WO2020041282A1 - Compositions de vasoconstriction et procédés d'utilisation - Google Patents

Compositions de vasoconstriction et procédés d'utilisation Download PDF

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Publication number
WO2020041282A1
WO2020041282A1 PCT/US2019/047225 US2019047225W WO2020041282A1 WO 2020041282 A1 WO2020041282 A1 WO 2020041282A1 US 2019047225 W US2019047225 W US 2019047225W WO 2020041282 A1 WO2020041282 A1 WO 2020041282A1
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Prior art keywords
brimonidine
composition
concentration
eye
selective
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PCT/US2019/047225
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English (en)
Inventor
Gerald Horn
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Eye Therapies, Llc
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Priority claimed from US16/108,727 external-priority patent/US20180360825A1/en
Application filed by Eye Therapies, Llc filed Critical Eye Therapies, Llc
Publication of WO2020041282A1 publication Critical patent/WO2020041282A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine

Definitions

  • Adrenergic receptors mediate physiological responses to the catecholamines
  • norephinephrine and epinephrine are members of the superfamily of G protein-coupled receptors having seven transmembrane domains. These receptors, which are divided
  • a-l adrenergic receptors are typically excitatory post-synaptic receptors which generally mediate responses in an effector organ, while a-2 adrenergic receptors are located postsynaptically as well as presynaptically, where they inhibit release of neurotransmitters.
  • Agonists of a-2 adrenergic receptors currently are used clinically 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 treatment 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 characterization: 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 norepinephrine 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
  • a-2A subtype also mediates potent constriction of the porcine, but not human, ciliary artery.
  • Many compounds having selective a-2 agonist activity 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 adrenergic
  • 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 brimonidine, to cause vasoconstriction. However, known formulations of brimonidine and other known a-2 adrenergic receptor 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 a adrenergic receptor agonists, patients may develop secondary rebound hyperemia or secondary vasodilation.
  • Brimonidine (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 treating glaucoma of about 0.1% to 0.2%.
  • 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.
  • Some applications include methods and compositions for: treating nasal congestion; inducing vasoconstriction; 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-l adrenergic receptors; and treating and preventing an allergic response with reduced rebound hyperemia.
  • 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 pharyngitis, acute sinusitis, acute tracheobronchitis, influenza, lower respiratory disease, acute bronchitis, bronchiolitis, and community acquired pneumonia (CAP).
  • prophylaxis of conditions including, but not limited to, asthma, upper respiratory disease, acute pharyngitis, acute sinusitis, acute tracheobronchitis, influenza, lower respiratory disease, acute bronchitis, bronchiolitis, and community acquired pneumonia (CAP).
  • CAP community acquired pneumonia
  • the invention also relates to a metered dose dispenser comprising the aqueous compositions of the invention.
  • the present invention is directed to a method selected from the group consisting of reversing rebound hyperemia, reducing eye redness, increasing eye whiteness and a combination thereof, comprising topically administering to a subject in need thereof a composition comprising, consisting essentially of or consisting of from about 0.01% to about 0.015% w/v or from about 0.03% to about 0.045% w/v brimonidine or a pharmaceutically acceptable salt thereof, preferably, 0.0125% w/v or 0.037% w/v.
  • the present invention is directed to a method selected from the group consisting of reversing rebound hyperemia, reducing eye redness, increasing eye whiteness and a combination thereof comprising, consisting essentially of or consisting of the steps of: i) inserting a contact lens in a solution comprising from about 0.005% to about 0.015% w/v brimonidine or a pharmaceutically acceptable salt thereof, preferably 0.008% w/v; and
  • the present invention is directed to a method selected from the group consisting of reversing rebound hyperemia, reducing eye redness, increasing eye whiteness and a combination thereof comprising, consisting essentially of or consisting of instilling a
  • composition comprising from about 0.005% to about 0.015% w/v brimonidine or a
  • Figure 1 is a graphical representation of the variation of vasoconstriction net clinical effectiveness of prior art compositions comprising naphazoline, oxymetazoline and tetrahydrozoline at various concentrations.
  • Figure 2 is a graphical representation of the variation of vasoconstriction clinical effectiveness of compositions of the present invention comprising brimonidine at low concentrations.
  • Figure 3 is a graphical representation of clinical effectiveness of the compositions of the present invention versus prior art compositions.
  • Figure 4A is a baseline visual appearance of two eyes of a patient with an ocular condition.
  • Figure 4B depicts the eyes of the patient 180 minutes after being treated with a prior art composition comprising tetrahydrozoline at 0.05% (right eye) and a composition of the present invention comprising brimonidine at 0.01% (left eye).
  • Figure 4C depicts the eyes of the patient 240 minutes after baseline (FIG. 4A) after being treated with a prior art composition comprising oxymetazoline at 0.025% (right eye) and a composition of the present invention comprising brimonidine at 0.02% (left eye).
  • Figure 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).
  • Figure 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%.
  • Figure 5 A is a baseline visual appearance of two eyes of a patient with an ocular condition of moderate hyperemia.
  • Figure 5B depicts a visual appearance of the right eye of the patient after being treated with a prior art composition comprising 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 brimonidine at 0.015%
  • Figure 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 hyperemia, 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 brimonidine at 0.015%.
  • Figure 6 is another graphical representation of clinical effectiveness of the compositions of the present invention versus prior art compositions.
  • low concentrations refers to concentrations from about 0.0001% to about 0.05%, from about 0.005% to about 0.01%; from about 0.01% to about 0.15%, from about 0.001% to about 0.025%, from about 0.03% to about 0.045%, from about 0.01% to about 0.025% and from about 0.01% to about 0.02% weight by volume.
  • the term“administered locally” refers to administering the compositions of the present invention approximately at the site where they will come into contact with a-2 adrenergic receptors. This term specifically excludes oral administration, 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, AlphaganTM, and UK14304.
  • treating refers to reversing, alleviating, inhibiting, or slowing the progress of the disease, disorder, or condition to which such term applies, or one or more symptoms of such disease, disorder, or condition.
  • 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.
  • swollen nasal turbinates condition includes, but is not limited to, nasal decongestion.
  • One aspect of the present invention refers to a surprising and unexpected finding that using highly selective a-2 agonists 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 vasoconstrictors and characterized by engorgement of blood vessels (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.
  • vasoconstriction wherein blood flow is reduced, causing attendant ischemia with some inflammatory cascade, precipitating rebound hyperemia in many cases and often leading to medicamentosa.
  • rebound hyperemia is primarily associated with a-l agonist activity.
  • the binding affinity of a-2 agonists for a-2 over a-l adrenergic receptors is sufficiently high, not sufficiently highly selective a-2 agonists will cause an undesirable a-l receptor stimulation with attendant rebound hyperemia. Accordingly, it is desired to minimize a-l agonist activity by using highly selective a-2 agonists.
  • the invention generally relates to a method of treating or preventing rebound hyperemia comprising administering to a patient in need thereof a selective a- 2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2 over a-l 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.
  • the invention relates to a surprising finding that an aqueous composition comprising a selective 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.
  • the invention generally relates to a composition for inducing vasoconstriction comprising a selective a-2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2 over a-l 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.
  • the invention generally relates to a composition for inducing vasoconstriction comprising a selective a-2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2b and/or a-2c receptors over a-l 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.
  • the binding affinity of the selective a-2 adrenergic receptor agonist is about 500-fold or greater for a-2 over a-l adrenergic receptors.
  • the selective a-2 adrenergic receptor agonist is present at a concentration from about 0.001% to about 0.025% weight by volume.
  • the selective a-2 adrenergic receptor agonist is selected from the group consisting of apraclonidine, mivazerol, clonidine, brimonidine, alpha methyl dopa, guanfacine, dexmedetomidine, (+)-(S)-4-[l-(2,3-dimethyl-phenyl)-ethyl]-l,3-dihydro-imidazole- 2-thione, l-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.
  • the composition comprises brimonidine at a concentration from about 0.001% to about 0.05% from about 0.005% to about 0.01%; from about 0.01% to about 0.15%, from about 0.001% to about 0.025%, from about 0.03% to about 0.045%, from about 0.01% to about 0.025% and from about 0.01% to about 0.02% weight by volume.
  • a pH of the composition comprising the selective a-2 adrenergic receptor agonist is from about 4.0 to about 6.5, preferably from about 5.5 to about 6.5.
  • the invention generally relates to a composition for inducing vasoconstriction comprising, consisting essentially of or consisting of brimonidine, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, wherein pH of said composition is from about 5.5 to about 6.5, and wherein said composition is formulated as an ocular drop.
  • the invention generally relates to a composition for inducing vasoconstriction comprising, consisting essentially of or consisting of brimonidine and potassium, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, wherein pH of said composition is from about 5.5 to about 6.5, and wherein said composition is formulated as an ocular drop.
  • potassium is in the form of potassium chloride and its concentration is from about 0.2% to about 0.9% weight by volume.
  • methods of the present invention allow to induce preferential vasoconstriction of smaller blood vessels, such as capillaries and venules, relative to larger blood vessels, such as arteries and arterioles. These methods reduce activation of a-l adrenergic receptors relative to a-2 adrenergic receptors.
  • the invention generally relates to a method of effectively inducing preferential vasoconstriction 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 lOO-fold or greater for a-2 over a-l 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.
  • 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 minimize 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.
  • this method allows achieving visibly effective whitening while optimizing total blood flow by minimizing arteriolar constriction to produce the best cosmetic and physiologic benefits of decongestant activity.
  • 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 pulmonary conditions.
  • a pulmonary condition may be associated with swollen nasal turbinates.
  • preferential vasoconstriction of smaller blood vessels allows decreasing ischemia, inflammation, rhinitis medicamentosa, and rebound hyperemia.
  • the invention also relates to compositions formulated for inducing preferential vasoconstriction.
  • a composition for inducing preferential vasoconstriction of smaller blood vessels relative to larger blood vessels comprises a selective a-2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2 over a-l 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.
  • the method comprises administering to a patient having an ocular condition a composition comprising brimonidine, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume.
  • the invention generally relates to a method for inducing preferential vasoconstriction of smaller blood vessels relative to larger blood vessels comprising topically administering to a patient having an ocular condition a composition comprising, consisting essentially of or consisting of brimonidine into ocular tissue, wherein pH of said composition is from about 5.5 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an ocular drop.
  • the invention generally relates to a composition for inducing preferential vasoconstriction comprising, consisting essentially of or consisting of brimonidine into ocular tissue, wherein pH of said composition is from about 5.5 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an ocular drop.
  • the invention generally relates to administering compositions of the present invention within about 24 hours after a Lasik surgery on the patient.
  • the invention generally relates to a method for inducing preferential vasoconstriction of smaller blood vessels relative to larger blood vessels comprising administering to a patient having an ocular or pulmonary condition a selective a-2 agonist having a binding affinity of 100 fold or greater for a-2b and or a-2c receptors over a-l 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.
  • 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-l 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 concentration below about 0.05% weight by volume.
  • the selective a-2 adrenergic receptor agonist is present at a concentration from about 0.001% to about 0.05% weight by volume, preferably from about 0.003% to about 0.005% w/v.
  • the present invention is directed to a method of treating a respiratory tract condition comprising administering to a subject in need thereof a composition comprising from about 0.001% to about 0.05% w/v of a selective a-2 adrenergic receptor agonist, preferably brimonidine, wherein the composition is administered to a respiratory tract region selected from the group consisting of the oropharynx via particles with an average diameter of about 7 microns or greater, the bronchioles via particles with an average diameter from about 3 to about 6 microns and the alveolar parenchyma via particles with an average diameter of less than about 3 microns.
  • a respiratory tract region selected from the group consisting of the oropharynx via particles with an average diameter of about 7 microns or greater, the bronchioles via particles with an average diameter from about 3 to about 6 microns and the alveolar parenchyma via particles with an average diameter of less than about 3 microns.
  • one or more nonionic surfactants can be used in the formulation at a total concentration from about 1% to about 7% w/v, preferably from about 1.5% to about 5% w/v, and more preferably from about 2% to about 4% w/v.
  • Common nonionic surfactants for this purpose include but are not limited to polysorbates, poloxamers, tyloxapols, polyoxyls, or cyclodextrins including polysorbate 80, poloxamer 407 and poloxamer 188.
  • lung parenchymal and alveolar tissue edema such as may occur in acute lung injury (“ALI”), lung edema secondary to toxic or septic shock, or secondary to infection such as pneumococcal pneumonia
  • delivery of such formulations may be lifesaving.
  • These formulations reduce cytokine / endotoxin triggered post-capillary venular leakage and would be preferred over dopamine drips and other attempts to reduce local or systemic microvascular leakage with alpha 1 agonist drugs that frequently lead to end organ ischemia and failure.
  • the present invention is directed to a method of treating septic, toxic, or anaphylactic shock comprising administering to a subject in need thereof a composition comprising brimonidine, wherein brimonidine is administered via subcutaneous or intramuscular injection at a concentration from about 0.01% to about 0.05% w/v or via intravenous injection at a concentration from about 0.0001% to about 0.01% w/v, more preferably from about 0.003% to about 0.005% w/v.
  • one or more nonionic surfactants can be used in the formulation at a total concentration from about 0.01% to about 7% w/v, preferably from about 0.1% to about 1% w/v.
  • Nonionic surfactants for this purpose include but are not limited to polysorbates, poloxamers, tyloxapols, polyoxyls, or cyclodextrins including polysorbate 80, poloxamer 407 and poloxamer 188.
  • the method can be used to treat various conditions, including, but not limited to, bronchitis, including respiratory syncytial virus (RSV) bronchitis.
  • bronchitis including respiratory syncytial virus (RSV) bronchitis.
  • RSV respiratory syncytial virus
  • a pulmonary condition may be associated with swollen nasal turbinates.
  • reducing capillary permeability allows decreasing ischemia, inflammation, rhinitis medicamentosa, and rebound hyperemia.
  • the invention also relates to compositions for reducing capillary permeability.
  • the invention generally relates to a composition for reducing capillary permeability comprising administering to a patient in need thereof a selective a-2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2 over a-l 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.
  • the composition for reducing capillary permeability comprises, consists essentially of or consists of brimonidine, wherein pH of said composition is from about 5.0 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an aerosolized composition.
  • the method comprises, consist essentially of or consists of administering to a patient in need thereof a composition comprising brimonidine, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%,.
  • brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%,.
  • Reducing capillary permeability can be exploited to decrease mucosal swelling and inflammation, such as occurs in the bronchial mucosal lumen of the respiratory tract from a variety of conditions, including influenza, bacterial pathogens, asthma, allergic asthma, and other causes of mucosal edema of the respiratory tract.
  • reducing capillary permeability allows reducing, alleviating or decreasing ischemia, inflammation, rhinitis medicamentosa, and rebound hyperemia.
  • reducing capillary permeability allows reducing and/or alleviating allergic or inflammatory conditions of the respiratory tract associated with a pulmonary condition, for example reducing the bronchiole mucosal edema and congestion.
  • the invention generally relates to a method of reducing capillary permeability in a pulmonary condition associated with swollen nasal turbinates comprising administering to a patient in need thereof a composition comprising, consisting essentially of or consisting of brimonidine, wherein pH of said composition is from about 3.5 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an aerosolized composition, and wherein the composition is administered into a nasal airway of the patient.
  • the invention generally relates to a method of reducing capillary permeability in a pulmonary condition associated with swollen nasal turbinates comprising administering to a patient in need thereof a composition comprises, consisting essentially of or consists of brimonidine, wherein pH of said composition is from about 5.0 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an aerosolized composition and administered into a nasal airway of the patient.
  • the invention generally relates to a method of treating respiratory syncytial virus (RSV) bronchitis comprising administering to a patient in need thereof a composition comprising, consisting essentially of or consisting of brimonidine, wherein pH of said composition is from about 5.0 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.07%, more preferably, from about 0.001% to about 0.03% weight by volume.
  • RSV respiratory syncytial virus
  • compositions suitable for the methods of the present invention can be administered thorough oral ingestion in about the same concentration ranges that are suitable for the topical application.
  • the invention generally relates to a method of reversing rebound hyperemia comprising administering to a patient currently or previously undergoing
  • an a-l adrenergic receptor agonist a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-l adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said first selective a-2 adrenergic receptor agonist is present at a concentration below about 0.05% weight by volume.
  • the selective a-2 adrenergic receptor agonist is present at a concentration from about 0.001% to about 0.05% weight by volume.
  • the method of reversing rebound hyperemia further decreases ischemia, inflammation, and rebound hyperemia associated with a-l agonist use.
  • the invention generally relates to a composition for reversing rebound hyperemia comprising brimonidine, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume.
  • the composition further comprises a buffer, and wherein pH of said composition is from about 5.5 to about 6.5.
  • the composition for reversing rebound hyperemia comprises, consists essentially of or consists of brimonidine, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, wherein pH of said composition is from about 5.5 to about 6.5, and wherein said composition is formulated as an ocular drop.
  • the invention generally relates to a composition for reversing rebound hyperemia comprises, consisting essentially of or consists of brimonidine and a second adrenergic receptor agonist, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, wherein pH of said composition is from about 5.5 to about 6.5, and wherein said composition is formulated as an ocular drop.
  • the present invention is directed to a method selected from the group consisting of reversing rebound hyperemia, reducing eye redness, increasing eye whiteness and a combination thereof, comprising topically administering to a subject in need thereof a composition comprising, consisting essentially of or consisting of from about 0.01% to about 0.015% w/v or from about 0.03% to about 0.045% w/v brimonidine or a pharmaceutically acceptable salt thereof, preferably, 0.0125% w/v or 0.037% w/v, wherein the composition optionally has a pH from about 5.5 to about 7.5 and is optionally formulated as an ocular drop. Reducing Activation of a-1 Receptors
  • the invention generally relates to a method of reducing activation of a-l adrenergic receptors comprising administering to a patient having an ocular or pulmonary condition a selective a-2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2 over a-l 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.
  • the selective a-2 adrenergic receptor agonist is present at a concentration from about 0.001% to about 0.05% weight by volume.
  • the method can be used to treat various ocular and pulmonary conditions.
  • a pulmonary condition may be associated with swollen nasal turbinates (e.g., nasal decongestion).
  • preferential vasoconstriction of smaller blood vessels allows decreasing ischemia, inflammation, rhinitis medicamentosa, and rebound hyperemia.
  • the method comprises administering to a patient having an ocular condition a composition comprising, consisting essentially of or consisting
  • brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%,.
  • compositions formulated for reducing activation of a-l receptors are also encompasses compositions formulated for reducing activation of a-l receptors.
  • the composition comprises, consists essentially of or consists of brimonidine, wherein pH of said composition is from about 5.5 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an ocular drop.
  • the invention generally relates to a method of reducing activation of a-l adrenergic receptors comprising topically administering to a patient having an ocular condition a composition comprising, consisting essentially of or consisting ofbrimonidine into ocular tissue, wherein pH of said composition is from about 5.5 to about 6.5, wherein said brimonidine concentration is from about 0.001% to about 0.05% weight by volume preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%, and wherein said composition is formulated as an ocular drop.
  • the invention generally relates to administering compositions of the present invention within about 24 hours after a Lasik surgery on the patient.
  • the invention generally relates to a method of reducing activation of a-l adrenergic receptors comprising administering to a patient having a nasal congestion, 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-l 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, whereby the reduced a-l adrenergic receptor activation is below the EDso for a-l induced vasoconstriction larger arteries and/or arterioles.
  • Selective a-2 Adrenergic Receptor Agonists that may be used for the purposes of the present invention have extremely high selectivity for a-2 adrenergic receptors, defined by their binding affinities (Ki) for a-2 over a-l receptors of more than 100: 1, more preferably 500: 1, even more preferably 700: 1, even more preferably 1000: 1 or greater, and most preferably, 1500: 1 or greater.
  • potency, activity or ECso at an a-2A receptor can be determined by assaying for inhibition of adenylate cyclase activity.
  • inhibition of adenylate cyclase activity can be assayed, without limitation, in PC12 cells stably expressing an a-2A receptor such as a human a-2A receptor.
  • potency, activity or EC so at an a-l A receptor can be determined by assaying for intracellular calcium. Intracellular calcium can be assayed, without limitation, in HEK293 cells stably expressing an a- 1 A receptor, such as a bovine a-l A receptor.
  • adrenergic receptor agonists for the purposes of the present invention are highly selective for a-2B and/or a- 2C receptors, as opposed to a-2A receptors.
  • the selective a-2 adrenergic receptor agonist is a compound which has binding affinity of about lOO-fold or greater for a-2 over a-l adrenergic receptors.
  • a concentration of the selective a-2 agonist is preferably from about 0.001% to about 0.07%; and is more preferably from about 0.02% to about 0.04%.
  • the selective a-2 adrenergic receptor agonist is a compound which has binding affinity of about 500-fold or greater for a-2 over a-l adrenergic receptors.
  • a concentration of the selective a- 2 agonist is preferably from about 0.001% to about 0.05%; and is more preferably from about 0.01% to about 0.02%.
  • the selective a-2 adrenergic receptor agonist is a compound which has binding affinity of about 700-fold or greater for a-2 over a-l adrenergic receptors.
  • a concentration of the selective a-2 agonist is preferably from about 0.001% to about 0.05%; and is more preferably from about 0.005% to about 0.01%.
  • the selective a-2 adrenergic receptor agonist is a compound which has binding affinity of about 1000-fold or greater for a-2 over a-l adrenergic receptors.
  • a concentration of the selective a-2 agonist is preferably from about 0.0005% to about 0.05%; and is more preferably from about 0.0025% to about 0.005%.
  • the selective a-2 adrenergic receptor agonist is a compound which has binding affinity of about 1500-fold or greater for a-2 over a-l adrenergic receptors.
  • a concentration of the selective a-2 agonist is preferably from about 0.0002% to about 0.05%; and is more preferably from about 0.001% to about 0.05%.
  • the selective a-2 adrenergic receptor agonist may be present at a concentration from about 0.0001% to about 0.05%, from about 0.005% to about 0.01%; from about 0.01% to about 0.15%, from about 0.001% to about 0.025%, from about 0.03% to about 0.045%, from about 0.01% to about 0.025% and from about 0.01% to about 0.02% weight by volume.
  • a concentration of a selective a-2 adrenergic receptor agonist be below its vasoconstriction vs. concentration plateau.
  • the optimal concentration is 10% to 90% above the minimal threshold of measurable vasoconstriction for a particular a-2 agonist, or below that of the plateau maximum concentration, and is preferably within the about 25% to about 75% range of either of these benchmarks.
  • plateau maximum concentration means the concentration above which there is no or minimal further vasoconstriction effect.
  • Other considerations in choosing a selective a-2 adrenergic receptor agonist are blood brain permeability and any possible side effects and other systemic reactions.
  • the selective a-2 adrenergic receptor is selected from the group consisting of apraclonidine, mivazerol, clonidine, brimonidine, alpha methyl dopa, guanfacine, dexmedetomidine, (+)-(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. Analogs of these compounds that function as highly selective a-2 agonists may also be used in compositions and methods of the present invention.
  • the selective a-2 adrenergic receptor is brimonidine in the form of tartrate salt.
  • the invention generally relates to a method of treating diseases associated with swollen nasal turbinates (e.g. nasal congestion), 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-l 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.
  • a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-l 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.
  • condition associated with swollen nasal turbinates is selected from the group consisting of nasal congestion, allergic rhinitis, asthma, sleep disorders, and sleep apnea.
  • the invention generally relates to compositions formulated for treating diseases associated with swollen nasal turbinates.
  • Compositions particularly useful for these purposes preferably comprise brimonidine at concentrations of from 0.001% to about 0.05%, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%.
  • Ocular conditions include, but are not limited to, red eye, including chronic red eye;
  • ocular vascular congestion after Lasik surgery prophylactic intraoperative and postoperative reduction of hemorrhage and hyperemia after Lasik surgery; preoperative hemorrhage and hyperemia prophylaxis prior to Lasik surgery; prophylactic diabetic retinopathy; macular edema such as that associated with diabetes; conditions of retinal degeneration such as glaucoma, macular degeneration such as age-related macular degeneration (ARMD) and retinitis
  • AMD age-related macular degeneration
  • retinal dystrophies elevated baseline hyperemia in glaucoma patients
  • inflammatory disorders of the retina vascular occlusive conditions of the retina such as retinal vein occlusions or branch or central retinal artery occlusions
  • retinopathy of prematurity retinopathy associated with blood disorders such as sickle cell anemia
  • elevated intraocular pressure ocular itch;
  • retinal damage following retinal detachment damage or insult due to vitrectomy, retinal or other surgery; and other retinal damage including therapeutic damage such as that resulting from laser treatment of the retina, for example, pan-retinal photocoagulation for diabetic retinopathy or photodynamic therapy of the retina.
  • Ocular conditions that can be prevented or alleviated by administering the topical formulations of the present invention further include, without limitation, generic and acquired optic neuropathies such as optic neuropathies characterized primarily by loss of central vision, for example, Leber's hereditary optic neuropathy (LEON), autosomal dominant optic atrophy (Kjer disease) and other optic neuropathies such as those involving mitochondrial defects aberrant dynamin-related proteins or inappropriate apoptosis; and optic neuritis such as that associated with multiple sclerosis, retinal vein occlusions or photodynamic or laser therapy.
  • LON Leber's hereditary optic neuropathy
  • Kjer disease autosomal dominant optic atrophy
  • optic neuropathies such as those involving mitochondrial defects aberrant dynamin-related proteins or inappropriate apoptosis
  • optic neuritis such as that associated with multiple sclerosis, retinal vein occlusions or photodynamic or laser therapy. See, for example, Carelli et al., Neurochem. Inti. 40:573-584
  • ocular condition also encompasses aesthetic conditions, for example, excessive redness of an eye.
  • the methods and compositions of the present invention can be used with other ocular procedures, particularly cataract surgery, retinal surgery, pterygiae removal, and motility surgery.
  • concentration range employed to eliminate hyperemia, endothelial cell pump dysfunction, and the high level of allergic reactions of the glaucoma class of brimonidine concentrations no intraocular pressure effects are noted. This is important because in cosmetic use, while retention of normal intraocular pressure is desired, lowering of intraocular pressure is not a necessary or desirable parameter to reduce in a normotensive population.
  • the preferred a-2 agonist is brimonidine at a concentration of from about 0.005% to about 0.05%, preferably from about 0.01% to about 0.015% or from about 0.03% to about 0.045%,
  • a selective a-2 agonist’s concentration has to be such that intraocular pressure is not substantially reduced and endothelial cell pump is not
  • brimonidine has the same hyperemic profile and high incidence of rebound hyperemia in clinical use as apraclonidine, when this class of more selective compounds is optimized to its vasoconstrictive dose response range, it is shown to have superior vasoconstrictive effect with less rebound (See, FIG. 3).
  • Pulmonary conditions include, but are not limited to vascular congestion, mucosal swelling of bronchi and bronchioles, bronchitis, respiratory syncytial virus (RSV) bronchitis, etc.
  • Other pulmonary uses include treatment of increases in capillary permeability that further shrink the available lumen size of an airway. Such increases in capillary permeability occur in allergic rhinitis, common cold; influenza; asthma, acute respiratory distress syndrome, and acute lung injury. Such conditions can cause alveolar capillary increased permeability and capillary changes along the mucosal surface that swell the mucosa into the lumen.
  • An increase in capillary permeability is known as one of the main features by which these pathogens are disseminated inside a host organism through cascade of inflammatory byproducts and other specific means of induction.
  • the invention generally relates to a method for treatment of a pulmonary condition comprising delivering compositions of the present invention as an aerosol having mass medium average diameter predominantly between 1 to 10m, produced by an inhaler, jet or ultrasonic nebulizer.
  • compositions of the present invention may also be used in other clinical indications for vasoconstriction, such as treating the subcutaneous epidermal swelling observed along and around the lower eyelids or the venous dilation of hemorrhoids.
  • the present invention further provides compositions formulated to relieve the vascular engorgement associated with dilated vessels of hemorrhoid tissue with less morbidity than epinephrine or phenylephrine used with prior art.
  • Compositions particularly useful for these purposes comprise brimonidine at concentrations of from 0.001% to 0.05%.
  • the present invention further provides compositions formulated to relieve the vascular engorgement associated with dilated vessels of pulmonary bronchi and bronchioles, via inhalant vehicle, to relieve more effectively than prior art, with less morbidity than epinephrine, norepinephrine, or pseudoephedrine, mucosal swelling and congestion associated with colds, flu, and other productive cough.
  • Compositions particularly useful for these purposes comprise brimonidine at concentrations of from 0.001% to 0.045%.
  • the methods and compositions of the present invention may be used during endotracheal intubation.
  • the invention relates to a method of treating sore throat, 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-l 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 concentration below about 0.01% weight by volume.
  • the invention generally relates to a method of scleral whitening without significant rebound hyperemia, comprising administering to a patient in need thereof a topical composition comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-l adrenergic receptors, or a
  • This method allows achieving a more effective scleral whitening (i.e., whiter shades of scleral color) than possible with prior art compositions and methods, as a result of more effective vasoconstriction that creates sufficient constriction of the capillary bed within the sclera to induce an overall whitening not observed with prior art, allowing for an improved cosmetic appearance.
  • scleral whitening i.e., whiter shades of scleral color
  • the preferred a-2 agonist is brimonidine at a concentration of from about 0.001% to about 0.05%, from about 0.005% to about 0.01%; from about 0.01% to about 0.15%, from about 0.001% to about 0.025%, from about 0.03% to about 0.045%, from about 0.01% to about 0.025% and from about 0.01% to about 0.02% weight by volume..
  • compositions of the present invention may also be used to treat noninfectious conjunctival hyperemia (caused, for example, by lack of sleep, consumption of alcohol, or other noninfectious causes).
  • the invention generally relates to a method of reducing redness in an eye, comprising administering to a patient in need thereof a topical composition comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-l 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.
  • the administering step of the topical composition may be done through the use of a hydrophilic contact lens, wherein the hydrophilic lens comprises a reservoir for retaining the topical compositions of the present invention.
  • the present invention is directed to a method selected from the group consisting of reversing rebound hyperemia, reducing eye redness, increasing eye whiteness and a combination thereof comprising, consisting essentially of or consisting of the steps of:
  • a contact lens in a solution comprising from about 0.005% to about 0.015% w/v brimonidine or a pharmaceutically acceptable salt thereof, preferably 0.008% w/v;
  • composition optionally has a pH from about 4.0 to about 7.5.
  • the present invention is directed to a method selected from the group consisting of reversing rebound hyperemia, reducing eye redness, increasing eye whiteness and a combination thereof comprising, consisting essentially of or consisting of instilling a
  • composition comprising from about 0.005% to about 0.015% w/v brimonidine or a
  • composition optionally has a pH from about 4.0 to about 7.5.
  • the preferred a-2 agonist is brimonidine at a concentration of from about 0.001% to about 0.05%, from about 0.005% to about 0.01%; from about 0.01% to about 0.15%, from about 0.001% to about 0.025%, from about 0.03% to about 0.045%, from about 0.01% to about 0.025% and from about 0.01% to about 0.02% weight by volume.
  • the invention generally relates to a method for lightening tissue coloration comprising administering locally to a patient in need thereof a topical composition comprising a selective a-2 adrenergic receptor agonist having a binding affinity of lOO-fold or greater for a-2 over a-l 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.
  • methods of the present invention allow administration of the selective a-2 agonists for approximately at least a week; for approximately two weeks; for approximately three weeks; for approximately one month; for approximately two months; for approximately between two months and one year; for approximately one year; and for approximately longer than one year. It is to be understood that it is within a skill in the art to determine the most appropriate time period of administration.
  • compositions of the present invention enable their relatively frequent and long-term use.
  • treatment can be repeated as often as every two hours, or commonly once every three to four hours.
  • vasoconstrictive agents can be applied for prolonged periods of time (for example, for several hours) for much greater therapeutic index in reaching affected superficial vascular regions.
  • vasoconstrictors is largely due to vascular abnormalities, inflammatory changes, or other vascular responses to chemical modulation by emotional changes (flushing).
  • systemic absorption is typically considerably reduced compared to mucous membranes.
  • Facial rosacea, and in particular, acne rosacea have distribution along either side of the nasal bridge, under the eyelids, and frequently includes the lower eyelids.
  • compositions of the present invention offer improved safety and efficacy as compared to higher concentrations of the prior art.
  • the application time of the compositions of the present invention lasts not more than about five minutes. In another embodiment, the application time of the compositions of the present invention is less than one minute.
  • the treatment for vasoconstriction can also be used to treat chronic conditions. For example, treatments can be repeated over a period of several months to a year, and most likely several years, as is currently common for glaucoma treatment with this class of molecules.
  • compositions of the present invention may be used every two hours, or more commonly, every three to four hours with low incidence of hyperemia.
  • concentrations should be optimized for their vasoconstrictive dose response curve, which may differ from other desired clinical effects.
  • the invention in addition to using low doses of highly selective a-2 agonists by themselves, the invention also provides methods for using these highly selective a-2 agonists in several combinatorial applications, for example in combinations with a-l antagonists and in combinations with antihistamines.
  • a-l antagonists have been shown to have the property of reducing scotopic and mesopic pupil dilation a-l agonists of prior art, such as naphazoline, tetrahydrozoline, and oxymetazoline, have an undesirable property of causing papillary dilation with attendant reduction in quality of vision in a significant percentage of individuals.
  • the highly selective a-2 agonists of the present invention at the claimed concentrations do not cause papillary dilations.
  • compositions and methods of the present invention may combine highly selective a-2 agonists, as defined by the present invention, with a-l antagonists and/or selective a-l antagonists to minimize hyperemia and optimize the concentration which can be used for maximum reduction of sympathomimetic induced low light pupil enlargement. This has important consequence for improving night vision in people with large pupils and increased higher order aberrations, or higher order aberrations from other causes (such as refractive surgery).
  • Phentolamine is a preferred pharmaceutical agent for such use. When combined with the present invention, its use is further optimized.
  • the highly selective a-2 agonists of the present invention are employed in ratios varying from about 0.02% to about 0.05%.
  • the a-l antagonist is phentolamine myrsalate, and its concentration is from about 0.01% to about 0.1%.
  • the invention generally relates to a composition formulated for treating and/or preventing an allergic response with reduced rebound hyperemia, comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-l adrenergic receptors, or a pharmaceutically acceptable salt thereof, and a histamine antagonist, wherein said selective a-2 adrenergic receptor agonist is present at a concentration below about 0.025% weight by volume.
  • the invention generally relates to a method of treating and/or preventing an allergic response with reduced rebound hyperemia comprising administering to a patient in need thereof the composition comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-l adrenergic receptors, or a pharmaceutically acceptable salt thereof, and a histamine antagonist, wherein said selective a-2 adrenergic receptor agonist is present at a concentration below about 0.025% weight by volume.
  • the a-2 agonist is brimonidine at a concentration of from about 0.001% to about 0.025% weight by volume; and the preferred histamine antagonist is selected from the group consisting of loratadine, desloratadine, cetirizine, fexofenadine, acrivastine, ebastine, norastemizole, levocetirizine, and mizolastine.
  • the composition for treating and/or preventing an allergic response with reduced rebound hyperemia is an aerosolized composition.
  • the invention generally relates to a composition
  • a composition comprising, consisting essentially of or consisting of brimonidine and pheniramine maleate, wherein said brimonidine concentration is from about 0.001% to about 0.025% weight by volume, wherein pH of said composition is from about 5.5 to about 6.5, and wherein said composition is formulated as an aerosolized composition.
  • the invention generally relates to a composition
  • a composition comprising, consisting essentially of or consisting of brimonidine and a nonsedating antihistamine, wherein said brimonidine concentration is from about 0.001% to about 0.025% weight by volume, wherein pH of said composition is from about 5.5 to about 6.5, and wherein said composition is formulated as an aerosolized composition.
  • compositions of the present invention are preferably formulated for a mammal, and more preferably, for a human.
  • compositions of the present invention are topical compositions.
  • topical composition is formulated for treating and/or preventing an ocular condition.
  • the topical compositions include, but are not limited to, ocular drops, ocular ointments, gels and creams. They may also include additional non-therapeutic components, which include, but are not limited to, preservatives, delivery vehicles, tonicity adjustors, buffers, pH adjustors, antioxidants, and water.
  • the preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, or phenylmercuric nitrate.
  • Vehicles useful in a topical ophthalmic composition include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Some of the preferred preservatives include Blink® (Abbott Medical Optics ®; active ingredient: polyethylene glycol 400 0.25%) and perborate. It is also possible to use a physiological saline solution as a major vehicle.
  • a tonicity adjustor also can be included, if desired, in a topical composition of the invention.
  • a tonicity adjustor can be, without limitation, a salt such as sodium chloride, potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmically acceptable tonicity adjustor.
  • Various buffers and means for adjusting pH can be used to prepare topical compositions of the invention.
  • Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. It is understood that acids or bases can be used to adjust the pH of the composition as needed.
  • Topically acceptable antioxidants useful in preparing a topical composition include, yet are not limited to, sodium metabi sulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • topical compositions of the present invention one can simply dilute, using methods known in the art, more concentrated solutions of selective a-2 agonists.
  • the precise method of carrying out the dilutions is not critical. Any commonly used diluents, including preservatives described above in the application, suitable for topical solutions can be used.
  • the topical compositions of the present invention are ophthalmic compositions.
  • An ophthalmic composition contains an ophthalmically acceptable carrier, which can be any carrier that has substantially no long term or permanent detrimental effect on the eye to which it is administered.
  • ophthalmically acceptable carriers include, but are not limited to, water, including distilled or deionized water; saline; and other aqueous media.
  • said composition is an aerosolized composition.
  • the aerosolized composition is formulated for treating and/or preventing a pulmonary condition. [161] It is within a skill in the art to prepare aerosolized compositions of the present invention.
  • the aerosolized compositions of the present invention are generally delivered via an inhaler Jet nebulizer, or ultrasonic nebulizer which is able to produce aerosol particles with size of from about 1 to about 10 pm.
  • the selective a-2 agonist may be formulated in about 5 ml solution of a quarter normal saline having pH from 5.5 to 6.5, preferably from 5.5 to 6.0.
  • the aerosolized composition comprises about 0.02% brimonidine in about 5 ml solution, which further comprises about 0.225% sodium chloride, and wherein said composition has a pH from about 5.5 to about 6.5, preferably from 5.5 to 6.0.
  • a pH of the compositions of the present invention is less than about 7.0, preferably, from about 5.5 to about 6.5, more preferably from 5.5 to 6.0.
  • compositions of the present invention further include potassium (i.e., K+).
  • potassium i.e., K+.
  • the term“potassium” includes, but is not limited to, potassium salt.
  • potassium is potassium chloride.
  • compositions of the present invention further include calcium (i.e., Ca 2+ ).
  • calcium i.e., Ca 2+
  • the term“calcium” includes, but is not limited to, calcium salt.
  • calcium is calcium chloride.
  • compositions of the present invention comprise nitrous oxide inhibitors.
  • the nitrous oxide inhibitors are selected from the group consisting of L-NAME, L-NIL, L-NIO, and L-canavine, or combinations thereof.
  • concentration of the nitrous oxide inhibitors is from about 0.005% to about 0.5% weight by volume.
  • compositions of the present invention can be included in a pharmaceutically suitable vehicle suitable for oral ingestion.
  • suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • compositions contemplated for use in the practice of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the active compounds contemplated for use herein, as active ingredients thereof, in admixture with an organic or inorganic carrier or excipient suitable for nasal, enteral or parenteral applications.
  • the active ingredients may be compounded, for example, with the usual non-toxic, pharmaceutically and physiologically acceptable carriers for tablets, pellets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, suppositories, solutions, emulsions, suspensions, hard or soft capsules, caplets or syrups or elixirs and any other form suitable for use.
  • the usual non-toxic, pharmaceutically and physiologically acceptable carriers for tablets, pellets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, suppositories, solutions, emulsions, suspensions, hard or soft capsules, caplets or syrups or elixirs and any other form suitable for use.
  • the carriers that can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • auxiliary, stabilizing, thickening and coloring agents may be used.
  • compositions of the present invention can be administered locally via an intraocular or periocular implant, which can be, without limitation, biodegradable or reservoir-based.
  • an intraocular or periocular implant which can be, without limitation, biodegradable or reservoir-based.
  • implant refers to any material that does not significantly migrate from the insertion site following implantation.
  • An implant can be biodegradable, non-biodegradable, or composed of both biodegradable and non-biodegradable materials; a non-biodegradable implant can include, if desired, a refillable reservoir.
  • Implants useful for preventing or alleviating an ocular condition include, for example, patches, particles, sheets, plaques, microcapsules and the like, and can be of any shape and size compatible with the selected site of insertion, which can be, without limitation, the posterior chamber, anterior chamber, suprachoroid or sub conjunctiva of the eye. It is understood that a useful implant generally releases the implanted ophthalmic composition at a therapeutically effective dose to the eye of the subject over an extended period of time.
  • a variety of ocular implants and extended release formulations suitable for ocular release are well known in the art, as described, for example, in U.S. Pat. Nos. 5,869,079 and 5,443,505.
  • FIG. 1 depicts vasoconstrictive net clinical effectiveness for prior art a-agonists.
  • Vasoconstrictive net clinical effectiveness is calculated by subtracting each compound’s rebound hyperemic dose response curve from vasoconstrictive dose response curve.
  • the general effectiveness and approximate optimal concentrations with the least rebound are revealed by the X-Y intersecting dashed lines. There is a slight peak for each molecule where its benefit to risk ratio is optimized.
  • the reference concentration mark at 0.08% is to the right of the dose response data.
  • FIG. 2 highlights the key discoveries of the present invention. It depicts a plot of vasoconstriction effect versus various concentrations of brimonidine, a selective a-2 agonist of the present invention. Vasoconstrictive effect when studied at reduced concentrations is shown to have been above its maximum dose response benefit, while intraocular pressure reduction and corneal endothelial cell pump inhibition are shown to have been just at their maximum at about 0.09%. As a result, there is an exponential drop-off in intraocular pressure reduction and endothelial cell pump inhibition just below 0.08%, while vasoconstrictive effect remains largely unchanged at these lower concentrations until much lower concentrations are reached.
  • FIG. 2 demonstrates that highly selective a-2 agonists defined by their binding affinities (Ki) for a-2 over a-l receptors of more than 100:1, more preferably 500: 1, even more preferably 700: 1, even more preferably 1000: 1 or greater, and most preferably, 1500: 1 or greater, results in an optimized concentration range for optimal vasoconstriction without rebound hyperemia.
  • Ki binding affinities
  • FIG. 3 depicts a graphical representation of clinical effectiveness of the compositions of the present invention versus prior art compositions. The net effect of this improved
  • vasoconstrictive benefit of a-2 predominant receptor activation and reduced rebound is highlighted for brimonidine in FIG. 3 relative to a-agonist vasoconstrictors in current clinical use.
  • the potency and reduced morbidity allow for additional benefits of the subclass of more highly selective a-2 agonists as defined by the present invention.
  • FIG. 4 contains graphical representations of results of Example 1 and will be explained more fully in the section of the application dealing with Example 1.
  • selective a-2 compositions of the present invention can reverse pre-induced rebound hyperemia of general alpha agonists.
  • FIG. 5A is a baseline visual appearance of two eyes of a patient with an ocular condition.
  • Figure 5B depicts a visual appearance of the right eye of the patient after being treated with a prior art composition comprising VISINE Original® (Johnson & Johnson’s registered trademark; active ingredient: tetrahydrozoline HCL 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 brimonidine at 0.015%.
  • VISINE Original® Johnson & Johnson’s registered trademark; active ingredient: tetrahydrozoline HCL 0.05%
  • brimonidine a composition of the present invention comprising brimonidine at 0.015%.
  • Figure 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 hyperemia, 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 brimonidine at 0.015%.
  • FIG. 6 depicts a graphical representation of a finding of the present invention that an increased rebound hyperemia begins at around 0.03% for brimonidine. It thus demonstrates that the net effectiveness of brimonidine as a decongestant is greatest from about 0.01% to about 0.03%; preferably, from about 0.012% to about 0.02%.
  • Fig 4A shows the base line for both eyes.
  • FIG 4B shows a comparison after 180 minutes, where the right eye has been treated with tetrahydrozoline at 0.05% and the left eye was treated with brimonidine at 0.01 %
  • Fig 4C shows a comparison four hours after baseline (Fig 4A), where the right eye has been treated with oxymetazoline at 0.025% and the left eye was treated with brimonidine at 0.02%
  • Fig 4D shows a comparison where after a further four hours, the right eye has been treated with naphazoline at 0.033%; and the left eye was treated with brimonidine at 0.02%.
  • Fig 4E shows the effect of brimonidine at 0.033% on the left eye only, 4 hrs after the effect shown in Fig 4D (showing the third application to be without rebound hyperemia).
  • compositions of the present invention may be used every three to four hours with low incidence of hyperemia.
  • Treatment group 1
  • Naphcon-A ® (Alcon, Inc; active ingredients: naphazoline hydrochloride 0.25% and pheniramine maleate 0.3%; preserved with benzalkoniurnm chloride) was used on a second group of 50 patients (85 procedures), 12% petichial or larger hemorrhage. 35% 1+ hyperemia; 35% 2+ hyperemia; 15% 2.5+ hyperemia; 15% 3+ hyperemia. Some clinical benefit noted. Flap dislocation rate: ⁇ 0.1 %.
  • the patients were assigned“cumulative red scores” , prior to each administration (as baseline) and then 10 min after each dose, by dividing the bulbar conjunctiva into six sectors, each scored with a grade 1-3 score and the total cumulative score.
  • the patients were calculated to have 68.71% reduction in redness score after administration of a single dose of brimonidine at 0.018%, and 31.06% reduction in redness score after administration of VISINE Original® after a single application.
  • Example 5 About 5 to 7.5% of individuals experience side effects when administered 0.025% brimonidine that the average population will only experience after administration at higher concentrations (i.e. 0.1%, 0.2%, etc.%) such as eye ache or strain, eye fatigue, general lethargy, eye lid irritation, and other side effects.
  • concentrations i.e. 0.1%, 0.2%, etc.
  • eye ache or strain i.e. 0.1%, 0.2%, etc.
  • eye fatigue i.e. 0.1%, 0.2%, etc.
  • eye lid irritation i.e. 0.1%, 0.2%, etc.

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Abstract

L'invention concerne de manière générale des compositions pour induire une vasoconstriction. Les compositions comprennent des agonistes du récepteur adrénergique alpha -2 hautement sélectifs, à de faibles concentrations, par exemple au-dessous de 0,05 % en poids par volume. Les compositions comprennent de préférence de la brimonidine. Les compositions ont de préférence un pH d'environ 4,0 à environ 7,5.
PCT/US2019/047225 2018-08-22 2019-08-20 Compositions de vasoconstriction et procédés d'utilisation WO2020041282A1 (fr)

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US16/108,727 US20180360825A1 (en) 2008-08-01 2018-08-22 Vasoconstriction compositions and methods of use

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021222525A1 (fr) * 2020-04-30 2021-11-04 Eye Therapies, Llc Compositions de brimonidine et procédés d'utilisation

Citations (4)

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Publication number Priority date Publication date Assignee Title
US20100029663A1 (en) * 2008-08-01 2010-02-04 Alpha Synergy Development, Inc. Compositions and methods for reducing activation of alpha-1 receptors
US20110003823A1 (en) * 2008-08-01 2011-01-06 Alpha Synergy Development, Inc. Compositions and methods for treatment of diseases and conditions associated with vasodilation and/or vascular leakage
US20120328687A1 (en) * 2009-07-27 2012-12-27 Alpha Synergy Development, Inc. Formulations of selective alpha-2 agonists and methods of use thereof
US20130143938A1 (en) * 2009-07-27 2013-06-06 Eye Therapies Llc Compositions and Methods for the Treatment of Migraine

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Publication number Priority date Publication date Assignee Title
US20100029663A1 (en) * 2008-08-01 2010-02-04 Alpha Synergy Development, Inc. Compositions and methods for reducing activation of alpha-1 receptors
US20110003823A1 (en) * 2008-08-01 2011-01-06 Alpha Synergy Development, Inc. Compositions and methods for treatment of diseases and conditions associated with vasodilation and/or vascular leakage
US20120328687A1 (en) * 2009-07-27 2012-12-27 Alpha Synergy Development, Inc. Formulations of selective alpha-2 agonists and methods of use thereof
US20130143938A1 (en) * 2009-07-27 2013-06-06 Eye Therapies Llc Compositions and Methods for the Treatment of Migraine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021222525A1 (fr) * 2020-04-30 2021-11-04 Eye Therapies, Llc Compositions de brimonidine et procédés d'utilisation

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