WO2002040030A1 - Combination therapy for lowering and controlling intraocular pressure - Google Patents
Combination therapy for lowering and controlling intraocular pressure Download PDFInfo
- Publication number
- WO2002040030A1 WO2002040030A1 PCT/US2000/031557 US0031557W WO0240030A1 WO 2002040030 A1 WO2002040030 A1 WO 2002040030A1 US 0031557 W US0031557 W US 0031557W WO 0240030 A1 WO0240030 A1 WO 0240030A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- cooh
- integer
- bond
- iop
- 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
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates generally to the field of ophthalmology.
- the invention relates to the treatment of glaucoma using a combination of an angiostatic agent which lowers intraocular pressure (IOP) and a second IOP lowering compound.
- IOP intraocular pressure
- glaucoma is characterized by damage to the optic nerve, accompanied by a decrease in the normal visual field.
- IOP One early warning sign of possible glaucomatous visual field loss is elevated IOP.
- angiostatic agents which are known to lower IOP, see, for example, U.S. Patent Nos., 4,876,250 and 5,371,078. These compounds are very effective in controlling ocular hypertension, but they usually exhibit a slow onset of action; that is, it can take several weeks before an IOP lowering effect is seen.
- IOP controlling agents such as miotics, sympathomemetics, beta-blockers, carbonic anhydrase inhibitors, and prostaglandins are immediately effective in lowering IOP.
- compositions of the present invention contain an angiostatic agent which provides effective, long duration control of IOP and a second IOP lowering compound to provide immediate control of a patient's elevated IOP.
- This combination is more effective in that a patient's IOP can be lowered and controlled with less IOP spiking.
- the effectiveness of the combination is at least additive because the angiostatic agents lower IOP via a different mechanism than any of the second IOP lowering compounds described in this invention.
- the present invention is directed to compositions useful in the treatment of glaucoma and ocular hypertension.
- the compositions contain a combination of at least one angiostatic agent and at least one other compound which lowers IOP ("second agent").
- the compositions are used to lower and control IOP by topical application to a patient's affected eye(s).
- angiogenesis The development of blood vessels for the purpose of sustaining viable tissue is known as angiogenesis or neovascularization.
- Agents which inhibit neovascularization are known by a variety of terms such as angiostatic, angiolytic, or angiotropic agents.
- angiostatic agents have significant IOP lowering activity, Clark et al., IOVS 35 (Suppl.): 1057, 1994.
- angiostatic agent means compounds which inhibit new blood vessel formation as well as lower and/or control intraocular pressure associated with glaucoma or ocular hypertension.
- angiostatic agents act to control intraocular pressure by inhibiting the accumulation or stimulating the dissolution of amorphous extracellular material in the trabecular meshwork of the eye.
- the presence of this amorphous extracellular material alters the integrity of the healthy trabecular meshwork and is a symptom associated with primary open angle glaucoma (POAG).
- POAG primary open angle glaucoma
- GAGs glycosaminoglycans
- basement membrane material see, Ophthalmology, Vol. 90, No.7 (July 1983); Mayo Clin.
- angiostatic agents function in the trabecular meshwork in a similar manner as shown by Ingber, et al., wherein it was shown that angiostatic steroids caused dissolution of the basement membrane scaffolding using a chick embryo neovascularization model; Endocrinology, 119, pp.1768-1775 (1986). It is believed that angiostatic agents prevent the accumulation, or promote the dissolution of, amorphous extracellular materials in the trabecular meshwork by inhibiting the formation of basement membrane materials and glycosaminoglycans.
- Preferred angiostatic agents are represented by the following structures:
- R j is H, -CH3 or -C2H5;
- R2 is F, C9-C11 double bond, C9-C1 ⁇ epoxy, H or Cl;
- ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (Cj -C ⁇ alkyl groups, or ARYL is - (CH 2 )f phenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C ⁇ -C3), alkoxy(C ⁇ -C3), thioalkoxy-(C 1 -C 3 ), CI3C-, F3C-, -NH 2 and -NHCOCH3 and R is hydrogen, alkyl (C j -C4), or phenyl and each R can be the same or different, and R7 is ARYL as herein defined, or alkyl(Cj-C ⁇ 2); R 4 is H, CH 3 , Cl or F; R 5 is H,
- Rj 8 is hydrogen or alkyl (C ⁇ - C4); each of R j g and Ri 7 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R j g and R17 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyI- piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;
- R 19 is -S-, -S(O , -S(O) 2 - > -SO 2 N(R 20 )-, or N(R 2 Q)SO 2 -; and R 2 o is hydrogen or lower alkyl-(C ⁇ -C4); with the proviso that the total number of carbon atoms in R 2 Q and (CH 2 ) r is not greater than 10; or
- R 2 ⁇ is H and R 2 2 is H, CH3, - CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 OH, -CH 2 SH, -CH 2 CH 2 SCH 3 , or -CH2PI1-OH wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R 2j and R22 taken together are -CH 2 CH 2 CH -; or -N(R 2 ] )CH(R 2 2)COOH taken together is -NHCH 2 CONHCH 2 COOH; and pharmaceutically acceptable salts thereof;
- R 24 C, C j -C 2 double bond, 0;
- IOP-lowering compounds useful in the present invention include all presently known IOP-lowering compounds, including miotics (e.g., pilocarpine, carbachol and acetylcholinesterase inhibitors); sympathomimetics (e.g., epinephrine, dipivalylepinephrine and para-amino clonidine); beta-blockers (e.g., betaxolol, levobunolol, cartelol, and timolol); prostaglandins and their analogues and derivatives (e.g., F series (such as PGF2 ), E series (such as PGE2), D series (such as PGD2) and compounds disclosed in U.S. Patent Nos. 4,599,353; 5,093,329; and
- the preferred IOP-lowering compounds are: timolol, betaxolol, levobetaxolol, levobunolol, carteolol, pilocarpine, carbachol, epinephrine, dipivalyl epinephrine, -methyl dipivalylepinephrine, Trusopt, latanoprost, apraclonidine, and clonidine.
- compositions contain an amount of an angiostatic agent between 0.0001 and 10.0 percent by weight (wt%) and an amount of a second agent between 0.00001 and 10.0 wt%.
- angiostatic agent concentration is between 0.001 and 5.0 wt%, especially preferred are concentrations between 0.01 and 2.5 wt%.
- the second agent concentration is preferably between 0.001 and 5.0 wt%, 0.01 to 2.5 wt% is especially preferred.
- compositions of the present invention may additionally include components to provide sustained release and/or comfort.
- Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference.
- DCS finely-divided drug carrier substrate
- finely divided silica such as fumed silica, silicates, and bentonites
- ion exchange resins which can be anionic, cationic, or non-ionic in nature
- soluble polymers such as, alginic acid, pectin, soluble carrageenans, Carbopol®, and polystyrene sulfonic acid.
- the DCS component is used at a level in the range of about 0.05 to about 10.0 wt%.
- the average particle size diameter ranges from 1 to 20 microns.
- the amount of DCS and its characteristics e.g., amount of cross-linking, particle size
- the anti-glaucoma compositions of the present invention may further comprise various formulatory ingredients, such as antimicrobial preservatives and tonicity agents.
- suitable antimicrobial preservatives include: benzalkonium chloride, fhimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M® and other agents equally well-known to those skilled in the art.
- Such preservatives, if utilized, will typically be employed in an amount between about 0.001 and about 1.0 wt%.
- agents which may be used to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol. Such agents, if utilized, will typically be employed in an amount between about 0.1 and about 10.0 wt%.
- compositions may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels, and erodible solid ocular inserts.
- the compositions are preferably aqueous suspensions or solutions.
- compositions of the present invention may also comprise non-aqueous formulations such as: substantially non-aqueous liquids substantially non-aqueous semi-solid compositions and solid compositions or devices.
- the first class, substantially non-aqueous liquids comprise an angiostatic agent and a second agent ("drug combination") dissolved or suspended in one or more of the following: vegetable and mineral oils, such as, liquid petrolatum, corn oil, castor oil, sesame oil, and peanut oil; triglycerides, such as the capric/caprylic triglycerides commonly used in foods and cosmetics; liquid lanolin and lanolin derivatives; and perfluorohydrocarbons.
- vegetable and mineral oils such as, liquid petrolatum, corn oil, castor oil, sesame oil, and peanut oil
- triglycerides such as the capric/caprylic triglycerides commonly used in foods and cosmetics
- liquid lanolin and lanolin derivatives such as the capric/caprylic triglycerides commonly used in foods and cosmetics
- perfluorohydrocarbons such as the capric/caprylic triglycerides commonly used in foods and cosmetics.
- the second class, semi-solid compositions comprise a drug combination dissolved or suspended in one or more of the following: various types of petrolatum, such as white, yellow, red and so on; lanolin and lanolin derivatives; gelled mineral oil having a hydrocarbon base, such as Plastibase®; petrolatum and ethylene carbonate mixtures; petrolatum in combination with surfactants and polyglycol, such as polyoxyl 40 stearate and polyethylene glycol.
- various types of petrolatum such as white, yellow, red and so on
- lanolin and lanolin derivatives such as gelled mineral oil having a hydrocarbon base, such as Plastibase®
- petrolatum and ethylene carbonate mixtures such as polyoxyl 40 stearate and polyethylene glycol.
- the third class, solid compositions or devices include non-erodible devices which are inserted into the co ⁇ junctival sac of the eye and later removed, such as the Alza-type diffusion or osmotic pressure controlled polymer membranes; and bioerodible polymers which do not have to be removed from the conjunctival sac, such as essentially anhydrous but water soluble polymers and resins (e.g., celluloses, polycarboxylic acids, and so on).
- non-erodible devices which are inserted into the co ⁇ junctival sac of the eye and later removed, such as the Alza-type diffusion or osmotic pressure controlled polymer membranes; and bioerodible polymers which do not have to be removed from the conjunctival sac, such as essentially anhydrous but water soluble polymers and resins (e.g., celluloses, polycarboxylic acids, and so on).
- bioerodible inserts described and detailed in US 4,540,408 (Lloyd) and US 4,730,013 (Bondi et al.), wherein drug combinations of the present invention would be entrained in a non- aqueous matrix consisting essentially of polyvinyl alcohol.
- US 4,540,408 Lioyd
- US 4,730,013 Nondi et al.
- the present invention is also directed to methods of treating glaucoma and ocular hypertension.
- the compositions described above are applied topically to the affected eye(s) of the patient.
- the frequency and amount of dosage will be determined by the clinician based on various clinical factors.
- the methods will typically comprise topical application of one or two drops (or an equivalent amount of a solid or semi-solid dosage form) to the affected eye one to four times per day.
- Example 2 represents the preferred combination.
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- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU1770901A AU1770901A (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
PCT/US2000/031557 WO2002040030A1 (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
AU2001217709A AU2001217709B2 (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
CA002428799A CA2428799A1 (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
JP2002542403A JP2004522711A (en) | 2000-11-16 | 2000-11-16 | Combination therapy for reducing and controlling intraocular pressure |
EP00980450A EP1341541A4 (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
AU2006200143A AU2006200143B2 (en) | 2000-11-16 | 2006-01-13 | Combination therapy for lowering and controlling intraocular pressure |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2000/031557 WO2002040030A1 (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002040030A1 true WO2002040030A1 (en) | 2002-05-23 |
WO2002040030A8 WO2002040030A8 (en) | 2002-11-07 |
Family
ID=21742004
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/031557 WO2002040030A1 (en) | 2000-11-16 | 2000-11-16 | Combination therapy for lowering and controlling intraocular pressure |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1341541A4 (en) |
JP (1) | JP2004522711A (en) |
AU (2) | AU1770901A (en) |
CA (1) | CA2428799A1 (en) |
WO (1) | WO2002040030A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7288536B2 (en) | 2003-07-11 | 2007-10-30 | Glaxo Group Limited | Specific glucocorticosteroid compound having anti-inflammatory activity |
US7579335B2 (en) | 2005-01-10 | 2009-08-25 | Glaxo Group Limited | Androstane 17α-carbonate derivatives for use in the treatment of allergic and inflammatory conditions |
CN108066283A (en) * | 2017-12-28 | 2018-05-25 | 兆科药业(广州)有限公司 | A kind of preparation method of hydrochloric acid Levobetaxolol eye drops |
US10183030B2 (en) | 2014-10-08 | 2019-01-22 | Cosmo Technologies Limited | 17α,21-diesters of cortexolone for use in the treatment of tumors |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201010727A (en) * | 2008-09-03 | 2010-03-16 | Alcon Res Ltd | Pharmaceutical composition having relatively low ionic strength |
Citations (3)
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 |
US5153192A (en) * | 1990-04-09 | 1992-10-06 | Alcon Laboratories, Inc. | Thiophene sulfonamides useful as carbonic anhydrase inhibitors |
US5371078A (en) * | 1988-10-31 | 1994-12-06 | Alcon Laboratories, Inc. | Angiostatic steroids and methods and compositions for controlling ocular hypertension |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4904649A (en) * | 1986-05-23 | 1990-02-27 | New England Medical Center Hospitals, Inc. | Method and solution for treating glaucoma |
WO1987007141A1 (en) * | 1986-05-23 | 1987-12-03 | New England Medical Center Hospitals, Inc. | Method for treating glaucoma |
US4876250A (en) * | 1988-10-31 | 1989-10-24 | Alcon Laboratories, Inc. | Methods for controlling ocular hypertension with angiostatic steroids |
US5153193A (en) * | 1991-10-01 | 1992-10-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Carbamate derivatives of 4-amino-3-isoxazolidinones, 3-amino-1-hydroxypyrrolidin-2-ones and 1-amino-1-cyclopropanecarboxylic acid analogs |
CA2123405C (en) * | 1991-11-22 | 2008-01-15 | Abbot F. Clark | Angiostatic steroids |
US5540930A (en) * | 1993-10-25 | 1996-07-30 | Pharmos Corporation | Suspension of loteprednol etabonate for ear, eye, or nose treatment |
ES2203103T3 (en) * | 1998-04-07 | 2004-04-01 | Alcon Manufacturing Ltd. | GELIFYING OPHTHALMIC COMPOSITIONS CONTAINING XANTANA GUM. |
WO2000018316A2 (en) * | 1998-09-25 | 2000-04-06 | Alcon Laboratories, Inc. | Sustained release, and comfortable ophthalmic composition and method for ocular therapy |
-
2000
- 2000-11-16 AU AU1770901A patent/AU1770901A/en active Pending
- 2000-11-16 WO PCT/US2000/031557 patent/WO2002040030A1/en not_active Application Discontinuation
- 2000-11-16 CA CA002428799A patent/CA2428799A1/en not_active Abandoned
- 2000-11-16 EP EP00980450A patent/EP1341541A4/en not_active Ceased
- 2000-11-16 JP JP2002542403A patent/JP2004522711A/en active Pending
- 2000-11-16 AU AU2001217709A patent/AU2001217709B2/en not_active Ceased
Patent Citations (3)
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 |
US5371078A (en) * | 1988-10-31 | 1994-12-06 | Alcon Laboratories, Inc. | Angiostatic steroids and methods and compositions for controlling ocular hypertension |
US5153192A (en) * | 1990-04-09 | 1992-10-06 | Alcon Laboratories, Inc. | Thiophene sulfonamides useful as carbonic anhydrase inhibitors |
Non-Patent Citations (1)
Title |
---|
See also references of EP1341541A4 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7288536B2 (en) | 2003-07-11 | 2007-10-30 | Glaxo Group Limited | Specific glucocorticosteroid compound having anti-inflammatory activity |
US7291609B2 (en) | 2003-07-11 | 2007-11-06 | Glaxo Group Limited | Specific glucocorticosteroid compound having anti-inflammatory activity |
US7524970B2 (en) | 2003-07-11 | 2009-04-28 | Glaxo Group Limited | Compounds |
US7638508B2 (en) | 2003-07-11 | 2009-12-29 | Glaxo Group Limited | Glucocorticosteroid compound having anti-inflammatory activity |
US7579335B2 (en) | 2005-01-10 | 2009-08-25 | Glaxo Group Limited | Androstane 17α-carbonate derivatives for use in the treatment of allergic and inflammatory conditions |
US10183030B2 (en) | 2014-10-08 | 2019-01-22 | Cosmo Technologies Limited | 17α,21-diesters of cortexolone for use in the treatment of tumors |
US10231980B2 (en) | 2014-10-08 | 2019-03-19 | Cosmo Technologies Ltd. | Cortexolone 17alpha-benzoate for use in the treatment of tumours |
US10646497B2 (en) | 2014-10-08 | 2020-05-12 | Cosmo Technologies Limited | 17α-monoesters and 17α,21-diesters of cortexolone for use in the treatment of tumors |
US10993949B2 (en) | 2014-10-08 | 2021-05-04 | Cosmo Technologies Limited | 17α-monoesters and 17α,21-diesters of cortexolone for use in the treatment of tumors |
US11712443B2 (en) | 2014-10-08 | 2023-08-01 | Cosmo Technologies Limited | 17α-monoesters and 17α,21-diesters of cortexolone for use in the treatment of tumors |
US11986484B2 (en) | 2014-10-08 | 2024-05-21 | Cosmo Technologies Limited | 17α-monoesters and 17α,21-diesters of cortexolone for use in the treatment of tumors |
CN108066283A (en) * | 2017-12-28 | 2018-05-25 | 兆科药业(广州)有限公司 | A kind of preparation method of hydrochloric acid Levobetaxolol eye drops |
CN108066283B (en) * | 2017-12-28 | 2020-03-24 | 兆科(广州)眼科药物有限公司 | Preparation method of levobetaxolol hydrochloride eye drops |
Also Published As
Publication number | Publication date |
---|---|
AU2001217709B2 (en) | 2005-10-13 |
CA2428799A1 (en) | 2002-05-23 |
AU1770901A (en) | 2002-05-27 |
JP2004522711A (en) | 2004-07-29 |
EP1341541A1 (en) | 2003-09-10 |
WO2002040030A8 (en) | 2002-11-07 |
EP1341541A4 (en) | 2004-11-17 |
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