EP0145710A1 - Solution ophtalmique - Google Patents

Solution ophtalmique

Info

Publication number
EP0145710A1
EP0145710A1 EP19830902185 EP83902185A EP0145710A1 EP 0145710 A1 EP0145710 A1 EP 0145710A1 EP 19830902185 EP19830902185 EP 19830902185 EP 83902185 A EP83902185 A EP 83902185A EP 0145710 A1 EP0145710 A1 EP 0145710A1
Authority
EP
European Patent Office
Prior art keywords
composition according
polymer
weight
viscosity
composition
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Withdrawn
Application number
EP19830902185
Other languages
German (de)
English (en)
Inventor
Philip D. Gressel
Robert E. Roehrs
Robert G. Harris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Vision LLC
Original Assignee
Alcon Laboratories Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Alcon Laboratories Inc filed Critical Alcon Laboratories Inc
Publication of EP0145710A1 publication Critical patent/EP0145710A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof

Definitions

  • the present invention relates to liquid ophthalmic compositions for human and veterinary use 5 .
  • liquid ophthalmic compositions for human and veterinary use 5 .
  • a class of polyanionic polymers which, because of their unique combination of mucomimetic, rheological, and lubricating properties, are useful as long lasting, topically applied agents for relief of dry eye syndrome, foreign 10 body sensation, burning, hyperemia, corneal staining, and the like.
  • the ophthalmic compositions are also • useful as lubricating and cushioning agents for the eye after traumatic injury or surgery. They may also be used as corneal wetting and lubricating agents for use 5 with contact lenses, and in various eye irritation disorders.
  • the present invention also relates to a method of treating eyes by topically applying the ophthalmic solutions of the present invention when indicated for ' 0 the relief of dry eye syndrome and when indicated to achieve the other effects mentioned above.
  • Dry eye syndrome, and related eye ailments are well known in the scientific and patent literature.
  • the following patents are 5 incorporated herein -by reference to the extent that they provide additional background on the syndrome and recognized indications for its relief: U.S. Patents 4,039,662; 3,987,163; 3,920,810; 3,843,782; and 4,131,651; and Belgian Patent 844,544.
  • OMPI have the potential for providing longer term symptomatic relief than liquids, few patients are willing to persist in using them since ' they are difficult to insert and, once in. place, tend to be uncomfortable, frequently
  • the ophthalmic formulations of the present invention are viscous aqueous solutions which are capable to being administered as liuqid drops, and which comprise, in addition to conventional ingredients 0 imparting, for example, bacteriostatic and formulatory balance functions, a critical polyanionic polymer.
  • POLYANIQNIC POLYMER COMPONENT The high molecular weights polymers useful in the present invention have a molecular weight of from 5 about 400,000 to about 6 million. The polymers are characterized as having carboxylic functional groups and preferably contain from 2 to 7 carbon atoms per functional group.
  • the viscous solutions which form during the preparation of the ophthalmic polymer 0 dispersion have a viscosity of from about 10 to about
  • the high molecular weight polymers used in the compositions of the present invention not only thicken the compositions to provide a semi-viscous state, but they also provide a special type of rheology, i.e.,
  • Plastic viscosity is indicative of a material that does not flow until a certain force or stress value is exceeded. This is referred to as the yield value. While not wishing to be bound by any theory, it is 0 believed that the increased duration of activity of the gel compositions of the invention is related not only to the apparent viscosity (thickness) , but is also related to the yield value.
  • the gel compositions of the present invention exhibit unique response to shear stress. When 5 the yield value is exceeded, the gel structure is altered temporarily, allowing the gel to flow under stress. In the eye, this corresponds to the blinking eyelid. When the stress is removed (eyelid at rest) the structure of the gel is partially re-established.
  • the high molecular weight polymers useful in the ophthalmic compositions of the present invention provide unique rheological characteristics, combining high viscosity with yield values at the levels set forth herein above. They confer lubricative properties, and 5 are polyanionic in charge character owing to their carboxyli ⁇ acid functional groups. While the claimed invention will not be limited by any theory of action, but in the sense of providing a functional definition, it will be noted that these polyanionic charged polymers 0 appear to function by maintaining or restoring the normal hydration equilibrium of the epithellial cells, protecting the cornea in a manner similar to that believed to be provided by the mucin component of normal tears. Therefore, in theory, the polymers, in addition 5 to being well retained in the eye and providing lubrication, can function as a mucin substitute in the dry eye syndrome where there is a deficiency or absence of the natural mucin component of the normal tears.
  • Suitable polymers useful in the present invention are carboxyl vinyl polymers.
  • Preferred polymers of this class include Carbomers, available under the trade name Carbopol from the B. F. Goodrich
  • Carbopol 934 and 940 are specifically preferred.
  • the polymers are used in the instant aqueous compositions at a level of from about 0.05 to about 0.25 percent by weight.
  • a stabilizing agent may be required to maintain the hydration state of the polymer during long storage. While not imposing any limitation by theory of action, but in the interest of describing function, it should be
  • associations appear to occur within or among the polymer chains which, after time, favor the reduction of hydration state of the polymer chains. These may be in the form of hydrogen bonds within and among the polymer chains. This can manifest itself as a
  • Agents which greatly decelerate or eliminate this aging process in the instant compositions are generically polyols at a concentration range of from 0.2% to 5% by weight. 5 Representative of such polyols are mannitol, sorbitol, glycerol, sucrose, related sugars, and the like, in the above-recited concentration range. An especially preferred stabilizing agent is mannitol at a concentration of from 0.2% to 5% by weight. 0 OTHER INGREDIENTS
  • Ophthalmic products are packaged in multiple use containers as a general rule.
  • Preservatives may be incorporated to prevent contamination of the products 5 when they are exposed to microorganisms during use.
  • One or more preservatives and ancillary agents may be chosen from, for example: benzalkonium chloride, thimerosal.
  • Onamer M is available from Onyx Chemical Company, Jersey City, New Jersey
  • agents known 5 . to those skilled in the art.
  • preservatives are employed at a level of from 0.001% to 1.0% by weight. If no preservative is desired, the gels may be sterile packaged in unit-of-use containers.
  • Onamer M co-pending, commonly 10 assigned U.S. Patent Application Serial Number 306,317 filed 9/28/81 is incorporated herein by reference to the extent that it describes Onamer M.
  • Neutralizing Agents is incorporated herein by reference to the extent that it describes Onamer M.
  • the polyanionic polymers may be neutralized to 5 the desired pH with basic chemicals such as sodium hydroxide, ammonium hydroxide, ethanolamine, urea, and selected amines.
  • Mineral acids such as hydrochloric, phosphoric or sulfuric may be used to adjust pH toward acidity.
  • the preferred pH range is from 4.5 to 8.5. 0 Tonicity Agents:
  • the tonicity of the gels can be adjusted to either hypotonicity, isotoni ⁇ ity or hypertonicity relative to normal tears by use of generally used materials known to the art.
  • Sodium chloride is a 5 preferred tonicity agent.
  • the stabilizing agents confer a proportion of the desired tonicity, or may provide sufficient tonicity so that no additional agents are required.
  • FORMULATION 0 The following compounding procedure may be used for sterile manufacturing.
  • a dispersion of polymer is made in either purified water or a dilute acid solution. All other components are dissolved in purified water and added to the polymer dispersion.
  • the 5 dispersion is sterilized by auto ⁇ laving or by heating in a pressurized vessel to sterilizing temperature 121°C, for thirty minutes.
  • the base is added aseptically by
  • the pH is measured and adjusted aseptically and the final weight is adjusted with sterilized purified water. Specific examples are detailed below.
  • the viscosity Brookfield RVT, measured at ambient room temperature, may be between 10 ⁇ entipoises and 20,000 centipoises using spindle 7. Preferably the viscosity is between 5,000 and 15,000 centipoises using
  • the artificial tear solutions represented by the present invention are intended for relief of dry eye syndromes, particularly kerato-conjunctivitis sicca. These symptoms include, inter alia, foreign body
  • the instant ophthalmic solutions can halt the progress of the syndrom and reverse its effects including, in moderate to severe cases of dry eye, corneal staining, which is made evident by use of Rose Bengal or
  • the dosage regimen is typically one or two drops dispensed from a standard ophthalmic dropping device, such as, glass or plastic dropping pipets or plastic bottles fitted with a dropper orifice. Individual drops are within the range of 5 to 75 g.
  • the drops are placed onto the corneal or scleral surface, or into the lower conjunctival sac. Frequency of dosing is variably dependent upon the severity of the syndrome. For severe cases dosing may occur four or more times per day. The frequency is reduced when signs
  • compositions of the present invention show improvement. At that time dosing may be as infrequent as one dose daily or once every two or three days.
  • dosing may be as infrequent as one dose daily or once every two or three days.
  • Carbopol 940 0.2 320 grams of slur Hydrochloroic Acid q.s. (5% Carbopol & 1. HC1)
  • a slurry is made in which 5% Carbopol is sifted into a dilute acid solution (1.9% of IN HCI) using a propeller mixer to form a vortex.
  • the slurry (A) is mixed until it is free from visible lumps. It is then filtered by pumping through a cartridge filter to remove small particles. Then it is autoclaved for 30 minutes at 121°C and subsequently handled aseptically using methods known to the art.
  • a stock solution (B) of .05% edetate disodium and 15% mannitol in purified water is prepared by heating to 60°C and sterile filtering through a 0.22 micron membrane filter maintained at a warm temperature. The sterile-filtered solution is also maintained warm until its use.
  • a stock solution (C) of benzalkonium chloride 10% in purified water is sterile filtered and handled aseptically.
  • the gel is compounded on a laminar-flow bench using aseptic technique.
  • the slurry (A) is weighted into a tared mixing bowl.
  • Solution C is added slowly with mixing.
  • solution B is incorporated and mixed well until the slurry is once again homogeneous.
  • the pH is adjusted with 6N sodium hydroxide with constant mixing while the base is added.
  • the Brookfield viscosity is obtained by S centrifuging a sample of the gel to remove visible air bubbles. Spindle 7 is inserted carefully into the centrifuge tube and positioned appropriately. The 20 RPM setting is used. Viscosity measurements are 12,400 centipoises and 12,600 centipoises. The pH is 7.17. 10 The appearance is that of a smooth, clear, pourable gel.
  • Viscosity measurements are 14,200 and 15,200 centipoises. Appearance is that of a smooth, clear, 5 pourable gel.
  • Carbopol 940 0.1 10 g of slurry 0 Hydrochloric Acid, IN q.s. 5% Carbopol an 1.9% IN HC1
  • Benzalkonium Chloride 0.008 4.4 is of 1% (plus 10% compounding excess) solution 5
  • suBSTiry O PI The procedure is as described in Example 1. Viscosity is 1,200 centipoises. Appearance is that of a smooth, clear, pourable gel.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition ophtalmique liquide avec des propriétés rhéologiques et lubrifiantes uniques, comportant, inter alia, un polymère polyanionique à utiliser comme larme artificielle de longue durée. Procédé de traitement comportant l'administration topique de la composition en cas d'indication pour soulager le syndrome de l'oeil sec, la sensation de la présence d'un corps étranger, une brûlure, l'hyperémie, la coloration cornéenne, et autres.
EP19830902185 1983-05-25 1983-05-25 Solution ophtalmique Withdrawn EP0145710A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1983/000841 WO1984004681A1 (fr) 1983-05-25 1983-05-25 Solution ophtalmique

Publications (1)

Publication Number Publication Date
EP0145710A1 true EP0145710A1 (fr) 1985-06-26

Family

ID=22175208

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19830902185 Withdrawn EP0145710A1 (fr) 1983-05-25 1983-05-25 Solution ophtalmique

Country Status (2)

Country Link
EP (1) EP0145710A1 (fr)
WO (1) WO1984004681A1 (fr)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL80298A (en) * 1986-10-14 1993-01-31 Res & Dev Co Ltd Eye drops
US4818537A (en) * 1986-10-21 1989-04-04 Liposome Technology, Inc. Liposome composition for treating dry eye
US4839342A (en) * 1987-09-03 1989-06-13 University Of Georgia Research Foundation, Inc. Method of increasing tear production by topical administration of cyclosporin
US5188826A (en) * 1988-02-08 1993-02-23 Insite Vision Incorporated Topical ophthalmic suspensions
US5192535A (en) * 1988-02-08 1993-03-09 Insite Vision Incorporated Ophthalmic suspensions
US5037647A (en) * 1988-09-15 1991-08-06 Alcon Laboratories, Inc. Aqueous antimicrobial opthalmic solutions comprised of quaternary ammonium compound, citric acid, citrate and sodium chloride
US5124154A (en) * 1990-06-12 1992-06-23 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5340572A (en) * 1993-02-08 1994-08-23 Insite Vision Incorporated Alkaline ophthalmic suspensions
IT1273011B (it) * 1994-07-25 1997-07-01 Trhecnopharma S A Preparato oftalmico per l'uso come lacrima artificiale
US6024954A (en) * 1994-12-12 2000-02-15 Allergan Compositions and methods for disinfecting contact lenses and preserving contact lens care products
FR2742336B1 (fr) 1995-12-19 1998-03-06 Chauvin Lab Sa Collyre destine notamment au traitement de l'oeil sec
WO1997045102A1 (fr) * 1996-05-31 1997-12-04 Schwadrohn, Gérard Nouvelle utilisation therapeutique de gels ophtalmiques
US5882687A (en) * 1997-01-10 1999-03-16 Allergan Compositions and methods for storing contact lenses
EP1318819A4 (fr) * 2000-08-23 2006-03-15 Phairson Medical Inc Traitements de traumas et autres indications
JP2005008596A (ja) * 2003-06-20 2005-01-13 Kobayashi Pharmaceut Co Ltd 眼科用組成物
US8569367B2 (en) * 2004-11-16 2013-10-29 Allergan, Inc. Ophthalmic compositions and methods for treating eyes
US9297928B2 (en) 2004-11-22 2016-03-29 Johnson & Johnson Vision Care, Inc. Ophthalmic compositions comprising polyether substituted polymers
US8168206B1 (en) 2005-10-06 2012-05-01 Allergan, Inc. Animal protein-free pharmaceutical compositions
DE102005055275A1 (de) * 2005-11-17 2007-05-24 Ursapharm Arzneimittel Gmbh & Co. Kg Phosphatfreie pharmazeutische Zusammensetzung sowie deren Verwendung

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Publication number Priority date Publication date Assignee Title
CH538863A (it) * 1969-03-14 1973-07-15 Finanz Kompensations Anst Eccipiente per cosmetici, contenente aminoacidi basici e polimeri carbossivinilici
US3592936A (en) * 1969-04-25 1971-07-13 Merck & Co Inc Method of treatment using pharmaceutical composition containing dimethyl sulfoxide
US3630200A (en) * 1969-06-09 1971-12-28 Alza Corp Ocular insert
US3618604A (en) * 1969-06-09 1971-11-09 Alza Corp Ocular insert
DK135267A (fr) * 1971-02-25
US3924004A (en) * 1971-11-24 1975-12-02 Syntex Corp Fatty alcohol-propylene carbonate-glycol solvent cream vehicle
US4003991A (en) * 1974-08-27 1977-01-18 National Patent Development Corporation Ophthalmic formulation
DE2441621A1 (de) * 1974-08-30 1976-03-11 Robugen Gmbh Arzneimittel zur behandlung von augenerkrankungen
JPS5144618A (en) * 1974-10-07 1976-04-16 Toko Yakuhin Kogyo Kk Kyokushoyozaino seizoho
JPS5842168B2 (ja) * 1974-12-20 1983-09-17 トウコウヤクヒンコウギヨウ カブシキガイシヤ 局所用剤の製造方法

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Also Published As

Publication number Publication date
WO1984004681A1 (fr) 1984-12-06

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Inventor name: ROEHRS, ROBERT, E.

Inventor name: HARRIS, ROBERT, G.

Inventor name: GRESSEL, PHILIP, D.