WO1998050024A1 - 8-iso-prostaglandins for glaucoma therapy - Google Patents
8-iso-prostaglandins for glaucoma therapy Download PDFInfo
- Publication number
- WO1998050024A1 WO1998050024A1 PCT/US1998/009090 US9809090W WO9850024A1 WO 1998050024 A1 WO1998050024 A1 WO 1998050024A1 US 9809090 W US9809090 W US 9809090W WO 9850024 A1 WO9850024 A1 WO 9850024A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- iso
- derivative
- prostanoid
- group
- following formula
- Prior art date
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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
- 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
- A61P27/06—Antiglaucoma agents or miotics
Definitions
- the present invention relates to the use of 8-iso prostaglandins and their derivatives for decreasing intraocular pressure, for example in the treatment of glaucoma. It is based, at least in part, on the discovery that 8-iso prostaglandin E 2 effectively decreased intraocular pressure by a trabecular meshwork outflow mechanism.
- Glaucoma is a major eye disease which can cause progressive loss of vision leading to blindness.
- the majority of human glaucomas are associated with increased intraocular pressure ("IOP") resulting from an imbalance in the rate of secretion of aqueous humor by the ciliary epithelium into the anterior and posterior chambers of the eye and the rate of aqueous humor outflow from these chambers, primarily via the canal of Schlemm.
- IOP intraocular pressure
- High IOP is considered the major risk factor for glaucomatous visual impairment resulting from the death of retinal ganglion cells, loss of the nerve fiber layer in the retina, and destruction of the axons of the optic nerve.
- Current treatments are directed toward reducing intraocular pressure.
- Glaucoma is typically classified, on the basis of its etiology, as primary or secondary.
- Primary glaucoma in adults a disorder in which the underlying cause is poorly understood, is associated with increased IOP due to an obstruction of aqueous humor outflow .
- the obstruction may be caused by a blockage located at the angle formed between the iris and the lateral cornea, categorized as either open angle or acute or chronic angle closure.
- the anterior chamber of the eye appears normal in chronic open angle glaucoma, despite impaired drainage of aqueous humor.
- the anterior chamber is shallow and the filtration angle is narrowed in chronic angle-closure glaucoma, wherein the trabecular meshwork and the canal of Schlemm may be obstructed by the iris.
- Secondary glaucoma is caused by another disorder which functionally interferes with the outflow of aqueous humor or the flow from the posterior to the anterior chamber. Such interference may be caused by inflammation, a tumor, an enlarged cataract, central retinal vein occlusion, trauma, or hemorrhage.
- beta adrenergic blockers e.g., timolol
- topical carbonic anhydrase inhibitors e.g., dorzolamide
- alpha-, -adrenergic receptor agonists e.g., clonidine derivatives
- Pilocarpine and epinephrine are clinical agents that also lower IOP in glaucomatous eyes, but these drugs act principally by decreasing the resistance in the trabecular meshwork outflow channels.
- a third mechanism for lowering IOP in the primate eye is by increasing the outflow of aqueous humor via the uveoscleral route.
- a prostaglandin derivative belonging to the F2 ⁇ series of prostanoids which acts primarily by this uveoscleral mechanism, has been introduced for glaucoma therapy.
- latanoprost is the isopropyl ester of a compound having the following
- Prostaglandins which may be used in the treatment of glaucoma are described in United States Patents Nos. 5,476,872 by Garst et al., 4,599,353 by Bito,
- the present invention relates to prostaglandins which are structurally different from latanoprost and other prostaglandins used in the treatment of glaucoma, and that belong to the 8-iso series of prostanoids, for example 8-iso PGE, , 8-iso PGE 2 and 8-iso-PGF 2 ⁇ .
- 8-isoPGE 2 In contrast to latanoprost, 8-isoPGE 2 lowers IOP primarily by decreasing the resistance to trabecular outflow of aqueous humor from the eye.
- the present invention relates to the use of 8-iso prostanoids in methods which decrease intraocular pressure ("IOP") in the eye, for example in the treatment of glaucoma.
- the 8-iso-prostanoids of the invention have a common structure according to formula I:
- the 8-iso prostanoid is 8-iso prostaglandin E 2 (prosta-5,13-dien-l-oic acid, l l,15-dihydroxy-9-oxo, (5Z, 8 ⁇ , 1 l ⁇ , 13E.15S), having Formula II:
- the 8-iso prostanoid is 8-iso, 5,6 dihydro prostaglandin E-, (referred to as 8-iso PGE,), having
- the 8-iso prostanoid is 8-iso PGF 2 ⁇ (prosta-5,13-dien-l-oic acid, 9, 11, 15-trihydroxy-, (5Z, 8 ⁇ , 9 , 1 l ⁇ , 13
- the present invention relates to the use of 8-iso prostanoids having basic Formula I to decrease intraocular pressure in a subject in need of such treatment.
- the 8-iso prostanoid may be selected from the group of (i) 8-iso prostaglandin E 2 (prosta-5,13-dien-l-oic acid, 1 l,15-hydroxy-9-oxo, (5Z, 8 ⁇ , 1 l ⁇ , 13E,15S) ("8-iso PGE-/'), having Formula II; (ii) the 5,6 dihydro derivative of 8-iso PGE ⁇ having Formula III and referred to as 8-iso PGE,; (iii) prosta-5,13-dien-l-oic acid, 9, 11, 15-trihydroxy-, (5Z, 8 ⁇ , 9 ⁇ , 1 l ⁇ , 13E, 15S) ("8-iso PGF 2 ⁇ "), having Formula IV; and (iv) derivatives of
- the main structural differences between the 8-iso prostanoids of the invention and latanoprost are the following: (i) the side chain substituents on the f ⁇ ve- membered rings have the opposite geometric arrangement with respect to the plane of the ring (cis for the 8-iso prostanoids of the invention and trans for latanoprost); (ii) the f ⁇ ve-membered ring has a keto or hydroxyl function at position 9 in the 8-iso prostanoids of the invention, whereas there is just a hydroxyl group in the same position in latanoprost; and (iii) the side chains beginning with the sixteenth carbon may have different structures, as, for example, latanoprost containing a terminal methyl phenyl group at this position.
- 8-iso prostanoid derivatives of the invention contain a five-membered ring and two side chains, and retain distinguishing features (i)-(iii) as set forth in the preceding sentence and in Formula I.
- such derivatives are esters of compounds having Formula II, III or IV.
- esterified derivatives of 8-iso PGE 2 may be used according to the invention, and may provide improved penetration into the eye.
- the present invention provides for a method for decreasing IOP comprising administering a therapeutically effective amount of an 8- iso prostanoid of the invention to a subject in need of such treatment.
- a method may be used in the treatment of glaucoma in a subject.
- suitable formulations include for example, and not by way of limitation, a topical solution which is a physiological saline solution, having a pH between about 4.5 and 8 and an appropriate buffer system (e.g., acetate buffers, citrate buffers, phosphate buffers, borate buffers) a neutral pH being preferred.
- the formulation may further comprise a pharmaceutically acceptable preservative (e.g.
- the formulation may also comprise a compound which aete as an anti-oxidant (e.g. sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxy toluene).
- a "therapeutically effective amount" of an 8-iso prostanoid of the invention refers to an amount of drug which decreases the IOP by at least about 10 percent, preferably at least about 15 percent, and more preferably at least about 20 percent.
- the administration of 8-iso prostanoid results in an increase in trabecular outflow facility of at least about 10 percent, preferably at least about 20 percent, and more preferably at least about 30 percent.
- a topical preparation of 8-iso prostanoid at a concentration of between .001 and 1 percent, preferably between .005 and .2 percent, and more preferably between about .05 and .1 percent may be used.
- IOP may be decreased, and/or glaucoma may be treated, using compositions comprising an 8-iso prostanoid of the invention as the sole active agent, or in conjunction with another active agent.
- an 8-iso prostanoid of the invention as the sole active agent, or in conjunction with another active agent.
- combinations of 8-iso prostanoid and another drug used to treat elevated intraocular pressure including but not limited to another prostaglandin derivative (including, but not limited to, latanoprost), pilocarpine, epinephrine, a beta adrenergic agent (e.g., timolol), a carbonic anhydrase inhibitor (e.g., dorzolamide), or an alpha ⁇ adrenergic receptor agonist (e.g., a clonidine derivative), may be used.
- another prostaglandin derivative including, but not limited to, latanoprost
- pilocarpine epinephrine
- EXAMPLE I Experiments were performed to evaluate the effects of single dose administration of 8-iso PGE 2 on IOP in normal (“N") and glaucomatous (“G”) monkey eyes, and to determine the mechanism by which 8-iso PGE-, alters IOP in N monkey eyes, when applied topically.
- a single 25 ⁇ l dose study was performed in 6 N and 8 G monkeys. IOP and pupil sizes were measured before and at 0 hr, 0.5 hr and then hourly for a total of 6 hrs after 0.05% or 0.1% drug concentrations were administered.
- Tonographic outflow facility (“C”) and fluorophotometric aqueous humor flow (F) were determined in 6 N monkeys before and after unilateral application of 25 ⁇ l of 0.1% 8-iso PGE 2 .
- 8-isoPGE- reduced IOP (p ⁇ 0.005) up to 2 hrs or 5 hrs following administration of the 0.05% or 0.1% concentration, respectively.
- the maximum reduction in IOP was 4.6 ⁇ 0.8(mean ⁇ SEM)mm Hg (0.05%) and 6.6 ⁇ 0.8 mm Hg (0.1%), as compared to baseline measurements.
- the IOP was lower (p ⁇ 0.01) in the treated eyes of 6 N monkeys for 4 hrs, with a maximum difference of 3.2 ⁇ 0.2 mmHg, as compared to the fellow contralateral control eyes.
- the pupil size was smaller (pO.Ol) for 4 hrs, up to 1.0 ⁇ 0.2 mm.
- C was greater (p ⁇ 0.005) by 48% at 2 hr after a single dose of 0.1% 8-iso PGE 2 .
- F was unchanged (p ⁇ .10) over a period of 4 hrs after drug administration. Mild eyelid edema, conjunctival edema, hyperemia, and discharge appeared in some eyes treated with the 0.1% concentration.
- Table 1A shows that 8-iso PGE 2 administered to the normal monkey eye lowers IOP significantly by 20.3% and increases outflow facility by 43.1%, an amount sufficient to account for the fall of IOP.
- Table IB latanoprost in the normal monkey eye also lowers IOP significantly (by 10.8%), but the drug has no significant effect on outflow facility.
- the lack of a major effect on outflow facility of latanoprost in the primate eye is in agreement with studies in the literature by other investigators.
- Table 2 shows the effect of 8-iso PGE 2 on IOP and outflow facility in glaucomatous monkey eyes. Because of the individual variability in laser-induced glaucomatous monkey eyes, the IOP and facility measurements are expressed in the table as ratios (value of the drug-treated eye ⁇ the value of the vehicle-treated eye). The ratios were calculated from the values of the same glaucomatous monkey eye determined immediately prior to administration of the drug or the vehicle (time 0 hrs.), and the values at 2 hours after administration of the drug or vehicle.
- EXAMPLE II IOP was measured one hour before and at intervals up to six hours after a single dose of 8-iso PGE, (the 13, 14 dihydro derivative of 8-iso PGE 2 ), 8-iso PGE 2 , or 8-iso PGF 2 ⁇ in laser-induced glaucomatous eyes in cynomolgus monkeys (wherein only one eye is rendered glaucomatous and the other serves as a control).
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- Animal Behavior & Ethology (AREA)
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU73686/98A AU725677B2 (en) | 1997-05-09 | 1998-05-06 | 8-iso-prostaglandins for glaucoma therapy |
EP98920974A EP1007028A4 (en) | 1997-05-09 | 1998-05-06 | 8-iso-prostaglandins for glaucoma therapy |
CA002293325A CA2293325C (en) | 1997-05-09 | 1998-05-06 | 8-iso-prostaglandins for glaucoma therapy |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US85380397A | 1997-05-09 | 1997-05-09 | |
US08/853,803 | 1997-05-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998050024A1 true WO1998050024A1 (en) | 1998-11-12 |
Family
ID=25316955
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/009090 WO1998050024A1 (en) | 1997-05-09 | 1998-05-06 | 8-iso-prostaglandins for glaucoma therapy |
Country Status (5)
Country | Link |
---|---|
US (2) | US6037368A (en) |
EP (1) | EP1007028A4 (en) |
AU (1) | AU725677B2 (en) |
CA (1) | CA2293325C (en) |
WO (1) | WO1998050024A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5977173A (en) * | 1997-09-09 | 1999-11-02 | Wos; John August | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists |
US6048895A (en) * | 1997-09-09 | 2000-04-11 | The Procter & Gamble Company | Aromatic C16-C20 substituted tetrahydro prostaglandins useful as FP agonists |
US6107338A (en) * | 1997-09-09 | 2000-08-22 | The Procter & Gamble Company | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists |
WO2009061721A1 (en) * | 2007-11-07 | 2009-05-14 | Alcon Research, Ltd. | Complement c1q inhibitors for the prevention and treatment of glaucoma |
USRE43372E1 (en) | 1999-03-05 | 2012-05-08 | Duke University | C16 unsaturated FP-selective prostaglandins analogs |
WO2014144781A1 (en) | 2013-03-15 | 2014-09-18 | Aerie Pharmaceuticals, Inc. | Combination therapy |
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 |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
US10112920B2 (en) | 2008-07-25 | 2018-10-30 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
US10174017B2 (en) | 2009-05-01 | 2019-01-08 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
US10472327B2 (en) | 2007-01-10 | 2019-11-12 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
US11389441B2 (en) | 2016-08-31 | 2022-07-19 | Aerie Pharmaceuticals, Inc. | Ophthalmic compositions |
US11427563B2 (en) | 2018-09-14 | 2022-08-30 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
Families Citing this family (8)
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US6894175B1 (en) * | 1999-08-04 | 2005-05-17 | The Procter & Gamble Company | 2-Decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use |
TWI290470B (en) | 1999-12-01 | 2007-12-01 | Sankyo Co | The composition for treating glaucoma |
US20020146439A1 (en) * | 2000-03-31 | 2002-10-10 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins |
US20020037914A1 (en) * | 2000-03-31 | 2002-03-28 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins |
US20050119262A1 (en) * | 2003-08-21 | 2005-06-02 | Pharmacia Corporation | Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent |
US8722739B2 (en) | 2008-10-29 | 2014-05-13 | Novaer Holdings, Inc. | Amino acid salts of prostaglandins |
US8623918B2 (en) * | 2008-10-29 | 2014-01-07 | Novaer Holdings, Inc. | Amino acid salts of prostaglandins |
EP3609871A4 (en) | 2017-03-31 | 2021-01-06 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
Citations (1)
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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 |
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US4132847A (en) * | 1977-07-22 | 1979-01-02 | Pfizer Inc. | 4-Pyrone prostaglandin antagonists |
US5151444B1 (en) * | 1987-09-18 | 1999-07-06 | R Tech Ueno Ltd | Ocular hypotensive agents |
US5565492A (en) * | 1988-07-18 | 1996-10-15 | Alcon Laboratories, Inc. | Prostaglandin combinations in glaucoma therapy |
US5173507A (en) * | 1988-07-18 | 1992-12-22 | Alcon Laboratories, Inc. | Prostaglandin combinations in glaucoma therapy |
DE03014533T1 (en) * | 1988-09-06 | 2004-07-15 | Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5208256A (en) * | 1990-05-22 | 1993-05-04 | R-Tech Ueno, Ltd. | Treatment of ocular hypertension with a synergistic combination for ocular administration |
US5262437A (en) * | 1990-12-10 | 1993-11-16 | Allergan, Inc. | Homo-prostaglandin derivatives as ocular hypotensives |
US6124353A (en) * | 1992-11-12 | 2000-09-26 | Allergan Sales, Inc. | Method of treating ocular hypertension with 8-epi prostaglandins |
US5476872A (en) * | 1993-10-18 | 1995-12-19 | Allergan, Inc. | 1,11-diesters of prostaglandin-F2α having a polar ester group at C-1 |
US5462968A (en) * | 1994-01-19 | 1995-10-31 | Allergan, Inc. | EP2 -receptor agonists as agents for lowering intraocular pressure |
US5631287A (en) * | 1994-12-22 | 1997-05-20 | Alcon Laboratories, Inc. | Storage-stable prostaglandin compositions |
-
1998
- 1998-05-06 AU AU73686/98A patent/AU725677B2/en not_active Ceased
- 1998-05-06 US US09/073,552 patent/US6037368A/en not_active Ceased
- 1998-05-06 EP EP98920974A patent/EP1007028A4/en not_active Withdrawn
- 1998-05-06 WO PCT/US1998/009090 patent/WO1998050024A1/en active IP Right Grant
- 1998-05-06 CA CA002293325A patent/CA2293325C/en not_active Expired - Fee Related
-
2002
- 2002-02-11 US US10/073,838 patent/USRE39609E1/en not_active Expired - Fee Related
Patent Citations (1)
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 |
Cited By (32)
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US5977173A (en) * | 1997-09-09 | 1999-11-02 | Wos; John August | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists |
US6048895A (en) * | 1997-09-09 | 2000-04-11 | The Procter & Gamble Company | Aromatic C16-C20 substituted tetrahydro prostaglandins useful as FP agonists |
US6107338A (en) * | 1997-09-09 | 2000-08-22 | The Procter & Gamble Company | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists |
USRE43372E1 (en) | 1999-03-05 | 2012-05-08 | Duke University | C16 unsaturated FP-selective prostaglandins analogs |
US9675539B2 (en) | 2000-03-31 | 2017-06-13 | Duke University | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
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 |
US9579270B2 (en) | 2000-03-31 | 2017-02-28 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US10472327B2 (en) | 2007-01-10 | 2019-11-12 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
WO2009061721A1 (en) * | 2007-11-07 | 2009-05-14 | Alcon Research, Ltd. | Complement c1q inhibitors for the prevention and treatment of glaucoma |
US11021456B2 (en) | 2008-07-25 | 2021-06-01 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
US10882840B2 (en) | 2008-07-25 | 2021-01-05 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
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US10316029B2 (en) | 2009-05-01 | 2019-06-11 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
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US10568878B2 (en) | 2013-03-15 | 2020-02-25 | Aerie Pharmaceuticals, Inc. | Combination therapy |
US9931336B2 (en) | 2013-03-15 | 2018-04-03 | Aerie Pharmaceuticals, Inc. | Combination therapy |
US9849122B2 (en) | 2013-03-15 | 2017-12-26 | Aerie Pharmaceuticals, Inc. | Combination therapy |
EP3811943A1 (en) | 2013-03-15 | 2021-04-28 | Aerie Pharmaceuticals, Inc. | Compound for use in the treatment of ocular disorders |
EP3461484A1 (en) | 2013-03-15 | 2019-04-03 | Aerie Pharmaceuticals, Inc. | Combination therapy |
WO2014144781A1 (en) | 2013-03-15 | 2014-09-18 | Aerie Pharmaceuticals, Inc. | Combination therapy |
US11185538B2 (en) | 2013-03-15 | 2021-11-30 | Aerie Pharmaceuticals, Inc. | Compositions for treating glaucoma or reducing intraocular pressure |
EP4335507A2 (en) | 2013-03-15 | 2024-03-13 | Aerie Pharmaceuticals, Inc. | Combination therapy |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
US11389441B2 (en) | 2016-08-31 | 2022-07-19 | Aerie Pharmaceuticals, Inc. | Ophthalmic compositions |
US11427563B2 (en) | 2018-09-14 | 2022-08-30 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
Also Published As
Publication number | Publication date |
---|---|
CA2293325A1 (en) | 1998-11-12 |
USRE39609E1 (en) | 2007-05-01 |
US6037368A (en) | 2000-03-14 |
AU725677B2 (en) | 2000-10-19 |
CA2293325C (en) | 2008-09-02 |
AU7368698A (en) | 1998-11-27 |
EP1007028A4 (en) | 2002-06-05 |
EP1007028A1 (en) | 2000-06-14 |
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