AU2001273251A1 - Method and kit for moisturizing the surface of the eye - Google Patents
Method and kit for moisturizing the surface of the eyeInfo
- Publication number
- AU2001273251A1 AU2001273251A1 AU2001273251A AU2001273251A AU2001273251A1 AU 2001273251 A1 AU2001273251 A1 AU 2001273251A1 AU 2001273251 A AU2001273251 A AU 2001273251A AU 2001273251 A AU2001273251 A AU 2001273251A AU 2001273251 A1 AU2001273251 A1 AU 2001273251A1
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- Australia
- Prior art keywords
- fluid
- eye
- less
- administered
- tear film
- Prior art date
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- Granted
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Description
METHOD AND KIT FOR MOISTURIZING THE SURFACE OF THE EYE
Field of the Invention
The invention pertains to the field of care and therapy of the surface of the eye, including the sclera, conjunctiva, and cornea. More particularly, the invention pertains to the application of therapeutic and other fluids for moisturizing and treating the surface of the eye.
BACKGROUND OF THE INVENTION In normal situations, the surface of the eye, including the sclera, the conjunctiva, and the cornea, is kept moist by the presence of a tear film. This tear film is found in virtually all terrestrial vertebrates, with the exception of snakes. The surface area of the eye in an adult human is about 2 cm2. It is covered by a complex tear film having a trilaminar structure, with each of the layers having a discrete and necessary function.
Nearest to the surface of the eye is an inner layer of mucus approximately 10 to 20 μm in thickness. The mucus in this layer stabilizes the tear film and provides for attachment of the tear film to the underlying cornea and conjunctiva. The mucus also reduces the surface tension between the . tear film and the eye and so permits the tear film to spread evenly across the eye.
The middle layer of the eye is an aqueous layer that is composed largely of water, electrolytes, and various proteins. This layer contains about 2 to 5 μl of aqueous fluid and forms the bulk of the tear film.
Within this layer, pH, osmotic pressure, oxygen tension, and the levels of electrolytes such as potassium,
calcium, chloride, inorganic phosphates, and acids such as lactic acid and citric acid, are maintained within narrow physiologic ranges. Proteins present in the aqueous layer of the tear film include albumin, and other proteins, such as immunoglobulins, interferon, β-lysin, and lysozyme which have antimicrobial activities.
Farthest from the surface of the eye is a lipid layer, which may range in thickness from a single monolayer to nearly 200 nm. Ordinarily, this layer is about 100 n thick. This layer serves to retard evaporation of the tear film.
The tear film rapidly decreases in thickness following a blink. Without a subsequent blink, holes will begin to form in the tear film, called tear breakup, within about 30 seconds. Tear breakup times lower than
10 seconds are considered to be abnormal. This can occur with decreased tear formation or deficiencies in the mucus layer of the tear film. Other situations that can result in dryness of the eye surface include environmental aridity, contact lens wearing, and upon waking.
Typically, dryness of the eye is treated with water based solutions containing electrolytes and preservatives which maintain sterility of the solution for multiple applications. Solutions without preservatives are usually packaged in containers that provide for a single use, with disposal of the container and any residual solution following the single application. The solutions are generally applied by drops, which provide about 20 to 25 μl of fluid to the eye surface. The application of eye drops results in rapid moisturizing of the eye. However, because the amount delivered is greater than the volume of the tear film,
these drops have the disadvantage of flooding the eye, which washes away the tear film and replaces the tear film with the fluid that comprises the drops. Immediately following this flooding there exists a period of time when the normal tear film, with its three layer structure and the constituents of each layer, is not present on the eye surface. This can result in incomplete eye moisturizing which lasts for several blink cycles. Other methods of administration of liquids onto the surface of the eye include eye cups, aerosol and pump sprays, and misters. Eye cups are used to bathe the surface of the eye in fluid, which results in flooding and washing away the tear film that is present on the eye surface. A mister that can be used to deliver a spray of droplets to the eye is described in Hahn, U.S. Patents Nos. 5,346,132 and 5,893,515, each of which is incorporated herein by reference. In these patents, Hahn discloses several disadvantages of delivering fluid to the eye by drops, including difficulty in positioning the dropper and incomplete delivery of medications due to missing the eye and spilling onto the face. Hahn does not address the issue of the quantity of fluid that is administered to the eye or the issue of washing away the tear film due to flooding. The mister of Hahn delivers a measurable quantity of fluid and can be used for household or medical purposes or to moisturize the eyes or the skin.
Another mister is described in Hutson, U.S. Patent No. 5,588,564, incorporated herein by reference.
Like the mister of Hahn, the mister of Hutson can be used to deliver an adjustable and repeatable dose of fluid to the surface of the eye. Hutson does not address the issue of the quantity of fluid that is administered to
the eye or the issue of washing away the tear film due to flooding.
A need exists for a method to moisturize the surface of the eye without flooding the eye or destroying the integrity of the natural tear film.
BRIEF SUMMARY OF THE INVENTION
It has been unexpectedly discovered that administering an amount of fluid to the surface of the eye at a level below that which results in flooding and washing away the tear film results in an improvement in eye moisturizing over prior art methods.
In one embodiment, the invention is a method for moisturizing the eye. The method according to the invention includes obtaining an applicator that can controllably deliver an aqueous fluid to the surface of the eye in a quantity below that which will flood the eye. In this manner, the method of the invention serves to rehydrate the aqueous layer of the tear film and leaves the normal trilaminar tear film intact. In accordance with the method of the invention, the quantity of fluid that is administered to the eye surface is less than about two times the volume of the normal aqueous layer of the tear film, that is less than about 10 μl . Preferably, between 0.5 and 6 μl is administered, and most preferably, between 2 and 5 μl is administered. The fluid may be administered to the eye surface in a single bolus, or may be administered over time, in ten seconds or less, preferably 5 seconds or less, in accordance with the invention. The fluid may be delivered as drops, but is most preferably delivered as a fine mist. It has been discovered that aqueous fluids in the form of a fine mist are extremely well suited for rehydrating the aqueous
portion of the tear film, without rinsing away the tear film.
In another embodiment, the invention is a kit for delivering a pharmaceutical composition for treating the eye, such as moisturizing the eye. In accordance with the invention, the kit contains an aqueous fluid pharmaceutical composition, a container that holds the pharmaceutical composition, and an applicator that, when actuated, controllably administers between about 0.5 and 50 μl of the pharmaceutical composition to a surface of about 2 cm2 in about 10 seconds or less, preferably about
5 seconds or less. Preferably, the kit further contains instructions to controllably apply the pharmaceutical composition to the surface of the eye using the kit.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows one embodiment of the kit of the invention for moisturizing the eye in accordance with the method of the invention.
DETAILED DESCRIPTION OF THE INVENTION It has been discovered that a sudden increase in humidity to the tear film, as opposed to a splash of fluid such as occurs with presently available droppers and misters, increases the water content of the tear film while causing little or no displacement of the tear film. In accordance with the invention, the volume of the tear film the surface of the eye is increased by applying a fluid in an amount not greater than about 100 to 200% of the volume of the aqueous portion of the tear film, which generally has a volume of 2 to 5 μl. Thus, in accordance with the invention, about 10 μl or less is applied to the surface of the eye. Preferably, 0.5 to
6 μl is applied, and most preferably 1 to 2 μl is
applied, especially when moisturizing the eye because of the presence of dry eye, in which the total tear volume is typically between 1 to 2 μl. The volume of fluid in accordance with the invention acts to rehydrate the aqueous portion of the tear film and maintains the integrity of the overlying lipid and the underlying mucus layers.
In contrast with the present state of the art in which 20 to 50 μl of fluid is applied to the eye by dropper or by spray, the method in accordance with the invention reestablishes the normal state in individuals with dry eye. Present methods merely wash away the existing tear film and replace the tear film, or at least the middle aqueous layer, with an aqueous solution. These solutions lack the structure of the intact tear film and also differs from the normal aqueous layer of the tear film.
Generally, the above amount of fluid which is applied in accordance with the invention is applied during one blink cycle, that is between blinks. However, the fluid may be applied during a period of time in which one or more blinks occurs. Preferably, the fluid is applied within a period of 5 to 10 seconds or less.
Although the fluid may be administered in any form, including drops, dispersed droplets in air (mist) , or a vapor, it is preferred that the fluid be administered in the form of a fine mist of discrete liquid droplets in which the average size of the fluid droplets is between about 5 and 150' microns in diameter. It has been found that a fine mist composed of droplets of this size range, preferably between about 0.1% to 1% of the tear volume per droplet, provides optimal hydration of the tear film and moisturization of the surface of the eye. Preferably, the average size of the
fluid droplets is less than 100 microns, and more preferably less than 75 microns. Most preferably, the droplets have a diameter between 10 and 50 microns, with a most preferred range between 15 and 30 microns in diameter. Droplets above about 100 microns in diameter tend to incompletely vaporize and will fall out and produce undesirable wetting of the face and on horizontal surfaces. Droplets below about 20 microns in diameter are generally considered to be inhalable and can be aspirated into the upper and lower respiratory passages. This is acceptable when delivering a substance to the surface of the eye which is not potentially harmful to the respiratory system, such as a water. However, this may be undesirable when topical or ophthalmic medications are incorporated in the solution to be administered into the eye, when such medications may be irritating or toxic if inhaled.
The fluid that is delivered to the surface of the eye in accordance with the invention is a water based fluid. For moisturizing the eye, the fluid preferably is an aqueous fluid having a pH of neutral to slightly acidic, such as between about 7 to about 6.5. Preferably, the fluid has a low concentration of solutes, less than that of the normal tear film. In accordance with a preferred embodiment of the invention, the osmotic pressure of the fluid is less than 350 mOsm and most preferably less than 311 mOsm.
It is further preferred that the water be hypoallergenic and substantially free of preservatives and other chemical compounds that have a potential to irritate the surface of the eye.
In a preferred embodiment, the aqueous fluid delivered to the surface of the eye consists essentially of water. In this preferred embodiment, the water may
contain trace amounts of minerals. The water may further contain constituents that do not irritate the eye and do not provide a therapeutic effect to the eye. Such constituents that are suitable for the aqueous fluid according to this preferred embodiment of the invention include lubricants, preservatives, buffering agents, and surfactants. It is most preferred, however, that the amount of minerals in the fluid be as small as possible and that the water be substantially free of such constituents, such as lubricants, preservatives, buffering agents and surfactants.
The method of the invention may be used to deliver a therapeutic medication to the surface of the eye. Present methods of administration of medications to the eye use relatively large drops, about 20 μl or larger, to deliver the medication. This results in overflowing the eyelid margins with runoff of a portion of the medication to the surface of the face.
In accordance with the method of the invention, medication in an aqueous solution is applied to the surface of the eye, wherein the volume of the solution is less than about 10 μl. Preferably, the volume of the medication-containing-solution that is administered in accordance with the invention is between 0.5 and 6 μl, and most preferably between 2 and 5 μl. The solution containing the medication is preferably administered within about 5 to 10 seconds, and most preferably within one blink cycle, although the administration of the solution may be during the time of several blinks. Any therapeutic medication that is soluble in water is suitable for the method of the invention. It is preferable that the medication not be irritating to the eye, although it is conceived that in some instances it may be desirable or necessary to administer therapeutic
medications to the surface of the eye, even though the medications cause irritation. Examples of suitable therapeutic medications that are suitable for use in the method of the invention include antibiotics, including antibacterial, antifungal, and antiviral agents, sympathetic and parasympathetic agents, anti-glaucoma agents, and anti-inflammatory agents such as steroids.
In another embodiment, the invention is a kit for administering a controlled dosage of between 0.5 and less than 20 μl of an aqueous fluid to the surface of the eye. Preferably, the controlled dosage is less than 10 μl and most preferably less than 5 μl. In the most preferred embodiment, the controlled dosage is between 1 and 2 μl of fluid. In accordance with the invention, the kit contains a container, an aqueous fluid within the container, and an actuator that delivers a spray or fine mist of fluid in the dosage described above. It is preferred that the mist be composed of discrete droplets having an average size of about 5 to 150 microns in diameter, most preferably less than 100 microns, even more preferably less than 75 microns, most preferably less between 10 and 50 microns with a most preferred range between 15 and 30 microns in diameter. The kit may further contain instructions to apply the controlled dosage of the aqueous fluid to the surface of the eye. Preferably, the container of the kit is hermetically sealed so that it may be used for multiple applications of the aqueous fluid over several days to months without the need to include a preservative in the fluid. A preferred embodiment of the kit of the invention is shown diagrammatically in FIG. 1. FIG. 1 shows a package such as a box 101 for containing a rigid, preferably metallic, hermetically sealed container 102, inside of which is an inner hermetically sealed flexible
pouch 103, which contains a fluid to be dispensed. There is a pressurization agent such as compressed air or nitrogen 104 between the hermetically sealed container 102 and the flexible pouch 103, and an actuator 105 that permits the proper dosage of the fluid in the pouch 103 to escape when depressed. The kit further contains instructions (not shown) for delivering a pre-determined dosage of the fluid into the eye.
The invention is further described in the following non-limiting examples.
Example 1 The volume of the tear film on the eyes of three adult human subjects is measured and determined to average 2.26 μl. The subjects are then treated by administering to surface of their eyes fine mist of between 50 and 100 micron average droplet size, with a total volume of between 2 to 5 μl within a period of 10 seconds per eye. Following administration, the tear volume is again measured and is determined to average 2.96 μl.
Example 2 Samples of the tear film from three adult human subjects are obtained and subjected to HPLC chromatography to determine the baseline level of proteins and other constituents in the tear film. One eye from each of the subjects is then moisturized by administration of a standard drop of artificial tears of between 25 and 50 μl . Samples of the tear film from the three treated eyes are then obtained and subjected to HPLC chromatography. After obtaining the second group of samples, the opposite eye of each of the subjects is then moisturized by administration of the same artificial
tears but in a fine mist made of droplets having a size between 50 and 100 microns for a total volume of about 5 μl. Samples of the tear film from the mist-treated eyes are then obtained and subjected to HPLC chromatography. The artificial tears are also subjected to HPLC chromatography.
The initial HPLC chromatography provides a profile of the constituents found in the normal tear film. It is found to contain various lipids, mucus, proteins, and electrolytes.
The HPLC chromatography following moisturization by a single large drop reveals that most if not all of the lipids and mucus remain in the tear film. The proteins and electrolytes that are present in the normal tear film are no longer present and the tear film has a chromatography profile similar to that of the artificial tears, minus the lipids and mucus.
The HPLC chromatography following moisturization by the fine mist reveals that the lipids and mucus remain in the tear film. The proteins and electrolytes that are present in the normal tear film are demonstrated by the chromatography to remain in the tear film following moisturization by the fine mist.
Further modifications, uses, and applications of the invention described herein will be apparent to those skilled in the art. It is intended that such modifications be encompassed in the following claims.
Claims (53)
1. A method for moisturizing the eye without washing away the aqueous layer of the tear film of the eye, comprising administering to the surface of said eye between 0.5 and 10 μl of an aqueous fluid consisting essentially of water, wherein said fluid is in the form of a mist comprised of droplets having an average size between 5 and 150 microns.
2. The method of claim 1 wherein the fluid comprises one or more of a preservative, a lubricant, a buffer, and a surfactant.
3. The method of claim 1 wherein the fluid is substantially free of preservatives.
4. The method of claim 3 wherein the fluid is substantially free of lubricants and surfactants.
5. The method of claim 4 wherein the fluid is substantially free of buffers.
6. The method of claim 1 wherein the average size of the droplets is between 10 and 50 microns in diameter.
7. The method of claim 6 wherein the average size of the droplets is between 15 and 30 microns in diameter.
8. The method of claim 1 wherein between about 0.5 and 6 μl of fluid is administered.
9. The method of claim 8 wherein between about 2 and 5 μl of fluid is administered.
10. The method of claim 1 wherein the fluid has an osmolarity of less than that of the normal aqueous layer of the tear film.
11. The method of claim 10 wherein the osmolarity is less than 311 mOsm.
12. The method of claim 1 wherein the pH of the fluid is less than 7.
13. The method of claim 12 wherein the pH is about 6.5.
14. A kit for moisturizing the eye comprising a container, a fluid consisting essentially of water within said container, an actuator that delivers an amount of the fluid that is sufficient to moisturize the aqueous layer of the tear film of the surface of the eye and less than an amount that washes away said aqueous layer, and instructions for delivering said dose of fluid to the surface of the eye.
15. The kit of claim 14 wherein the amount delivered by the actuator is between 0.5 and 20 μl.
16. The kit of claim 15 wherein the fluid contains one or more of a preservative, a lubricant, a buffer, and a surfactant.
17. The kit of claim 14 wherein the fluid is substantially free of preservatives.
18. The kit of claim 17 wherein the fluid is substantially free of lubricants and surfactants.
19. The kit of claim 18 wherein the fluid is substantially free of buffers.
20. The kit of claim 14 wherein the actuator delivers the fluid as a mist having an average droplet size between 5 and 150 microns in diameter.
21. The kit of claim 20 wherein the average droplet size is between 10 and 50 microns in diameter.
22. The kit of claim 21 wherein the average droplet size is between about 15 and 30 microns in diameter.
23. A method for moisturizing the eye comprising administering to the surface of the eye an aqueous fluid in the form of a mist, wherein the fluid that is administered to the eye is in an amount that is sufficient to increase the volume of the aqueous layer of the tear film by at least 5% of the volume of the normal aqueous layer and which amount is less than that which causes runoff of the tear film from the eye, and permitting the fluid to moisturize the aqueous layer of the tear film.
24. The method of claim 23 wherein the aqueous fluid consists essentially of water.
25. The method of claim 23 wherein the volume of aqueous fluid administered to the eye is less than 3 microliters.
26. The method of claim 25 wherein the volume of aqueous fluid administered to the eye is less than about 2 microliters.
27. The method of claim 26 wherein the volume of aqueous fluid administered to the eye is from 1 to 2 microliters .
28. The method of claim 23 wherein the average size of the droplets in the mist is less than 20 microns in diameter.
29. The method of claim 28 wherein the average size of the droplets is between 10 and less than 20 microns in diameter.
30. A method for moisturizing the eye comprising administering to the surface of the eye an aqueous fluid, wherein the volume of fluid that is administered to the eye is less than 3 microliters, and permitting the fluid to moisturize the aqueous layer of the tear film.
31. The method of claim 30 wherein the volume of fluid administered to the eye is less than about 2 microliters.
32. The method of claim 31 wherein the volume of fluid administered to the eye is 1 to 2 microliters.
33. The method of claim 30 wherein the fluid is administered to the eye in the form of a mist.
34. The method of claim 33 wherein the average size of the droplets in the mist is less than 20 microns in diameter.
35. The method of claim 34 wherein the average size of the droplets is between 10 and less than 20 microns in diameter.
36. The method of claim 30 wherein the fluid consists essentially of water.
37. A method for moisturizing the eye comprising administering to the surface of the eye an aqueous fluid in the form of a multiplicity of droplets having an average diameter of less than 20 microns, wherein the fluid that is administered to the eye is in an amount that is sufficient to increase the volume of the aqueous layer of the tear film by at least 5% of the volume of the normal aqueous layer and which amount is less than that which causes runoff of the tear film from the eye, and permitting the fluid to moisturize the aqueous layer of the tear film.
38. The method of claim 37 wherein the average diameter of the droplets is between 10 and less than 20 microns.
39. The method of claim 37 wherein the volume of fluid that is administered to the eye is less than 3 microliters.
40. The method of claim 39 wherein the volume of fluid that is administered to the eye is less than about 2 microliters.
41. The method of claim 40 wherein the volume of fluid that is administered to the eye is 1 to 2 microliters.
42. The method of claim 37 wherein the droplets that are administered are administered in the form of a mist.
43. The method of claim 37 wherein the aqueous fluid consists essentially of water.
44. A method for moisturizing the eye comprising administering to the surface of the eye an aqueous fluid consisting essentially of water in an amount that is sufficient to increase the volume of the aqueous layer of the tear film by at least 5% of the volume of the normal aqueous layer and which amount is less than that which causes runoff of the tear film from the eye, and permitting the fluid to moisturize the aqueous layer of the tear film.
45. The method of claim 44 wherein the aqueous fluid is in the form of a mist of droplets having an average diameter of less than 20 microns.
46. The method of claim 45 wherein the average diameter of the droplets is 10 to less than 20 microns.
47. The method of claim 44 wherein the amount of fluid administered to the eye is less than 3 microliters.
48. The method of claim 47 wherein the amount of fluid administered is less than about 2 microliters.
49. The method of claim 48 wherein the amount of fluid administered to the eye is 1 to 2 microliters.
50. A method for moisturizing the eye comprising administering to the surface of the eye an aqueous fluid consisting essentially of water in the form of a mist of droplets having an average size less than 20 microns in diameter, wherein the amount of fluid that is administered to the eye is between 1 and less than 3 microliters, and permitting the fluid to moisturize the aqueous layer of the tear film.
51. The method of claim 50 wherein the average size of the droplets is between 10 and less than 20 microns.
52. The method of claim 50 wherein the amount of fluid that is administered is less than about 2 microliters.
53. The method of claim 52 wherein the amount of fluid that is administered is 1 to 2 microliters.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/614,790 US7524511B1 (en) | 2000-07-12 | 2000-07-12 | Method and kit for moisturizing the surface of the eye |
US09/614,790 | 2000-07-12 | ||
US82338501A | 2001-03-30 | 2001-03-30 | |
US09/823,385 | 2001-03-30 | ||
PCT/US2001/021490 WO2002003924A1 (en) | 2000-07-12 | 2001-07-06 | Method and kit for moisturizing the surface of the eye |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2001273251A1 true AU2001273251A1 (en) | 2002-04-18 |
AU2001273251B2 AU2001273251B2 (en) | 2005-03-24 |
Family
ID=27087329
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2001273251A Ceased AU2001273251B2 (en) | 2000-07-12 | 2001-07-06 | Method and kit for moisturizing the surface of the eye |
AU7325101A Pending AU7325101A (en) | 2000-07-12 | 2001-07-06 | Method and kit for moisturizing the surface of the eye |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU7325101A Pending AU7325101A (en) | 2000-07-12 | 2001-07-06 | Method and kit for moisturizing the surface of the eye |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP1304991B1 (en) |
JP (1) | JP2004502497A (en) |
KR (1) | KR20030026973A (en) |
AU (2) | AU2001273251B2 (en) |
CA (1) | CA2414950C (en) |
CY (1) | CY1116016T1 (en) |
DK (1) | DK1304991T3 (en) |
ES (1) | ES2523101T3 (en) |
IL (2) | IL153892A0 (en) |
MX (1) | MXPA03000352A (en) |
PT (1) | PT1304991E (en) |
WO (1) | WO2002003924A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1848541A4 (en) * | 2005-02-07 | 2013-01-16 | Pharmalight Inc | Method and device for ophthalmic administration of active pharmaceutical ingredients |
US20110014294A1 (en) * | 2008-03-03 | 2011-01-20 | Pharmalight Inc. | Stimulation of ocular retrobulbar blood flow using ocular irritants |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4753945A (en) * | 1986-02-19 | 1988-06-28 | Eye Research Institute Of Retina Foundation | Stimulation of tear secretion with phosphodiesterase inhibitors |
US5032392A (en) * | 1986-09-04 | 1991-07-16 | Vision Pharmaceuticals | Aqueous ophthalmic solutions for the treatment of dryness and/or irritation of human or animal eyes |
ES2084722T3 (en) * | 1990-05-29 | 1996-05-16 | Boston Ocular Res | COMPOSITION FOR DRY EYE TREATMENT. |
US5346132A (en) | 1992-11-12 | 1994-09-13 | Gary S. Hahn | Mist generator |
WO1996000050A1 (en) * | 1994-06-23 | 1996-01-04 | R.P. Scherer Corporation | Ocular treatment device |
US5588564A (en) | 1995-08-21 | 1996-12-31 | Hutson; Clifford L. | Eye spray mist dispenser |
AU1201297A (en) * | 1995-12-21 | 1997-07-17 | Pharmacia & Upjohn Ab | Ophthalmic treatment |
US5997518A (en) * | 1998-01-14 | 1999-12-07 | Laibovitz; Robert A. | Apparatus and method for delivery of small volumes of liquid |
-
2001
- 2001-07-06 PT PT1952509T patent/PT1304991E/en unknown
- 2001-07-06 EP EP01952509.6A patent/EP1304991B1/en not_active Expired - Lifetime
- 2001-07-06 ES ES01952509.6T patent/ES2523101T3/en not_active Expired - Lifetime
- 2001-07-06 IL IL15389201A patent/IL153892A0/en active IP Right Grant
- 2001-07-06 JP JP2002508380A patent/JP2004502497A/en active Pending
- 2001-07-06 WO PCT/US2001/021490 patent/WO2002003924A1/en not_active Application Discontinuation
- 2001-07-06 AU AU2001273251A patent/AU2001273251B2/en not_active Ceased
- 2001-07-06 AU AU7325101A patent/AU7325101A/en active Pending
- 2001-07-06 KR KR10-2003-7000518A patent/KR20030026973A/en not_active Application Discontinuation
- 2001-07-06 DK DK01952509.6T patent/DK1304991T3/en active
- 2001-07-06 CA CA2414950A patent/CA2414950C/en not_active Expired - Lifetime
- 2001-07-06 MX MXPA03000352A patent/MXPA03000352A/en active IP Right Grant
-
2003
- 2003-01-12 IL IL153892A patent/IL153892A/en not_active IP Right Cessation
-
2014
- 2014-10-29 CY CY20141100881T patent/CY1116016T1/en unknown
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