EP1100491A1 - Compositions ophtalmiques destinees au traitement de l'hypertension oculaire - Google Patents

Compositions ophtalmiques destinees au traitement de l'hypertension oculaire

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Publication number
EP1100491A1
EP1100491A1 EP99935726A EP99935726A EP1100491A1 EP 1100491 A1 EP1100491 A1 EP 1100491A1 EP 99935726 A EP99935726 A EP 99935726A EP 99935726 A EP99935726 A EP 99935726A EP 1100491 A1 EP1100491 A1 EP 1100491A1
Authority
EP
European Patent Office
Prior art keywords
formulation
prostaglandin
carbonic anhydrase
ophthalmologically acceptable
acceptable salt
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.)
Withdrawn
Application number
EP99935726A
Other languages
German (de)
English (en)
Inventor
Gerald S. Ponticello
Michael F. Sugrue
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1100491A1 publication Critical patent/EP1100491A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/557—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • 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

Definitions

  • Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may 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 the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
  • pilocarpine and ⁇ -adrenergic antagonists reduce intraocular pressure
  • none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to aqueous humor formation made by the carbonic anhydrase pathway.
  • carbonic anhydrase decrease the formation of aqueous humor by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire body. Such a 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.
  • Prostaglandins are members of a class of organic carboxylic acids that are contained in human and most other mammalian tissues or organs and that exhibit a wide range of physiological activities. Naturally occurring Pgs possess a common structural feature, the prostanoic acid skelton, depicted in Formula I below:
  • the primary PG's are classified based on the structural feature of the five-membered cycle moiety into PGA's, PGB's, PGC's, PGD's PGE's, PGF's PGG's PGH's PGFs and PGJ's and also on the presence or absence of unsaturation and oxidation in the chain moiety as: Subscript 1 13,14-unsaturated-15-OH, Subscript 2 5,6- and 13,14-diunsaturated -15-OH, Subscript 3 5,6-13,14-, and 17,18-triunsaturated- 15-OH
  • PGFs are subclassified as or ⁇ according to the configuration of the hydroxy group at position 9.
  • Prostaglandins and prostaglandin derivatives are known to lower intraocular pressure.
  • U.S. Patent 4,824,857 to Goh et al. describes the use and synthesis of PGD2 and derivatives thereof in lowering intraocular pressure including derivatives wherein C-10 is replaced with nitrogen.
  • U.S. Patent 5,001,153 to Ueno et al. describes the use and synthesis of 13,14-dihydro-15-keto prostaglandins and prostaglandin derivatives to lower intraocular pressure.
  • U.S. Patent 4,599,353 describes the use of eicosanoids and eicosanoid derivatives including prostaglandins and prostaglandin inhibitors in lowering intraocular pressure.
  • Prostaglandin and prostaglandin derivatives lower intraocular pressure by increasing uveoscleral outflow. This is true for both the F type and A type of Pgs and hence presumably also for the B,C,D,E and J types of prostaglandins and derivatives thereof.
  • a problem with using prostaglandin derivatives to lower intraocular pressure is that these compounds often induce an initial increase in intraocular pressure.
  • the combination of the carbonic anhydrase inhibitor and the prostaglandin derivative can be used for the treatment of diseases and conditions in which the lowering of intraocular pressure is desired, for example glaucoma, ocular hypertension and other disease accompanied by an increase in intraocular pressure.
  • the activity of the carbonic anhydrase inhibitor currently marketed wanes 6 to 8 hours post-dose, meaning that as single agents these carbonic anhydrase inhibitors must be administered at least three times day to maintain the desired lowering of intraocular pressure.
  • the combination of this invention maintains the desired lowering of intraocular pessure for a full twelve hours. Because of this increased duration of action, the combination disclosed herein is effective when administered only twice a day. Patient compliance is anticipated to be greater with twice a day administration than with three times a day administration.
  • the combinations disclosed herein are effective either by co-administration of the medicaments in one solution or as a combined therapy achieved by prior administration of either the carbonic anhydrase inhibitor or the prostaglandin derivative followed by administration of the other solution.
  • the use of a single solution containing both active medicaments is preferred.
  • This invention relates to novel ophthalmic compositions comprising a topical carbonic anhydrase inhibitor or an ophthamologically acceptable salt thereof and a prostaglandin or prostaglandin derivative thereof or a hypotensive lipid derived from a prostaglandin or prostaglandin derivative such as a PGF2 prostaglandin.
  • composition comprising 0.025 to 5% (w/w) of a topical carbonic anhydrase inhibitor such as 5,6- dihy dro-4-ethy lamino-6-methy l-4H-thieno- [2,3 -b] thiopyran-2- sulfonamide-7,7 dioxide hydrochloride or 2H-thieno[3,2-e]-l,2-thiazine- 6-sulfonamide-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-l,l- dioxide and their trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material and 0.005 to 2% a hypotensive lipid derived from prostaglandins and their trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material is disclosed.
  • Said composition can optionally contain a gum belonging
  • Another aspect of the invention is concerned with the use of the novel ophthalmic compositions in the treatment of ocular hypertension or glaucoma.
  • This invention relates to novel ophthalmic combinations comprising a topical carbonic anhydrase inhibitor or an ophthamologically acceptable salt thereof and a prostaglandin or prostaglandin derivative thereof, or a topical carbonic anhydrase inhibitor or an ophthalmologically acceptable salt thereof and a hypotensive lipid derived from a prostaglandin or prostaglandin derivative, which are used in the treatment of ocular hypertension and glaucoma.
  • An aspect of this invention is realized when the prostaglandin is
  • (+)-isopropyl fluprostenol [2R(1E, 3R),3S(4Z),4Rl-isopropyl-7-(tetrahydro-2-[4-(3- chlorophenoxy)-3-hydroxy-l-butenyl)-4-hydroxy-3-furanyl]-4- heptanoate;
  • hypotensive lipids derived from PGF 2 ⁇ prostaglandins in which the carboxylic acid group on the ⁇ -chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents, is used.
  • An example of a hypotensive lipid is that in which the carboxylic acid group is replaced with a C,_ 6 alkoxy group such as OCH 3 (PGF 2a 1- OCH 3 ), or a hydroxy group (PGF 2a 1-OH).
  • PGF 2 ⁇ prostaglandin is derived from PGF 2 ⁇ prostaglandins, in which the carboxylic acid group on the ⁇ -chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents.
  • An example of a hypotensive lipid is that in which the carboxylic acid group is replaced with a C,_ 6 alkoxy group such as OCH 3 (PGF 2a 1- OCH 3 ), or a hydroxy group (PGF 2a 1-OH).
  • Another embodiment of the invention is concerned with a novel ophthalmic composition
  • a novel ophthalmic composition comprising an ophthalmologically acceptable carrier, 0.025 to 5% (w/w) of a topical carbonic anhydrase inhibitor, 5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3- b]thiopyran-2-sulfonamide-7,7 dioxide hydrochloride, and its trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material and 0.005 to 2% (w/w) of a prostaglandin and its trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material, wherein the prostaglandin isl l, 15-dipivaloyl PGF2 ; (- ⁇ -)-isopropyl fluprostenol; or [2R(1E, 3R),3S(4Z),4R
  • prostaglandin or prostaglandin derivative refers to those naturally occurring prostaglandins that are useful for lowering intraocular pressure, specifically prostaglandins A,B,C,D,E,F and J class as well as synthetically modified prostaglandins including but not limited to 15-keto (oxo group in place of OH at 15) 13,14-dihydro (single bond in place of double bond between positions 13 and 14), and esters thereof.
  • Prostaglandins of the F class particularly PGF 2 ⁇ derivatives are known to be particularly potent at lowering intraocular pressure.
  • PGF 2 ⁇ prostaglandin derived hypotensive lipids in which the carboxylic acid group on the ⁇ -chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents, are also known to be particularly potent at lowering intraocular pressure.
  • the hypotensive lipids intended for the claimed invention are those compounds which increase aqueous humor outflow without any meaningful interaction with the FP prostaglandin receptor and little or no stimulation of the other prostanoid receptors (DP, EP1-4, IP, TP). Examples of such lipids are taught in US Patent Nos. 4,494,274; 5,034,413; 5,656,635; 5,516,791, 5,385,945, 5,688,819, 5,352,708 and 5,607978 all incorporated herein by reference.
  • Formula I shows a basic skeleton having twenty carbon atoms
  • the prostaglandin compounds used in the present invention are not limited to those having the same number of carbon 10 atoms.
  • the carbon atoms in Formula (I) are numbered 2 to 7 on the ( ⁇ -chain starting from the ⁇ -carbon atom adjacent to the carboxylic carbon atom which is numbered I and towards the five membered ring 8 to 12 on the ring starting from the carbon atom on which the ⁇ -chain is attached, and 13 to 20 on the ⁇ -chain starting from the carbon atom adjacent to the ring.
  • hypotensive lipids contemplated by the claimed invention include PGF 2 ⁇ lipid analogs which, unlike PGF 2 ⁇ initiative exhibit no meaningful interaction with recombinant or constitutively expressed FP receptors (human, moust, cat). Further the PGF 2 ⁇ lipid analogs exhibit only either minimal or absent interaction with other prostanoid receptors (DP, EP,_ 4 , TP). Even with their inability to interact with with prostanoid receptors the subject PGF 2 ⁇ lipid analogs, having electrochemically neutral substituents, are potent and efficacious at lowering elevated intraocular pressure (IOP). Examples of such lipids are taught in US Patent Nos.
  • a particular ocular hypotensive agent is referred to as AGN 192024, disclosed in VanDenburgh et al., Investigative Oph. and Vis. Sci. March 15, 1998, Vol. 39, No.4.
  • p. S258 abstract 1177 and at the May 10-15, 1998 Association for Research in Vision and Ophthalmology (ARVO) meeting by Allergan of Irvine, California.
  • novel ophthalmic formulations of this invention comprise about 0.025 to 5% (w/w) of the carbonic anhydrase inhibitors discussed herein, preferably 5,6-dihydro-4-ethylamino-6-methyl-4H- thieno-[2,3-b]thiopyran-2-sulfonamide-7,7 dioxide hydrochloride or 2H- thieno[3,2-e]-l,2-thiazine-6-sulfonamide-4-(ethylamino)-3,4-dihydro-2- (3-methoxypropyl)- 1,1 -dioxide and their trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material, usually about 0.5 to 3% (w/w) and more preferably about 0.7 to about 2% (w/w) and about 0.005 to 2.0% (w/w), preferably about 0.1 to 1 % (w/w) of the prostaglandin or prostaglandin derivative
  • a novel method of this invention comprises the topical ocular administration of about 0.025 to about 5 mg per day, preferably about 0.25 to about 3 mg per day of a carbonic anhydrase inhibitor and concomitant, prior, or previous administration of about 0.005 to 2 mg per day, preferably about 0.1 to 1.0 mg per day, of prostaglandin or prostaglandin derivative to each eye.
  • Suitable subjects for the administration of the formulation of the present invention include mammals, primates, man, and other animals, particularly man and domesticated animals such as cats and dogs.
  • the novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of each active component or some submultiple thereof.
  • Typical ophthalmologically acceptable carriers for the novel formulations 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 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, phenylethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetate, or gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine
  • the formulation may also include a gum such as gellan gum at a concentration of 0.1% to 2% by weight so that the aqueous eyedrops gel on contact with the eye, thus providing the advantages of a solid ophthalmic insert as described in U.S. Patent 4,861,760.
  • a gum such as gellan gum at a concentration of 0.1% to 2% by weight so that the aqueous eyedrops gel on contact with the eye, thus providing the advantages of a solid ophthalmic insert as described in U.S. Patent 4,861,760.
  • the formulation may also include a gum such as xanthan gum at a concentration of 0.1 to 2%, preferably 0.4 to 0.7%(w/w). Particularly preferred is KELTROLTMT xanthan gum from Monsanto Performance Materials.
  • the formulation of the instant invention employing xanthan gum will be a hypotonic solution, with a freezing point depression between about -0.28°C and -0.4°C, and preferably between about -0.31°C and -0.37°C.
  • the hypotonicity of the ophthalmic solutions of the present invention employing xanthan gum will be between about 150 and 215 mOs/kg, and preferably between 170 and 200 mOs/kg.
  • Coventional ophthalmic solutions are usually prepared as isotonic solutions using tonicity adjusting agents as potassium chloride, sodium chloride, mannitol, dextrose and glycerin.
  • An isotonic solution will have a freezing point depression of approximately -0.54 C.
  • Tonicity may also be measured by the osmolality of the solution, an isotonic solution having an osmolality of about 290 milliosmoles per kilogram (mOs/kg).
  • the pharmaceutical preparation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact as described in U.S. Patents 4,256,108; 4,160,452; and 4,265,874; or a bio-erodible insert that either is soluble in lacrimal fluids, or otherwise disintegrates as described in U.S. Patent 4,287,175 or EPO publication 0,077,261.
  • the pharmaceutical preparation may also be in the form of a suspension utilizing carbonic anhydrase inhibitors (CAI's) having aqueous solubilities greater than 10 ⁇ g/mL but less than 1000 ⁇ g/mL at pH 7.4, octanol/water distribution coefficients (DC) measured at pH 7.4 of from 1.0 to 150 and dissociation constants (Ki) of 1.0 nM or lower.
  • CAI's carbonic anhydrase inhibitors
  • the aqueous solubility is measured, for example, by mixing the CAI, in its neutral or salt form in 0.1M phosphate buffer at a pH of 7.4. The mixture is then agitated for approximately 16 to 24 hours, while maintaining a pH of 7.4. If the mixture is a solution, a small amount of a seed crystal of the neutral CAI is added and the mixture is stirred for approximately 16 to 24 hours. The solid/liquid mixture is filtered throught a 0.45 ⁇ m filter and the filtrated is assayed by HPLC against standards.
  • the solubility as measured includes both the neutral and ionized forms of the CAI.
  • the suspension encompassed within the meaning of this invention is one which comprises 0.1-10.9 wt% of a carbonic anhydrase inhibitor and 0.01-10.0 wt.% of a polyethoxylated derivative of castor oil resulting from the reaction of from 2-200 moles of ethylene oxide per 1 mole of castor oil, wherein the derivatives can be hydrogenated.
  • the measure of the dissociation constant is determined using the fluorescence competition assay which uses the fluorescent HCAILdansylamide complex and is well known in the art, Chen et al., J. Biol. Chem., 242, 5813 (1967) and Ponticello et al., J. Med. Chem., 30, 591 (1987).
  • the relative Kis for the suspension are less than 3.3 nM.
  • the suspension may be prepared by heating 400 mL of purified water to boiling. HPMC (30.0g) is added and the mixture stirred vigorously until homegeneous. To this is added a solution consisting of sodium chloride (7.0 g), dibasic sodium phosphate (2.0g), disodium edta (O.lg), polysorbate 80 (0.5g) and benzalkonium chloride (10.5 mL of a 1% solution) and purified water is added to a final volume of 900 mL. The mixture is stirred and cooled in an ice bath to room temperature and the pH is adjusted to 7.2 employing HCl (3.5 mL of a 1 N solution. The mixture is q.s.
  • the formulation is prepared by the addition of the above HPMC vehicle (15.014 g) to the above TCAI (0.3074 g) and prostaglandin (1.0 g) and the mixture ias ball milled with 3 mm glass beads (5 g) for approximately 45 hours.
  • the active compounds, sodium chloride and benzalkonium chloride are dissolved in water for injection.
  • the pH of the composition is adjusted to 5.6 by addition of 0.2N sodium hydroxide solution, and water for injection is added until the weight of the composition is equal to 75 parts of the final weight (I) or 65 parts of the final weight (II).
  • the composition is sterilized by filtration, and the solution flushed with sterile nitrogen. Then a clarified, steam sterilized concentrate of 2% xanthan gum is added to the solution of drug and the resulting solution is homogenized by stirring. The solution is aseptically subdivided into sterile vials and sealed.
  • EXAMPLES 31-35 Following the procedures of Example 30, solutions are prepared substituting the compounds below for the carbonic anhydrase inhibitors:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des combinaisons d'une prostaglandine, d'un dérivé de prostaglandine, d'un lipide hypotenseur dérivé d'une prostaglandine ou d'un dérivé de prostaglandine ou d'un sel ophtalmologiquement acceptable de ceux-ci et d'un inhibiteur topique de l'anhydrase carbonique ou d'un sel ophtalmologiquement acceptable de celui-ci, qui sont utilisées en particulier dans le traitement de l'hypertension oculaire et du glaucome. Ces combinaisons sont caractérisées par un effet amélioré et des effets secondaires réduits.
EP99935726A 1998-07-21 1999-07-20 Compositions ophtalmiques destinees au traitement de l'hypertension oculaire Withdrawn EP1100491A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11995198A 1998-07-21 1998-07-21
US119951 1998-07-21
PCT/US1999/016374 WO2000004899A1 (fr) 1998-07-21 1999-07-20 Compositions ophtalmiques destinees au traitement de l'hypertension oculaire

Publications (1)

Publication Number Publication Date
EP1100491A1 true EP1100491A1 (fr) 2001-05-23

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EP (1) EP1100491A1 (fr)
JP (1) JP2002521333A (fr)
AU (1) AU5114499A (fr)
CA (1) CA2337349A1 (fr)
WO (1) WO2000004899A1 (fr)

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FR2754712B1 (fr) * 1996-10-17 1999-09-03 Merck Sharp Dohme Chibret Lab Compositions ophtalmiques
ES2232434T3 (es) 1999-03-05 2005-06-01 Duke University Analogos de prostaglandinas c-16 fp selectivas insaturadas.
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
AU2001261360A1 (en) * 2000-05-10 2001-11-20 Alcon, Inc. R-eliprodil for treating glaucoma
AU2002256471B2 (en) * 2001-05-03 2007-05-24 Allergan, Inc. Compositions having enhanced pharmacokinetic characteristics
US7993634B2 (en) 2004-04-30 2011-08-09 Allergan, Inc. Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods
US9498457B2 (en) 2004-04-30 2016-11-22 Allergan, Inc. Hypotensive prostamide-containing biodegradable intraocular implants and related implants
US8722097B2 (en) 2004-04-30 2014-05-13 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US7799336B2 (en) 2004-04-30 2010-09-21 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
EP1797888A4 (fr) 2004-09-28 2009-12-16 Senju Pharma Co Composition ophtalmique contenant de la gomme xanthane et un acide amine
US7998942B2 (en) 2005-07-11 2011-08-16 Senju Pharamaceutical Co., Ltd. Eye drop preparation comprising xanthan gum and terpenoid
GB2423711B (en) * 2005-10-24 2007-02-14 Fortune Apex Dev Ltd Method for preparing a pharmaceutical composition with enhanced mucoadhesion
WO2007108541A1 (fr) 2006-03-23 2007-09-27 Senju Pharmaceutical Co., Ltd. Composition ophtalmique comprenant de la gomme de xanthane et du glucose
US8969415B2 (en) 2006-12-01 2015-03-03 Allergan, Inc. Intraocular drug delivery systems

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WO1994008585A1 (fr) * 1992-10-13 1994-04-28 Alcon Laboratories, Inc. Combinaisons de prostaglandines et de derives de clonidine pour le traitement du glaucome

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CA2337349A1 (fr) 2000-02-03
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JP2002521333A (ja) 2002-07-16

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