WO2001058438A1 - Ophthalmic use of alpha adrenergic blocking agents - Google Patents
Ophthalmic use of alpha adrenergic blocking agents Download PDFInfo
- Publication number
- WO2001058438A1 WO2001058438A1 PCT/US2001/004316 US0104316W WO0158438A1 WO 2001058438 A1 WO2001058438 A1 WO 2001058438A1 US 0104316 W US0104316 W US 0104316W WO 0158438 A1 WO0158438 A1 WO 0158438A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmic solution
- alpha adrenergic
- adrenergic blocking
- agents
- blocking agents
- Prior art date
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Classifications
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- 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
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
Definitions
- the present invention relates to methods and compositions for inhibiting undesirable visual anomalies commonly experienced by individuals who have undergone refractive eye surgery.
- the methods and compositions of the invention provide a means for inhibiting photophobia, glare, secondary images and haloing.
- the methods of the invention comprise the post-operative administration of an ophthalmic solution comprising alpha adrenergic blocking agents to the surface of the eye.
- the invention is based on the observation that when alpha adrenergic blocking agents are applied to the surface of the eye, the composition is well tolerated and the pupil is made smaller by relaxing the iris without induced myopia.
- the invention further provides for the use of an ophthalmic solution comprising alpha adrenergic blocking agents to eliminate symptoms developed by conditions wherein the diameter of the pupil exceeds the diameter desired for the respective optic zone.
- the present invention by enabling a method for the use of an ophthalmic solution comprising alpha adrenergic blocking agents, provides a safer and less severe treatment than those methods that utilize the administration of pilocarpine or other compositions that forcibly make the pupil smaller.
- refractive eye surgery is currently limited by the high incidence of undesirable visual anomalies, such as photophobia, glare, secondary images and haloing, experienced by individuals who have undergone refractive eye surgery.
- Refractive procedures include and are not limited to the surgical implantation of an intraocular lens, laser surgery, and radial keratotomy.
- Post-operative complications exist because the refractive procedure causes a differential between the corrected optic zone and the diameter of the pupil. Such a differential generally leads to persistent incidence of undesirable visual anomalies, particularly in certain situations, including but not limited to mesopic conditions of reduced illumination and, conversely, conditions of bright light experienced while driving a motor vehicle at night.
- a method of treating individuals who experience undesirable visual anomalies after refractive eye surgery does not exist without causing induced myopia and headaches caused by contraction of the ciliary body associated with the application of pilocarpine or other compositions that forcibly make the pupil smaller. These agents may create risk of retinal detachment as well as photopsia. It is known that pilocarpine has been used after an ophthalmologist has induced dilation of the pupil in order to forcibly hasten the return of the iris at the conclusion of an examination or procedure to a constricted state. It is also known that dapiprazole, manufactured by Storz Instruments Co.
- Rev Eyes (which was acquired by Bausch & Lomb) under the tradename Rev Eyes, is used to hasten the return of the pupil to normal size after dilation by an examiner.
- Rev Eyes is instilled in the patient by the physician or optometrist in the doctor's office. Further, this product is limited by its short shelf life.
- the cyclotonic agents hasten the return of the iris to a normal position, they create induced myopia and cause headaches in patients. Most patients suffer from the side-effects associated with the usage of these conventional drugs. It is known that alpha adrenergic blocking agents have been used for the treatment of angle closure glaucoma, which condition causes an increased pressure within the eyeball causing a gradual loss of sight.
- alpha adrenergic blocking agents such as thymoxamine
- thymoxamine have been used to reverse mydriasis induced by sympathomimetic agents during the implantation of an intraocular lens in order to increase the success of fixating the lens inside the eye.
- Other anti-mydriatic uses of thymoxamine are discussed in Wand & Grant, Arch. Ophthalmol. 96:1009-1011 (July 1978) and Wand & Grant, Surv. Ophthalmol. 25(2):75-84 (Sept.-Oct. 1980).
- alpha adrenergic blocking agents may be used to eliminate undesirable visual anomalies experienced by patients who have undergone refractive eye surgery.
- the present invention provides compositions and methods for using an ophthalmic solution comprising alpha adrenergic blocking agents that inhibit undesirable visual sequelae commonly experienced by individuals who have undergone refractive eye surgery.
- the invention further provides for the use of an ophthalmic solution comprising alpha adrenergic blocking agents to eliminate symptoms developed by conditions wherein the diameter of the pupil exceeds the diameter desired for the respective optic zone.
- the compositions and methods of the invention provide a means for inhibiting photophobia, glare, secondary images and haloing.
- the methods of the present invention comprise topically applying an ophthalmic solution to the eye wherein the ophthalmic solution contains a therapeutically effective amount of one or more alpha adrenergic blocking agents to an individual who has undergone refractive eye surgery.
- the composition may be topically applied in approximately a one drop dose, which may be instilled on an as needed basis depending upon the concentration and rate of release of the one or more alpha adrenergic blocking agents within the ophthalmic solution.
- the methods comprise topically applying an ophthalmic solution to the eye wherein the ophthalmic solution contains a therapeutically effective amount of one or more alpha adrenergic blocking agents to an individual who has one or more symptoms developed by a condition wherein the diameter of the pupil exceeds the diameter desired for the respective optic zone of the eye.
- Such conditions include but are not limited to post surgical persistent mydriasis, traumatic mydriasis, anisocoria, photorefractive keratectomy, treatment of aphakia, and certain cases of cataract extraction and retinal detachment.
- compositions comprising one or more alpha adrenergic blocking agents in a physiologically acceptable carrier, which can be administered to a subject at an effective dose to be therapeutically effective in concentration and rate of release.
- compositions used in the practice of the present invention comprise both rapid and sustained release of an effective dose.
- the alpha adrenergic blocking agents may be used preoperatively in cases where small pupils are demanded. This is particularly valuable in refractive implantation, glaucoma surgery, and keratoplasty to mention a few.
- the invention further provides for compositions comprising a therapeutically effective amount of one or more alpha adrenergic blocking agents in combination with one or more anti-irritant agents and/or one or more anti-inflammatory agents.
- compositions comprising a therapeutically effective amount of one or more alpha adrenergic blocking agents in combination with one or more anti-irritant agents and/or one or more anti-inflammatory agents.
- the invention is based on the observation that administration of one or more alpha adrenergic blocking agents to the surface of the eye is well tolerated and is effective in eliminating one or more undesirable visual problems without experiencing a change in focal length, headache, photopsia, floaters, etc, which are ordinarily experienced with induced cyclotonic miosis.
- the present invention by enabling a method for use of an ophthalmic solution comprising one or more alpha adrenergic blocking agents, provides a safer, less risky, and asymptomatic treatment than experienced with the administration of pilocarpine or other compositions that forcibly make the pupil smaller.
- the present invention relates to compositions and methods for inhibiting one or more undesirable visual anomalies commonly experienced by patients who have undergone refractive eye surgery.
- the invention further relates to compositions and methods for inhibiting one or more symptoms developed by a condition wherein the diameter of the pupil exceeds the diameter desired for the respective optic zone of an eye.
- Subjects treated with an ophthalmic solution comprising one or more alpha adrenergic blocking agents have experienced reduced visual anomalies due to a relaxation of the iris causing a reduction in the diameter of the pupil without inducing myopia caused by forcibly making the pupil smaller.
- compositions and methods of the present invention provide a means for inhibiting photophobia, glare, secondary images and haloing, as well as other symptoms developed wherein the pupil diameter exceeds the desired diameter, while avoiding the adverse side effects, such as induced myopia, headaches, photopsia, retinal, detachment, and floaters, associated with the use of pilocarpine or other cyclotonic compositions that forcibly make the pupil smaller.
- compositions suitable for use in the present invention include ophthalmic solutions comprising a therapeutically effective amount of one or more alpha adrenergic blocking agents. More specifically, a therapeutically effective amount means an amount sufficient to relax the iris to reduce the diameter of the pupil thereby inhibiting one or more undesirable visual anomalies experienced by an individual who has undergone refractive eye surgery.
- the effective amounts of one or more alpha adrenergic blocking agents is well within the capability of those skilled in the art and may be adjusted depending upon the number, kind and concentration of the one or more alpha adrenergic blocking agents, and upon the intended duration of use from rapid to sustained delivery of the ophthalmic solution.
- Suitable alpha adrenergic blocking agents among others include thymoxamine (thymoxamine hydrochloride), phentolamine (phentolamine hydrochloride), azapetine (azapetine hydrochloride), phenoxybenzamine (phenoxybenzamine hydrochloride), clonidine (clonidine hydrochloride), and totazoline (totazoline hydrochloride).
- the one or more alpha adrenergic blocking agents includes thymoxamine.
- the one or more alpha adrenergic blocking agents for use in the practice of this invention are commercially available.
- a suitable ophthalmic solution containing one or more alpha adrenergic blocking agents is one having a concentration of the agent of from about 0.1% to about 1% by weight. It is preferred that the ophthalmic solution containing the one or more alpha adrenergic blocking agents has a concentration of the agent of about 0.5% by weight.
- the preferred solvent is water.
- An exemplary aqueous ophthalmic solution would have a pH of about 5.6 - 7 and would be clear and colorless.
- composition administered is also dependent upon the subject to whom the ophthalmic solution is administered and the judgement of the physician overseeing the subject. It should be noted, however, that one of the advantages of the inventive compositions and methods allows for the subject to self administer the ophthalmic solution prior to experiencing the circumstances that ordinarily result in one or more undesirable visual anomalies.
- the total dosage range of the one or more alpha adrenergic blocking agents should be such as to achieve a sufficient period of duration in order to inhibit the one or more undesirable visual anomalies for the duration of the desired period. Adjustments of the number and kind of the one or more alpha adrenergic blocking agents in the ophthalmic composition, the overall and relative concentrations of the one or more alpha adrenergic blocking agents in the ophthalmic composition, and the frequency of application are contemplated herein. It may be necessary to use dosages outside the ranges disclosed herein in some cases as will be apparent to those of ordinary skill in the art.
- the composition may be administered by a physician or by the individual in need thereof in order to inhibit one or more undesirable visual anomalies, including photophobia, glare, secondary images and haloing, on a regular basis or on an as needed basis, and may be administered before or after experiencing the one or more visual anomalies.
- the one or more alpha adrenergic blocking agents is delivered to the eye in an ophthalmic solution by topically applying the solution in approximately a one drop dose.
- the approximately one drop dose may be thereafter topically applied on an as needed basis.
- the dosage may vary in amount and frequency depending upon the concentration and rate of release of the one or more alpha adrenergic blocking agents within the ophthalmic solution.
- compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers.
- physiologically acceptable carriers include viscoelastic polymers, as described in U.S. Patent Nos. 5,972,326, 5,965,152, 5,766,580, 5,759,532, and 5,612,027, the disclosures of which are incorporated herein by reference.
- other suitable carriers presently known in the art including solvents such as water are contemplated.
- the present invention provides for novel compositions comprising a physiologically acceptable carrier for one or more alpha adrenergic blocking agents for the rapid and sustained release of the one or more alpha adrenergic blocking agents in doses sufficient to reduce or ameliorate the one or more undesirable visual anomalies in a subject in need thereof.
- the present invention provides for novel compositions comprising any of the above-described ophthalmic solutions further containing one or more anti-irritant agents and/or one or more anti-inflammatory agents.
- Suitable anti-irritant agents include naphthazoline, oxymetazoline, and tetrahydrozaline.
- Suitable anti-inflammatory agents include dexamethasone, fluoromethalone, loteprednol, prednisone, and diclofenac. It is preferred that the ophthalmic solution contain one or more anti-irritant agents in a concentration of from about .025% by weight to about .1% by weight.
- the ophthalmic solution contain one or more anti-inflammatory agents in a concentration of from about .5% by weight to about 1% by weight. It is preferred that the ophthalmic solution containing a combination of one or more anti-irritant agents with one or more anti-inflammatory agents contain a concentration of from about .025% by weight to about 0.1%) by weight of the anti-irritant agents and from about .25% by weight to about 1% by weight of the anti-inflammatory agents.
- Thymoxamine Hydrochloride 500 mg Sodium Acetate NF: 90 mg
- Phenylmercuric Nitrate NF 2 mg
- aqueous ophthalmic solution was prepared by dissolving the sodium acetate, boric acid and phenylmercuric nitrate in most of the purified water. Dissolution was promoted by heating the solution. Upon cooling the solution to room temperature, the thymoxamine hydrochloride was added and was dissolved without further heating. The remainder of the purified water was then added to reach a final volume of 100 ml. Sterilization of the solution was achieved by filtering it through a sterilizing filter.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL15117101A IL151171A0 (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of aplha adrenergic blocking agents |
AU2001236868A AU2001236868A1 (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of alpha adrenergic blocking agents |
MXPA02007698A MXPA02007698A (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of alpha adrenergic blocking agents. |
CA002398158A CA2398158A1 (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of alpha adrenergic blocking agents |
BR0108219-1A BR0108219A (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of alpha-adrenergic blocking agents |
JP2001557549A JP2003535817A (en) | 2000-02-10 | 2001-02-09 | Use of alpha-adrenergic blockers in the eye |
EP01909077A EP1255540A1 (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of alpha adrenergic blocking agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/501,400 US6730691B1 (en) | 2000-02-10 | 2000-02-10 | Uses of alpha adrenergic blocking agents |
US09/501,400 | 2000-02-10 |
Publications (1)
Publication Number | Publication Date |
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WO2001058438A1 true WO2001058438A1 (en) | 2001-08-16 |
Family
ID=23993399
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/004316 WO2001058438A1 (en) | 2000-02-10 | 2001-02-09 | Ophthalmic use of alpha adrenergic blocking agents |
Country Status (10)
Country | Link |
---|---|
US (1) | US6730691B1 (en) |
EP (1) | EP1255540A1 (en) |
JP (1) | JP2003535817A (en) |
KR (1) | KR20030061301A (en) |
AU (1) | AU2001236868A1 (en) |
BR (1) | BR0108219A (en) |
CA (1) | CA2398158A1 (en) |
IL (1) | IL151171A0 (en) |
MX (1) | MXPA02007698A (en) |
WO (1) | WO2001058438A1 (en) |
Cited By (3)
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WO2018230713A1 (en) * | 2017-06-16 | 2018-12-20 | 学校法人同志社 | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
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US5972326A (en) | 1995-04-18 | 1999-10-26 | Galin; Miles A. | Controlled release of pharmaceuticals in the anterior chamber of the eye |
US5612027A (en) | 1995-04-18 | 1997-03-18 | Galin; Miles A. | Controlled release of miotic and mydriatic drugs in the anterior chamber |
US5731339A (en) | 1995-04-28 | 1998-03-24 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
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US6273092B1 (en) | 2000-09-22 | 2001-08-14 | Gerard M. Nolan | Methods for treating various eye disorders |
US6540990B2 (en) | 2000-09-22 | 2003-04-01 | Gerard M. Nolan | Physiological method of improving vision |
-
2000
- 2000-02-10 US US09/501,400 patent/US6730691B1/en not_active Expired - Fee Related
-
2001
- 2001-02-09 KR KR1020027010368A patent/KR20030061301A/en not_active Application Discontinuation
- 2001-02-09 IL IL15117101A patent/IL151171A0/en unknown
- 2001-02-09 CA CA002398158A patent/CA2398158A1/en not_active Abandoned
- 2001-02-09 JP JP2001557549A patent/JP2003535817A/en active Pending
- 2001-02-09 EP EP01909077A patent/EP1255540A1/en not_active Withdrawn
- 2001-02-09 MX MXPA02007698A patent/MXPA02007698A/en unknown
- 2001-02-09 BR BR0108219-1A patent/BR0108219A/en not_active IP Right Cessation
- 2001-02-09 WO PCT/US2001/004316 patent/WO2001058438A1/en not_active Application Discontinuation
- 2001-02-09 AU AU2001236868A patent/AU2001236868A1/en not_active Abandoned
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US4443441A (en) * | 1981-08-07 | 1984-04-17 | Galin Miles A | Fixation of intraocular lenses |
US5635172A (en) * | 1984-10-31 | 1997-06-03 | Alcon Laboratories, Inc. | Sustained release comfort formulation for glaucoma therapy |
WO1989010126A1 (en) * | 1988-04-26 | 1989-11-02 | Alcon Laboratories, Inc. | Antiglaucoma compositions containing combinations of alpha-2 agonists and beta-blockers |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10849928B2 (en) | 2006-03-14 | 2020-12-01 | Clarus Cls Holdings, Llc | Methods of using ophthalmic compositions comprising povidone-iodine |
WO2018230713A1 (en) * | 2017-06-16 | 2018-12-20 | 学校法人同志社 | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
US11433090B2 (en) | 2017-06-16 | 2022-09-06 | The Doshisha | mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof |
Also Published As
Publication number | Publication date |
---|---|
EP1255540A1 (en) | 2002-11-13 |
JP2003535817A (en) | 2003-12-02 |
CA2398158A1 (en) | 2001-08-16 |
IL151171A0 (en) | 2003-04-10 |
BR0108219A (en) | 2004-04-27 |
AU2001236868A1 (en) | 2001-08-20 |
US6730691B1 (en) | 2004-05-04 |
KR20030061301A (en) | 2003-07-18 |
MXPA02007698A (en) | 2004-09-10 |
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