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WO1996013267A2 - Combinaisons de prostaglandines et de brimonidine ou de leurs derives pour le traitement du glaucome - Google Patents

Combinaisons de prostaglandines et de brimonidine ou de leurs derives pour le traitement du glaucome Download PDF

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Publication number
WO1996013267A2
WO1996013267A2 PCT/US1995/013624 US9513624W WO9613267A2 WO 1996013267 A2 WO1996013267 A2 WO 1996013267A2 US 9513624 W US9513624 W US 9513624W WO 9613267 A2 WO9613267 A2 WO 9613267A2
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Prior art keywords
pgf
dihydro
methyl
pgf2α
deoxy
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PCT/US1995/013624
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English (en)
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WO1996013267A3 (fr
Inventor
Michael E. Garst
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Allergan
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Publication date
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Publication of WO1996013267A2 publication Critical patent/WO1996013267A2/fr
Publication of WO1996013267A3 publication Critical patent/WO1996013267A3/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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin

Definitions

  • the invention described herein relates generally to the field of glaucoma therapy.
  • the invention relates to the treatment of glaucoma and ocular hypertension by use of a combination of at least one compound chosen from brimonidine and its derivatives, and at least one prostaglandin or derivative.
  • Glaucoma is an ocular disorder associated with elevated intraocular pressure (IOP) which is too high for normal ocular physiology and may result in irreversible loss of visual function. Owing to the progressive nature of glaucoma, the disease may begin with elevated IOP, progress through loss of visual field and eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest stage of glaucoma.
  • IOP intraocular pressure
  • 3- ⁇ - morpholino-l,2,5-thiadiazol-3-yl)oxy]-2-propanol also known as timolol
  • timolol a ⁇ -adrenergic blocking agent
  • a decrease in aqueous formation by the ciliary processes is thought to be the mechanism of action of beta- adrenoceptor antagonists, but the physiological basis for this action has not been clearly demonstrated.
  • a newer beta-blocker, betaxolol has relatively selective ⁇ i blocking activity.
  • Standard treatment modalities include parasympathomimetic agents such as pilocarpine, carbachol, and phospholine iodide, which lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork.
  • IOP intraocular pressure
  • a newer form of pilocarpine as a gel produces a longer action.
  • Adrenergic agonist medications such as epinephrine
  • dipivefrine dipivalyl epinephrine
  • alpha2 adrenergics Certain members of the class of compounds known as alpha2 adrenergics have also been found useful in the treatment of glaucoma. Members of this class of compounds include clonidine and apraclonidine (aplonidine, ALO 2145), which has been released for clinical use.
  • Apraclonidine hydrochloride is a derivative of clonidine hydrochloride, an alpha 2 adrenergic agonist.
  • Clonidine has previously been shown to lower IOP significantly, but has the potential to produce marked lowering of both systolic and diastolic blood pressures. Its major ocular effect appears to be a decrease in aqueous production.
  • apraclonidine decreases corneal absorption and the drug's ability to cross the blood-brain barrier, minimizing the risk of centrally mediated cardiovascular side effects.
  • Apraclonidine may also influence secondary avenues of aqueous outflow, such as uveoscleral outflow, and may also affect conjunctival and episcleral vascular flow.
  • Another 0:2 receptor agonist currently in clinical trials for use in ⁇ eating glaucoma and elevated IOP is brimonidine (UK 14304-18). Disclosures of this family of compounds and methods of using same are made in United States Patent No. 3,890,319 and United States Patent No. US 4,029,792.
  • carbonic anhydrase 5 inhibitors block or impede aqueous inflow into the anterior chamber by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by oral, intravenous or other systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire 0 body. Such gross disruption of a basic enzyme system is justified only during an acute attack of alarmingly elevated intraocular pressure, or when no other agent is effective. Almost 50% of patients taking these medications are unable to tolerate them because of their adverse effects, and there is thus much interest in the development of a topical 5 carbonic anhydrase inhibitor with the potential for fewer adverse effects.
  • MK 507 is the most recent and most potent compound in the series of topically active carbonic anhydrase inhibitors. It produces a mean decrease in IOP of 25% for as long as 12 hours. Adverse effects include blanching of the conjunctiva, minimal mydriasis and eyelid 0 retraction. This drug has been approved in the US for use in prevention of elevated IOP after argon laser trabeculoplasty and iridotomy, and has potential uses in preventing an IOP rise after YAG laser posterior capsulotomy and cataract surgery in patients already on other anti-glaucoma medications. For a recent review of therapeutics 5 in the treatment of glaucoma see Hurvitz L.M.; Kaufman P.L.; Robin
  • prostaglandins are believed to lower IOP by increasing the outflow of aqueous humor via the uveoscleral route.
  • prostaglandins may possibly have other effects in the eye, such as enhancing vascular support of ocular tissues; however, there is no understanding of that mechanism at this time.
  • miotics such as pilocarpine can cause blurring of vision and other visual side effects which may lead either to decreased patient compliance with the dosing regimen or to termination of therapy
  • carbonic anhydrase inhibitors can also cause serious side effects which affect patient compliance and/or necessitate the withdrawal of treatment
  • at least one beta-blocker, timolol has increasingly become associated with serious pulmonary side effects attributable to its effect on ⁇ 2 receptors in pulmonary tissue
  • prostaglandins often produce hyperemia and edema of the conjunctiva, resulting in redness and hyperesthesia of the eye, which may affect patient compliance.
  • a therapy regimen which includes the use of two or more pharmaceutical compositions containing drugs selected from two or more of the above-cited classes requires the patient to apply the compositions to the affected eye(s) in separate, spaced dosages, several times per day.
  • Patient compliance with such complicated dosage regimens can be very poor, particularly in elderly patients. Since the majority of glaucoma patients are elderly, problems with patient compliance are significant considerations to the prescribing physician.
  • compositions, methods and articles of manufacture useful for the treatment of glaucoma and ocular hypertension.
  • the compositions contain a combination of at least one brimonidine derivative and at least one prostaglandin which is effective in reducing or controlling IOP, and which has a reduction or elimination of the side effects normally associated with topical application of prostaglandins.
  • the above combinations may further include liquid formulations that contain resins which gel as a result of the increase of pH and /or temperature of the solution on administration to the eye, or polymeric drug vehicles that are suspended in perfluorocarbon or fluorinated silicone carriers which can advantageously be used in administration of non-preserved doses of the present drug combinations with enhanced bioavailability.
  • United States Patent Numbers 5 173 298 and 5 292 517 respectively disclose these improved ocular delivery systems and are herein incorporated by reference in their entirety.
  • US 5 292 517 discloses a sustained release pharmaceutical composition with long-term storage stability and comprises: porous ion exchange resin particles of 1-50 micron diameter incorporated in an aqueous solution of at least one reversibly gelling polymer selected from pH-sensitive and temp .-sensitive gelling polymers.
  • the aqueous solution has a free flowing, drop instillable viscosity at room temperature and pH 2.5-4.0, and a gel-like viscosity at about 35" C and pH 7.4.
  • the pharmaceutical compounds are ionically bound within the pores of the ion exchange resin particles. The pores are sufficiently small to prevent the polymer from diffusing into the pores.
  • he pH-Scnsitive gelling polymers are polyacryhc acids, polymeihacrylic &ci ⁇ s, polycrotonic acids, carboxypolymethylene and poly(methylvinylether/maleic acids).
  • the thermally- sensitive gelling polymers are alkylcelluloses and hydroxyalkyl celluloses.
  • the ion exchange resin particles preferably have exchange functionalities selected from sulfonic and carboxylic acids.
  • the pharmaceutical combination remains bound within the pores of the ion exchange resin particles until after administration to the target tissue where small ions migrate into the pores and initiate ion exchange.
  • the bioadhesiveness of the composition makes it useful for delivering ophthalmic pharmaceuticals to the surface of the eye, since it resists lachrymal drainage without interfering with vision.
  • Non-aqueous compositions which comprise (a) a non-aqueous fluorinated liquid carrier, which is a perfluorocarbon or a fluorinated silicone; and (b) polymeric drug delivery vehicle(s), associated with therapeutic or diagnostic compounds, suspended in the fluorinated solvent.
  • the perfluorocarbons may preferably contain N or O in the structure.
  • a preferred embodiment of the polymeric carrier is poly(methylvinylether / maleic anhydride) copolymer.
  • the composition has improved shelf life due to the absence of water to cause hydrolytic changes in the active agent or polymer, and the agent does not leach out into the carrier, and such stability allows multi-dose packaging.
  • the composition is transparent and non-irritant. Low administration volumes make the composition especially suitable for ophthalmic purposes, allowing efficient delivery into the tear film without overflow that is blinked away and lost, or vision blurring as with, for example, oils.
  • the volume to be delivered may be less than 10 ⁇ l in comparison to the 35 ⁇ l minimum of prior art water and oil based systems, and to the 7 ⁇ l accommodation volume of the tear film.
  • the present invention utilizes combinations of at least one bumonidine derivative and at least one prostaglandin to treat glaucoma d d ocular hypertension.
  • Brimonidine is a known adrenergic compound, and is described for example in US 3,890,319; the contents of this patent relating to the structure, preparation, and physical properties of this compound are incorporated herein by reference. It is also known that brimonidine and certain derivatives thereof are effective in lowering intraocular pressure when applied topically to the eye; this discovery is described in US 5,021,416 (Gluchowski), the entire contents of which are incorporated herein by reference.
  • the brimonidine derivatives described in this patent are those represented by formula (I) below
  • Ri is hydrogen, lower alkyl or oxo
  • R2, R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl
  • n is an integer from 1 to 3
  • prostaglandin and "PG” are generally used to describe a class of compounds which are analogs and derivatives of prostanoic acid (II)
  • PG's may be further classified according to their 5-membered ring structure, using a letter designation. Ring structures given a letter designation are:
  • Prostaglandins of the E series PGE's
  • Prostaglandins of the F series PGE's
  • PG's may be further classified based on the number of unsaturated bonds on the side chain:
  • prostaglandins which may be utilized in the present invention include all pharmaceutically acceptable prostaglandins, their derivatives and analogs, and their pharmaceutically acceptable esters and salts (hereinafter collectively referred to as "prostaglandins" or "PG's"), which are capable of reducing intraocular pressure when applied topically to the eye.
  • Such prostaglandins include the natural compounds: PGEi, PGE2, PGE3, PGD 2 , PGFi ⁇ , PGF 2 oc, PGF 3 ⁇ , PGI 2 (prostacyclin), as well as analogs and derivatives of these compounds which have similar biological activities of either greater or lesser potencies.
  • Analogs of the natural prostaglandins include but are not limited to: alkyl substitutions (e.g., 15-methyl or 16,16-dimethyl), which confer enhanced or sustained potency by reducing biological metabolism or alter selectivity of action; saturation (e.g. 13,14-dihydro) or unsaturation (e.g., 2,3-didehydro, 13,14-didehydro), which confer sustained potency by reducing biological metabolism or alter selectivity of action; deletions or replacements (e.g.
  • prostaglandins include all pharmaceutically acceptable salts and esters, which may be attached to the 1-carboxyl group or any of the hydroxyl groups of the prostaglandin by use of the corresponding alcohol or organic acid reagent, as appropriate. It should be understood that the terms “analogs” and “derivatives” include compounds which exhibit functional and physical responses similar to those of prostaglandins per se.
  • prostaglandins which are useful in the present invention include: PGF2 ⁇ PGE2, PGE1, prostacyclin, 15(S)-methyl- PGF2 ⁇ , 16,16-dimethyl-PGF2o/ 15(S)-methyl-PGE2, 16,16-dimethyl-PGE2, 17,18,19,20-tetranor-16-phenoxy-PGE2, 17, 18, 19, 20-tetranor-16- phenoxy-PGF2 ⁇ , 18, 19 ,20-trinor-17-phenyl-PGE2, 18, 19, 20-trinor-17- phenyl-PGF2 ⁇ / trimoprostil, RS-84-135, rioprostil, S-1033 (15- deshydroxy PGF2 ⁇ , sodium salt), S-747260, nocloprost, CS-412, YPG-209, K-10134, cloprostenol, fluprostenol, luporstiol, etiproston, tiaprost, SQ 27986, ZK 13
  • prostaglandins are: PGr2orll-pivalyl ester, the l-amido-15-methy; ethev of PGF 2 ,- ⁇ . 1- ethylamido-18,19,20-trincr-17-phenyl-PGF2 ⁇ / the free acid and lower alkyl ester derivatives of PGF2 0C wherein the omega chain has been replaced with phenylethylsulfonamidomethyl- as represented by the structure below,
  • R H, Me, Et, a-Pr, i-Pr, etc
  • PGF 2 ⁇ -l-ethyl ester PGF ⁇ -l-isopropyl ester, RO-229648, SQ 27986, ZK 5 138519, 13,14-dihydro-ZK 138519, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41, and 18,19,20-trinor-17-phenyl-PGF2 ⁇ -l-methyl ester. All of the foregoing compounds are known.
  • compositions of the present invention will include one or 0 more brimonidine derivatives in an amount between about 0.02 and about 2.0 percent by weight (wt%) and one or more prostaglandins an amount between about 0.00001 and about 0.2 wt%. It is preferred to use one or more brimonidine derivatives in an amount between about 0.05 and about 1.0 wt%, and it is especially preferred to use an amount 5 between about 0J and about 0.25 wt%. It is preferred to use one or more prostaglandins in an amount between about 0.0001 and about 0.01 wt%, depending on the potency of the prostaglandin.
  • the ratio by weight of brimonidine derivative to prostaglandin is generally between about 1:1 to about 10,000:1 and preferably between about 5:1 to 0 about 1000:1. It should be understood that the ratio by weight of brimonidine derivative to prostaglandin will greatly depend on the potency of the prostaglandin used, since the potency of different prostaglandins may differ by as much as a factor of 10 5 .
  • the anti-glaucoma compositions of the present invention may further comprise various formulatory ingredients, such as anti-microbial preservatives and tonicity agents.
  • suitable anti-microbial preservatives include: benzalkonium chloride, thimerosal, • " . chlorobutanol . methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodiurn, sorbic acid, Poly quad ® , Dymed ® , and other agents equally well known to those skilled in the art.
  • Such preservatives, if utilized, will typically be employed in an amount between about 0.001 and about 1.0 wt%.
  • agents which may be utilized to adjust the tonicity or osmolality of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. Such agents, if utilized, will be employed in an amount between about OJ and about 10.0 wt%. 5
  • compositions of the present invention may additionally include components to provide sustained release and comfort.
  • Such components include: porous ion exchange resin particles in aqueous solutions of reversibly gelling polymers with the therapeutic agent(s) 0 bound in the resin pores; or drop instilled, low dose volume compositions for high bioavailability which have non aqueous perfluorocarbon or fluorinated silicone liquid carriers and a polymeric drug delivery vehicle.
  • compositions of the present invention may further include non-aqueous, fluorinated drug delivery vehicles, pH sensitive, reversible gelling erodible delivery systems, or a combination of these components.
  • additional components provide compositions which are 0 comfortable and have sustained release.
  • the active compound When administered for the treatment of elevated intraocular pressure of glaucoma, the active compound is most desirably administered topically to the eye, although systemic treatment is also 5 satisfactory.
  • the drug can be given by any route, although the oral route is preferred.
  • oral administration the drug can be employed in any of the usual dosage forms such as tablets or 0 capsules, either in a contemporaneous delivery or sustained release form. Any number of the usual excipients or tableting aids can likewise be included.
  • the activ e drug of this invention is most suitably administered in : ' the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye such as a suspension, ointment, or as a solid insert.
  • ophthalmic pharmaceutical compositions adapted for topical administration to the eye
  • the herein before described dosage values are believed accurate for human patients and are based on the known and presently understood pharmacology of the compounds, and the activity of other similar entities in the human eye. As with all medications, dosage requirements are variable and must be individualized on the basis of the disease and the response of the patient.
  • the pharmaceutical preparation which contains the active compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier.
  • a non-toxic pharmaceutical organic carrier Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, buffering ingredients such as sodium chloride, sodium borate, sodium acetate, and other conventional ingredients such as sorbitan monolaurate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid, and the like.
  • auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols, antibacterial components such as quaternary ammonium compounds,
  • suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.
  • the pharmaceutical preparation may also be in the form of a solid insert.
  • the carbonic anhydrase inhibiting agent can be included with a non-bioerodable insert, i.e., one which after dispensing the drug remains essentially intact, or a bioerodable insert, i.e., one that either is soluble in lachrymal fluids, or otherwise disintegrates.
  • a solid water soluble polymer as the carrier for the medicament.
  • the polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, or a hydroxy lower alkyl cellulose such a hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like; acrylates such as polyacrylic acid salts, ethyl acrylates, polyacrylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum
  • the present invention is also directed to methods of treating glaucoma and other ophthalmic diseases and abnormalities.
  • the methods comprise topically applying to the affected eye(s) of the patient a therapeutically effective amount of a composition according to the present invention.
  • the frequency and amount of dosage will be determined by the clinician based on carious clinical factors.
  • the methods will typically comprise topical application of one or two drops (approximately 30 microliters) of a liquid composition, or an equivalent amount of a solid or semi-solid dosage form, to the affected eye one or two times per day.
  • the present invention is also directed to articles of manufacture which include the active ingredients of the invention in suitable pharmaceutical compositions packaged for distribution in conjunction with labeling or package inserts describing indications and giving dosage instruction-.
  • I ackaging can be accomplished by any of a numbei of means utilized in the pharmaceutical industry. Examples of such packaging are: unit dose containers for dispensing liquid compositions enclosed in a box or container along with package inserts; plastic and/or foil wrappers holding solid ocular inserts which contain the active ingredients of the invention and which are enclosed in a box or container along with package inserts.
  • Other modes of packaging would be readily apparent to one skilled in the pharmaceutical packaging arts.

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Abstract

L'invention concerne des combinaisons d'agents adrénergiques alpha tels que la brimonidine et ses dérivés tels que représentés par la formule (I), dans laquelle chaque Y est choisi séparément dans le groupe consistant en N, N-CH3, O, S et C-R1; R1 représente hydrogène, oxo ou alkyle inférieur; R2, R3 et R4 sont choisis séparément dans le groupe consistant en hydrogène, halogène, alkyle inférieur et alcényle inférieur; n vaut un entier de 1 à 3; et une ligne en pointillés à côté d'une ligne pleine indique soit une liaison simple soit une liaison double, à condition que lorsque n=1, les deux liaisons entre Y et C-R1 ne puissent être des liaisons doubles, et des prostaglandines connues en soi utilisées pour induire une baisse de la pression intraoculaire. Ces combinaisons sont utiles dans des compositions, des méthodes de traitement et des articles produits, destinés au traitement du glaucome et à l'atténuation d'une pression intraoculaire élevée.
PCT/US1995/013624 1994-10-27 1995-10-20 Combinaisons de prostaglandines et de brimonidine ou de leurs derives pour le traitement du glaucome WO1996013267A2 (fr)

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US33005094A 1994-10-27 1994-10-27
US08/330,050 1994-10-27

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001339A1 (fr) * 1995-06-28 1997-01-16 Allergan Procede d'utilisation de (2-imidazolin-2-ylamino) quinoxalines pour traiter des lesions nerveuses oculaires
US6172109B1 (en) 1997-03-07 2001-01-09 Alcon Laboratories, Inc. 13-Thia prostaglandins for use in glaucoma therapy
US6194415B1 (en) 1995-06-28 2001-02-27 Allergan Sales, Inc. Method of using (2-imidazolin-2-ylamino) quinoxoalines in treating neural injury
US6242442B1 (en) * 1998-12-17 2001-06-05 Alcon Laboratories, Inc. Brinzolamide and brimonidine for treating ocular conditions
US6353014B1 (en) 1996-11-12 2002-03-05 Alcon Laboratories, Inc. 15-ketal postaglandins for the treatment of glaucoma or ocular hypertension
US8053427B1 (en) 2010-10-21 2011-11-08 Galderma R&D SNC Brimonidine gel composition
US8231885B2 (en) 2003-05-27 2012-07-31 Galderma Laboratories Inc. Compounds, formulations, and methods for ameliorating telangiectasis
WO2013013143A1 (fr) * 2011-07-20 2013-01-24 Allergan, Inc. Combinaison à dose fixe de bimatoprost et brimonidine
US8394800B2 (en) 2009-11-19 2013-03-12 Galderma Laboratories, L.P. Method for treating psoriasis
US8410102B2 (en) 2003-05-27 2013-04-02 Galderma Laboratories Inc. Methods and compositions for treating or preventing erythema
US8513249B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US8916562B2 (en) 2010-03-26 2014-12-23 Galderma Research & Development Snc Methods and compositions for safe and effective treatment of telangiectasia
US9186358B2 (en) 2009-11-18 2015-11-17 Galderma Laboratories, L.P. Combination therapy for treating or preventing an inflammatory skin disorder
US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69311361T2 (de) * 1992-10-13 1998-01-08 Alcon Lab Inc Zusammensetzungen zur behandlung von glaukoma die prostaglandine und clonidinderivate enthalten

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001339A1 (fr) * 1995-06-28 1997-01-16 Allergan Procede d'utilisation de (2-imidazolin-2-ylamino) quinoxalines pour traiter des lesions nerveuses oculaires
US5856329A (en) * 1995-06-28 1999-01-05 Allergan Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular neural injury
US6194415B1 (en) 1995-06-28 2001-02-27 Allergan Sales, Inc. Method of using (2-imidazolin-2-ylamino) quinoxoalines in treating neural injury
US6248741B1 (en) 1995-06-28 2001-06-19 Allergan Sales, Inc. Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular neural injury
US6465464B2 (en) 1995-06-28 2002-10-15 Allergan, Inc. Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular neural injury
EP1611891A3 (fr) * 1995-06-28 2007-03-14 Allergan, Inc. Utilisation de (2-imidazolin-2-ylamino) quinoxalines pour le traitement de pathologie oculaire nerveuse
US8455492B2 (en) 1995-06-28 2013-06-04 Allergan, Inc. Methods for treating retinal diseases
US6353014B1 (en) 1996-11-12 2002-03-05 Alcon Laboratories, Inc. 15-ketal postaglandins for the treatment of glaucoma or ocular hypertension
US6172109B1 (en) 1997-03-07 2001-01-09 Alcon Laboratories, Inc. 13-Thia prostaglandins for use in glaucoma therapy
US6242442B1 (en) * 1998-12-17 2001-06-05 Alcon Laboratories, Inc. Brinzolamide and brimonidine for treating ocular conditions
US8410102B2 (en) 2003-05-27 2013-04-02 Galderma Laboratories Inc. Methods and compositions for treating or preventing erythema
US8586586B2 (en) 2003-05-27 2013-11-19 Galderma Laboratories Inc. Methods and compositions for treating or preventing erythema
US8993571B2 (en) 2003-05-27 2015-03-31 Galderma Laboratories, L.P. Compounds, formulations, and methods for treating or preventing inflammatory skin disorders
US8231885B2 (en) 2003-05-27 2012-07-31 Galderma Laboratories Inc. Compounds, formulations, and methods for ameliorating telangiectasis
US8426410B2 (en) 2003-05-27 2013-04-23 Galderma Laboratories, Inc. Compounds, formulations, and methods for treating or preventing inflammatory skin disorders
US9186358B2 (en) 2009-11-18 2015-11-17 Galderma Laboratories, L.P. Combination therapy for treating or preventing an inflammatory skin disorder
US8394800B2 (en) 2009-11-19 2013-03-12 Galderma Laboratories, L.P. Method for treating psoriasis
US9072739B2 (en) 2009-11-19 2015-07-07 Galderma Laboratories, L.P. Method for treating psoriasis
US8513247B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US8916562B2 (en) 2010-03-26 2014-12-23 Galderma Research & Development Snc Methods and compositions for safe and effective treatment of telangiectasia
US8513249B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US9861631B2 (en) 2010-03-26 2018-01-09 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US9861632B2 (en) 2010-03-26 2018-01-09 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
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US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use
CN103747786A (zh) * 2011-07-20 2014-04-23 阿勒根公司 比马前列素和溴莫尼定的固定剂量组合
WO2013013143A1 (fr) * 2011-07-20 2013-01-24 Allergan, Inc. Combinaison à dose fixe de bimatoprost et brimonidine

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