001; 24(7): 748-9.
`by
`Vacoconstriction
`Potent
`a2A-Adrenoceptor-Mediated
`Brimonidine in Porcine Ciliary Arteries, Anna Wikberg-Matsson, et
`al., IOVS, 2001, vol. 42, No. 9, 2049-55.
`Medical Management of Chronic Rhinosinusitus—Jean P. Fong,
`MD, Matthew Ryan, MD (May 2006).
`Preven Drugs from Going Missing in Action—Mark B. Abelson,
`MD, and Sarah A. Rosner MPH; Review of Ophthalmology; www.
`revophth.com/index.asp?page=1—357.htm.
`Interactions Between CA2+ and H+ and Functional Consequences in
`Vascular Smooth Muscle—C. Austin and S. Wray, Journ. of Amer.
`Heart Association (Circ Res. 2000;86:355-363).
`A Useful New Topical Treatment for Glaucoma and Ocular Hyper-
`tension—Drug Ther Perspect 13(1):1-4, 1999.
`Brimonidine in the Treatment of Glaucoma and Ocular Hyperten-
`sion—Louis B. Cantor, Therapeutics and Clinical Risk Management
`2006:2(4) 337-346.
`Silent Bedpartners—Nancy A. Collop, Chest 2002; 122; 1111-1112.
`Traitement Des Glaucomes Par La Brimonidine (Alphagan® 0,2
`%)—M. Detry-Morel, C. Dutrieux, J FR. Ophtalmol., 2000; 23, 8,
`763-768.
`Vasopressin-Induced Vasoconstriction: Two Concentration-Depen-
`dent Signaling Pathways—Kyle K. Henderson and Kenneth L.
`Bryon, J Appl Physiol 102: 1402-1409, 2007.
`The Effect of Correction of Sleep-Disordered Breathing on Bp in
`Untreated Hypertension—K. Mae Hla, J. B. Skatrud, L. Finn, M.
`Palta and T. Young, Chest 2002;122; 1125-1135.
`
`(Continued)
`
`Primary Examiner — Sreeni Padmanabhan
`Assistant Examiner — Sahar Javanmard
`(74) Attorney, Agent, or Firm — Wood, Phillips, Katz, Clark
`& Mortimer
`
`(57)
`
`ABSTRACT
`
`The invention generally relates to compositions and methods
`for preferential vasoconstriction of smaller blood vessels
`relative to larger blood vessels. The compositions comprise
`highly selective alpha-2 adrenergic receptor agonists, at low
`concentrations, such as below 0.05% weight by volume. The
`compositions preferably comprise brimonidine. The compo-
`sitions preferably have pH between about 5.5 and about 6.5.
`
`6 Claims, 7 Drawing Sheets
`(5 of 7 Drawing Sheet(s) Filed in Color)
`
`Eye Therapies Exhibit 2161, 1 of 20
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`US 8,293,742 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Myogenic Tone and Reactivity of the Rat Ophthalmic Artery—Y. P.
`R. Jarajapu, M. B. Grant, and H. J. Knot, Invest. Ophth. & Visual
`Science, Jan. 2004, vol. 45, No. 1.
`Correspondence A Propos De L’article: <<Traitement Des
`Claucomes Par La Brimonidine>>, M. Detry-Morel Et C. Dutrieux,
`J Fr Ophtalmol. 2000; 23(8): 763-8.
`Prospective Study of the Association Between Sleep-Disordered
`Breathing and Hypertension—P. Peppard, et. al., The New England J
`of Med., vol. 342, No. 19:1378-1384 (2000).
`Catecholamines
`and Sympathomimetic Drugs—Goodman &
`Gilman’s Pharmacology, Ch. 10; www.accessmedicine.com/popup.
`aspx?aID-936314&pring=yes—chapter.
`
`Rhinitis Medicamentosa—JT Ramey, E Bailen, RF Lockey, J
`Investig Allergol Clin Immunol 2006; vol. 16(3); 148-155.
`Characterization of three inhibitors of endothelial nitric oxide
`synthase in vitro and in vivo—D.D. Rees, et al., br. J. Pharmacol.
`(1990) 101, 746-752.
`Inhibition of α-adrenergic vasoconstriction in exercising human
`thigh muscles—D. Walter Wray, et al., J Physiol 555, 2 pp. 545-264
`(2003).
`Dexmedetomidine Enhances the Local Anesthetic Action of
`Lidocaine via . . . TatsushiYoshitomi DDS et al., Anesth Analg 2008;
`107:96-101.
`Adding Dexmedetomidine to Lidocaine for Intravenous Regional
`Anesthesia, Dilek Memis, MD et al., Anesth Analg 2004;98:835-40.
`
`* cited by examiner
`
`Eye Therapies Exhibit 2161, 2 of 20
`Slayback v. Eye Therapies - IPR2022-00142
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`U.S. Patent
`
`Oct. 23, 2012
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`Sheet 1 of 7
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`US 8,293,742 B2
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`Eye Therapies Exhibit 2161, 3 of 20
`Slayback v. Eye Therapies - IPR2022-00142
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`U.S. Patent
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`Oct. 23, 2012
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`Sheet 2 of 7
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`US 8,293,742 B2
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`Eye Therapies Exhibit 2161, 4 of 20
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`U.S. Patent
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`Oct. 23, 2012
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`Sheet 3 of 7
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`Eye Therapies Exhibit 2161, 5 of 20
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`U.S. Patent
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`Oct. 23, 2012
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`Sheet 4 of 7
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`Eye Therapies Exhibit 2161, 6 of 20
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`U.S. Patent
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`Oct. 23, 2012
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`Sheet 5 of 7
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`U.S. Patent
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`Oct. 23, 2012
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`Sheet 6 of 7
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`Eye Therapies Exhibit 2161, 8 of 20
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`U.S. Patent
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`Oct. 23, 2012
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`Sheet 7 of 7
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`US 8,293,742 B2
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`Eye Therapies Exhibit 2161, 9 of 20
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`US 8,293,742 B2
`
`1
`PREFERENTIAL VASOCONSTRICTION
`COMPOSITIONS AND METHODS OF USE
`
`BACKGROUND OF THE INVENTION
`
`Dilation of small blood vessels, particularly arterioles, cap-
`illaries, and venules, causes many clinically undesirable
`events including surface hemorrhage and hyperemia follow-
`ing Lasik surgery, eye redness (conjunctival hyperemia), and
`nasal congestion (turbinate mucosal swelling secondary to
`vasodilation).
`Adrenergic receptors mediate physiological responses to
`the catecholamines, norephinephrine and epinephrine, and
`are members of the superfamily of G protein-coupled recep-
`tors having seven transmembrane domains. These receptors,
`which are divided pharmacologically into a-1, a-2 and β-adr-
`energic receptor types, are involved in diverse physiological
`functions including functions of the cardiovascular and cen-
`tral nervous systems. The a-adrenergic receptors mediate
`excitatory and inhibitory functions: a-1 adrenergic receptors
`are typically excitatory post-synaptic receptors which gener-
`ally mediate responses in an effector organ, while a-2 adren-
`ergic receptors are located postsynaptically as well as presyn-
`aptically, where they inhibit release of neurotransmitters.
`Agonists of a-2 adrenergic receptors currently are used clini-
`cally in the treatment of hypertension, glaucoma, spasticity,
`and attention-deficit disorder, in the suppression of opiate
`withdrawal, as adjuncts to general anesthesia and in the treat-
`ment of cancer pain. Vascular constriction is known to be
`mediated by a-adrenergic receptors.
`a-2 adrenergic receptors are presently classified into three
`subtypes based on their pharmacological and molecular char-
`acterization: a-2A/D (a-2A in human and a-2D in rat); a-2B;
`and a-2C (Bylund et al., Pharmacol. Rev. 46:121-136 (1994);
`and Hein and Kobilka, Neuropharmacol. 34:357-366 (1995)).
`The a-2A, a-2B, and a-2C subtypes appear to regulate arterial
`and/or venular contraction in some vascular beds, and the
`a-2A and a-2C subtypes mediate feedback inhibition of nore-
`pinephrine release from sympathetic nerve endings. The a-2A
`subtype also mediates many of the central effects of a-2
`adrenergic agonists (Calzada and ArtiZano, Pharmacol. Res.
`44: 195-208 (2001); Hein et al., Ann. NY Acad. Science
`881:265-271 (1999); and Ruffolo (Ed.), a-Adrenoreceptors:
`Molecular Biology, Biochemistry and Pharmacology S.
`Karger Publisher’s Inc. Farmington, Conn. (1991)). The a-2A
`subtype also mediates potent constriction of the porcine, but
`not human, ciliary artery.
`Many compounds having selective a-2 agonist activity are
`known and include brimonidine (which has been used for
`lowering intraocular pressure in patients with open-angle
`glaucoma or ocular hypertension), guanfacine (which has
`been used to control high blood pressure), dexmetidomidine
`(which has been used as a sedative, analgesic, sympatholytic
`and anxiolytic), and methyl dopa (which has been used as a
`centrally-acting ad renergic anti hypertensive).
`The patent or application file contains at least one drawing
`executed in color. Copies of this patent or patent application
`publication with color drawing(s) will be provided by the
`Office upon request and payment of the necessary fee.
`The clinically available compounds belong to the general
`category of a adrenergic receptor agonists. It is a known
`property of all a adrenergic receptor agonists, including bri-
`monidine, to cause vasoconstriction. However, known formu-
`lations of brimonidine and other known a-2 adrenergic recep-
`tor agonists are associated with a high incidence of rebound
`hyperemia, or other side effects, in clinical use. For example,
`after as few as three doses of applying known formulations of
`
`2
`a adrenergic receptor agonists, patients may develop second-
`ary rebound hyperemia or secondary vasodilation. Brimoni-
`dine (5-bromo-6-(2-imidazolidinylideneamino)quinoxaline
`L-tartrate), a known selective alpha 2 agonist is associated
`with significant rebound hyperemia (primary or delayed
`onset vasodilation) in its current concentration range for treat-
`ing glaucoma of about 0.1% to 0.2%.
`Commercially available general alpha agonists for topical
`mucosal decongestant use (ophthalmic and nasal applica-
`tions) include tetrahydrozoline, naphazoline, oxymetazoline,
`xylometazoline, methoxamine and phenylephrine. These
`agonists have high alpha 1 receptor agonist activity and are
`known to cause rebound hyperemia and medicamentosa.
`Accordingly, their clinical use is usually restricted to several
`hours or a few days, at most. Many individuals with mucosal
`congestion or hyperemia from chronic conditions such as dry
`eye, contact lens wear, allergic conjunctivitis, allergic rhini-
`tis, nonallergic rhinitis, acute or chronic sinusitis, nasal poly-
`posis, rhinitis secondary to pregnancy, or rhinitis due to nasal
`septal deviation or obstruction and asthma, particularly, aller-
`gic asthma require longer term agonist use. To the best of the
`inventor’s knowledge, there are currently no means to induce
`effective vasoconstriction without concomitant
`ischemia
`caused by an excessive reduction in blood flow and a cascade
`of inflammatory mediators, resulting in undesirable clinical
`sequelae of rebound hyperemia, and or medicamentosa, a
`potentially prolonged inflammatory state that can last for
`several weeks or months of rebound mucosal congestion.
`Thus, there is a need for new methods and formulations that
`would provide safe and long term vasoconstriction with
`reduced or minimized side effects, such as rebound hyper-
`emia.
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`SUMMARY OF THE PRESENT INVENTION
`
`The present invention is generally related to compositions
`and methods. for inducing vasoconstriction. One of the key
`discoveries of the present invention lies in using low doses of
`highly selective a-2 adrenergic receptor agonists to achieve
`vasoconstriction with significantly reduced hyperemia.
`There are a variety of applications and dosage forms that
`can be utilized to apply the findings of the invention. For
`example, some applications include methods and composi-
`tions for: treating nasal congestion; inducing vasoconstric-
`tion; inducing preferential vasoconstriction of smaller blood
`vessels relative to larger blood vessels; reducing capillary
`permeability in a pulmonary condition; reversing rebound
`hyperemia; reducing activation of a-1 adrenergic receptors;
`and treating and preventing an allergic response with reduced
`rebound hyperemia.
`The invention also encompasses using the compositions
`and methods of this invention for prophylactic reasons, for
`example, for prophylaxis of conditions including, but not
`limited to, asthma, upper respiratory disease, acute pharyn-
`gitis, acute sinusitis, acute tracheobronchitis, influenza, lower
`respiratory disease, acute bronchitis, bronchiolitis, and com-
`munity acquired pneumonia (CAP).
`The invention also relates to a metered dose dispenser
`comprising the aqueous compositions of the invention.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`The patent or application file contains at least one drawing
`executed in color. Copies of this patent or patent application
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`Eye Therapies Exhibit 2161, 10 of 20
`Slayback v. Eye Therapies - IPR2022-00142
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`US 8,293,742 B2
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`3
`publication with color drawing(s) will be provided by the
`Office upon request and payment of the necessary fee.
`FIG. 1 is a graphical representation of the variation of
`vasoconstriction net clinical effectiveness of prior art com-
`positions comprising naphazoline, oxymetazoline and tet-
`rahydrozoline at various concentrations.
`FIG. 2 is a graphical representation of the variation of
`vasoconstriction clinical effectiveness of compositions of the
`present invention comprising brimonidine at low concentra-
`tions.
`FIG. 3 is a graphical representation of clinical effectiveness
`of the compositions of the present invention versus prior art
`compositions.
`FIG. 4A is a baseline visual appearance of two eyes of a
`patient with an ocular condition.
`FIG. 4B depicts the eyes of the patient 180 minutes after
`being treated with a prior art composition comprising tetrahy-
`drozoline at 0.05% (right eye) and a composition of the
`present invention comprising brimonidine at 0.01% (left eye).
`FIG. 4C depicts the eyes of the patient 240 minutes after
`baseline (FIG. 4A) after being treated with a prior art com-
`position comprising oxymetazoline at 0.025% (right eye) and
`a composition of the present invention comprising brimoni-
`dine at 0.02% (left eye).
`FIG. 4D depicts the eyes of the patient 240 minutes after
`treatment described in FIG. 4C after being treated with a prior
`art composition comprising naphazoline at 0.033% (right
`eye) and a composition of the present invention comprising
`brimonidine at 0.02% (left eye).
`FIG. 4E depicts the left eye of the patient 240 minutes after
`treatment described in FIG. 4D after being treated with a
`composition of the present invention comprising brimonidine
`at 0.033%.
`FIG. 5A is a baseline visual appearance of two eyes of a
`patient with an ocular condition of moderate hyperemia.
`FIG. 5B depicts a visual appearance of the right eye of the
`patient after being treated with a prior art composition com-
`prising VISINE Original® (tetrahydrozoline 0.05%) and the
`induction of rebound hyperemia, and the visual appearance of
`the left eye of the patient after being treated simultaneously
`with a composition of the present invention comprising bri-
`monidine at 0.015%
`FIG. 5C depicts a visual appearance of the right eye of the
`patient after then being treated with the novel composition of
`the present invention comprising brimonidine at 0.015%,
`reversing the VISINE Original® induced rebound hyper-
`emia, and a visual appearance of the left eye of the patient
`after being treated simultaneously with an additional drop of
`the composition of the present invention comprising brimoni-
`dine at 0.015%.
`FIG. 6 is another graphical representation of clinical effec-
`tiveness of the compositions of the present invention versus
`prior art compositions.
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`DETAILED DESCRIPTION OF THE INVENTION
`
`55
`
`Definitions
`For purposes of the present invention, the terms below are
`defined as follows.
`The term “low concentrations” refers to concentrations
`from between about 0.0001% to about 0.05%; more prefer-
`ably, from about 0.001% to about 0.025%; even more pref-
`erably, from about 0.01% to about 0.025%; and even more
`preferably, from about 0.01% to about 0.02% weight by vol-
`ume.
`The term “administered locally” refers to administering the
`compositions of the present invention approximately at the
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`4
`site where they will come into contact with a-2 adrenergic
`receptors. This term specifically excludes oral administra-
`tion, intravenous injection, or transdermal patches which are
`not applied approximately at the spatial location of the area
`which is desired to be treated by the compositions of the
`present invention.
`The term “brimonidine” encompasses, without limitation,
`brimonidine salts and other derivatives, and specifically
`includes, but is not limited to, brimonidine tartrate, 5-bromo-
`6-(2-imidazolin-2-ylamino)quinoxaline
`D-tartrate,
`Alphagan™, and UK14304.
`The term “treating” refers to reversing, alleviating, inhib-
`iting, or slowing the progress of the disease, disorder, or
`condition to which such term applies, or one or more symp-
`toms of such disease, disorder, or condition.
`The term “preventing” refers to prophylactic use to reduce
`the likelihood of a disease, disorder, or condition to which
`such term applies, or one or more symptoms of such disease,
`disorder, or condition. It is not necessary to achieve a 100%
`likelihood of prevention; it is sufficient to achieve at least a
`partial effect of reducing the risk of acquiring such disease,
`disorder, or condition.
`The term “swollen nasal turbinates condition” includes,
`but is not limited to, nasal decongestion.
`Vasoconstriction with Reduced Hyperemia
`One aspect of the present invention refers to a surprising
`and unexpected finding that using highly selective a-2 ago-
`nists at low concentrations allows reducing, minimizing, and/
`or eliminating rebound hyperemia while optimally providing
`clinically equal or more effective vasoconstriction. Rebound
`hyperemia refers to induced vasodilation (instead of intended
`vasoconstriction) occurring, often with a lag time, after an
`application or, more typically, repeated applications of vaso-
`constrictors and characterized by engorgement of blood ves-
`sels (such as those in the conjunctiva or nasal mucosa),
`increased capillary permeability and leakage, and, in some
`cases, inflammatory sequelae (medicamentosa), frequently
`due to the use of an alpha 1 constricting drug and particularly,
`chronic use of a vasoconstricting drug.
`Many, if not all, references in the prior art associated
`rebound hyperemia with all alpha agonists and considered the
`complication of rebound hyperemia to be intrinsic to vaso-
`constriction, wherein blood flow is reduced, causing atten-
`dant ischemia with some inflammatory cascade, precipitating
`rebound hyperemia in many cases and often leading to medi-
`camentosa.
`Contrary to these teachings, it was surprisingly and unex-
`pectedly found that selective alpha-2 (a-2) adrenergic recep-
`tor agonists (which are also interchangeably referred to as
`“a-2 agonists” throughout the application) with extremely
`high selectivity for a-2 adrenergic receptors at low concen-
`trations, well below those previously contemplated, can
`induce effective vasoconstriction with low incidence of
`rebound hyperemia as compared to the prior art, and low
`incidence of allergic reaction, including allergic blepharitis
`and follicular conjunctivitis. Further,
`the incidence of
`ischemia is significantly reduced through the use of compo-
`sitions and methods of the present invention.
`While not wishing to be bound to any particular theory, the
`inventor believes that rebound hyperemia is primarily asso-
`ciated with a-1 agonist activity. Thus, unless the binding
`affinity of a-2 agonists for a-2 over a-1 adrenergic receptors is
`sufficiently high, not sufficiently highly selective a-2 agonists
`will cause an undesirable a-1 receptor stimulation with atten-
`dant rebound hyperemia. Accordingly, it is desired to mini-
`mize a-1 agonist activity by using highly selective a-2 ago-
`nists.
`
`Eye Therapies Exhibit 2161, 11 of 20
`Slayback v. Eye Therapies - IPR2022-00142
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`US 8,293,742 B2
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`5
`Accordingly, in one embodiment, the invention generally
`relates to a method of treating or preventing rebound hyper-
`emia comprising administering to a patient in need thereof a
`selective a-2 adrenergic receptor agonist having a binding
`affinity of 100 fold or greater for a-2 over a-1 adrenergic
`receptors, or a pharmaceutically acceptable salt thereof,
`wherein said selective a-2 adrenergic receptor agonist is
`present at a concentration below about 0.05% weight by
`volume.
`In another embodiment, the invention relates to a surpris-
`ing finding that an aqueous composition comprising a selec-
`tive a-2 adrenergic receptor agonist, or a pharmaceutically
`acceptable salt thereof, can be used for the prevention or
`treatment of a disease or a condition by administering said
`aqueous composition to a patient in need thereof, wherein the
`concentration of said agonist in said aqueous composition is
`substantially lower than the concentration of said agonist
`normally used in the treatment of glaucoma.
`In another embodiment, the invention generally relates to a
`composition for inducing vasoconstriction comprising a
`selective a-2 adrenergic receptor agonist having a binding
`affinity of 100 fold or greater for a-2 over a-1 adrenergic
`receptors, or a pharmaceutically acceptable salt thereof, and
`wherein said selective a-2 adrenergic receptor agonist is
`present at a concentration below about 0.05% weight by
`volume.
`In yet another embodiment, the invention generally relates
`to a composition for inducing vasoconstriction comprising a
`selective a-2 adrenergic receptor agonist having a binding
`affinity of 100 fold or greater for a-2b and/or a-2c receptors
`over a-1 adrenergic receptors, or a pharmaceutically accept-
`able salt thereof, and wherein said selective a-2 adrenergic
`receptor agonist is present at a concentration below about
`0.05% weight by volume.
`Further, it was surprisingly and unexpectedly found that
`selective a-2 adrenergic receptor agonists used at a concen-
`tration below about 0.05% weight by volume can reverse
`general/alpha 1 agonist induced hyperemia (instead of caus-
`ing further ischemia from the induced vasoconstriction as
`would be expected for all agonists from prior art teachings),
`thereby providing a useful treatment for such patients and
`possibly alleviating medicamentosa from such drug applica-
`tions, and possibly demonstrating a different mechanism of
`action for vasoconstriction than for alpha 1 agonists (FIGS.
`5A-C).
`In a preferred embodiment, the binding affinity of the
`selective a-2 adrenergic receptor agonist is about 500 fold or
`greater for a-2 over a-1 adrenergic receptors.
`In a preferred embodiment, the selective a-2 adrenergic
`receptor agonist is present at a concentration between about
`0.001% and about 0.025% weight by volume.
`In a further preferred embodiment, the selective a-2 adren-
`ergic receptor agonist is selected from the group consisting of
`apraclonidine, mivazerol, clonidine, brimonidine, alpha
`methyl dopa, guanfacine, dexemeditomidine, (+)-(S)-4-[1-
`(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-
`thione, 1-[(imidazolidin-2-yl)imino]indazole, and mixtures
`of these compounds.
`In another preferred embodiment, the composition com-
`prises brimonidine at a concentration between about 0.001%
`and about 0.025% weight by volume.
`In a more preferred embodiment, a pH of the composition
`comprising the selective a-2 adrenergic receptor agonist is
`between about 5.5 and about 6.5.
`In one embodiment, the invention generally relates to a
`composition for inducing vasoconstriction consisting essen-
`tially of brimonidine, wherein said brimonidine concentra-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`tion is from between about 0.01% to about 0.02% weight by
`volume, wherein pH of said composition is between about 5.5
`and about 6.5, and wherein said composition is formulated as
`an ocular drop.
`In another embodiment, the invention generally relates to a
`composition for inducing vasoconstriction consisting essen-
`tially of brimonidine and potassium, wherein said brimoni-
`dine concentration is from between about 0.01% to about
`0.02% weight by volume, wherein pH of said composition is
`between about 5.5 and about 6.5, and wherein said composi-
`tion is formulated as an ocular drop.
`In the most preferred embodiment, potassium is in the form
`of potassium chloride and its concentration is between about
`0.2% to about 0.9% weight by volume.
`Preferential Vasoconstriction
`In one embodiment, methods of the present invention allow
`to induce preferential vasoconstriction of smaller blood ves-
`sels, such as capillaries and venules, relative to larger blood
`vessels, such as arteries and arterioles. These methods reduce
`activation of a-1 adrenergic receptors relative to a-2 adrener-
`gic receptors.
`Accordingly, in one embodiment, the invention generally
`relates to a method of effectively inducing preferential vaso-
`constriction of capillaries relative to arteries, and/or terminal
`arterioles, microvessels including capillary beds and/or
`venules with lower oxygen saturation than larger, proximal
`higher oxygen saturated arteries and or arterioles, comprising
`administering to a patient having an ocular or pulmonary
`condition, a selective a-2 adrenergic receptor agonist having
`a binding affinity of 100 fold or greater for a-2 over a-1
`adrenergic receptors, or a pharmaceutically acceptable salt
`thereof, wherein said selective a-2 adrenergic receptor ago-
`nist is present at a concentration below about 0.05% weight
`by volume.
`By the term “effectively” it is understood that preferential
`vasoconstriction results in minimizing and/or eliminating
`ischemia.
`While not wishing to be bound to any particular theory, this
`method allows constricting the blood flow to visible surface
`area with maximal constriction of microvasculature, together
`with minimal additional vasoconstriction of larger arterioles
`to maximize per unit area vasoconstrictive benefit and mini-
`mize ischemic consequence. This can be roughly analogized
`to reducing water flow at a sprinkler head rather than at the
`connection of the hose leading from the water supply to the
`sprinkler. Accordingly, this method allows achieving visibly
`effective whitening while optimizing total blood flow by
`minimizing arteriolar constriction to produce the best cos-
`metic and physiologic benefits of decongestant activity. Thus,
`the compositions and methods of the present invention make
`it possible to induce maximal microvessel constriction with
`the least arteriolar constriction.
`The method can be used to treat various ocular and pulmo-
`nary conditions. In a preferred embodiment, a pulmonary
`condition may be associated with swollen nasal turbinates. In
`addition, preferential vasoconstriction of smaller blood ves-
`sels allows decreasing ischemia, inflammation, rhinitis medi-
`camentosa, and rebound hyperemia.
`The invention also relates to compositions formulated for
`inducing preferential vasoconstriction.
`In one embodiment, a composition for inducing preferen-
`tial vasoconstriction of smaller blood vessels relative to larger
`blood vessels comprises a selective a-2 adrenergic receptor
`agonist having a binding affinity of 100 fold or greater for a-2
`over a-1 adrenergic receptors, or a pharmaceutically accept-
`
`Eye Therapies Exhibit 2161, 12 of 20
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`US 8,293,742 B2
`
`7
`able salt thereof, wherein said selective a-2 adrenergic recep-
`tor agonist is present at a concentration below about 0.05%
`weight by volume.
`In another preferred embodiment, the method comprises
`administering to a patient having an ocular condition a com-
`position comprising brimonidine, wherein said brimonidine
`concentration is between about 0.001% and about 0.025%
`weight by volume.
`In a preferred embodiment, the invention generally relates
`to a method for inducing preferential vasoconstriction of
`smaller blood vessels relative to larger blood vessels com-
`prising topically administering to a patient having an ocular
`condition a composition consisting essentially of brimoni-
`dine into ocular tissue, wherein pH of said composition is
`between about 5.5 and about 6.5, wherein said brimonidine
`concentration is from between about 0.001% to about 0.025%
`weight by volume and wherein said composition is formu-
`lated as an ocular drop.
`Thus, in one embodiment, the invention generally relates to
`a composition for inducing preferential vasoconstriction con-
`sisting essentially of brimonidine into ocular tissue, wherein
`pH of said composition is between about 5.5 and about 6.5,
`wherein said brimonidine concentration is from between
`about 0.001% to about 0.025% weight by volume and
`wherein said composition is formulated as an ocular drop.
`In one embodiment, the invention generally relates to
`administering compositions of the present invention within
`about 24 hours after a Lasik surgery on the patient.
`In yet another embodiment, the invention generally relates
`to a method for inducing preferential vasoconstriction of
`smaller blood vessels relative to larger blood vessels com-
`prising administering to a patient having an ocular or pulmo-
`nary condition a selective a-2 agonist having a binding affin-
`ity of 100 fold or greater for a-2b and or a-2c receptors over
`a-1 adrenergic receptors, or a pharmaceutically acceptable
`salt thereof, wherein said selective a-2 adrenergic receptor
`agonist is present at a concentration below about 0.05%
`weight by volume.
`Reducing Capillary Permeability
`In another embodiment, the invention generally relates to a
`method of
`reducing capillary permeability comprising
`administering locally to a patient in need thereof a selective
`a-2 adrenergic receptor agonist having a binding affinity of
`100 fold or greater for a-2 over a-1 adrenergic receptors, or a
`pharmaceutically acceptable salt thereof, in the absence of a
`substantial amount of another therapeutic agent, wherein said
`selective a-2 adrenergic receptor agonist is present at a con-
`centration below about 0.05% weight by volume.
`In a preferred embodiment, the selective a-2 adrenergic
`receptor agonist is present at a concentration between about
`0.001% and about 0.05% weight by volume.
`The method can be used to treat various pulmonary condi-
`tions, including, but not limited to, bronchitis, including res-
`piratory syncytial virus (RSV) bronchitis. In a preferred
`embodiment, a pulmonary