WO1995033456A2 - Reducing intraocular pressure using aryloxy- and aryl-acetic acids - Google Patents
Reducing intraocular pressure using aryloxy- and aryl-acetic acids Download PDFInfo
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- WO1995033456A2 WO1995033456A2 PCT/US1995/007152 US9507152W WO9533456A2 WO 1995033456 A2 WO1995033456 A2 WO 1995033456A2 US 9507152 W US9507152 W US 9507152W WO 9533456 A2 WO9533456 A2 WO 9533456A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
Definitions
- This invention relates to products and methods for lowering intraocular pressure within the eye, including treating conditions of glaucoma, by applying analogs of aryloxyand aryl-acetic acids to the affected eye.
- Glaucoma is any condition of the eye characterized by the therapeutic need to lower intraocular pressure. It may be chronic or acute, and it may result from disease, injury or conventional operative techniques. Glaucoma is a serious condition in that it can cause loss of sight, loss of perception and intense pain.
- ethacrynic acid topical aqueous solutions of ethacrynic acid can cause eye irritation.
- the sulfhydryl-reactive groups of ethacrynic acid have been said to cause this irritation by interacting with sulfhydryl groups in the cornea.
- ethacrynic acid lacks long term stability in aqueous solution.
- Ethacrynic acid is a member of the (aryloxy)acetic acid family of diuretics.
- the subfamily which ethacrynic acid and its analogs comprise is known as the
- (acryloylphenoxy)acetic acids Another subfamily of the (aryloxy)acetic acids are known as the (4-acylphenoxy)acetic acids.
- This group of compounds which includes ticrynafen (tienilic acid) and its analogs, differs from the ethacrynic acid-like compounds in that the molecules within this group do not contain sulfhydryl-reactive groups, which can interact with the sulfhydryl groups of the trabecular meshwork.
- compounds such as ticrynafen, which do not contain sulfhydryl reactive groups could not be used effectively to reduce intraocular pressure and treat glaucoma.
- the methods and products of the invention are particularly useful in treating or preventing the chronic elevation of intraocular pressure that can be associated with glaucoma, as well as the acute elevation of intraocular pressure resulting from conventional operative techniques. They are also useful in therapeutically lowering normal intraocular pressure needed because of damage to the optic nerve.
- a method for treating or preventing glaucoma is provided.
- a molecule is administered to the eye in an ophthalmic preparation containing an effective amount of the molecule for treating or preventing glaucoma.
- the molecule has the formula:
- R is selected from the group consisting of
- R 2 being selected from the group consisting of hydroxy (OH), lower alkoxy (-O-(CH 2 ) n CH 3 ), aminoalkoxy (O-(CH 2 ) m -NR 3 R 4 ), aminoalkylamino (-NH(CH 2 ) m NR 3 R 4 ), R 3 and R 4 being, independently, hydrogen (H) or lower alkyl, n being 0 to 4, and m being 2 to 6;
- R 1 is selected from the group consisting of
- R 5 being hydrogen or lower alkyl ((CH 2 ) p CH 3 ),
- R 6 being lower alkyl ((CH 2 ) q CH 3 ),
- heteroaromatic or substituted heteroaromatic rings consisting of 5 or 6 atoms of which up to two atoms can be a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein the substituent on the heteroaromatic ring may be lower alkyl (C 1 -C 4 ) or halogen selected from bromo or chloro; and
- X and Y are independently hydrogen, lower alkyl of from 1-3 carbon atoms, chlorine or bromine.
- 2,3-dichlorophenoxy acetic acid Another preferred compound is: 4-(2-N-methylpyrroloyl keto) 2,3-dichlorophenoxy acetic acid.
- the most preferred compound is: 4-[2-(5-methylthienyl) keto] 2,3-dichlorophenoxy acetic acid.
- the heteroaromatic ring is substituted with a lower alkyl, that substituent is methyl.
- the topical treatment may include administration of an ophthalmic delivery enhancing agent as well.
- an ophthalmic preparation includes an effective amount of a molecule for treating or preventing glaucoma and a delivery enhancing agent, formulated as a pharmaceutically acceptable, ophthalmic topical preparation, wherein the molecule is embraced by the general formula set forth above.
- the active compounds and delivery enhancing agents may be contained in containers constructed and arranged to deliver topically to the eye the ophthalmic preparations.
- a device constructed and arranged to deliver topically to the eye the above formulation is provided.
- a syringe for delivering an ophthalmic preparation is provided.
- the syringe delivers to the eye a pharmaceutically acceptable ophthalmic preparation that includes an effective amount of a molecule for treating or preventing glaucoma, the molecule being embraced by the general formula set forth above.
- the invention provides effective, non-surgical treatment of glaucoma.
- the invention involves the lowering of intraocular pressure such as in the treatment of glaucoma. It is known that when therapeutically active molecules bearing sulfhydryl reactive groups are applied to the eye, medically unacceptable side effects can follow. Animal studies have indicated that treatment with these compounds have been associated with irritation such as burning or stinging manifested by prolonged eye closure after topical administration, superficial punctate keratopathy, corneal epithelial stippling, conjunctival hyperemia and discharge. Another such side effect is corneal edema. Corneal edema is a condition evidenced by abnormal accumulation of fluid within the intercellular spaces of the cornea. Clinical symptoms of corneal edema include corneal haziness and increased corneal thickness, apparent upon ophthalmoscopic examination. A major cause of corneal edema is impaired function of the corneal endothelium, the cell layer covering the inner surface of the cornea, in response to certain chemicals or conditions. The corneal endothelium is known to possess sulfhydryl groups.
- the present invention involves the unexpected finding that ticrynafen and analogs thereof can accomplish a reduction in intraocular pressure, despite the fact that they do not include sulfhydryl reactive groups which are capable of undergoing a Michael Reaction.
- medically unacceptable side effects in particular corneal edema, can be avoided by using a compound which lacks the sulfhydryl reactive groups of the ethacrynic acid molecules.
- the use of the compounds embraced by the formula above can increase the margin of safety over the use of therapeutic compounds containing sulfhydryl-reactive groups, allowing for a safe and effective treatment for glaucoma.
- the preferred molecules useful in the methods of the invention have a number of properties, now discussed in greater detail.
- the molecules useful according to the invention are of the general formula set forth above. Particular examples are as follows.
- Ticrynafen has the following chemical formula.
- a preferred compound is 4-(2-furyl keto) 2,3-dichlorophenoxy acetic acid with the following chemical formula.
- Another preferred compound is 4-(2-N-methylpyrrolyl keto) 2,3-dichlorophenoxy acetic acid with the following chemical formula.
- the most preferred compound is 4-[2-(5-methylthienyl) keto] 2,3-dichlorophenoxy acetic acid.
- the preferred compound has the following chemical formula.
- R 1 can be, of course, any of the R 1 moieties of general formula I.
- Representative compounds of general formula I that are oxyacetic acid molecules include:
- Exemplary molecules include:
- R 1 can be any of the R 1 moieties of general formula I, including for example those R 1 moieties shown in the oxyacetic acid series above.
- Exemplary molecules in the ⁇ -methylacetic acid series include:
- R 1 can be any of the R 1 moieties of general formula I, including those R 1 moieties shown in the oxyacetic acid series above.
- Exemplary molecules in the acetic acid residue series include:
- the invention is useful whenever it is desirable to reduce intraocular pressure or inhibit or prevent intraocular pressure increases. This includes treatment of existing chronic and acute conditions, as well as prophylactic treatment to prevent such conditions.
- the formulations of the invention may be administered topically to the eye, instilled in the eye or injected intracamerally into the eye. The preferred manner of administration is topical.
- the formulations of the invention When administered, the formulations of the invention are applied in ophthalmologically acceptable amounts and in ophthalmologically acceptable solutions. Such amounts and solutions are those that cause no medically unacceptable side-effects when administered to an intraocular chamber of the eye according to the methods described herein.
- Preferred ophthalmologically acceptable solutions for intracameral delivery are sterile solutions which are iso-osmotic with respect to the fluid in intraocular chambers. Such solutions are non-irritating to the eye and maintain the osmotic stability of the tissues defining the chamber.
- the osmolality preferably is between about 250 and about 350 mOsm and most preferably about 280-320 mOsm.
- the solutions also are pH compatible with the environment of the selected intraocular chamber.
- the pH of the solution preferably is between about 6.5 and about 8.0 and more preferably between about 7.2-7.8. Most preferably the pH is 7.4.
- the solutions optionally contain particular buffering agents and other factors to support metabolism of the eye tissue.
- the solution may contain bicarbonate at a concentration of between about 10 and 50 mM.
- the solution also may contain, for example, glucose and glutathione.
- the buffer preferably is a phosphate buffer whereby the final phosphate concentration is between about 1 and 5 mM.
- additives include sodium and potassium salts such as sodium and potassium chlorides, sulfates, acetates, citrates, lactates, and gluconates. Calcium and magnesium chlorides also may be added.
- Such preparations When administered topically, such preparations may routinely contain
- a delivery enhancing agent is a substance that facilitates the delivery of the therapeutic compound of the invention into the aqueous humor, including substances which increase corneal permeability, such as surfactants, wetting agents, liposomes, DMSO, and agents which mildly disrupt the corneal surface.
- a wetting agent is a substance which evenly coats the outer corneal surface.
- a preferred wetting agent is benzalkonium chloride.
- Other examples of wetting agents include sorbitan esters and polyoxyethylene ethers.
- Suitable buffering agents include: acetic acid and a salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2%
- Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V).
- Suitable chelating agents include edetate disodium (0.01-0.2%) W/V).
- Suitable thickening agents include hydroxypropyl methylcellulose (0.2-5% W/V); polyvinyl alcohol (0.6-10% W/V); and carboxymethyl cellulose sodium (0.5-1.5%) W/V).
- the topical preparation may be a solution iso-osmotic with tears. It also can be prepared as a semi-solid dosage form such as a sterile hydrophilic gel base (made of carbomers, sodium alginate, cellulose derivatives, montmorillonite clays, gums and the like) or a sterile oleaginous ointment base (made of, for example, white petrolatum, mineral oil, polyethelene glycols and the like).
- a sterile hydrophilic gel base made of carbomers, sodium alginate, cellulose derivatives, montmorillonite clays, gums and the like
- a sterile oleaginous ointment base made of, for example, white petrolatum, mineral oil, polyethelene glycols and the like.
- compositions of the invention are administered in therapeutically effective amounts.
- a therapeutically effective amount is one which causes a medically useful decrease in intraocular pressure or prevents or inhibits to a medically useful degree an increase in intraocular pressure. Such amounts will depend upon the condition being treated and the condition of the patient and can be determined using no more than routine experimentation.
- margin of safety refers to the ratio of the dosage of the intraocular pressure reducing molecules which causes medically unacceptable side effects, and the dosage which causes a substantial (i.e., medically useful) reduction in intraocular pressure in treating or preventing glaucoma (e.g., in a typical patient with open angle glaucoma).
- the margin of safety of the formulations must be at least 2.0, and more preferably at least 4.0. It is also important that the molecules not produce, at effective dosages, long-term deleterious changes in the eye.
- the formulations of the invention are for treatment of glaucomatous conditions in eyes of mammalian subjects (e.g., humans, dogs and cats).
- the formulations of the invention may be supplied in different containers and forms. In one embodiment, they will be supplied in the form of a solution in a bottle constructed and arranged to facilitate administration of the solution as eyedrops.
- a bottle may have a dropper tip as the upper part, with a detachable cap which seals the dropper tip when the cap is replaced on the bottle.
- An alternative bottle may have a separable dropper instrument which is attached to the bottle cap, and which is contained inside the bottle when the cap is replaced.
- the compound is supplied as a lyophilized powder.
- a diluent also can be provided and can include sterile water, organic and inorganic electrolytes, and buffering agents.
- inorganic electrolytes include, but are not limited to, the chlorides of sodium, potassium, calcium and magnesium.
- Suitable buffering agents may include the sodium or potassium salts of boric acid, citric acid, phosphoric acid, acetic acid and the like.
- the lyophilized powder of the invention may contain, in addition to the active ingredients, other pharmaceutically acceptable inert ingredients such as bulking agents. Suitable bulking agents include mannitol and dextran.
- the components in the lyophilized powder and the vehicle for reconstitution may be adjusted such that the final formulation for injection is compatible with the osmolality and pH of the aqueous humor.
- Acceptable osmolality may be in the range of 150 to 400 mOsm/kg, while the pH of the formulation may vary from 4.5 - 7.8.
- kits may include instructions for use, useful additional implements, and may be supplied in a sterile condition with an impervious protective covering.
- the method used to prepare ticrynafen was as follows.
- EY-1 17 (ticrynafen) Ointment A 150 ml beaker was used to weigh out 11.22 grams of mineral oil, USP (Fisher). 0.75 grams of ticrynafen (tienilic acid, Sodepharm) was ground with a mortar and pestle and 0.50 grams of the ground powder was slowly added to the mineral oil while stirring with a stir bar. The solution was mixed until a homogenous milky white suspension was formed. 38.37 grams of petrolatum, white USP (Spectrum) was weighed out in a container and heated to 90°C. The petrolatum was then slowly added to the
- EY-1 17 (ticrynafen) Ointment A 150 ml beaker was used to weigh out 11.04 grams of mineral oil, USP (Fisher). 1.5 grams of ticrynafen (tienilic acid, Sodepharm) was ground with a mortar and pestle and 1.00 grams of the ground powder was slowly added to the mineral oil while stirring with a stir bar. The solution was mixed until a homogenous milky white suspension was formed. 37.99 grams of petrolatum, white USP (Spectrum) was weighed out in a container and heated to 90°C.
- Study 1 Various formulations of ticrynafen were tested for efficacy in lowering intraocular pressure (IOP) in ocular normotensive cynomologus monkeys.
- IOP intraocular pressure
- Six animals were treated with 1.0% EY-117 ointment in one eye, placebo ointment in the contralateral eye, once daily for 7 consecutive days followed by twice daily treatment for an additional 4 days.
- Each monkey was randomly assigned one experimental and one control eye. Slit lamp examination was done to ensure normal, healthy eyes prior to the experiment.
- the monkeys were
- the monkeys were carefully examined with a slit lamp on days 1, 3, 5, and 11 at 0 and 3 hours and additional pressures were taken with topical 0.5% proparacaine HCl at 0, 1, and 3 hours.
- the mean ⁇ SEM IOP values for treated versus control eyes at 1 and 3 hours were 13.3 ⁇ 1.12 versus 13.0 ⁇ 0.86 and 12.0 ⁇ 0.52 versus 13.0 ⁇ 1.24 mmHg, respectively.
- day 11 the fourth day in which doses were administered twice daily
- slight but significant reductions in IOP were observed.
- the mean IOP values for treated versus control eyes at 0 and 3 hours were
- Results from the slit lamp exams were similar for both EY-117 and control eyes. Mild superficial punctate keratopathy was observed on Days 3, 5, and 11 and very mild corneal stippling on Day 11 in some eyes treated with either EY-117 or vehicle. Corneal irregularity was observed in one control eye on Days 1 and 3. There were no apparent differences in ocular irritation between EY-117 and control eyes as examined by slit lamp.
- EY-117 was administered twice daily to both eyes of glaucomatous monkeys for 5 consecutive days. The monkeys were anesthetized with 1-5 mg/kg of ketamine hydrochloride. A one centimeter strip of 2.0% EY-117 was administered to the lower cul de sac of the eye. A 1 centimeter strip of 2% EY-117 contains on the average 250ug/cm of ticrynafen. The eye was then held closed for approximately 30 seconds. The excess ointment was not wiped away.
- IOP was measured at 0, 0.5, 1, 2, 3, 4, 5, and 6 hours. Slit lamp exams were performed at 2, 4, and 6 hours each day. There was an effective IOP reduction with EY-117 treatment which increased with each successive day of dosing after the first day of treatment. There was only a slight reduction in IOP observed on Day 2 but large reductions were observed by Day 4 of treatment. Maximum mean IOP reductions on Days 4 and 5 were 7.5 and 9.8 mmHg, respectively.
- Study 3 Another study was performed to measure the effect of 2.0% EY-117 ointment administered twice daily on IOP and outflow facility in ocular normotensive cynomolgus monkeys. Six monkeys were treated with 2.0% EY-117 in one eye and a vehicle control in the contralateral eye, twice daily for 5 consecutive days. EY-117 was administered under the same conditions as described in study 1 and IOP was measured at 0, 1 , and 3 hour timepoints on Day 5. Slip lamp exams were also performed on Day 5 at 0 and 3 hours. Outflow facility was measured on Day 5 following the 3 hour IOP measurement.
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Abstract
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Application Number | Priority Date | Filing Date | Title |
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US25522894A | 1994-06-07 | 1994-06-07 | |
US08/255,228 | 1994-06-07 |
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WO1995033456A2 true WO1995033456A2 (en) | 1995-12-14 |
WO1995033456A3 WO1995033456A3 (en) | 1996-01-04 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0749303A1 (en) * | 1994-01-12 | 1996-12-27 | Duke University | Method of treating disorders of the eye |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3758506A (en) * | 1969-10-10 | 1973-09-11 | Cerpha Arcueil | Phenoxyacetic acid derivatives |
EP0306984A1 (en) * | 1987-09-11 | 1989-03-15 | Syntex (U.S.A.) Inc. | Preservative system for ophtalmic formulations |
WO1992016199A1 (en) * | 1991-03-14 | 1992-10-01 | Massachusetts Eye And Ear Infirmary | Method and products for treating the eye |
EP0628313A1 (en) * | 1993-06-07 | 1994-12-14 | Takeda Chemical Industries, Ltd. | Combination of benzimidazoles having angiotensin-II antagonistic activity with dinretics or calcium antagonists |
WO1995019165A1 (en) * | 1994-01-12 | 1995-07-20 | Duke University | Method of treating disorders of the eye |
-
1995
- 1995-06-06 WO PCT/US1995/007152 patent/WO1995033456A2/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3758506A (en) * | 1969-10-10 | 1973-09-11 | Cerpha Arcueil | Phenoxyacetic acid derivatives |
EP0306984A1 (en) * | 1987-09-11 | 1989-03-15 | Syntex (U.S.A.) Inc. | Preservative system for ophtalmic formulations |
WO1992016199A1 (en) * | 1991-03-14 | 1992-10-01 | Massachusetts Eye And Ear Infirmary | Method and products for treating the eye |
EP0628313A1 (en) * | 1993-06-07 | 1994-12-14 | Takeda Chemical Industries, Ltd. | Combination of benzimidazoles having angiotensin-II antagonistic activity with dinretics or calcium antagonists |
WO1995019165A1 (en) * | 1994-01-12 | 1995-07-20 | Duke University | Method of treating disorders of the eye |
Non-Patent Citations (1)
Title |
---|
OPHTHALMIC SURGERY, vol. 25, no. 5, May 1994 pages 336-337, MCNEILL J. I. ET AL 'Uncontrolled Tearing Supressed by Topical Suprofen' * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0749303A1 (en) * | 1994-01-12 | 1996-12-27 | Duke University | Method of treating disorders of the eye |
EP0749303A4 (en) * | 1994-01-12 | 1998-09-02 | Univ Duke | Method of treating disorders of the eye |
US6126957A (en) * | 1994-01-12 | 2000-10-03 | Duke University | Method of treating disorders of the eye |
US6534082B1 (en) | 1994-01-12 | 2003-03-18 | Duke University | Method of treating disorders of the eye |
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WO1995033456A3 (en) | 1996-01-04 |
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