US20100203165A1 - Compositions and methods for treatment of disorders or conditions of the eye - Google Patents

Compositions and methods for treatment of disorders or conditions of the eye Download PDF

Info

Publication number
US20100203165A1
US20100203165A1 US12/767,394 US76739410A US2010203165A1 US 20100203165 A1 US20100203165 A1 US 20100203165A1 US 76739410 A US76739410 A US 76739410A US 2010203165 A1 US2010203165 A1 US 2010203165A1
Authority
US
United States
Prior art keywords
composition
eye
potassium
calcium
selective
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/767,394
Other languages
English (en)
Inventor
Gerald Horn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alpha Synergy Development Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44167711&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20100203165(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US12/460,942 external-priority patent/US8338421B2/en
Application filed by Individual filed Critical Individual
Priority to US12/767,394 priority Critical patent/US20100203165A1/en
Publication of US20100203165A1 publication Critical patent/US20100203165A1/en
Assigned to Alpha Synergy Development, Inc. reassignment Alpha Synergy Development, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HORN, GERALD
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • a variety of diseases and conditions can cause reddening of an eye, including, but not limited to such conditions as dry eye, contact lens wear, allergic conjunctivitis, glaucoma, topical glaucoma medications, idiopathic, smoking, alcohol abuse, drug use, lack of sleep, allergic rhinitis, nonallergic rhinitis, and acute or chronic sinusitis.
  • healthy individuals may have natural off white or slightly yellow shading of their sclera and or episclera.
  • a normal healthy eye has a certain baseline level of whiteness, which slightly varies from person to person.
  • Whiter eyes are traditionally a societal symbol of natural healthy eyes, and excellent overall hygiene and health.
  • a human eye has a lot of ⁇ -2 adrenergic receptors.
  • Selective agonists of these receptors i.e., compounds which preferentially bind to ⁇ -2 adrenergic receptors
  • This may result in vasoconstriction, and more particularly, microvessel lumen size reduction, which in turn may increase the per unit surface area degree of microvessel constriction, and therefore, improve cosmetic appearance of eyes with insignificant to minimal reduction of larger vessels thereby preventing ischemia.
  • compositions comprising low concentrations of selective ⁇ -2 adrenergic receptor agonists in combination with potassium and/or calcium.
  • compositions are used for treatment of eye disorders or conditions.
  • the invention provides a composition for use in treatment of eye disorders or conditions, wherein said composition comprises a selective ⁇ -2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said ⁇ -2 adrenergic receptor is present at a concentration from between about 0.001% to about 0.05% weight by volume of the composition, and wherein said composition comprises potassium and/or calcium.
  • potassium is in the form of potassium chloride
  • calcium is in the form of calcium chloride
  • the concentration of potassium chloride is between about 5 mM to about 100 mM; in more preferred embodiments between about 10 mM to about 70 mM; and in even more preferred embodiments between about 10 mM to about 50 mM; and the concentration of calcium chloride is between about 0.05 mM to about 5 mM; and in even more preferred embodiments between about 1 mM to about 2 mM.
  • Selective ⁇ -2 adrenergic receptor agonists include, but are not limited to, lofexidine, 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.
  • the invention provides a composition for use in treatment of eye disorders or conditions, wherein said composition comprises between about 0.001% to about 0.05% weight by volume of brimonidine, between about 0.2% to about 0.3% weight by volume of boric acid, between about 10 mM to about 70 mM of potassium chloride, between about 0.05 mM and about 2 mM of calcium chloride, wherein pH of said composition is between about 5.5 and about 7.5, and wherein osmolality of said composition is between about 250 mOsm/kg and about 300 mOsM/kg.
  • compositions of the invention comprise hypromellose.
  • the invention provides methods of treatment of eye disorders or conditions, comprising administering to an eye of a patient in need thereof a composition, wherein said composition comprises a selective ⁇ -2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said ⁇ -2 adrenergic receptor is present at a concentration from between about 0.001% to about 0.05% weight by volume of the composition, and wherein said composition comprises potassium and/or calcium.
  • a composition comprises a selective ⁇ -2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said ⁇ -2 adrenergic receptor is present at a concentration from between about 0.001% to about 0.05% weight by volume of the composition, and wherein said composition comprises potassium and/or calcium.
  • the invention also provides methods of enhancing vasoconstricting activity of a selective ⁇ -2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors comprising adding potassium and/or calcium to a pharmaceutical composition which comprises said selective ⁇ -2 adrenergic receptor agonist.
  • Eye disorders and conditions include both therapeutic and cosmetic conditions. For example, one might wish to cause an eye whitening either for cosmetic reasons or to reverse an eye reddening effect of various diseases and conditions.
  • diseases and conditions may be ocular, pulmonary or others, and include, but are not limited to, dry eye, contact lens wear, allergic conjunctivitis, allergic rhinitis, nonallergic rhinitis, acute or chronic sinusitis, nasal polyposis, rhinitis secondary to pregnancy, rhinitis due to nasal septal deviation or obstruction, asthma, particularly, allergic asthma and others.
  • selective ⁇ -2 adrenergic receptor agonists encompasses all ⁇ -2 adrenergic receptor agonists which have a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors.
  • the term also encompasses pharmaceutically acceptable salts, esters, prodrugs, and other derivatives of selective ⁇ -2 adrenergic receptor agonists.
  • concentrations refers to concentrations from between about 0.0001% to about 0.05%; more preferably, from about 0.001% to about 0.05%; even more preferably, from about 0.01% to about 0.025%; and even more preferably, from about 0.01% to about 0.02% weight by volume of the composition.
  • concentrations of the selective ⁇ -2 adrenergic receptor agonists are substantially lower than the concentrations normally used in the treatment of glaucoma.
  • substantially refers to such concentration that would not previously be considered effective for the treatment of glaucoma.
  • 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.
  • potassium encompasses potassium salts and specifically includes, but is not limited to, potassium chloride.
  • calcium encompasses calcium salts and specifically includes, but is not limited to, calcium chloride.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
  • treating and “treatment” refer to reversing, alleviating, inhibiting, or slowing the progress of the disease, disorder, or condition to which such terms apply, or one or more symptoms of such disease, disorder, or condition.
  • preventing and prevention refer 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.
  • selective alpha-2 ( ⁇ -2) adrenergic receptor agonists (which are interchangeably referred to as “ ⁇ -2 agonists” throughout the application) at sufficiently low concentrations, in combination with potassium alone and/or potassium and calcium together, allow significant improvement in tissue hemodynamics and can be used for treatment of eye disorders or conditions.
  • the selective ⁇ -2 agonists at low concentrations promote vasoconstriction and allow reducing, minimizing, and/or eliminating hyperemia, including rebound hyperemia while optimally providing clinically equal or more effective vasoconstriction. While not wishing to be bound to any particular theory, it is believed that rebound hyperemia is primarily associated with ⁇ -1 agonist activity. Thus, unless the binding affinity of ⁇ -2 agonists for ⁇ -2 over ⁇ -1 adrenergic receptors is sufficiently high, not sufficiently selective ⁇ -2 agonists will cause undesirable ⁇ -1 receptor stimulation with attendant rebound hyperemia. Accordingly, it is desired to minimize ⁇ -1 agonist activity by using selective ⁇ -2 agonists.
  • Potassium and/or calcium are able to potentiate the effects of selective ⁇ -2 agonists. While not wishing to be bound to any specific theory, it is believed that potassium and calcium ions are able to create a mini electric current which can stimulate the constriction of the smooth muscle of a vessel, provided intracellular calcium is present. In the presence of ⁇ -2 agonists, even small amounts of potassium with or without exogenous calcium ions, even if not themselves sufficient for such voltage potential changes, may enhance ⁇ -2 agonists' vasoconstrictive activity, including onset, degree of vasoconstriction, and duration. Thus, potassium and/or calcium are believed to enhance and/or improve vasoconstrictive effects of ⁇ -2 agonists.
  • the present invention provides compositions comprising low concentrations of selective ⁇ -2 adrenergic receptor agonists in combination with potassium alone and/or potassium and calcium together.
  • compositions are used for treatment of eye disorders or conditions.
  • the invention provides methods of treatment of eye disorders and conditions comprising administering to an eye of a patient in need thereof a composition, wherein said composition comprises low concentrations of selective ⁇ -2 agonists in combination with potassium and/or potassium and calcium together, and in some cases, calcium alone.
  • the methods and compositions of the invention may be used to reduce eye reddening and/or achieve eye whitening by reducing hyperemia caused by a disease or a condition.
  • the methods and compositions of the invention may be used to achieve eye whitening in healthy eyes.
  • the methods and compositions of the invention may be used to both achieve cosmetic eye whitening and to reduce eye reddening due to a disease or a condition.
  • any ⁇ -2 agonist activity may be enhanced by the addition of K and Ca.
  • ⁇ -2 agonist activity in nasal decongestion, pulmonary uses, and/or other uses of ⁇ -2 agonists such as described in U.S. patent application Ser. Nos. 12/460,942; 12/460,968; 12/460,941; 12/460,967; 12/460,970; 12/460,954; 12/460,969; 61/287,533; and 61/287,518 may be enhanced and is intended to be covered here by this application. Further, for pulmonary use such enhancement is at sufficiently low dose of potassium and calcium to facilitate ⁇ -2 agonist activity without causing bronchiole constriction.
  • selective ⁇ -2 adrenergic receptor agonists have binding affinities (K i ) for ⁇ -2 over ⁇ -1 receptors of 100:1 or greater.
  • selective ⁇ -2 adrenergic receptor agonists have K i for ⁇ -2 over ⁇ -1 receptors of 500:1 or greater, more preferably 700:1 or greater, even more preferably 1000:1 or greater, and most preferably, 1500:1 or greater.
  • the particularly preferred adrenergic receptor agonists for the purposes of the present invention have higher selectivity for ⁇ -2B and/or ⁇ -2C receptors, as compared to ⁇ -2A receptors.
  • concentrations of selective ⁇ -2 adrenergic receptor agonists are from between about 0.0001% to about 0.05%; more preferably, from about 0.001% to about 0.05%; even more preferably, from about 0.01% to about 0.025%; and even more preferably, from about 0.01% to about 0.02% weight by volume of the composition.
  • any selective ⁇ -2 adrenergic receptor agonist may be suitable for the purposes of the present invention.
  • the selective ⁇ -2 adrenergic receptor 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-[(imidazolid in-2-yl)imino]indazole, and mixtures of these compounds.
  • compositions and methods of the inventions encompass all isomeric forms of the described ⁇ -2 adrenergic receptor agonists, their racemic mixtures, enol forms, solvated and unsolvated forms, analogs, prodrugs, derivatives, including but not limited to esters and ethers, and pharmaceutically acceptable salts, including acid addition salts.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, furmaric, succinic, ascorbic, maleic, methanesulfonic, tartaric, and other mineral carboxylic acids well known to those in the art.
  • the salts may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid salts are equivalent to their respective free base forms for purposes of the invention. (See, for example S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference).
  • a selective ⁇ -2 adrenergic receptor agonist functions as a selective ⁇ -2 agonist, it may be used for the purposes of the present invention.
  • ⁇ -2 adrenergic receptor agonist When choosing a particular ⁇ -2 adrenergic receptor agonist, one may take into account various considerations including blood brain permeability and any possible side effects and other systemic reactions.
  • the selective ⁇ -2 adrenergic receptor is brimonidine or its salt.
  • the selective ⁇ -2 adrenergic receptor agonist is the tartrate salt of brimonidine.
  • the present invention provides compositions comprising low concentrations of selective ⁇ -2 adrenergic receptor agonists in combination with potassium and/or calcium.
  • the compositions are used for treatment of eye disorders or conditions.
  • the invention provides a composition for use in treatment of eye disorders or conditions, wherein said composition comprises a selective ⁇ -2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said ⁇ -2 adrenergic receptor is present at a concentration from between about 0.001% to about 0.05% weight by volume of the composition, wherein said composition comprises potassium and/or calcium.
  • potassium is in the form of potassium chloride
  • calcium is in the form of calcium chloride
  • the concentration of potassium chloride is between about 5 mM to about 100 mM; more preferably between about 10 mM to about 70 mM; and even more preferably between about 10 mM to about 50 mM, and most preferably about 40 mM; and the concentration of calcium chloride is between about 0.05 mM to about 5 mM, more preferably between about 0.05 mM to about 2 mM, and most preferably about 1 mM.
  • a pH of the compositions of the present invention is less than about 8.0, preferably, between about 5.5 and about 8.0, more preferably between about 5.5 and about 7.5, even more preferably between about 6.0 and about 7.0, and most preferably about 6.5.
  • osmolality of the compositions of the present invention is between about 250 mOsm/kg and about 300 mOsm/kg; most preferably, about 270 mOsm/kg.
  • compositions of the present invention are preferably formulated for a mammal, and more preferably, for a human.
  • the invention provides a composition for inducing vasoconstriction consisting essentially of brimonidine and/or potassium, wherein said brimonidine 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 composition is formulated as an ocular drop.
  • the invention provides an aqueous composition for treatment of eye disorders or conditions, comprising between about 0.01% to about 0.025% weight by volume of brimonidine and from between about 0.1 to about 0.5% weight by volume of potassium chloride, wherein pH of said composition is between about 7.0 and about 8.0, and wherein said composition is formulated as an ocular drop.
  • the invention provides a composition for use in treatment of eye disorders or conditions, wherein said composition comprises between about 0.001% to about 0.05% weight by volume of brimonidine, between about 0.2% to about 0.3% weight by volume of boric acid, between about 10 mM to about 70 mM of potassium chloride, between about 0.05 mM and about 2 mM of calcium chloride, wherein pH of said composition is between about 6.0 and about 7.0, and wherein osmolality of said composition is between about 250 mOsm/kg and about 300 mOsm/kg.
  • compositions of the invention may also comprise a solubility stabilizer which preferably contains an anionic component, such as peroxide class preservatives.
  • the solubility stabilizer allows one to achieve greater penetration of lipophilic membranes.
  • the solubility stabilizer comprises a stabilized oxychloro complex, chlorite, and sodium perborate.
  • compositions of the present invention may comprise nitrous oxide inhibitors.
  • the nitrous oxide inhibitors are selected from the group consisting of L-NAME (L-N G -Nitroarginine methyl ester), L-NIL (N-6-(1-Iminoethyl)-L-lysine dihydrochloride), L-NIO (N-5-(1-Iminoethyl)-L-ornithine dihydrochloride), and L-canavine, or combinations thereof.
  • concentration of the nitrous oxide inhibitors is between about 0.005% and about 0.5% weight by volume.
  • compositions are delivered as ophthalmic solutions into the eyes.
  • topical compositions which include, but are not limited to, 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, tenacity adjusting agents, viscosity adjusting agents, and water.
  • Preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, or phenylmercuric nitrate.
  • Delivery vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water. It is also possible to use a physiological saline solution as a major vehicle.
  • Tonicity adjustors include, but are not limited to, a salt such as sodium chloride, potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmically acceptable tonicity adjustor.
  • Tenacity adjusting agents include, but are not limited to, glycerin.
  • Viscosity adjusting agents include, but are not limited to, hypromellose (HPMC).
  • Buffers and pH adjustors include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers, such as boric acid. It is understood that various acids or bases can be used to adjust the pH of the composition as needed. pH adjusting agents include, but are not limited to, sodium hydroxide and hydrochloric acid.
  • Antioxidants include, but are not limited to, sodium metabisulfite, 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 ⁇ -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.
  • compositions of the invention may be formulated and delivered as intravenous, oral, aerosolized, and nebulized compositions.
  • the invention provides the following compositions:
  • the invention provides methods of treatment of eye disorders and conditions comprising administering to an eye of a patient in need thereof a composition, wherein said composition comprises low concentrations of selective ⁇ -2 agonists in combination with potassium and/or calcium.
  • the methods and compositions of the invention may be used to reduce eye reddening and/or achieve eye whitening by reducing hyperemia caused by a disease or a condition.
  • the methods and compositions of the invention may be used to achieve eye whitening in healthy eyes.
  • the methods and compositions of the invention may be used to both achieve cosmetic eye whitening and to reduce eye reddening due to a disease or a condition.
  • the invention also provides methods of enhancing vasoconstricting activity of a selective ⁇ -2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for ⁇ -2 over ⁇ -1 adrenergic receptors comprising adding potassium and/or calcium to a pharmaceutical composition which comprises said selective ⁇ -2 adrenergic receptor agonist.
  • Eye disorders and 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 pigmentosa; 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; damage following retinal detachment; damage or insult due to
  • eye disorders and conditions 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.
  • 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.
  • compositions of the present invention are concentration-dependent.
  • a skilled artisan would have to take into account kinetics and absorption characteristics of the particular selective ⁇ -2 adrenergic receptor agonist.
  • the dosage may be dependent on the route of administration.
  • the dosages may also de dependent on the type of a particular disorder and/or condition and also on the degree of whitening desired by a patient.
  • the following experiment may be set up. To assess the effect of calcium and potassium on increasing the effectiveness of selective ⁇ -2 receptor agonists, one can compare the results of administrating a selective ⁇ -2 receptor agonist with and without potassium and calcium.
  • a patient who has redness in both eyes may be treated as follows:
  • composition may be administered comprising about 0.025% weight by volume of brimonidine;
  • compositions may be administered comprising about 0.025% weight by volume of brimonidine; about 50 mM of potassium chloride and about 1 mM of calcium chloride.
  • compositions may be re-administered, for example, after the four hours assessment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Inorganic Chemistry (AREA)
US12/767,394 2008-08-01 2010-04-26 Compositions and methods for treatment of disorders or conditions of the eye Abandoned US20100203165A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/767,394 US20100203165A1 (en) 2008-08-01 2010-04-26 Compositions and methods for treatment of disorders or conditions of the eye

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US13771408P 2008-08-01 2008-08-01
US19277708P 2008-09-22 2008-09-22
US20312008P 2008-12-18 2008-12-18
US20748109P 2009-02-12 2009-02-12
US12/460,942 US8338421B2 (en) 2008-08-01 2009-07-27 Compositions and methods for reversing rebound hyperemia
US28754809P 2009-12-17 2009-12-17
US12/767,394 US20100203165A1 (en) 2008-08-01 2010-04-26 Compositions and methods for treatment of disorders or conditions of the eye

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US12/460,942 Continuation-In-Part US8338421B2 (en) 2008-08-01 2009-07-27 Compositions and methods for reversing rebound hyperemia

Publications (1)

Publication Number Publication Date
US20100203165A1 true US20100203165A1 (en) 2010-08-12

Family

ID=44167711

Family Applications (3)

Application Number Title Priority Date Filing Date
US12/767,394 Abandoned US20100203165A1 (en) 2008-08-01 2010-04-26 Compositions and methods for treatment of disorders or conditions of the eye
US12/928,749 Active 2032-04-24 US8765758B2 (en) 2009-07-27 2010-12-17 Compositions and methods for eye whitening
US14/044,929 Active 2030-12-25 US9259425B2 (en) 2009-12-17 2013-10-03 Compositions and methods for eye whitening

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/928,749 Active 2032-04-24 US8765758B2 (en) 2009-07-27 2010-12-17 Compositions and methods for eye whitening
US14/044,929 Active 2030-12-25 US9259425B2 (en) 2009-12-17 2013-10-03 Compositions and methods for eye whitening

Country Status (7)

Country Link
US (3) US20100203165A1 (fr)
EP (1) EP2515917B1 (fr)
JP (1) JP5738890B2 (fr)
KR (1) KR101817928B1 (fr)
CA (1) CA2782817C (fr)
ES (1) ES2550473T3 (fr)
WO (1) WO2011075617A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012106537A1 (fr) * 2011-02-03 2012-08-09 Alpha Synergy Development, Inc. Compositions et procédés pour le traitement du glaucome
EP2696874A4 (fr) * 2011-04-13 2015-06-10 Eye Therapies Llc Compositions et méthodes utilisées de traitement d'affections nasales
WO2015097600A3 (fr) * 2013-12-24 2015-10-29 Sentiss Pharma Private Limited Solution ophthalmique topique de tartrate de brimonidine
US20210338666A1 (en) * 2020-04-30 2021-11-04 Eye Therapies, Llc Brimonidine combinations and uses thereof

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5671459B2 (ja) 2008-08-01 2015-02-18 アイ・セラピーズ・エル・エル・シー 血管収縮組成物および使用方法
US8445526B2 (en) * 2011-02-03 2013-05-21 Glaucoma & Nasal Therapies Llc Compositions and methods for treatment of glaucoma
UA109359C2 (xx) * 2011-11-10 2015-08-10 Лікування захворювань і станів шкіри 7-(1h-імідазол-4-ілметил)-5,6,7,8-тетрагідрохіноліном
US9283217B2 (en) 2011-11-10 2016-03-15 Allergan, Inc. Pharmaceutical compositions comprising 7-(1 H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline for treating skin diseases and conditions
GB201217522D0 (en) 2012-10-01 2012-11-14 Sharma Anant ophthalmic therapy
WO2015050670A1 (fr) * 2013-10-03 2015-04-09 Eye Therapies, Llc Compositions et méthodes de blanchiment des yeux
GB2548424B (en) * 2016-06-28 2018-02-14 Syri Ltd Liquid pharmaceutical composition of clonidine
MX2019014748A (es) * 2017-06-08 2020-08-03 Eye Therapies Llc Combinaciones de brimonidina de dosis baja y usos de las mismas.
KR20210053926A (ko) * 2018-08-29 2021-05-12 셀릭스 바이오 프라이빗 리미티드 눈 질환 및 피부 질환의 치료를 위한 안과용 조성물 및 방법
CA3168748A1 (fr) 2020-02-20 2021-08-26 Mohammed DIBAS Agonistes du recepteur alpha-2-adrenergique destines a reduire les rougeurs et a augmenter la blancheur des yeux et a d'autres fins ophtalmiques
US20240307355A1 (en) * 2023-03-18 2024-09-19 Alcon Inc. Pharmaceutical compositions comprising apraclonidine for ocular redness relief

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770628A (en) * 1994-07-25 1998-06-23 Laboratoire Medidom S.A. Ophthalmic preparation for use as artificial tear
US20010031754A1 (en) * 2000-02-15 2001-10-18 Gil Daniel W. Method for treating ocular pain

Family Cites Families (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2567514B1 (fr) 1984-07-13 1987-08-28 Najer Henry Nouveaux ether-oxydes derives de cyclopropylphenols
IL92351A (en) * 1988-11-29 1994-02-27 Allergan Inc Irvine Optimal aqueous solutions containing stabilized chlorine acid and inorganic salt
US5077292A (en) 1989-10-12 1991-12-31 Allergan, Inc. (2-imidazolin-2-ylamino) tetrahydroquinoxalines and methods for using same
US5021416A (en) * 1989-10-31 1991-06-04 Allergan, Inc. Method for using (2-imidazolin-2-ylamino) quinoxalines to reduce or maintain intraocular pressure
US5304569A (en) * 1989-11-13 1994-04-19 Orion-Yhtyma Oy Compositions and their use in lowering intraocular pressure
US5965595A (en) 1993-07-01 1999-10-12 The Procter & Gamble Company 2-Imidazolinylamino heterocyclic compounds useful as alpha-2 adrenoceptor agonists
GB2281206A (en) * 1993-08-25 1995-03-01 Orion Yhtymae Oy Use of dexmedetomidine
ES2187533T3 (es) 1993-10-13 2003-06-16 Allergan Inc Usdo de derivados de (2-imidazolin-2-ilamino)quinoxalina.
US6117871A (en) 1993-12-17 2000-09-12 The Procter & Gamble Company 6-(2-imidazolinylamino)quinoxaline compounds useful as alpha-2 adrenoceptor agonists
US5605911A (en) * 1995-01-31 1997-02-25 Washington University Use of alpha-2 adrenergic drugs to prevent adverse effects of NMDA receptor hypofunction (NRH)
US6087361A (en) 1995-05-12 2000-07-11 Allergan Sales, Inc. Aryl-imidazolines and aryl-imidazoles useful as α-2 adrenergic agonists without cardiovascular side effects
US5914342A (en) 1995-06-07 1999-06-22 The Procter & Gamble Company 2-imidazolinylamino heterocyclic compounds useful as alpha-2 adrenoceptor agonists
US6194415B1 (en) * 1995-06-28 2001-02-27 Allergan Sales, Inc. Method of using (2-imidazolin-2-ylamino) quinoxoalines in treating neural injury
US5804587A (en) 1995-06-29 1998-09-08 The Procter & Gamble Company 6-(2-imidazolinylamino) quinolines useful as alpha-2 adrenoceptor agonists
US5916900A (en) 1995-06-29 1999-06-29 The Procter & Gamble Company 7-(2-imidazolinylamino)quinoline compounds useful as alpha-2 adrenoceptor agonists
US5677321A (en) 1996-02-29 1997-10-14 Synaptic Pharmaceutical Corporation 5- and 6-(2-imidazolin-2-ylamino) and -(2-thiazolin-2-ylamino)-benzothiazoles as alpha-2 adrenergic ligands
KR20000069128A (ko) 1996-11-25 2000-11-25 데이비드 엠 모이어 알파-2 아드레날린수용체 아고니스트로서 유용한 2-이미다졸리닐아미노벤즈옥사졸 화합물
CZ180599A3 (cs) 1996-11-25 1999-11-17 The Procter & Gamble Company 2-Imidazolinylaminoindolová sloučenina, farmaceutický prostředek ji obsahující a její použití
US6329369B1 (en) * 1997-12-04 2001-12-11 Allergan Sales, Inc. Methods of treating pain and other conditions
US6446548B2 (en) 1998-08-03 2002-09-10 New Holland North America, Inc. Round baler twine wrap control with automatic restart
WO2004073708A1 (fr) * 1998-12-17 2004-09-02 Dean Thomas R Brinzolamide et brimonidine pour le traitement d'etats oculaires
US20020197300A1 (en) * 1999-02-22 2002-12-26 Schultz Clyde L. Drug delivery system for anti-glaucomatous medication
GB9913677D0 (en) * 1999-06-11 1999-08-11 Imperial College Formulation
DE19933130A1 (de) 1999-07-19 2001-01-25 Giesecke & Devrient Gmbh Operandenstapelspeicher und Verfahren zum Betreiben eines Operandenstapelspeichers
US6653354B2 (en) * 1999-07-29 2003-11-25 Protexeon Limited NMDA antagonist comprising xenon
US6730065B1 (en) 2000-09-15 2004-05-04 Ocularis Pharma, Inc. Night vision composition
US6147102A (en) 1999-10-26 2000-11-14 Curatek Pharmaceuticals Holding, Inc. Clonidine preparations
US20010049369A1 (en) 2000-02-10 2001-12-06 Jablonski Monica M. Brimonidine compositions and methods for retinal degeneration
US20050026924A1 (en) * 2000-07-14 2005-02-03 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
RU2291685C2 (ru) * 2000-07-14 2007-01-20 Аллерган Инк. Композиции, содержащие терапевтически активные компоненты, обладающие повышенной растворимостью
HUP0303197A3 (en) * 2000-07-14 2008-03-28 Allergan Inc Compositions containing alpha-2 adrenergic agonist components
WO2003048165A1 (fr) * 2001-11-30 2003-06-12 Schering Corporation Antagonistes du recepteur a2a d'adenosine
IL147921A0 (en) * 2002-01-31 2002-08-14 Abdulrazik Mohammad A method for treating central nervous system disorders by ocular dosing
US7030149B2 (en) * 2002-04-19 2006-04-18 Allergan, Inc. Combination of brimonidine timolol for topical ophthalmic use
US6982079B2 (en) * 2002-04-26 2006-01-03 Allergan, Inc. Compositions for treating hyperemia
US7345065B2 (en) * 2002-05-21 2008-03-18 Allergan, Inc. Methods and compositions for alleviating pain
US20040266776A1 (en) * 2003-06-25 2004-12-30 Gil Daniel W. Methods of preventing and reducing the severity of stress-associated conditions
EP1517688A2 (fr) * 2002-06-19 2005-03-30 Solvay Pharmaceuticals GmbH Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph
US20040216749A1 (en) * 2003-01-23 2004-11-04 Hosheng Tu Vasomodulation during glaucoma surgery
US20050059664A1 (en) * 2003-09-12 2005-03-17 Allergan, Inc. Novel methods for identifying improved, non-sedating alpha-2 agonists
US20050020600A1 (en) 2003-07-23 2005-01-27 Scherer Warren J. Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists
US20050058696A1 (en) * 2003-09-12 2005-03-17 Allergan, Inc. Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions
US20070203085A1 (en) * 2004-03-11 2007-08-30 Florian Lang Methods For Interfering With Fibrosis
US8147865B2 (en) * 2004-04-30 2012-04-03 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
US8119154B2 (en) * 2004-04-30 2012-02-21 Allergan, Inc. Sustained release intraocular implants and related methods
US7589057B2 (en) * 2004-04-30 2009-09-15 Allergan, Inc. Oil-in-water method for making alpha-2 agonist polymeric drug delivery systems
US8425929B2 (en) * 2004-04-30 2013-04-23 Allergan, Inc. Sustained release intraocular implants and methods for preventing retinal dysfunction
WO2005115375A1 (fr) * 2004-05-25 2005-12-08 Othera Pharmaceuticals, Inc. Medicaments et promedicaments oculoselectifs
WO2006082588A2 (fr) 2005-02-07 2006-08-10 Pharmalight Inc. Procede et dispositif d'administration ophtalmique d'ingredients pharmaceutiquement actifs
US20060264442A1 (en) * 2005-05-18 2006-11-23 Allergan, Inc. Methods for the treatment of ocular and neurodegenerative conditions in a mammal
FR2891459B1 (fr) * 2005-09-30 2007-12-28 Flamel Technologies Sa Microparticules a liberation modifiee d'au moins un principe actif et forme galenique orale en comprenant
CA2657481A1 (fr) * 2006-07-21 2008-01-24 Queen's University At Kingston Procedes et therapies permettant de potentialiser l'action therapeutique d'un agoniste du recepteur adrenergique alpha-2 et inhiber et/ou inverser la tolerance aux agonistes du recepteur adrenergique alpha-2
GB0715790D0 (en) 2007-08-13 2007-09-26 Summit Corp Plc Drug combination for the treatment of sialorrhoea
US7902247B2 (en) * 2008-01-09 2011-03-08 Allergan, Inc. Substituted-aryl-2-phenylethyl-1H-imidazole compounds as subtype selective modulators of alpha 2B and/or alpha 2C adrenergic receptors
WO2009124755A1 (fr) 2008-04-08 2009-10-15 European Molecular Biology Laboratory (Embl) Composés à nouvelles utilisations médicales et procédés d'identification de ces composés
JP5671459B2 (ja) * 2008-08-01 2015-02-18 アイ・セラピーズ・エル・エル・シー 血管収縮組成物および使用方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770628A (en) * 1994-07-25 1998-06-23 Laboratoire Medidom S.A. Ophthalmic preparation for use as artificial tear
US20010031754A1 (en) * 2000-02-15 2001-10-18 Gil Daniel W. Method for treating ocular pain

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012106537A1 (fr) * 2011-02-03 2012-08-09 Alpha Synergy Development, Inc. Compositions et procédés pour le traitement du glaucome
JP2014504645A (ja) * 2011-02-03 2014-02-24 グローコマ・アンド・ナサル・セラピー，エル・エル・シー 緑内障の治療のための組成物および方法
EP2696874A4 (fr) * 2011-04-13 2015-06-10 Eye Therapies Llc Compositions et méthodes utilisées de traitement d'affections nasales
WO2015097600A3 (fr) * 2013-12-24 2015-10-29 Sentiss Pharma Private Limited Solution ophthalmique topique de tartrate de brimonidine
EA030615B1 (ru) * 2013-12-24 2018-08-31 Сентисс Фарма Прайвет Лимитед Офтальмологический раствор бримонидина для местного применения
US10517869B2 (en) 2013-12-24 2019-12-31 Sentiss Pharma Private Limited Topical brimonidine tartrate ophthalmic solution
US20210338666A1 (en) * 2020-04-30 2021-11-04 Eye Therapies, Llc Brimonidine combinations and uses thereof

Also Published As

Publication number Publication date
JP2013514985A (ja) 2013-05-02
ES2550473T3 (es) 2015-11-10
US9259425B2 (en) 2016-02-16
JP5738890B2 (ja) 2015-06-24
EP2515917A1 (fr) 2012-10-31
WO2011075617A1 (fr) 2011-06-23
US20110160214A1 (en) 2011-06-30
CA2782817C (fr) 2018-09-11
EP2515917B1 (fr) 2015-10-07
KR20120128610A (ko) 2012-11-27
EP2515917A4 (fr) 2013-06-26
US8765758B2 (en) 2014-07-01
KR101817928B1 (ko) 2018-01-12
US20140038973A1 (en) 2014-02-06
CA2782817A1 (fr) 2011-06-23

Similar Documents

Publication Publication Date Title
US20100203165A1 (en) Compositions and methods for treatment of disorders or conditions of the eye
US11833245B2 (en) Vasoconstriction compositions and methods of use
CA2807084C (fr) Solutions de brimonidine et de timolol sans conservateur
CA2832953A1 (fr) Compositions et methodes utilisees de traitement d'affections nasales
US20240277704A1 (en) Vasoconstriction compositions and methods of use
US20120277239A1 (en) Compositions and Methods for Improving Night Vision
US20110257188A1 (en) Compositions and methods for the treatment of nasal conditions
US20110152271A1 (en) Compositions and methods for ophthalmic delivery of nasal decongestants
US20180369240A1 (en) Preferential Vasoconstriction Compositions and Methods of Use
US20140038974A1 (en) Compositions and Methods for Eye Whitening
WO2020041282A1 (fr) Compositions de vasoconstriction et procédés d'utilisation
WO2015050670A1 (fr) Compositions et méthodes de blanchiment des yeux

Legal Events

Date Code Title Description
AS Assignment

Owner name: ALPHA SYNERGY DEVELOPMENT, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HORN, GERALD;REEL/FRAME:024983/0070

Effective date: 20100909

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION