Comfortable ophthalmic device and methods of its production

Information

  • Patent Grant
  • 9052529
  • Patent Number
    9,052,529
  • Date Filed
    Friday, March 15, 2013
    11 years ago
  • Date Issued
    Tuesday, June 9, 2015
    9 years ago
Abstract
This invention relates to comfortable ophthalmic devices and methods of producing such devices. The ophthalmic devices are contacted with a polyamide wetting agent and heated to a temperature of at least about 50° C. to about 150° C.
Description
FIELD OF THE INVENTION

This invention relates to comfortable ophthalmic devices and methods of producing such devices.


BACKGROUND

Contact lenses have been used commercially to improve vision since the 1950s. The first contact lenses were made of hard materials. Although these lenses are currently used, they are not suitable for all patients due to their poor initial comfort. Later developments in the field gave rise to soft contact lenses, based upon hydrogels, which are extremely popular today. These lenses have higher oxygen permeabilities and such are often more comfortable to wear than contact lenses made of hard materials. However, these new lenses are not without problems.


Contact lenses can be worn by many users for 8 hours to several days in a row without any adverse reactions such as redness, soreness, mucin buildup and symptoms of contact lens related dry eye. However, some users begin to develop these symptoms after only a few hours of use. Many of those contact lens wearers use rewetting solutions to alleviate discomfort associated with these adverse reactions with some success. However the use of these solutions require that users carry extra solutions and this can be inconvenient. For these users a more comfortable contact lens that does not require the use of rewetting solutions would be useful. Therefore there is a need for such contact lenses and methods of making such contact lenses. It is this need that is met by the following invention.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 Plot of the change in diameter of treated lenses versus control.





DETAILED DESCRIPTION OF THE INVENTION

This invention includes a method of producing ophthalmic lenses comprising, consisting essentially of, or consisting of, treating a polymerized ophthalmic lens with a wetting agent, provided that the ophthalmic lens formulation does not comprise said wetting agent prior to its polymerization.


As used herein, “ophthalmic lens” refers to a device that resides in or on the eye. These devices can provide optical correction or may be cosmetic. Ophthalmic lenses include but are not limited to soft contact lenses, intraocular lenses, overlay lenses, ocular inserts, and optical inserts. The preferred lenses of the invention are soft contact lenses made from silicone elastomers or hydrogels, which include but are not limited to silicone hydrogels, and fluorohydrogels. Soft contact lens formulations are disclosed in U.S. Pat. No. 5,710,302, WO 9421698, EP 406161, JP 2000016905, U.S. Pat. No. 5,998,498, U.S. Pat. No. 6,087,415, U.S. Pat. No. 5,760,100, U.S. Pat. No. 5,776,999, U.S. Pat. No. 5,789,461, U.S. Pat. No. 5,849,811, and U.S. Pat. No. 5,965,631. The foregoing references are hereby incorporated by reference in their entirety. The particularly preferred ophthalmic lenses of the inventions are known by the United States Approved Names of acofilcon A, alofilcon A, alphafilcon A, amifilcon A, astifilcon A, atalafilcon A, balafilcon A, bisfilcon A, bufilcon A, comfilcon, crofilcon A, cyclofilcon A, darfilcon A, deltafilcon A, deltafilcon B, dimefilcon A, drooxifilcon A, epsifilcon A, esterifilcon A, etafilcon A, focofilcon A, genfilcon A, govafilcon A, hefilcon A, hefilcon B, hefilcon D, hilafilcon A, hilafilcon B, hioxifilcon B, hioxifilcon C, hixoifilcon A, hydrofilcon A, lenefilcon A, licryfilcon A, licryfilcon B, lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilcon B, mafilcon A, mesifilcon A, methafilcon B, mipafilcon A, nelfilcon A, netrafilcon A, ocufilcon A, ocufilcon B, ocufilcon C, ocufilcon D, ocufilcon E, ofilcon A, omafilcon A, oxyfilcon A, pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A, polymacon, silafilcon A, siloxyfilcon A, tefilcon A, tetrafilcon A, trifilcon A, and xylofilcon A. More particularly preferred ophthalmic lenses of the invention are genfilcon A, lenefilcon A, comfilcon, lotrafilcon A, lotraifilcon B, and balafilcon A. The most preferred lenses include etafilcon A, nelfilcon A, hilafilcon, and polymacon.


The term “formulation” refers to the un-polymerized mixture of components used to prepare ophthalmic lenses. These components include but are not limited to monomers, pre-polymers, diluents, catalysts, initiators tints, UV blockers, antibacterial agents, polymerization inhibitors, and the like. These formulations can be polymerized, by thermal, chemical, and light initiated curing techniques described in the foregoing references as well as other references in the ophthalmic lens field. As used herein, the terms “polymerized” or “polymerization” refers to these processes. The preferred methods of polymerization are the light initiated techniques disclosed in U.S. Pat. No. 6,822,016, which is hereby incorporated by reference in its entirety.


As used herein the term “treating” refers to physical methods of contacting the wetting agents and the ophthalmic lens. These methods exclude placing a drop of a solution containing wetting agent into the eye of an ophthalmic lens wearer or placing a drop of such a solution onto an ophthalmic lens prior to insertion of that lens into the eye of a user. Preferably treating refers to physical methods of contacting the wetting agents with the ophthalmic lenses prior to selling or otherwise delivering the ophthalmic lenses to a patient. The ophthalmic lenses may be treated with the wetting agent anytime after they are polymerized. It is preferred that the polymerized ophthalmic lenses be treated with wetting agents at temperature of greater than about 50° C. For example in some processes to manufacture contact lenses, an un-polymerized, or partially polymerized formulation is placed between two mold halves, spincasted, or static casted and polymerized. See, U.S. Pat. Nos. 4,495,313; 4,680,336; 4,889,664, 3,408.429; 3,660,545; 4,113,224; and 4,197,266, all of which are incorporated by reference in their entirety. In the case of hydrogels, the ophthalmic lens formulation is a hardened disc that is subjected to a number of different processing steps including treating the polymerized ophthalmic lens with liquids (such as water, inorganic salts, or organic solutions) to swell, or otherwise equilibrate this polymerized ophthalmic lens prior to enclosing the polymerized ophthalmic lens in its final packaging. Polymerized ophthalmic lenses that have not been swelled or otherwise equilibrated are known as un-hydrated polymerized ophthalmic lenses. The addition of the wetting agent to any of the liquids of this “swelling or “equilibrating” step at room temperature or below is considered “treating” the lenses with wetting agents as contemplated by this invention. In addition, the polymerized un-hydrated ophthalmic lenses may be heated above room temperature with the wetting agent during swelling or equilibrating steps. The preferred temperature range is from about 50° C. for about 15 minutes to about sterilization conditions as described below, more preferably from about 50° C. to about 85° C. for about 5 minutes.


Yet another method of treating is physically contacting polymerized ophthalmic lens (either hydrated or un-hydrated) with a wetting agent at between about room temperature and about 85° C. for about 1 minute to about 72 hours, preferably about 24 to about 72 hours, followed by physically contacting the polymerized ophthalmic lens with a wetting agent at between about 85° C. and 150° C. for about 15 minutes to about one hour.


Many ophthalmic lenses are packaged in individual blister packages, and sealed prior to dispensing the lenses to users. As used herein, these polymerized lenses are referred to as “hydrated polymerized ophthalmic lenses”. Examples of blister packages and sterilization techniques are disclosed in the following references which are hereby incorporated by reference in their entirety, U.S. Pat. Nos. D435,966 S; 4,691,820; 5,467,868; 5,704,468; 5,823,327; 6,050,398, 5,696,686; 6,018,931; 5,577,367; and 5,488,815. This portion of the manufacturing process presents another method of treating the ophthalmic lenses with wetting agents, namely adding wetting agents to packaging solution prior to sealing the package, and subsequently sterilizing the package. This is the preferred method of treating ophthalmic lenses with wetting agents.


Sterilization can take place at different temperatures and periods of time. The preferred sterilization conditions range from about 100° C. for about 8 hours to about 150° C. for about 0.5 minute. More preferred sterilization conditions range from about 115° C. for about 2.5 hours to about 130° C. for about 5.0 minutes. The most preferred sterilization conditions are about 124° C. for about 30 minutes.


It is a benefit of the present invention that no pretreatment step is required. Pretreatment steps that can be foregone include coating, contacting or treating the lens with a positively charged polyelectrolyte, treatment of the lens with a separate coupling agent, including a cationic component in the reactive mixture from which the contact lens is made and the like. Thus, the ophthalmic lenses are contacted directly with the wetting agent.


The “packaging solutions” that are used in methods of this invention may be water-based solutions. Typical packaging solutions include, without limitation, saline solutions, other buffered solutions, and deionized water. The preferred aqueous solution is deioinized water or saline solution containing salts including, without limitation, sodium chloride, sodium borate, sodium phosphate, sodium hydrogenphosphate, sodium dihydrogenphosphate, or the corresponding potassium salts of the same. These ingredients are generally combined to form buffered solutions that include an acid and its conjugate base, so that addition of acids and bases cause only a relatively small change in pH. The buffered solutions may additionally include 2-(N-morpholino)ethanesulfonic acid (MES), sodium hydroxide, 2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol, n-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediamine tetraacetic acid and the like and combinations thereof. Preferably, the packaging solution is a borate buffered or phosphate buffered saline solution or deionized water. In one embodiment the packaging solution contains about 1,850 ppm to about 18,500 ppm sodium borate, and in another about 3,700 ppm of sodium borate. In another the packaging solutions comprises a phosphate buffered saline solution.


The “wetting agents” of the present invention are water soluble polymers which are capable of becoming permanently embedded in the lenses without covalent bonding and impart a moist feeling when contact lenses containing them are worn. Molecular weights, Mn of about 400,000 or greater, and Mn of about 400,000 to about 5,000,000, about 450,000 to about 3,000,000, 500,000 to about 3,000,000 and 500,000 to about 2,000,000 are suitable. In one embodiment the polymers have a polydispersity of less than about 2, and between about 1 and about 2. It will be appreciated by those of skill in the art that polymers with molecular weights at the higher ranges will have higher polydispersities than lower molecular weight wetting agents. The wetting agents of the present invention are non-crosslinked and do not contain free radical reactive groups.


Examples of preferred wetting agents include but are not limited to poly(meth)acrylamides [i.e. poly N,N-dimethylacrylamide), poly(N-methylacrylamide) poly(acrylamide), poly(N-2-hydroxyethylmethacrylamide), and poly(glucosamineacrylamide)], poly(itaconic acid), hyaluronic acid, xanthan gum, gum Arabic (acacia), starch, polymers of hydroxylalkyl(meth)acrylates [i.e. poly(2-hydroxyethylmethacrylate), poly(2,3-dihydroxypropylmethacrylate, and poly(2-hydroxyethylacrylate)], and polyvinylpyrrolidone.


Additional preferred wetting agents include but are not limited to co-polymers and graft co-polymers of the aforementioned preferred wetting agents, such co-polymers and graft co-polymers include repeating units of hydrophilic or hydrophobic monomers, preferably in amounts of about less than ten percent by weight, more preferably less than about two percent. Such repeating units of hydrophilic or hydrophobic monomers include but are not limited to alkenes, styrenes, cyclic N-vinyl amides, acrylamides, hydroxyalkyl(meth)acrylates, alkyl(meth)acrylates, siloxane substituted acrylates, and siloxane substituted methacrylates. Specific examples of hydrophilic or hydrophobic monomers which may be used to form the above co-polymers and graft co-polymers include but are not limited to ethylene, styrene, N-vinylpyrrolidone, N,N-dimethylacrylamide, 2-hydroxyethylmethyacrylate, methyl methacrylate and butyl methacrylate, methacryloxypropyl tristrimethylsiloxysilane and the like. The preferred repeating units of hydrophilic or hydrophobic monomers are N-vinylpyrrolidone, N,N-dimethylacrylamide, 2-hydroxyethylmethacrylate, methyl methacrylate, and mixtures thereof. Further examples of wetting agents include but are not limited to polymers with carbon backbones and pendant polyethylene glycol chains [i.e. polymers of polyethylene glycol monoomethacrylate] copolymers of ethylene glycol [copolymers with 1,2,propyleneglycol, 1,3-propylene glycol, methyleneglycol, and tetramethylene glycol]. In one embodiment, the preferred wetting agents are polyvinylpyrrolidone, graft co-polymers and co-polymers of polyvinylpyrrolidone, the particularly preferred wetting agent is polyvinylpyrrolidone. Polyvinylpyrrolidone (“PVP”) is the polymerization product of N-vinylpyrrolidone. PVP is available in a variety of molecular weights from about 500 to about 6,000,000 Daltons. These molecular weights can be expressed in term of K-values, based on kinematic viscosity measurements as described in Encyclopedia of Polymer Science and Engineering, John Wiley & Sons Inc, and will be expressed in these numbers throughout this application. The use of PVP having the following K-values from about K-30 to about K-120 is contemplated by this invention. The more preferred K-values are about K-60 to about K-100, most preferably about K-80 to about K-100. For the treatment of etafilcon A lenses, the particularly preferred K-value of PVP is about K-80 to about K-95, more preferably about K-85 to about K-95, most preferably about K-90.


The wetting agents can be added to the packaging solution at a variety of different concentrations such as about 100 ppm to about 150,000 ppm. For example if the wetting agents are added to packaging solutions containing un-hydrated polymerized ophthalmic lenses, the wetting agents may be present at a concentration of about 30,000 ppm to about 150,000 ppm. If the wetting agents are added to packaging solutions containing hydrated polymerized ophthalmic lenses, the wetting agents are preferably present at a concentration of about 100 ppm to about 3000 ppm, 150 ppm to about 1,000 ppm or about 200 ppm to about 1000 ppm.


For example when etafilcon A lenses are used in this invention and the wetting agent is K-90 PVP, the preferred packaging solution concentration of PVP K-90 is about 250 ppm to about 2,500 ppm, more preferably about 300 to about 500 ppm, most preferably about 350 to about 440 ppm.


In another embodiment, convention, the contact lenses comprise non-silicone containing lenses, polyHEMA lenses, and polyHEMA lenses comprising methacrylic acid, such as etalfilcon A lenses, the wetting comprises at least one poly(meth)acrylamide, in another embodiment poly(N,N-dimethylacrylamide), poly(N-methylacrylamide), poly(N-2-hydroxyethylmethacrylamide), or poly(glucosamineacrylamide), and in another embodiment comprises poly(N,N-dimethylacrylamide), or poly(N-2-hydroxyethylmethacrylamide), a packaging solution concentration of wetting agent of about 150 ppm to about 2,000 ppm.


When etafilcon A contact lenses are heated with K-90 PVP at a temperature greater than about 120° C. for about 30 minutes at a concentration of about 400 to about 500 ppm, the treated lenses are more comfortable to users than untreated lenses. Further, this particular molecular weight and concentration of PVP does not distort or shift the diameter of the lenses during the treatment cycle or distort the user's vision. While not wishing to be bound by any particular mechanism of incorporation, it is known that K-90 PVP is incorporated into the matrix of the lens after it is treated with K-90 PVP. In an etafilcon A contact lens, the preferred amount of incorporated K-90 PVP is about 0.01 mg to about 1.0 mg, more preferred about 0.10 mg to about 0.30 mg, most particularly preferred about 0.10 mg to about 0.20 mg. Lenses that have been treated in this manner are worn by users for up to 12 hours still maintain the incorporated PVP.


The contact lenses of the present invention desirably uptake between about 10 and about 200 ppm wetting agent, in some embodiments between about 20 and about 150 ppm wetting agent and in others between about 30 and about 150 ppm wetting agent. Wetting agents having higher molecular weights (for example 1,000,000 weight average MW or higher) can produce the desired improvements with a lower concentration of wetting agent uptake. Lenses that have been treated in this manner are worn by users for up to 12 hours still maintain the incorporated wetting agent, including polyamide wetting agents, and in some embodiments, polyDMA.


Further the invention includes an ocular device comprising, consisting essentially of, or consisting of a polymerized ophthalmic lens wherein said polymerized ophthalmic lens is treated with a wetting agent, provided that the ophthalmic lens formulation does not comprise said wetting agent prior to its polymerization. The terms “ophthalmic lens,” “wetting agent,” “polymerized,” and “formulation” all have their aforementioned meanings and preferred ranges. The term “treated” has the equivalent meaning and preferred ranges as the term treating.


Still further the invention includes an ocular device prepared by treating a polymerized ophthalmic lens with a wetting agent, provided that the ophthalmic lens formulation does not comprise said wetting agent prior to its polymerization. The terms “ophthalmic lens,” “wetting agent,” “polymerized,” “treated” and “formulation” all have their aforementioned meanings and preferred ranges.


The application of the invention is described in further detail by use of the following examples. These examples are not meant to limit the invention, only to illustrate its use. Other modifications that are considered to be within the scope of the invention, and will be apparent to those of the appropriate skill level in view of the foregoing text and following examples.


EXAMPLES
Example 1

Cured etafilcon A contact lenses (sold as 1-Day Acuvue® brand contact lenses by Johnson & Johnson Vision Care, Inc.) were equilibrated in deionized water, and packaged in solutions containing PVP in borate buffered saline solution ((1000 mL, sodium chloride 3.55 g, sodium borate 1.85 g, boric acid 9.26 g, and ethylenediamine tetraacetic acid 0.1 g: 5 rinses over 24 hours, 950±μL), sealed with a foil lid stock, and sterilized (121° C., 30 minutes). Before the addition of PVP each solution contained water, 1000 mL, sodium chloride 3.55 g, sodium borate 1.85 g, boric acid, 9.26 g, and ethylenediamine tetraacetic acid 0.1 g. A variety of different weights and concentrations of PVP were used as shown in Table 1, below.


The amount of PVP that is incorporated into each lens is determined by removing the lenses from the packaging solution and extracting them with a mixture 1:1 mixture of N,N-dimethylforamide, (DMF) and deionized water (DI). The extracts are evaluated by high performance liquid chromatography (HPLC). Three lenses were used for each evaluation. The results and their standard deviation are presented in Table 1.












TABLE 1








mg of PVP


Sample #
Type of PVP
Conc. (ppm)
in lens







Control
None
None
None


1
K-12
3000
0.24 (0.01)


2
K-12
20,000
1.02 (0.01)


3
K-30
1500
1.39 (0.05)


4
K-30
2000
1.50 (0.01)


5
K-60
1000
0.56 (0.00)


6
K-60
1500
0.85 (0.02)


7
K-60
2500
1.02 (0.03)


8
K-90
250
0.10 (0.00)


9
K-90
500
0.14 (0.00)


10
K-90
1000
 0.2 (0.01)


11
K-90
2500
0.25 (0.02)


12
K-120
500
0.07 (0.00)









Example 2

Samples of treated etafilcon A lenses were prepared via the treatment and sterilization methods of Example 1 from K-12, K-30, K-60, K-90, and K-120 PVP at concentrations of 0.30%, 1.65%, and 3.00%. After sterilization, the diameter of the lenses was, compared to an untreated lens and evaluated to determine if the process changed those diameters. The results, FIG. 1, plot the change in diameter vs. the type of PVP at a particular concentration. This data shows that K-12, K-90, and K-120 have a minimal effect on the diameter of the lenses.


Example 3

Several etafilcon A lenses were treated with K-90 PVP at a concentration of 500 ppm and sterilized according to the methods of Example 1. The lenses were stored in their packages for approximately 28 days at room temperature and were then measured for diameter, base curve, sphere power, and center thickness. Thereafter, lenses were heated at 55° C. for one month. The diameter, base curve, sphere power, and center thickness of the lenses was measured and the results were evaluated against an untreated lens and data is presented in Table 2. This data illustrates that the parameters of lenses treated with K-90 PVP are not significantly affected by time at elevated temperature.












TABLE 2








Change from




Baseline of Sample




after one month



Baseline
storage at 55° C.




















Diameter (mm)
14.37 (0.02) 
0.02



Base curve (mm)
8.90 (0.03)
−0.01



Power (diopter)
−0.75 (0.05) 
0.00



Center Thickness
0.127 (0.005)
0.002



(mm)










Example 4

Etafilcon-A lenses treated with PVP K-90 at a concentration of 440 ppm and sterilized (124° C., approximately 18 minutes) were sampled from manufacturing lines and measured for diameter, base curve, sphere power, and center thickness and compared to similar measurements made on untreated 1-Day Acuvue® brand lenses. The data presented in Table 3 illustrates that K-90 PVP does not significantly affect these parameters.












TABLE 3







Treated
Untreated


















Diameter (mm)
14.24 (0.04) 
14.18 (0.04) 


Base curve (mm)
8.94 (0.03)
8.94 (0.04)


Sphere Power Deviation from
−0.01 (0.04) 
−0.02 (0.04) 


Target (diopter)


Center Thickness Deviation from
0.000 (0.004)
0.002 (0.005)


Target (mm)









Example 5

Etafilcon A lenses were prepared according to Example 1 at the concentrations of Table 1. The treated lenses were clinically evaluated in a double-masked studies of between 9 and 50 patients. The patients wore the lenses in both eyes for 3-4 days with overnight removal and daily replacement, and wore untreated 1-Day Acuvue® brand contact lenses for 3-4 days with overnight removal and daily replacement as a control. Patients were not allowed to use rewetting drops with either type of lens. Patients were asked to rate the lens using a questionnaire. All patients were asked a series of questions relating to overall preference, comfort preference, end of day preference, and dryness. In their answers they were asked to distinguish if they preferred the treated lens, the 1-Day control lens, both lenses or neither lens. The results are shown in Tables 4 and 5. The numbers in the columns represent the percentage of patients that positively responded to each of the four options. The “n” number represents the number of patients for a particular sample type. “DNT” means did not test and n/a means non applicable. The numbers illustrate that lenses treated with K-90 PVP at a concentration of about 500 ppm have good clinical comfort on the eye. The sample # refers to the sample numbers in Table 1.












TABLE 4









Overall Preference, %
Comfort Preference, %
















Sam-

PVP
1-

Nei-
PVP
1-

Nei-


ple #
n
treated
Day
Both
ther
treated
Day
Both
ther



















1
9
67
22
11
0
67
22
11
0


2
37
27
49
22
3
30
46
19
5


3
41
34
49
15
2
27
56
12
5


4
10
30
20
50
0
30
40
30
0


5
41
27
61
10
2
22
49
29
0


6
42
33
33
33
0
33
29
38
0


7
37
51
27
19
3
49
11
38
3


8
41
27
37
32
5
24
34
37
5


9
48
33
27
40
0
33
23
44
0


10
45
18
27
51
4
16
20
58
7



















TABLE 5









Dryness Preference %
End of Day Preference %
















Sam-

PVP
1-

Nei-
PVP
1-

Nei-


ple #
n
treated
Day
Both
ther
treated
Day
Both
ther



















1
9
33
33
11
0
56
22
44
0


2
37
24
43
22
8
27
43
27
5


3
41
32
51
17
2
29
49
17
2


4
10
20
40
30
10
20
10
60
10


5
41
20
46
32
2
20
41
37
2


6
31
42
24
38
0
38
35
16
6


7
42
36
19
38
3
41
24
40
0


8
41
27
22
49
7
22
24
41
7


9
48
38
21
46
0
33
19
44
0


10
45
24
20
58
4
18
20
51
4









Example 6

An etafilcon A contact lens was treated with 500 ppm of K-90 PVP using the methods of Example 1. The treated lenses were briefly rinsed with phosphate buffered saline solution and rinsed lenses were placed in the well of a cell culture cluster container (Cellgrow XL) that mimics the dimensions of a human eye. See, Farris R L, Tear Analysis in Contact Lens Wears, Tr. Am. Opth. Soc. Vol. LXXXIII, 1985. Four hundred microliters of phosphate buffered saline solution (KH2PO4 0.20 g/L, KCl.0.20 g/L, NaCl 8.0 g/L, Na2HPO4 [anhydrous] 1.15 g/L) was added to each container. The wells were covered and the container was stored in an oven at 35° C.


Three lenses were removed from the oven at various times and analyzed by HPLC to determine whether PVP was released into the phosphate buffered saline solution. The average results are presented in Table 6. The limit of quantification for PVP is 20 ppm. The test did not detect any PVP in the analyzed samples. This data shows that PVP is not released at levels greater than 20 ppm.












TABLE 6








PVP



Time
Released









30 min.
<20 ppm



 1 hr.
<20 ppm



 2 hr.
<20 ppm



 4 hr.
<20 ppm



 8 hr.
<20 ppm



16 hr.
<20 ppm



24 hr
<20 ppm










Example 7-9

Cured etafilcon A contact lenses (sold as 1-Day Acuvue® brand contact lenses by Johnson & Johnson Vision Care, Inc.) were equilibrated in deionized water, and packaged in solutions containing 750 ppm poly(N,N-dimethylacrylamide) (pDMA, Mn 450,000, Pd 1.3) in borate buffered saline solution ((1000 mL, sodium chloride 3.55 g, sodium borate 1.85 g, boric acid 9.26 g, and ethylenediamine tetraacetic acid 0.1 g: 5 rinses over 24 hours, 950±μL), sealed with a foil lid stock, and sterilized (121° C., 30 minutes). Before the addition of polyDMA each solution contained water, 1000 mL, sodium chloride 3.55 g, sodium borate 1.85 g, boric acid, 9.26 g, and ethylenediamine tetraacetic acid 0.1 g. Lenses were subjected to 1-3 autoclave cycles.


The amount of pDMA that is incorporated into each lens is determined by removing the lenses from the packaging solution and extracting them with a mixture 1:1 mixture of N,N-dimethylforamide, (DMF) and deionized water (DI). The extracts are evaluated by high performance liquid chromatography (HPLC). Three lenses were used for each evaluation.


After sterilization, the diameter of the lenses were measured and compared to an untreated lens. The results, are shown in Table 7. This data shows that polyDMA has a minimal effect on the diameter of the lenses, even through multiple sterilization cycles.














TABLE 7







[pDMA]soln
ppm




Ex #
#cycle
(ppm)
pDMAlens
% H20
diameter







Control
1
None
None
59.1
14.01


7
1
750
72
58.9
14.10


8
2
750
84
59.6
14.16


9
3
750
102 
59.5
14.22









When lenses are allowed to sit in their package for 2 to 4 weeks or morem the diameters decrease or settle, in some cases 10% or more. Also, the amount of wetting agent uptake by the lens was insufficient to alter the water content of the lens material, even though improvements in lubricity and wettability were achieved.


Examples 10-14

Samples of treated etafilcon A lenses were prepared via the treatment and sterilization method of Example 7 from polyDMA at the concentrations shown in Table 8. After sterilization, the lenses were tested for bacterial adhesion using P. aureginosa (1×106) in a tear like fluid (TLF) after 4 and 18 hour incubation periods and 18 hour incubation in phosphate buffered saline (PBS). The preparation for TLF is described below. Untreated etafilcon A lenses, and untreated etafilcon A contact lenses with PVP (sold as 1-Day Acuvue® Moist brand contact lenses by Johnson & Johnson Vision Care, Inc.) were used as controls and are reported as Comparative Examples 1 and 2, respectively.













TABLE 8







TLF-BA4 hr
TLF-BA18 hr
PBS-BA18 hr


Ex#
[pDMA] (ppm)
(105 cfu)
(105 cfu)
(105 cfu)



















10
200
6.25
20.2
4.05


11
350
10.3
12.3
1.55


12
500
0.843
13.6
1.54


13
1000
1.04
14.8
0.657


CE1
0
27.5
36.2
9.67


CE2
0
8.65
17.9
5.25









Example 15

Example 10 was repeated using 250 ppm polyDMA and measuring the bacterial adhesion at both 4 and 20 hours, using P. aureginosa (1×106) in a tear like fluid and etafilcon A lenses as a control (Comparative Example 1).


Example 16

Etafilcon A lenses were prepared according to Example 7, but with 350 ppm polyDMA. The treated lenses were clinically evaluated in a double-masked, bilateral, randomized, 1 week dispensing study of 48 patients. The patients wore the lenses in both eyes for 7 days with overnight removal, and wore untreated 1-Day Acuvue® brand contact lenses for 7 days with overnight removal. Optifree RepleniSH was used as the care solution. Wettability and deposits were evaluated at the 1 week follow up visit using a slit lamp. The results are shown in Table 9.












TABLE 9







Ex 16
CE1




















uniform lens wetting
83.3
  75%



Trace to mild non-uniform
16.7%
20.8%



wetting



Moderate-severe non-
  0%
 4.2%



wetting



No deposits
78.1
60.4



Slight deposits
13.5
24



Mild deposits
8.3
11.5



Moderate deposits
0
2.1



Severe deposits
0
2.1










Thus, the lenses of the present invention improve on-eye wettability and reduce deposits compared to the same less without a wetting agent of the present invention.


TLF Preparation


Tear-like fluid buffer solution (TLF Buffer) was prepared by adding the 0.137 g sodium bicarbonate (Sigma, 58875) and 0.01 g D-glucose (Sigma, G5400) to PBS containing calcium and magnesium (Sigma, D8662). The TLF buffer was stirred at room temperature until the components were completely dissolved (approximately 5 min).


A lipid stock solution was prepared by mixing the following lipids in TLF Buffer, with thorough stirring, for about 1 hour at about 60° C., until clear:


















Cholesteryl linoleate (Sigma, C0289)
24 mg/mL



Linalyl acetate (Sigma, L2807)
20 mg/mL



Triolein (Sigma, 7140)
16 mg/mL



Oleic acid propyl ester (Sigma, O9625)
12 mg/mL



undecylenic acid (Sigma, U8502)
 3 mg/mL



Cholesterol (Sigma, C8667)
1.6 mg/mL 










The lipid stock solution (0.1 mL) was mixed with 0.015 g mucin (mucins from Bovine submaxillary glands (Sigma, M3895, Type 1-S)). Three 1 mL portions of TLF Buffer were added to the lipid mucin mixture. The solution was stirred until all components were in solution (about 1 hour). TLF Buffer was added Q.S. to 100 mL and mixed thoroughly


The following components were added one at a time, and in the order listed, to the 100 mL of lipid-mucin mixture prepared above. Total addition time was about 1 hour.















acid glycoprotein from Bovine plasma (Sigma, G3643)
0.05 mg/mL 


Fetal Bovine serum (Sigma, F2442)
0.1%


Gamma Globulins from Bovine plasma (Sigma, G7516)
0.3 mg/mL


β lactoglobulin (bovine milk lipocaline) (Sigma, L3908)
1.3 mg/mL


Lysozyme from Chicken egg white (Sigma, L7651)
  2 mg/mL


Lactoferrin from Bovine colostrums (Sigma, L4765)
  2 mg/mL









The resulting solution was allowed to stand overnight at 4° C. The pH was adjusted to 7.4 with 1N HCl. The solution was filtered and stored at −20° C. prior to use.

Claims
  • 1. A method of producing an ophthalmic lens comprising, treating a polymerized ophthalmic lens that does not comprise a wetting agent prior to its polymerization with about 350 to about 1000 ppm wetting agent having a number average molecular weight of about 400,000 or greater, a polydispersity of less than about 2 and selected from the group consisting of poly(N,N-dimethylacrylamide), poly(N-methylacrylamide), poly(N-2-hydroxyethylmethacrylamide), and poly(glucosamineacrylamide)], and mixtures thereof, and heating said lens to a temperature of at least about 50° C. to about 150° C.
  • 2. The method of claim 1 wherein treating comprises heating the polymerized ophthalmic lens and wetting agent in a packaging solution.
  • 3. The method of claim 2 wherein the packaging solution comprises deionized water, or saline solution.
  • 4. The method of claim 2 wherein the packaging solution comprises a borate buffer or a phosphate buffer.
  • 5. The method of claim 1 wherein the wetting agent comprises poly(N-2-hydroxyethylmethacrylamide).
  • 6. The method of claim 1 wherein said wetting agent is water soluble polymer and has a number average molecular weight of 500,000 to about 3,000,000.
  • 7. The method of claim 6 wherein said wetting agent has a polydispersity of between about 1 and about 2.
  • 8. The method of claim 1 wherein treating comprises heating the polymerized ophthalmic lens in a packaging solution at a temperature of greater than about 80° C.
  • 9. The method of claim 1 wherein treating comprises heating the polymerized ophthalmic lens in a packaging solution comprising at a temperature of greater than about 120C to about 150° C.
  • 10. The method of claim 6 wherein the treating step is conducted in an individual sealed contact lens package.
  • 11. The method of claim 1 wherein the treating step is conducted in an individual sealed contact lens package.
  • 12. The method of claim 6 wherein the ophthalmic lens is selected from the group consisting of acofilcon A, alofilcon A, alphafilcon A, amifilcon A, astifilcon A, atalafilcon A, balafilcon A, bisfilcon A, bufilcon A, comfilcon, crofilcon A, cyclofilcon A, darfilcon A, deltafilcon A, deltafilcon B, dimefilcon A, drooxifilcon A, epsifilcon A, esterifilcon A, etafilcon A, focofilcon A, genfilcon A, govafilcon A, hefilcon A, hefilcon B, hefilcon D, hilafilcon A, hilafilcon B, hioxifilcon B, hioxifilcon C, hixoifilcon A, hydrofilcon A, lenefilcon A, licryfilcon A, licryfilcon B, lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilcon B, mafilcon A, mesifilcon A, methafilcon B, mipafilcon A, nelfilcon A, netrafilcon A, ocufilcon A, ocufilcon B, ocufilcon C, ocufilcon D, ocufilcon E, ofilcon A, omafilcon A, oxyfilcon A, pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A, polymacon, silafilcon A, siloxyfilcon A, tefilcon A, tetrafilcon A, trifilcon A, and xylofilcon A.
  • 13. The method of claim 6 wherein the ophthalmic lens is selected from the group consisting of genfilcon A, lenefilcon A, lotrafilcon A, lotrafilcon B, balafilcon A, comfilcon, etafilcon A, nelfilcon A, hilafilcon, and polymacon.
  • 14. The method of claim 6 wherein the ophthalmic lens is selected from the group consisting of genfilcon A, lenefilcon A, etafilcon A, nelfilcon A, hilafilcon, and polymacon.
  • 15. The method of claim 6 wherein the ophthalmic lens is selected from the group consisting of etafilcon A, nelfilcon A, hilafilcon, and polymacon.
  • 16. The method of claim 1 wherein the ophthalmic lens is selected from the group consisting of etafilcon A, nelfilcon A, hilafilcon, and polymacon.
  • 17. The method of claim 6 wherein the ophthalmic lens is selected from the group consisting of etafilcon A.
  • 18. The method of claim 1 wherein the ophthalmic lens is selected from the group consisting of etafilcon A.
  • 19. The method of claim 6 wherein the polymerized ophthalmic lens is an un-hydrated polymerized ophthalmic lens.
  • 20. The method of claim 19 wherein treating comprises contacting the un-hydrated polymerized ophthalmic lens with a packaging solution comprising a borate buffer or a phosphate buffer.
  • 21. The method of claim 20 wherein the treating further comprises heating the un-hydrated polymerized ophthalmic lens and the packaging solution to a temperature of at least about 50° C. to about 100° C.
  • 22. The method of claim 20 wherein the treating further comprises maintaining the un-hydrated polymerized ophthalmic lens and the packaging solution at a temperature of at least about 10° C. to about room temperature.
  • 23. An ocular device comprising a polymerized ophthalmic lens wherein said polymerized ophthalmic lens does not comprise a wetting agent prior to its polymerization, and is treated with about 350 to about 1000 ppm wetting agent, having a number average molecular weight of about 400,000 or greater, a polydispersity of less than about 2 and selected from the group consisting of poly(N,N-dimethylacrylamide), poly(N-methylacrylamide), poly(N-2-hydroxyethylmethacrylamide), and poly(glucosamineacrylamide)], and mixtures thereof.
  • 24. The method of claim 23 wherein the wetting agent comprises poly(N-2-hydroxyethylmethacrylamide).
  • 25. The device of claim 23 wherein said device does not distort the user's vision.
  • 26. The device of claim 23 wherein said wetting agent remains in the ophthalmic lens after about 6 hours to about 24 hours of wear by a user.
  • 27. The method of claim 1, 14 or 15 wherein the wetting agent comprises poly(N,N-dimethyl acrylamide).
RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No. 12/896,930, filed on Oct. 4, 2010, which is a continuation of U.S. application Ser. No. 11/351,907, filed Feb. 10, 2006 and issued as U.S. Pat. No. 7,841,716 on Nov. 30, 2010.

US Referenced Citations (189)
Number Name Date Kind
2847407 Hosmer Aug 1958 A
3311577 Rankin Mar 1967 A
3408429 Wichterle Oct 1968 A
3621079 Leeds Nov 1971 A
3660545 Wichterle May 1972 A
3700761 O'Driscoll Oct 1972 A
3721657 Seiderman Mar 1973 A
3767731 Seiderman Oct 1973 A
3767788 Rankin Oct 1973 A
3808178 Gaylord Apr 1974 A
3841598 Grucza Oct 1974 A
3841985 O Driscoll Oct 1974 A
3888782 Boghosian Jun 1975 A
3894129 Hoffman Jul 1975 A
3947573 Rankin Mar 1976 A
3959102 Wajs May 1976 A
3966847 Seiderman Jun 1976 A
3978164 Le Boeuf Aug 1976 A
4018853 Le Boeuf Apr 1977 A
RE29231 Leeds May 1977 E
4029817 Blanco Jun 1977 A
4038264 Rostoker Jul 1977 A
4042552 Grucza Aug 1977 A
4045547 Le Boeuf Aug 1977 A
4054624 Le Boeuf Oct 1977 A
4062627 Wajs Dec 1977 A
4113224 Clark Sep 1978 A
4120570 Gaylord Oct 1978 A
4123408 Gordon Oct 1978 A
4136250 Mueller Jan 1979 A
4153641 Deichert May 1979 A
4157892 Tanaka Jun 1979 A
4190277 England Feb 1980 A
4197266 Clark Apr 1980 A
4321261 Ellis Mar 1982 A
4407791 Stark Oct 1983 A
4451629 Tanaka et al. May 1984 A
4460573 Huth Jul 1984 A
4495313 Larsen Jan 1985 A
4529535 Sherman Jul 1985 A
4560491 Sherman Dec 1985 A
4615882 Stockel Oct 1986 A
4626292 Sherman Dec 1986 A
4670178 Huth Jun 1987 A
4680336 Larsen Jul 1987 A
4691820 Martinez Sep 1987 A
4729914 Kliment Mar 1988 A
4731192 Kenjo Mar 1988 A
4740533 Su Apr 1988 A
4866148 Geyer Sep 1989 A
4889664 Kindt Larsen Dec 1989 A
4910277 Bambury Mar 1990 A
4961954 Goldberg Oct 1990 A
4976969 Plamondon Dec 1990 A
5006622 Kunzler Apr 1991 A
5034461 Lai Jul 1991 A
5039459 Kindt Larsen Aug 1991 A
5057578 Spinelli Oct 1991 A
5070170 Robertson Dec 1991 A
5070215 Bambury Dec 1991 A
5094876 Goldberg Mar 1992 A
5100689 Goldberg Mar 1992 A
5117165 Cassat May 1992 A
5135297 Valint, Jr. Aug 1992 A
5141665 Sherman Aug 1992 A
5244981 Seidner Sep 1993 A
5256751 Vanderlaan Oct 1993 A
5300296 Holly Apr 1994 A
5311223 Vanderlaan May 1994 A
5312588 Gyulai May 1994 A
5314960 Spinelli May 1994 A
5314961 Anton May 1994 A
5321108 Kunzler Jun 1994 A
5322667 Sherman Jun 1994 A
5331067 Seidner Jul 1994 A
5338480 Dziabo Aug 1994 A
5338814 Wu Aug 1994 A
5356555 Huth Oct 1994 A
5362815 Shih Nov 1994 A
5364918 Valint, Jr. Nov 1994 A
5373074 Wu Dec 1994 A
5380303 Holly Jan 1995 A
5387662 Kunzler Feb 1995 A
5436068 Kobayashi Jul 1995 A
5443801 Langford Aug 1995 A
5451303 Heiler Sep 1995 A
5466853 Koinuma Nov 1995 A
5467868 Abrams Nov 1995 A
5486579 Lai Jan 1996 A
5488815 Abrams Feb 1996 A
5496871 Lai Mar 1996 A
5525691 Valint, Jr. Jun 1996 A
5539016 Kunzler Jul 1996 A
5577367 Abrams Nov 1996 A
5603897 Heiler Feb 1997 A
5641450 Kobayashi Jun 1997 A
5652638 Roffman Jul 1997 A
5696686 Sanka Dec 1997 A
5704468 Lust Jan 1998 A
5710302 Kunzler Jan 1998 A
5726733 Lai Mar 1998 A
5760100 Nicolson Jun 1998 A
5773396 Zhang Jun 1998 A
5776999 Nicolson Jul 1998 A
5782992 Frangione Jul 1998 A
5789461 Nicolson Aug 1998 A
5800807 Hu Sep 1998 A
5805260 Roffman Sep 1998 A
5807944 Hirt Sep 1998 A
5823327 Wu Oct 1998 A
5840671 Fujimura Nov 1998 A
5849811 Nicolson Dec 1998 A
5885566 Goldberg Mar 1999 A
5944853 Molock Aug 1999 A
5965631 Nicolson Oct 1999 A
5998498 Vanderlaan Dec 1999 A
6018931 Byram Feb 2000 A
6039913 Hirt Mar 2000 A
6050398 Wilde Apr 2000 A
6087415 Vanderlaan Jul 2000 A
6093686 Nakada Jul 2000 A
6126706 Matsumoto Oct 2000 A
6162393 De Bruiju Dec 2000 A
D435966 Duis Jan 2001 S
6180093 De Jan 2001 B1
6183082 Clutterbuck Feb 2001 B1
6190651 Nakada Feb 2001 B1
6258591 Yoneda Jul 2001 B1
6274133 Hu Aug 2001 B1
6338847 Thomas Jan 2002 B1
6367929 Maiden Apr 2002 B1
6372815 Sulc Apr 2002 B1
6440366 Salpekar Aug 2002 B1
6444776 Holland Sep 2002 B1
6488965 Karageozian Dec 2002 B1
6511949 Nitta Jan 2003 B1
6528048 Koike Mar 2003 B1
6565776 Li May 2003 B1
6617373 Sulc Sep 2003 B2
6733123 Polzhofer May 2004 B2
6815074 Aguado Nov 2004 B2
6822016 McCabe Nov 2004 B2
6849671 Steffen Feb 2005 B2
6861123 Turner Mar 2005 B2
6992118 Sulc Jan 2006 B2
7147844 Hamano Dec 2006 B2
7262232 Sulc Aug 2007 B2
7431152 Marmo Oct 2008 B2
7435452 Shimoyama Oct 2008 B2
7841716 McCabe et al. Nov 2010 B2
8672475 Liu et al. Mar 2014 B2
8696115 McCabe et al. Apr 2014 B2
20010036556 Jen Nov 2001 A1
20010044482 Hu Nov 2001 A1
20020039984 Ketelson Apr 2002 A1
20020058601 Jordan May 2002 A1
20020163619 Matsuzawa Nov 2002 A1
20030008154 Aguado Jan 2003 A1
20030021829 Hamano Jan 2003 A1
20030109390 Salpekar Jun 2003 A1
20030125498 McCabe Jul 2003 A1
20030134132 Winterton Jul 2003 A1
20030162862 McCabe Aug 2003 A1
20030164562 Li Sep 2003 A1
20030191043 Becker Oct 2003 A1
20040097504 Bethiel May 2004 A1
20040114105 Shimoyama Jun 2004 A1
20040130676 Doshi Jul 2004 A1
20040137079 Cook Jul 2004 A1
20040142829 Tsao Jul 2004 A1
20040186028 Hu Sep 2004 A1
20040192872 Iwata Sep 2004 A1
20040214914 Marmo Oct 2004 A1
20050059639 Wei Mar 2005 A1
20050074467 Fujita Apr 2005 A1
20050117112 Nayiby et al. Jun 2005 A1
20050154080 McCabe Jul 2005 A1
20050179862 Steffen Aug 2005 A1
20070010595 McCabe Jan 2007 A1
20070043140 Lorenz Feb 2007 A1
20070119721 Marmo May 2007 A1
20070229758 Matsuzawa Oct 2007 A1
20080045612 Rathore et al. Feb 2008 A1
20080100796 Pruitt May 2008 A1
20080299179 Rathore Dec 2008 A1
20090059165 Pruitt Mar 2009 A1
20090182067 Liu Jul 2009 A1
20130293831 Norris et al. Nov 2013 A1
20140016086 Liu et al. Jan 2014 A1
Foreign Referenced Citations (60)
Number Date Country
80539 May 1986 EP
349487 Jan 1990 EP
358447 Mar 1990 EP
472496 Feb 1992 EP
487994 Jun 1992 EP
406161 Feb 1995 EP
482836 Mar 1995 EP
482837 Mar 1995 EP
486653 May 1996 EP
600828 Mar 1997 EP
437179 Apr 1998 EP
836111 Apr 1998 EP
580662 Jun 1998 EP
577143 Jan 1999 EP
456467 Apr 1999 EP
650354 Dec 1999 EP
979659 Feb 2005 EP
1327893 Jul 2006 EP
1212758 Nov 1970 GB
1983216222 Dec 1983 JP
2059346 Feb 1990 JP
2086643 Mar 1990 JP
19923701971 Dec 1992 JP
5173098 Jul 1993 JP
6312013 Nov 1994 JP
2000016905 Jan 2000 JP
2000-056277 Feb 2000 JP
2002025690 Jan 2002 JP
2002243190 Aug 2002 JP
2003311762 Nov 2003 JP
2004085655 Mar 2004 JP
567215 Dec 2003 TW
592738 Jun 2004 TW
WO 9309154 May 1993 WO
WO 9404028 Mar 1994 WO
WO 9409794 May 1994 WO
WO 9415648 Jul 1994 WO
WO 9416743 Aug 1994 WO
WO 9421698 Sep 1994 WO
WO 9520969 Aug 1995 WO
WO 9631792 Oct 1996 WO
WO 9749740 Dec 1997 WO
WO 9811875 Mar 1998 WO
WO 9830248 Jul 1998 WO
WO 0002937 Jan 2000 WO
WO 0019981 Apr 2000 WO
WO 0037048 Jun 2000 WO
WO 0037541 Jun 2000 WO
WO 0059970 Oct 2000 WO
WO 0109211 Feb 2001 WO
WO 0171392 Sep 2001 WO
WO 0182984 Nov 2001 WO
WO 02092143 Nov 2002 WO
WO 03022321 Mar 2003 WO
WO 03022322 Mar 2003 WO
WO 03057270 Jul 2003 WO
WO 2004010204 Jan 2004 WO
WO 2004028536 Apr 2004 WO
WO 2006012000 Feb 2006 WO
WO 2006088758 Aug 2006 WO
Non-Patent Literature Citations (31)
Entry
Annals of Sofia University named after Kliment Ohridski College of Chemistry, Development of a Medium for Improving the Tolerance of Contact Lenses, Their Maintenance and Storage, S.D. Chal'ovska et al., Department of Physical Chemistry, Pharmaceutical College, Medical Academy, Apr. 1, 1981.
Aquavela, Jackson, Guy, Therapeutic effects of bionite lenses: mechanisms of action Annals of Ophthalmology (12):1341-1345, 1971.
Barabas, E.S., Encyclopedia of Polymer Science and Engineering, “N-Vinyl Amide Polymers”; 1989, 198-257, vol. 17, John Wiley and Sons, New York.
Brewitt, H., et al, Contactologia, International Medical Contact Lens Journal, German Edition, vol. 16, No. 3, 3rd Quarter 1994 (III), pp. 87-142, Rewetting of Contact Lenses: Clinical Data on Efficacy and Necessity.
Comelli, Francesoni, Lanzi, Estimation of molecular weight distribution of PVP from diaphragm-cell Polymer Engineering & Science (Mar. 1980, vol. 20 No. 5).
Crivello, et al, XI Commercial Sources of Free Radical Photoinitiators, vol. III, Photoinitiators for Free Radical Cationic & Anionic Photopolymerisation, 1998, 275-298, 2nd Edition by edited by G. Bradley; John Wiley and Sons; New York.
Das, et al, Rapid sterilization of wide field contact lens used in vitreo-retinal surgery Investigative ophthalmology & visual science 40(4):s946, 1999.
Das, T; Sharma, S; Singh, J; Rao, V; Chalam, K V, Evaluation of glutaraldehyde and povidone iodine for sterilization of wide-field contact vitrectomy lenses Ophthalmic surgery and lasers 32(4):300-4, Jul. 2001.
De la Iglesia, Mitchell, Schwartz, Soft contact lens studies in rabbit eyes Toxicology and Applied Pharmacology 29(1):96-97, 1974.
Dexter RW, Interactions of anionic surfactants and polymers used as spray tank adjuvants ASTM special technical publication (1312):77-92, 1996.
Federov, Kedik, Liquid chromatographic study of the molecular mass and composition heterogeneity of random copolymers of n-vinylpyrrolidone and 2-methyl-5-vinylpyridine Polymer Science Series A 36(9):1291-1294, 1994.
Fleig, Rodriguez, The effect of column geometry on separation effectiveness of agarose for PVP Chemical Engineering Communications 13(4-6):219-229, 1982.
Hoefle, F B, Contact lens materials: past, present, and future Transactions—American Academy of Ophthalmology and Otolaryngology 78(3):OP386-90, May 1974.
Hornbrook, J; Waddy, P, Soft flexible contact lenses Medical journal of Australia 2(13):649-53, Sep. 29, 1973.
Jiang, Miller, Li, Hansen, Marcia, Characterization of water-soluble polymers by flow FFF-MALS American laboratory 32(3):, 2000.
Kuenzler, J.F., “Silicone Hydrogels for Contact Lens Application”, Trends in Polymer Science, Elsevier Science Publishers B.V., Amsterdam, NL, vol. 4, No. 2, Feb. 1, 1996.
Leonard-stibbe et al, Cationic polymerisation of n-vinyl-2-pyrrolidone initiated electrochemically by anodic polarisation on a platinum surface Journal of polymer science. Polymer chemistry edition 32(8):1551-5, 1994.
Manning AJ, Application of centrifugation to polymer fractionation Dissertation abstracts international. Section B, The Sciences and engineering 32(9):5164-5, 1972.
McCarey, B E; Andrews, D M, Refractive keratoplasty with intrastromal hydrogel lenticular implants Investigative ophthalmology & visual science 21(1 Part 1):107-15, Jul. 1981.
Pilyugina, SA, In vitro epithelialization of a synthetic polymer for generation of cornealonlay/keratoprosthesis Investigative ophthalmology & visual science 44():U321, May 2003.
Princz, M.A. et al., “Relesae of Wetting Agents from Nelfilcon Contact Lenses”, Investigative Ophthalmology & Visual Science, Association for Research in Vision, vol. 46, No. Suppl S, May 2005, p. 907FF.
Refojo, Miguel Fernandez, Contact Lenses and Pharmaceutical Solutions for Their Care, Storage and Disinfection, Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA, An. Real Acad, Farm., 1996, 62: 401-420.
Riedhammer, T M, Colorimetric determination of poly(N-vinyl-2-pyrrolidone) in contact lens solutions Journal of the Association of Official Analytical Chemists 62(1):52-5, Jan. 1979.
Riedhammer, T M; Falcetta, J J, Effects of long-term heat disinfection on Soflens (polymacon) contact lenses Optometry (Saint Louis, Mo.);;Optometry : journal of the American Optometric Association 51(3):287-9, Mar. 1980.
Rucker, Kettrey, BAch, Zeleznick, A safety test for contact lens wetting solutions Annals of Ophthalmology (11):1000-6, 1972.
Udupa, Tatwawadi, Gode, Studies on physicochemical properties of viscosity building agents used in contact lens solutions Indian journal of hospital pharmacy : official publication of the Indian Hospital Pharmacists' Association 13():184-9, 1976.
Ye, Quiang, et al, Formation of monodisperse polyacrylamide particles by radiation-induced dipsersion polymerization I Journal of Applied Polymer Science 86(10):2567, 2002.
Special 510 (k) Summary of Safety and Efficacy for VISTAKON®, dated Nov. 1, 2006.
PCT International Preliminary Report on Patentability dated Aug. 14, 2007, or PCT Int'l. Appln. No. PCT/US2006/04877.
PCT International Search Report, dated Feb. 9, 2007, for PCT Int'l. Appln. No. PCT/US2006/004877.
International Search Report for International Application No. PCT/US2011/032413 date of Mailing Jul. 15, 2011.
Related Publications (1)
Number Date Country
20130208236 A1 Aug 2013 US
Continuations (1)
Number Date Country
Parent 11351907 Feb 2006 US
Child 12896930 US
Continuation in Parts (1)
Number Date Country
Parent 12896930 Oct 2010 US
Child 13836133 US