WO1984004681A1 - Ophthalmic solution - Google Patents
Ophthalmic solution Download PDFInfo
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- WO1984004681A1 WO1984004681A1 PCT/US1983/000841 US8300841W WO8404681A1 WO 1984004681 A1 WO1984004681 A1 WO 1984004681A1 US 8300841 W US8300841 W US 8300841W WO 8404681 A1 WO8404681 A1 WO 8404681A1
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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
- 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.
Abstract
A liquid ophthalmic composition of unique rheological and lubricating properties comprising, inter alia, a polyanionic polymer for use as a long lasting artificial tear. Also disclosed is a method of treatment comprising topically administering the composition when indicated for relief of dry eye syndrome, foreign body sensation, burning, hyperemia, corneal staining, and the like.
Description
OPHTHALMIC SOLUTION BACKGROUND OF THE INVENTION The present invention relates to liquid ophthalmic compositions for human and veterinary use 5. comprising, inter alia, in an aqueous vehicle, 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, including mere transitory discomforts, 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. 0 However, none of these prior art formulations meet all of the important criteria for an effective and long lasting treatment of dry eye syndrome, particularly the moderate to severe kerata-conjunctivitis sicca (KCS) patient. These prior art attempts fall into three 5 categories corresponding to their physical state: liquids, anhydrous ointments, and solids. The solids are in the form of ocular inserts which slowly dissolve or erode to provide a thickened tear film. While these
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
5. themselves causing the foreign body sensation they were meant to treat. Prior to liquid and ointment formulations, while giving the sensation of relief, are strictly palliatives without long-term effect.
Thus, the search for an easy to use (especially
10 by infirmed patients via self-medication) , long lasting (4 to 24 hours) ophthalmic preparation for treating the effects described collectively under the dry eye syndrome and having the ancillary utilities mentioned above continues. 5 DETAILED DESCRIPTION OF THE INVENTION
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
20,000 cps (spindle 7 at 20 RPM) at 25°C generated by an RVT Brookfield Viscometer, preferably from about 5,000 to about 20,000 cps. The solutions further are characterized as having a yield value of from about 50
2 to about 1,500 dyne/cm as determined by a
Ferranti-Shirley Viscometer at 25°C.
O PI
.A,
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.,
5. plastic viscosity.
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. 0 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 carboxyliσ 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.
SUBSTITUTE SHEET
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
5. Company. The known and readily available polymers
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.
10 STABILIZING AGENT
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
15 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
20 change in viscosity and texture of the ophthalmic solutions of the present invention. 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
Antimicrobial Preservative:
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.
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, isotoniσity 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 autoσlaving or by heating in a pressurized vessel to sterilizing temperature 121°C, for thirty minutes. The base is added aseptically by
5. PHYSICAL PROPERTIES
The viscosity, Brookfield RVT, measured at ambient room temperature, may be between 10 σentipoises and 20,000 centipoises using spindle 7. Preferably the viscosity is between 5,000 and 15,000 centipoises using
10 spindle 7 at 20 RPM. Viscosity measurements are made after entrapped air is removed. The pH is between 4.5 and 8.5; the especially preferred range in 5.5. to 8.0. The final ophthalmic solution is clear or nearly clear, smooth, homogeneous, and pourable.
15 USE
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
2o sensation, burning, and hyperemia. Additionally, 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
25 Fluorescein. 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.
30 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
35 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.
The following Examples are intended to further illustrate, but not to limit, the compositions of the present invention.
EXAMPLE 1
% by wej .ght Amounts
Carbopol 940 0.2 320 grams of slur Hydrochloroic Acid q.s. (5% Carbopol & 1. HC1)
Mannitol 3 2133 ml of soluti Edetate Disodium 0.01
Benzalkonium Chloride 0.008 7.04 ml of Soluti (plus 10% compounding excess)
Sodium Hydroxide q.S. pH 7 25 ml of 6N
Purified Water q.s. ad 100 q.s. ad 8000 gram
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. When it is well dispersed, 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.
SUBSTSTU ? K "ϊ* BU RE4 £>
OΛtPI
The final weight is adjusted to 8000 grams with sterile purified water. The gel is once again mixed until it is homogeneous.
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.
EXAMPLE 2
% by weight Amounts
Carbopol 940 0. .2 20 g of slurry of Hydrochloric Acid, IN q- ,s. 5% Carbopol & 1.9% 5 IN HC1
Edetate Disodium 0. .01 50 ml of' 10X solu Onamer M 0. .0001 1.0 ml of 0.5% solution
0 Sodium Hydroxide, 6N q- .s. ad pH 7 1.7 ml Purified Water q. .s ad 100 q.s. ad 500 g
The procedure is as described in Example 1. Viscosity measurements are 14,200 and 15,200 centipoises. Appearance is that of a smooth, clear, 5 pourable gel.
EXAMPLE 3
% by weight Amounts
Carbopol 940 0.1 10 g of slurry 0 Hydrochloric Acid, IN q.s. 5% Carbopol an 1.9% IN HC1
Edetate Disodium 0.01 50 ml of 10X solution
Benzalkonium Chloride 0.008 4.4 is of 1% (plus 10% compounding excess) solution 5
Sodium Hydroxide, 6N q.s. ad pH 7 About 1 ml: q. ad pH 7 Purified Water q.s. ad 100 q.s. ad 500
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.
EXAMPLE 4
% by weight Amounts
Carbopol 934 0.2 320 grams of Hydrochloric Acid q.s. slurry A (5% Carbopol and 1 IN HCl) Mannitol 3 2133 ml of sol
Edetate Disodium 0.01 B
Benzalkonium Chloride 0.008 7.04 mis of so
(plus 10% compounding excess) C
Sodium Hydroxide q.s. pH 7 Approx. 25 ml Purified Water q.s. ad 100 q.s. ad 8000 g
Procedure is as described in Example 1.
SUEST1TU" ©if ,&.
_QMPI
Claims
1. A viscous ophthalmic pharmaceutical liquid composition comprising 0.05% to 0.25% by weight of a polyanionic polymer.
2. The composition according to Claim 1 wherein the polymer is a carboxy vinyl polymer having a molecular weight greater than 400,000 and wherein said composition has a viscosity up to 20,000 centipoises (cps) .
3. A composition according to Claim 1 wherein said polymer has a molecular weight of from 400,000 to
6,000,000.
4. A composition according to Claim 1 having a viscosity up to 15,000 cps.
5. A composition according to Claim 1 wherein the pH of said solution is 4.5 to 8.5.
6. A composition according to Claim 1 wherein the polymer concentration ranges from 0.1% to 0.2% by weight.
7. A viscous ophthalmic pharmaceutical liquid composition comprising 0.05 to 0.25% by weight of a polyanionic polymer and a stabilizing agent therefor.
8. A composition according to Claim 7 wherein the stability agent is a polyol.
9. A composition according to Claim 8 wherein the polyol is mannitol.
10. A composition according to Claim 8 where the polyol is present in the range of from 0.2% to 5.0% by weight.
11. A method for treating dry eye syndrome comprising installing the composition according to
Claims 1-9, or 10 in the eye.
SUϊ- i3 I a 3 i a. <-3--ϊ-.--i
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP19830902185 EP0145710A1 (en) | 1983-05-25 | 1983-05-25 | Ophthalmic solution |
| PCT/US1983/000841 WO1984004681A1 (en) | 1983-05-25 | 1983-05-25 | Ophthalmic solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1983/000841 WO1984004681A1 (en) | 1983-05-25 | 1983-05-25 | Ophthalmic solution |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1984004681A1 true WO1984004681A1 (en) | 1984-12-06 |
Family
ID=22175208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1983/000841 WO1984004681A1 (en) | 1983-05-25 | 1983-05-25 | Ophthalmic solution |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0145710A1 (en) |
| WO (1) | WO1984004681A1 (en) |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2604906A1 (en) * | 1986-10-14 | 1988-04-15 | Res & Dev Co Ltd | EYE DROPS |
| US4839342A (en) * | 1987-09-03 | 1989-06-13 | University Of Georgia Research Foundation, Inc. | Method of increasing tear production by topical administration of cyclosporin |
| EP0327580A1 (en) * | 1986-10-21 | 1989-08-16 | Liposome Technology, Inc. | Liposome composition for treating dry eye |
| WO1990002555A1 (en) * | 1988-09-15 | 1990-03-22 | Alcon Laboratories, Inc. | Aqueous antimicrobial ophthalmic solutions |
| 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 |
| US5332582A (en) * | 1990-06-12 | 1994-07-26 | Insite Vision Incorporated | Stabilization of aminosteroids for topical ophthalmic and other applications |
| US5340572A (en) * | 1993-02-08 | 1994-08-23 | Insite Vision Incorporated | Alkaline ophthalmic suspensions |
| EP0698388A1 (en) | 1994-07-25 | 1996-02-28 | Laboratoire Medidom S.A. | Ophthalmic preparation for use as artificial tear |
| EP0780121A1 (en) | 1995-12-19 | 1997-06-25 | Laboratoire Chauvin S.A. | Eye lotion in particular for dry eye treatment |
| WO1997045102A1 (en) * | 1996-05-31 | 1997-12-04 | Schwadrohn, Gérard | Novel therapeutic use of ophthalmic gels |
| WO1998005365A2 (en) * | 1996-08-02 | 1998-02-12 | Allergan Sales, Inc. | Compositions and methods for disinfecting contact lenses and preserving contact lens care products |
| WO1998030248A2 (en) * | 1997-01-10 | 1998-07-16 | Allergan Sales, Inc. | Compositions and methods for storing contact lenses |
| EP1318819A1 (en) * | 2000-08-23 | 2003-06-18 | Phairson Medical, Inc. | Treatment of trauma, and other indications |
| EP1647273A1 (en) * | 2003-06-20 | 2006-04-19 | Kobayashi Pharmaceutical Co. Ltd. | Ophthalmic composition |
| WO2006057823A1 (en) | 2004-11-22 | 2006-06-01 | Johnson & Johnson Vision Care, Inc. | Ophthalmic compositions comprising polyether substituted polymers |
| DE102005055275A1 (en) * | 2005-11-17 | 2007-05-24 | Ursapharm Arzneimittel Gmbh & Co. Kg | Phosphate-free pharmaceutical composition and its use |
| EP3777836A1 (en) * | 2004-11-16 | 2021-02-17 | Allergan, Inc. | Ophthalmic compositions and methods for treating eyes |
| US11033625B2 (en) | 2005-10-06 | 2021-06-15 | Allergan, Inc. | Method for stabilizing a toxin |
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|---|---|---|---|---|
| FR2040954A5 (en) * | 1969-03-14 | 1971-01-22 | Finanz Kompensations Anst | Carboxy vinyl polymer excipients for - cosmetics |
| US3592936A (en) * | 1969-04-25 | 1971-07-13 | Merck & Co Inc | Method of treatment using pharmaceutical composition containing dimethyl sulfoxide |
| US3618604A (en) * | 1969-06-09 | 1971-11-09 | Alza Corp | Ocular insert |
| US3630200A (en) * | 1969-06-09 | 1971-12-28 | Alza Corp | Ocular insert |
| GB1316556A (en) * | 1971-02-25 | 1973-05-09 | Warner Lambert Co | Topical ointment base |
| US3924004A (en) * | 1971-11-24 | 1975-12-02 | Syntex Corp | Fatty alcohol-propylene carbonate-glycol solvent cream vehicle |
| DE2441621A1 (en) * | 1974-08-30 | 1976-03-11 | Robugen Gmbh | Cysteine-contg ophthalmic preparations - in the form of an oxygen-free polyacrylic acid gel |
| JPS5144618A (en) * | 1974-10-07 | 1976-04-16 | Toko Yakuhin Kogyo Kk | Kyokushoyozaino seizoho |
| US4003991A (en) * | 1974-08-27 | 1977-01-18 | National Patent Development Corporation | Ophthalmic formulation |
| US4008321A (en) * | 1974-12-20 | 1977-02-15 | Toko Yakuhin Kogyo Kabushiki Kaisha | Composition for a topical preparation and a process for producing the same |
-
1983
- 1983-05-25 WO PCT/US1983/000841 patent/WO1984004681A1/en unknown
- 1983-05-25 EP EP19830902185 patent/EP0145710A1/en not_active Withdrawn
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| US3592936A (en) * | 1969-04-25 | 1971-07-13 | Merck & Co Inc | Method of treatment using pharmaceutical composition containing dimethyl sulfoxide |
| US3618604A (en) * | 1969-06-09 | 1971-11-09 | Alza Corp | Ocular insert |
| US3630200A (en) * | 1969-06-09 | 1971-12-28 | Alza Corp | Ocular insert |
| GB1316556A (en) * | 1971-02-25 | 1973-05-09 | Warner Lambert Co | Topical ointment base |
| 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 (en) * | 1974-08-30 | 1976-03-11 | Robugen Gmbh | Cysteine-contg ophthalmic preparations - in the form of an oxygen-free polyacrylic acid gel |
| JPS5144618A (en) * | 1974-10-07 | 1976-04-16 | Toko Yakuhin Kogyo Kk | Kyokushoyozaino seizoho |
| US4008321A (en) * | 1974-12-20 | 1977-02-15 | Toko Yakuhin Kogyo Kabushiki Kaisha | Composition for a topical preparation and a process for producing the same |
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| DE3734835A1 (en) * | 1986-10-14 | 1988-06-01 | Res & Dev Co Ltd | MEDICINES FOR OPHTHALMOLOGICAL USE |
| FR2604906A1 (en) * | 1986-10-14 | 1988-04-15 | Res & Dev Co Ltd | EYE DROPS |
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| EP0327580A4 (en) * | 1986-10-21 | 1989-11-07 | Liposome Technology Inc | Liposome composition for treating dry eye. |
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| WO1990002555A1 (en) * | 1988-09-15 | 1990-03-22 | Alcon Laboratories, Inc. | Aqueous antimicrobial ophthalmic solutions |
| US5332582A (en) * | 1990-06-12 | 1994-07-26 | Insite Vision Incorporated | Stabilization of aminosteroids for topical ophthalmic and other applications |
| EP0538313A1 (en) * | 1990-07-06 | 1993-04-28 | Insite Vision, Inc. | Topical ophthalmic suspensions |
| EP0538313A4 (en) * | 1990-07-06 | 1994-04-13 | Insite Vision, Inc. | |
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| US5770628A (en) * | 1994-07-25 | 1998-06-23 | Laboratoire Medidom S.A. | Ophthalmic preparation for use as artificial tear |
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| EP0780121A1 (en) | 1995-12-19 | 1997-06-25 | Laboratoire Chauvin S.A. | Eye lotion in particular for dry eye treatment |
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| WO1998005365A2 (en) * | 1996-08-02 | 1998-02-12 | Allergan Sales, Inc. | Compositions and methods for disinfecting contact lenses and preserving contact lens care products |
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| US8648057B2 (en) | 2005-11-17 | 2014-02-11 | Ursapharm Arzneimittel Gmbh & Co. Kg | Pharmaceutical composition free from dexpanthenol, calcium ions, and phosphate and use of calcium chelating agent and ophthalmologically compatible viscosity regulator |
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| EP0145710A1 (en) | 1985-06-26 |
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