EP0145714A1 - Gel ophtalmique - Google Patents

Gel ophtalmique

Info

Publication number
EP0145714A1
EP0145714A1 EP19830902330 EP83902330A EP0145714A1 EP 0145714 A1 EP0145714 A1 EP 0145714A1 EP 19830902330 EP19830902330 EP 19830902330 EP 83902330 A EP83902330 A EP 83902330A EP 0145714 A1 EP0145714 A1 EP 0145714A1
Authority
EP
European Patent Office
Prior art keywords
gel
composition according
polymer
weight
viscosity
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Withdrawn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
EP19830902330
Other languages
German (de)
English (en)
Inventor
Philip D. Gressel
Robert E. Roehrs
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 EP0145714A1 publication Critical patent/EP0145714A1/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Withdrawn legal-status Critical Current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
    • 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
    • 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

Definitions

  • the present invention relates to ophthalmic gel compositions for human and veterinary use comprising, inter alia, in an aqueous vehicle, a class of polyanionic polymers which, because of their unique combination of ucominetic, rheological, and lubricating properties, are useful as long lasting, topically applied agents for relief of dry eye syndrome, foreign 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 with- contact lenses, and in various eye irritation disorders.
  • the present invention also relates to a method of treating eyes by topically applying the gel compositions of the present invention when indicated for the relief of dry eye syndrome and when indicated to achieve the other effects mentioned above.
  • Dry eye syndrome, and related eye ailments including mere transitory discomforts, are well known in the scientific and patent literature.
  • the following patents are 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.
  • the ophthalmic formulations of the present invention are aqueous gels comprising, in addition to conventional ' ingredients imparting, for example, bacteriostatic and formulatory balance functions, a 0 critical polyanionic polymer, and, in a preferred embodiment, a stabilizing agent therefor.
  • 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 gels which form during the preparation of the ophthalmic polymer dispersion have a 0 viscosity of from about 15,000 to about 300,000 cps
  • Viscometer preferably from about 20,000 to about
  • the viscosity of the gels is too high to be measured with a No. 3 spindle.
  • the gels further are 5 characterized as having a yield value of from about
  • the high molecular weight polymers used in the compositions of the present invention not only thicken the compositions to provide a gel, but they also provide a special type of rheology, i.e., plastic viscosity. 5. 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 believed that the increased duration of activity of the 0 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.
  • the yield value is exceeded, the gel structure is 5 altered temporarily, allowing the gel to flow under stress. In the eye, this corresponds to the blinking eyelid.
  • the stress is removed (eyelid at rest) the structure of the gel is partially re-established.
  • the high molecular weight polymers useful in 0 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 are polyanionic in charge character owing to their 5 carboxylic 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 appear to function by maintaining or restoring the 0 normal hydration equilibrium of the epithelial cells, protecting the cornea in a manner similar to that believed to be provided by the mucin component of normal tears.
  • the polymers in addition 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 carboxy vinyl polymers.
  • Preferred polymers of this class include Carbomers, available under the trade name Carbopol from the B. F. Goodrich - Company.
  • the known and readily available polymers Carbopol 934 and 940 are specifically preferred.
  • the polymers are used in the aqueous gel compositions at a level of from about 0.25% to about 8% 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 5 noted that 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 0 change in viscosity and texture of the gels. Agents which greatly decelerate or eliminate this aging process in the instant compositions of high polymer content are generically polyols at a concentration range of from 0.2% to 5% by weight.
  • Such polyols 5 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.
  • Ophthalmic products are packaged in multiple use containers as a general rule. Preservatives may be incorporated to prevent contamination of the products when they are exposed to microorganisms during use.
  • One or more preservatives and ancillary agents may be chosen from, for example: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben. phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M (Onamer M is available from Onyx Chemical Company, Jersey City, New Jersey) , or other agents known to those skilled in the art. Typically such 5.
  • 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 assigned U.S. Patent Application Serial Number 306,317 _o filed 9/28/81 is incorporated herein by reference to the extent that it describes Onamer M.
  • the polyanionic polymers may be neutralized to the desired pH with basic chemicals such as sodium hydroxide, ammonium hydroxide, 5 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.
  • the tonicity of the gels can 0 be adjusted to either hypotonicity, isotonicity or hypertonicity relative to normal tears by use of generally used materials known to the art.
  • Sodium chloride is a preferred tonicity agent.
  • the stabilizing agents confer a proportion of the desired tonicity, or 5 may provide sufficient tonicity so that no additional agents are required.
  • a dispersion of polymer is 0 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 dispersion is sterilized by autoclaving or by heating in a pressurized vessel to sterilizing temperature 121°C, 5 for thirty minutes.
  • the base is added aseptically by methods generally known to the art.
  • the pH is measured and adjusted aseptically . and the final weight is
  • ambient room temperature may be between 15,000 and 300,000 centipoises using spindle 7.
  • the viscosity is between 20,000 and 200,000 centipoises using spindle 7 at 20 RPM. The viscosity is too high to measure with spindle 3.
  • the artificial tear gels represented by the present invention are intended for relief of dry eye syndromes, particularly kerato-conjunctivitis sicca. 0 These symptoms include, inter alia, foreign body sensation, burning, and hyperemia. Additionally, these gels can halt the progress of the syndrome and reverse its effects including, in moderate to severe cases of dry eye, corneal staining, which is made evident by use 5 of Rose Bengal or Fluorescein.
  • the dosage regimen is typically 5-50 mg, preferably 5-15 mg, of gel squeezed from an ophthalmic tip of a container into the lower conjunctival sac of the affected eye. Frequency of dosing is variably dependent upon the severity of the 0 syndrome. For severe cases dosing may occur four or more times per day. The frequency is reduced when signs of the disease state show improvement. At that time dosing may be as infrequent as one dose daily or once every two or three days. 5 The following Examples are intended to further illustrate, but not to limit, the compositions of the present invention.
  • 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 1.1% 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 weighed 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 final weight is adjusted to 1000 grams with sterile purified water.
  • the gel is once again mixed until it is homogeneous.
  • the Brookfield viscosity is obtained by 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 103,200 centipoises and 101,800 centipoises. The pH is 6.94. The appearance is that of a smooth, clear, self-supporting gel.
  • Carbopol 940 0.75 450 grams of 5% Carbopol Slurry Hydrochloric Acid q.s. pH 7 8.55 ml of IN from slurry A
  • Example 2 The procedure for compounding is similar to that in Example 1.
  • the Brookfield viscosity, spindle 7, 20 RPM is 47,600.
  • the initial pH is 7.02.
  • the appearance is that of a smooth, clear, self-supporting gel.
  • Carbopol 940 3.5 8,000 grams of 4.375% Carbopol
  • Example 2 The procedure is essentially the same as that in Example 1. A solution of 40 grams of sodium chloride and 1 gram of edetate disodium is made in 500 ml of water. A separate solution of benzalkonium chloride 1% is added, and the gel is completed as before. Brookfield viscosity, spindle 7, 20 RPM, is 97,900 centipoises. The pH is 7.24. The appearance is that of a smooth, clear, self-supporting gel.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)

Abstract

Composition de gel ophtalmique avec des propriétés rhéologiques lubrifiantes, comportant, inter alia, un polymère polyanionique à utiliser comme larme artificielle de longue durée. Procédé de traitement comportant l'administration totale de ladite 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.
EP19830902330 1983-05-25 1983-05-25 Gel ophtalmique Withdrawn EP0145714A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1983/000840 WO1984004680A1 (fr) 1983-05-25 1983-05-25 Gel ophtalmique

Publications (1)

Publication Number Publication Date
EP0145714A1 true EP0145714A1 (fr) 1985-06-26

Family

ID=22175207

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19830902330 Withdrawn EP0145714A1 (fr) 1983-05-25 1983-05-25 Gel ophtalmique

Country Status (2)

Country Link
EP (1) EP0145714A1 (fr)
WO (1) WO1984004680A1 (fr)

Families Citing this family (9)

* 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
KR920003601B1 (ko) * 1987-09-03 1992-05-04 유니버시티 어브 죠지아 리서취 화운데이션 인코포레이티드 점안 싸이클로스포린(cyclosporin)의 조성물
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
US5124154A (en) * 1990-06-12 1992-06-23 Insite Vision Incorporated Aminosteroids for ophthalmic use
DE4209722C3 (de) * 1992-03-25 1997-06-19 Medproject Pharma Entwicklungs Tropfbares Gel für die Augenheilkunde
US5340572A (en) * 1993-02-08 1994-08-23 Insite Vision Incorporated Alkaline ophthalmic suspensions
FR2742336B1 (fr) 1995-12-19 1998-03-06 Chauvin Lab Sa Collyre destine notamment au traitement de l'oeil sec
DE19619238A1 (de) * 1996-05-13 1997-11-20 Hoechst Ag Antiadhäsive Eigenschaften von Polyacrylsäuren und Polymethacrylsäuren

Family Cites Families (10)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8404680A1 *

Also Published As

Publication number Publication date
WO1984004680A1 (fr) 1984-12-06

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