WO1998053809A1 - Compositions ophtalmiques pour traitement de l'hypertension oculaire - Google Patents

Compositions ophtalmiques pour traitement de l'hypertension oculaire Download PDF

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Publication number
WO1998053809A1
WO1998053809A1 PCT/US1998/010606 US9810606W WO9853809A1 WO 1998053809 A1 WO1998053809 A1 WO 1998053809A1 US 9810606 W US9810606 W US 9810606W WO 9853809 A1 WO9853809 A1 WO 9853809A1
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WO
WIPO (PCT)
Prior art keywords
thieno
dihydro
sulfamoyl
thiazine
formulation
Prior art date
Application number
PCT/US1998/010606
Other languages
English (en)
Inventor
Gerald S. Ponticello
Michael F. Sugrue
Original Assignee
Merck & 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
Priority claimed from GBGB9719842.8A external-priority patent/GB9719842D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP98924874A priority Critical patent/EP0998277A1/fr
Priority to AU76943/98A priority patent/AU7694398A/en
Priority to CA002291777A priority patent/CA2291777A1/fr
Priority to JP50079399A priority patent/JP2002501533A/ja
Publication of WO1998053809A1 publication Critical patent/WO1998053809A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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

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 PGI's and PGJ's and also on the presence or absence of unsaturation and oxidation in the chain moiety as:
  • 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 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.
  • composition comprising 0.025 to 5% (w/w) of a topical carbonic anhydrase inhibitor such as 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)-l,l- dioxide and their trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material and 0.005 to 2% (w/w) of a prostaglandin such as 13,14-dihydro-15(R)-17-phenyl- 18,19,20-trinor-PGF2 ester or 13, 14-dihydro-15-keto-20-ethyl- PGF2oc
  • Another aspect of the invention is concerned with a novel ophthalmic composition
  • a novel ophthalmic composition comprising comprising 0.025 to 5% (w/w) of a topical carbonic anhydrase inhibitor or an ophthamologically acceptable salt thereof belonging to the group consisting of a compound of structural formula:
  • Z is (H, H), oxo or thioxo
  • C,_ 6 alkyl either unsubstituted or substituted with one or more of hydroxy, C,_ 3 alkoxy, C 3 alkoxy-(C 2 - 4 alkoxy)m-, wherein m is as defined above, or;
  • R and R taken together with the nitrogen atom to which they are attached represent a saturated heterocycle of 5-7 members which may include a second hetero group selected from N, O, S(0) n , such as piperidine, morpholine, piperazine, N-Cl-3 alkylpiperazine, thiomorpholine, thiomorpholine-S-oxide, or thiomorpholineS,S-dioxide;
  • composition can be a suspension or a solution.
  • 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, which are used in the treatment of ocular hypertension and glaucoma.
  • the novel ophthalmic compositions of this invention comprise a pharmaceuticallly acceptable carrier, a therapeutically effective amount of 13,14-dihydro-15(R)-17- ⁇ henyl-18,19,20-trinor-PGF2 ⁇ esters, or 13, 14-dihydro-15-keto-20- ethyl-PGF2 isopropryl esters, and a topical carbonic anhydrase inhibitor belonging to the group consisting of 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 ophthal
  • 11-pivaloyl prostaglandin F2 hydroxy ethyl ester (+)-(Z)-sodium-7-[lR, 2R, 3R, 5S)-3,5-dihydroxy-2-[(E)-l- octenyllcyclopentyl]-5-heptenoate sesquihydrate, [l ⁇ ,2 ⁇ ,3 ⁇ ,5 ]methyl-5-cis-2-(phenylethylsulfonamidomethyl)-3,5- dihydroxycyclopentyl heptenoate,
  • a further aspect of this invention is realized when the prostaglandin is isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R> 3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate, (+)-(Z)-sodium-7- [1R, 2R, 3R, 5S)-3,5-dihydroxy-2-[(E)-l-octenyl]cyclopentyl]-5- heptenoate sesquihydrate, or 13,14-dihydro-15-keto-20-ethyl-PGF2 ⁇ isopropyl ester trimethylphenol- 1 -acetate and the topical carbonic anhydrase inhibitor is 5,6-dihydro-4-ethylamino-6-methyl-4H-thieno- [2,3-b]thiopyran-2-sulfonamide-7,7 dioxide hydrochloride or 2H- thieno
  • a second embodiment of the invention concerns a composition
  • a composition comprising a topical carbonic anhydrase inhibitor of a compound of structural formula: or an ophthalmologically or pharmaceutically acceptable salt thereof, wherein:
  • Z is (H, H), oxo or thioxo
  • Cj_ 6 alkyl either unsubstituted or substituted with one or more of hydroxy, C,. 3 alkoxy, C 3 alkoxy-(C 2 - 4 alkoxy)m-, wherein m is as defined above, or;
  • R and R taken together with the nitrogen atom to which they are attached represent a saturated heterocycle of 5-7 members which may include a second hetero group selected from N, O, S(0) n , such as piperidine, morpholine, piperazine, N-Cl-3 alkylpiperazine, thiomorpholine, thiomorpholine-S-oxide, or thiomorpholineS,S-dioxide;
  • R is Cj. 6 alkyl
  • n is 0, 1 or 2, preferably where Rl is hydrogen, Z is (H,H) or oxo, R2 is a Cl-6 substituted alkyl, n is 0 or 2 and a prostaglandin or prostaglandin derivative.
  • topical carbonic anhydrase inhibitor is 2,3-dihydro-2-oxo-6-sulfamoyl-H-thieno-[2,3-bl[l,4]thiazine; (2,3-dihydro-2-oxo-6-sulfamoyl-H-thieno-[2,3-b][l,4]thiazin-3-yl)acetic acid;
  • 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 such as 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 PGF2 derivatives are known to be particularly potent at lowering intraocular pressure.
  • 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.
  • 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.
  • 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 solutoins 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 0.1 M 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 I s for the suspension are less than 3.3.
  • the active compounds, phosphate buffer salts, benzalkonium chloride, and Polysorbate 80 are added to and suspended or dissolved in water.
  • the pH of the composition is adjusted to 5.5-6.0 and diluted 30 to volume.
  • the composition is rendered sterile by filtration through a sterilizing filter.
  • the suspension may be prepared by heating 400 mL of purified water to boiling. HPMC (30. Og) 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.
  • PGF2 ⁇ isopropyl ester trimethylphenol-1-acetate 0.1 mg 1.0 mg
  • the active compounds Gelrite' gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water.
  • the pH of the composition is adjusted to 5.5-6.0 and diluted to volume.
  • the composition is rendered sterile by ionizing radiation.
  • PGF2 ⁇ isopropyl ester trimethylphenol-1-acetate 0.1 % 1.0 %
  • 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.

Abstract

La présente invention concerne des combinaisons d'une prostaglandine ou d'un sel ophtalmologiquement acceptable de celle-ci, et d'un inhibiteur topique d'anhydrase carbonique ou d'un sel ophtalmologiquement acceptable de celui-ci, qui sont particulièrement utiles pour le traitement de l'hypertension oculaire et du glaucome. Ces combinaisons sont caractérisées par un effet amélioré et des effets secondaires réduits.
PCT/US1998/010606 1997-05-30 1998-05-26 Compositions ophtalmiques pour traitement de l'hypertension oculaire WO1998053809A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98924874A EP0998277A1 (fr) 1997-05-30 1998-05-26 Compositions ophtalmiques pour traitement de l'hypertension oculaire
AU76943/98A AU7694398A (en) 1997-05-30 1998-05-26 Ophthalmic compositions for treating ocular hypertension
CA002291777A CA2291777A1 (fr) 1997-05-30 1998-05-26 Compositions ophtalmiques pour traitement de l'hypertension oculaire
JP50079399A JP2002501533A (ja) 1997-05-30 1998-05-26 高眼圧症治療のための眼科用組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US4814097P 1997-05-30 1997-05-30
US60/048,140 1997-05-30
GB9719842.8 1997-09-18
GBGB9719842.8A GB9719842D0 (en) 1997-09-18 1997-09-18 Ophthalmic compositions for treating ocular hypertension

Publications (1)

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WO1998053809A1 true WO1998053809A1 (fr) 1998-12-03

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PCT/US1998/010606 WO1998053809A1 (fr) 1997-05-30 1998-05-26 Compositions ophtalmiques pour traitement de l'hypertension oculaire

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EP (1) EP0998277A1 (fr)
JP (1) JP2002501533A (fr)
AU (1) AU7694398A (fr)
CA (1) CA2291777A1 (fr)
WO (1) WO1998053809A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174524B1 (en) 1999-03-26 2001-01-16 Alcon Laboratories, Inc. Gelling ophthalmic compositions containing xanthan gum
US6261547B1 (en) 1998-04-07 2001-07-17 Alcon Manufacturing, Ltd. Gelling ophthalmic compositions containing xanthan gum
US6331540B1 (en) 1999-11-01 2001-12-18 Alcon Universal Ltd. Pharmaceutical compositions containing a fluoroquinolone antibiotic drug and xanthan gum
US6352978B1 (en) 2000-07-28 2002-03-05 Alcon Universal Ltd. Pharmaceutical compositions containing tobramycin and xanthan gum
WO2004022063A1 (fr) * 2002-09-09 2004-03-18 Santen Pharmaceutical Co., Ltd. Collyre transparent contenant du latanoprost
WO2009117316A3 (fr) * 2008-03-17 2010-09-10 Alcon Research, Ltd. Compositions pharmaceutiques ayant la biodisponibilité souhaitable
WO2010130462A2 (fr) * 2009-05-14 2010-11-18 Ursapharm Arzneimittel Gmbh & Co. Kg Composition pharmaceutique sans phosphates pour le traitement du glaucome
US7939511B2 (en) 2004-09-28 2011-05-10 Senju Pharmaceutical Co., Ltd. Ophthalmic composition containing xanthan gum and amino acid
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives

Families Citing this family (2)

* Cited by examiner, † Cited by third party
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KR101118935B1 (ko) * 2003-08-21 2012-03-13 가부시키가이샤 아루떼꾸 우에노 안과용 조성물
WO2007108541A1 (fr) 2006-03-23 2007-09-27 Senju Pharmaceutical Co., Ltd. Composition ophtalmique comprenant de la gomme de xanthane et du glucose

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US4599353A (en) * 1982-05-03 1986-07-08 The Trustees Of Columbia University In The City Of New York Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma
US4797413A (en) * 1986-05-14 1989-01-10 Merck & Co., Inc. Thieno thiopyran sulfonamide derivatives, pharmaceutical compositions and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599353A (en) * 1982-05-03 1986-07-08 The Trustees Of Columbia University In The City Of New York Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma
US4797413A (en) * 1986-05-14 1989-01-10 Merck & Co., Inc. Thieno thiopyran sulfonamide derivatives, pharmaceutical compositions and use
US4797413B1 (fr) * 1986-05-14 1992-11-24 Merck & Co Inc

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6261547B1 (en) 1998-04-07 2001-07-17 Alcon Manufacturing, Ltd. Gelling ophthalmic compositions containing xanthan gum
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US6174524B1 (en) 1999-03-26 2001-01-16 Alcon Laboratories, Inc. Gelling ophthalmic compositions containing xanthan gum
US6331540B1 (en) 1999-11-01 2001-12-18 Alcon Universal Ltd. Pharmaceutical compositions containing a fluoroquinolone antibiotic drug and xanthan gum
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US9579270B2 (en) 2000-03-31 2017-02-28 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US6352978B1 (en) 2000-07-28 2002-03-05 Alcon Universal Ltd. Pharmaceutical compositions containing tobramycin and xanthan gum
US8183291B2 (en) 2002-09-09 2012-05-22 Santen Pharmaceutical Co., Ltd. Clear ophthalmic solution comprising latanoprost as active ingredient
US8143312B2 (en) 2002-09-09 2012-03-27 Santen Pharmaceutical Co., Ltd. Transparent eye drops containing latanoprost
WO2004022063A1 (fr) * 2002-09-09 2004-03-18 Santen Pharmaceutical Co., Ltd. Collyre transparent contenant du latanoprost
US7939511B2 (en) 2004-09-28 2011-05-10 Senju Pharmaceutical Co., Ltd. Ophthalmic composition containing xanthan gum and amino acid
US8450295B2 (en) 2004-09-28 2013-05-28 Senju Pharmaceutical Co., Ltd. Ophthalmic composition containing xanthan gum and amino acid
US8178582B2 (en) 2008-03-17 2012-05-15 Alcon Research, Ltd. Pharmaceutical compositions having desirable bioavailability
WO2009117316A3 (fr) * 2008-03-17 2010-09-10 Alcon Research, Ltd. Compositions pharmaceutiques ayant la biodisponibilité souhaitable
US8722735B2 (en) 2008-03-17 2014-05-13 Alcon Research, Ltd. Pharmaceutical compositions having desirable bioavailability
US8754123B2 (en) 2008-03-17 2014-06-17 Alcon Research, Ltd. Pharmaceutical compositions having desirable bioavailability
US9144561B2 (en) 2008-03-17 2015-09-29 Alcon Research, Ltd. Pharmaceutical compositions having desirable bioavailability
CN102421425A (zh) * 2009-05-14 2012-04-18 乌尔萨法姆药物两合公司 用于治疗青光眼的不含磷酸盐的药物组合物
WO2010130462A3 (fr) * 2009-05-14 2011-01-27 Ursapharm Arzneimittel Gmbh Composition pharmaceutique sans phosphates pour le traitement du glaucome
DE102009021372A1 (de) * 2009-05-14 2010-11-18 Ursapharm Arzneimittel Gmbh Phosphatfreie pharmazeutische Zusammensetzung zur Glaukombehandlung
WO2010130462A2 (fr) * 2009-05-14 2010-11-18 Ursapharm Arzneimittel Gmbh & Co. Kg Composition pharmaceutique sans phosphates pour le traitement du glaucome
EP2429507B1 (fr) 2009-05-14 2017-07-19 URSAPHARM Arzneimittel GmbH Composition pharmaceutique sans phosphates pour le traitement du glaucome

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JP2002501533A (ja) 2002-01-15
AU7694398A (en) 1998-12-30
CA2291777A1 (fr) 1998-12-03

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