EP0521009A1 - 5-trans-prostaglandine-2-alpha comme agent hypotensif oculaire - Google Patents
5-trans-prostaglandine-2-alpha comme agent hypotensif oculaireInfo
- Publication number
- EP0521009A1 EP0521009A1 EP91905501A EP91905501A EP0521009A1 EP 0521009 A1 EP0521009 A1 EP 0521009A1 EP 91905501 A EP91905501 A EP 91905501A EP 91905501 A EP91905501 A EP 91905501A EP 0521009 A1 EP0521009 A1 EP 0521009A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- trans
- prostaglandin
- pgf
- pharmaceutically acceptable
- ocular
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a means of reducing or maintaining intraocular pressure, and, more particularly, to a method .and composition for reducing or maintaining intraocula pressure involving the administration of a compositio containing 5-trans prostaglandin F 2 ⁇ in a pharmaceuticall acceptable carrier.
- compositions and method of the present invention ar particularly useful for the management of glaucoma, a diseas of the eye characterized by increased intraocular pressure.
- glaucoma On the basis of its etiology, glaucoma has been classifie as primary or secondary.
- primary glaucoma ,i adults may be either open-bangle or acut or chronic angle-closure.
- Secondary glaucoma results from pre existing ocular diseases such as uveitis, intraocular tumor o an enlarged cataract.
- the underlying causes of primary glaucoma are not ye known.
- the increased intraocular tension is due to th obstruction of aqueous humor outflow.
- the anterior chamber . and its anatomic structure appear normal, but drainage of the aqueous humor is impeded
- acute or chronic angle-closure glaucoma the anterio chamber is shallow, the filtration angle is narrowed, and th iris may obstruct the trabecular meshwork at the entrance o the canal of Schlemm. Dilation of the pupil may push the roo of iris forward against the angle, and may produce pupillar block and thus precipitate an acute attack.
- Eyes with narro anterior chamber angles are predisposed to acute angle-closu glaucoma attacks of various degrees of severity.
- Secondary glaucoma is caused by any interference with t flow of aqueous humor from the posterior chamber into t anterior chamber and subsequently, into the canal of Schlem Inflammatory disease of the anterior segment may preve aqueous escape by causing complete posterior synechia in ir bombe, and may plug the drainage channel with exudates.
- Oth common causes are intraocular tumors, enlarged cataract central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
- glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
- topical ⁇ -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
- Eicosanoids and their derivatives have been reported to possess ocular hypotensive activity, and have been recommended for use in glaucoma management.
- Eicosanoids and derivative include numerous biologically important compounds such as Prostaglandins and their derivatives.
- Prostaglandins can be described as derivatives of prostanoic acid which has the following structural formula:
- Prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of Prostaglandin [e.g.,.Prostaglandin E-, (PGE-,) , Prostaglandin E 2 (PGE 2 ) ] , and on the configuration of the substituents on the alicyclic ring indicated by ⁇ or 5 [e.g. Prostaglandin F 2 ⁇ (PGF 2 ⁇ ) ].
- PGE- Prostaglandin E 2
- PGE 2 Prostaglandin E 2
- Prostaglandins were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last decade shows that some prostaglandins are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection With Prosta ⁇ landins Cohen, M. M. , ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds.. New York, Grune & Stratton, 1984, pp.
- Prostaglandins include PGF 2 ⁇ , PGF 1(r , PGE 2 , and certain lipid-soluble esters/ such as C, to C 2 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
- PGF 2 ⁇ PGF 1(r , PGE 2
- certain lipid-soluble esters/ such as C to C 2 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
- the isopropyl ester of PGF 2 ⁇ has been shown to have significantly greater hypotensive potency than the parent compound, presumably as a result of its more effective transfer through the cornea.
- Prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistentl associated with the topical ocular use of such compounds, i particular PGF 2a and its prodrugs, e.g. its 1-isopropyl ester, in humans.
- PGF 2a a progenitor derived neuropeptide
- prodrugs e.g. its 1-isopropyl ester
- Intraocula pressure reducing 15-acyl Prostaglandins are disclosed in th co-pending application USSN 357,394 (filed 25 May 1989)
- 11,15- 9,15- and 9,11-diesters of Prostaglandins for example 11,15-dipivaloyl PGF 2 ⁇ are known to have ocula hypotensive activity.
- USSN Nos. 385,645, 386,312 and 386,834 all filed 27 Jul 1989.
- the disclosures of all of these patent applications ar hereby expressly incorporated by reference.
- the present invention relates to the use of 5-trans Prostaglandin F 2 ⁇ , formulated in a pharmaceutically acceptable vehicle, for the treatment of glaucoma and ocular hypertension.
- 5-trans Prostaglandin F 2 ⁇ where the 5-6 double bond is in the trans rather than the natural cis configuration, has pronounced ocular hypotensive activity with significantly reduced adverse side effects, notably ocular surface hyperemia.
- 5-trans Prostaglandin F 2 ⁇ is, therefore, excellent candidate for therapeutic treatment of a variety of ocular hypertensive conditions such as open-angle glaucoma, closed-angle glaucoma, ocular hypertensive episodes, post- surgical and post-laser trabeculectomy, and as a presurgical adjuvant.
- a topically applicable pharmaceutical composition for treating ocular hypertension which comprises 5- trans Prostaglandin F 2 ⁇ of the formula (I) :
- composition of the present invention may further comprise co-solvents, pH buffers, viscosity enhancers, antibiotics or other advantageous adjuvants.
- a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of 5- trans Prostaglandin PGF 2 ⁇ ; or a pharmaceutically acceptable salt thereof.
- the present invention relates to an ophthalmic solution comprising a therapeutically effective amount of PGF 2 ⁇ , or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle, packaged in a container suitable for metered application.
- the present invention relates,to a pharmaceutical product, comprising a container adapted to dispense its contents in metered form; and an ophthalmic solution therein, as hereinabove defined.
- PGF 2 ⁇ an pharmaceutically acceptable salts thereof as ocula hypotensives.
- PGF 2a has the following structural formula (I)
- thickened solid line attachmen indicates the beta configuration.
- the broken line attachment of th hydroxyl groups indicate that these substituents are i alpha con iguration.
- Prostaglandin F 2 ⁇ produces side effects such as conjunctiva hyperemia, smarting, and foreign body sensations which range i degree from undesirable to unacceptable, depending upon t particular patient and the dosage necessary to produce sufficient pressure regulating effect.
- additio Prostaglandin F 2 ⁇ may produce transient ocular hypertension. to 6 carbons, either the mono- or diacids.
- Quaternary ammonium compounds can be prepared from alkylating agents such as methyl iodide and the like.
- compositions may be prepared by combining a therapeutically efficient amount of 5-trans PGF 2 ⁇ or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use.
- the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v) , preferably about 0.001 to about 0.1% (w/v) in liquid formulations.
- solutions are prepared using a physiological saline solution as a major vehicle.
- the pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system.
- the formulations may also contain conventional, pharmaceutically acceptable preservatives and stabilizers.
- Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol , thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
- various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water- *
- Tonicity adjusters may be added as needed or convenient. They- include, but are not limited to, salts, pazrticularl sodium chloride, potassium chloride, mannitol and glycerin, o any other suitable opthalmically acceptable tonicity adjuster.
- buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may b used to adjust the pH of these formulations as needed.
- an ophthalmically acceptable antioxidan for use in the present invention includes, but is not limitation
- an ocular hypotensive which comprises 5-trans Prostaglandin F 2 ⁇ .
- 5-trans Prostaglandin F 2 ⁇ where the 5-6 double bond is in the trans configuration, has substantially the same ocular hypotensive activity as natural Prostaglandin F 2 ⁇ with significantly reduced adverse side effects, notably ocular surface hyperemia.
- 5-trans Prostaglandin F 2a is less potent in causing ocular hypertension, an undesirable side-effect in glaucoma therapy.
- the PGF 2tf compound illustrated in Formula (I) is in the free acid form.
- any of a variety of the corresponding salts may also be utilized in the ophthalmic formulations of the present invention.
- the carboxylic acid group at C-l of the Formula (I) compound is designated:
- A may be -OH to produce the free acid, or -OR where R may be either the anion component of any of a variety of pharmaceutically acceptable salts.
- a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to which it is administered and in the context in which it is administered. Suitable pharmaceutically acceptable salts may be derived from either an organic or inorganic base. Such a salt may comprise a mono- or polyvalent ion. Of particular interest are inorganic cations such as sodium, potassium, calcium, magnesium and zinc. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines.
- Salts may also be formed with caffeine, tromethamine and similar molecules. Where acid addition salts are formed from amines, any inorganic or organic acid may be used. Preferred salts are hydrogen chloride salts, sulfate salts, phosphate salts and salts of simple organic acids of 2 to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
- excipient components which may be included in the ophthalmic preparations are chelating agents.
- the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.
- the ingredients are usually used in the following amounts: Ingredient Afflpymt f% w/y) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed purified water as needed to make 100%
- the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
- the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate the application to the eye.
- Containers suitable for dropwise application are usually made of suitable inert, non- toxic plastic material, and generally contain between about 0.5 and about 15 ⁇ l solution.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US49687990A | 1990-03-19 | 1990-03-19 | |
US496879 | 1990-03-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0521009A1 true EP0521009A1 (fr) | 1993-01-07 |
EP0521009A4 EP0521009A4 (en) | 1993-02-24 |
Family
ID=23974569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19910905501 Withdrawn EP0521009A4 (en) | 1990-03-19 | 1991-02-12 | Use of 5-trans prostaglandin f 2-g(a)? as an ocular hypotensive agent |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0521009A4 (fr) |
JP (1) | JPH05505605A (fr) |
CA (1) | CA2076023A1 (fr) |
FI (1) | FI924205A (fr) |
HU (1) | HUT61666A (fr) |
IE (1) | IE910865A1 (fr) |
WO (1) | WO1991014428A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8616427B2 (en) | 2002-10-04 | 2013-12-31 | Covidien Lp | Tool assembly for surgical stapling device |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5468778A (en) * | 1992-09-24 | 1995-11-21 | Allergan, Inc. | Method of lowering intraocular pressure by administering a pharmaceutical composition containing 7-(5-substituted cyclopentyl) and 7-(5-substituted-cyclopentenyl) 5-heptenoic acids and derivatives |
WO1994008585A1 (fr) * | 1992-10-13 | 1994-04-28 | Alcon Laboratories, Inc. | Combinaisons de prostaglandines et de derives de clonidine pour le traitement du glaucome |
US6294563B1 (en) | 1994-10-27 | 2001-09-25 | Allergan Sales, Inc. | Combinations of prostaglandins and brimonidine or derivatives thereof |
US6414021B1 (en) * | 2000-08-25 | 2002-07-02 | Sucampo Ag | Control of intraocular pressure during surgery |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2106534A1 (fr) * | 1970-09-15 | 1972-05-05 | Upjohn Co | |
WO1989003384A1 (fr) * | 1987-10-07 | 1989-04-20 | Pharmacia Ab | Derives de prostaglandine servant au traitement du glaucome ou de l'hypertension oculaire |
Family Cites Families (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 |
-
1991
- 1991-02-12 JP JP91505356A patent/JPH05505605A/ja active Pending
- 1991-02-12 CA CA002076023A patent/CA2076023A1/fr not_active Abandoned
- 1991-02-12 EP EP19910905501 patent/EP0521009A4/en not_active Withdrawn
- 1991-02-12 HU HU922572A patent/HUT61666A/hu unknown
- 1991-02-12 WO PCT/US1991/000986 patent/WO1991014428A1/fr not_active Application Discontinuation
- 1991-03-15 IE IE086591A patent/IE910865A1/en unknown
-
1992
- 1992-09-18 FI FI924205A patent/FI924205A/fi not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2106534A1 (fr) * | 1970-09-15 | 1972-05-05 | Upjohn Co | |
WO1989003384A1 (fr) * | 1987-10-07 | 1989-04-20 | Pharmacia Ab | Derives de prostaglandine servant au traitement du glaucome ou de l'hypertension oculaire |
Non-Patent Citations (2)
Title |
---|
INVEST. OPHTHALM. VISUAL SC. vol. 16, no. 12, December 1977, PHILADELPHIA pages 1125 - 1134 C. B. CAMRAS 'Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits.' * |
See also references of WO9114428A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8616427B2 (en) | 2002-10-04 | 2013-12-31 | Covidien Lp | Tool assembly for surgical stapling device |
Also Published As
Publication number | Publication date |
---|---|
HUT61666A (en) | 1993-03-01 |
CA2076023A1 (fr) | 1991-09-20 |
FI924205A0 (fi) | 1992-09-18 |
WO1991014428A1 (fr) | 1991-10-03 |
HU9202572D0 (en) | 1992-12-28 |
EP0521009A4 (en) | 1993-02-24 |
JPH05505605A (ja) | 1993-08-19 |
FI924205A (fi) | 1992-09-18 |
IE910865A1 (en) | 1991-09-25 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 19951017 |