Ophthalmic contact lens solutions containing forms of vitamin B

Information

  • Patent Grant
  • 10064410
  • Patent Number
    10,064,410
  • Date Filed
    Monday, January 23, 2017
    7 years ago
  • Date Issued
    Tuesday, September 4, 2018
    6 years ago
  • Inventors
  • Original Assignees
  • Examiners
    • Basquill; Sean M
    Agents
    • Mikesell; Peter J.
    • Blank, Esq.; Christopher E.
    • Schmeiser, Olsen & Watts, LLP
Abstract
The present invention relates to improved ophthalmic solutions that employ select B vitamins; pyridoxine and its salts; and thiamine and its salts in order to more effectively preserve solutions and to reduce the degree to which cationic preservatives will deposit on contact lenses. Ophthalmic solutions are here understood to include contact lens treatment solutions, such as cleaners, soaking solutions, conditioning solutions and lens storage solutions, as well as wetting solutions and in-eye solutions for treatment of eye conditions.
Description
BACKGROUND OF THE INVENTION

The present invention relates to the field of ophthalmic solutions and their uses. In particular the invention relates to contact lens cleaning solutions, contact lens rinsing and storing solutions, solution to deliver active pharmaceutical agents to the eye, solutions for disinfecting ophthalmic devices and the like.


The present invention relates to the field of ophthalmic solutions and especially to the aspects of preservative efficacy and comfort after prolonged use. These ophthalmic solutions have been used for some period of time and are available as over the counter products. Solutions that are used in direct contact with corneal tissue such as the delivery of active pharmaceutical agent to the eye, or indirectly, such as the cleaning, conditioning or storage of devices that will come in contact with corneal tissue, such as contact lenses, there is a need to insure that these solution do not introduce sources of bacterial or other microbial infection. Thus preservatives are included to reduce the viability of microbes in the solution and to lessen the chance of contamination of the solution by the user since many of the solutions are bought, opened, used, sealed and then reused.


State of the art preservative agents include polyhexamethylene biguanide (PHMB), POLYQUAD™, chlorhexidine, and benzalkonium chloride, and the like, all of which at some concentration irritate corneal tissue and lead to user discomfort. Therefore, a solution that employs a given amount of a preservative agent, but which is made more effective by addition of an agent that is not a preservative agent would be desired.


BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to improved ophthalmic solutions that employ select B vitamins; pyridoxine and its salts; and thiamine and its salts in order to more effectively preserve solutions and to reduce the degree to which cationic preservatives will deposit on contact lenses. Ophthalmic solutions are here understood to include contact lens treatment solutions, such as cleaners, soaking solutions, conditioning solutions and lens storage solutions, as well as wetting solutions and in-eye solutions for treatment of eye conditions.







DETAILED DESCRIPTION OF THE INVENTION

The solutions specifically described herein have 0.001 to about 10.0 weight percent of select B vitamins; pyridoxine and its salts; and thiamine and its salts in combination with other active ingredients useful in ophthalmic solutions such as tonicity agent, buffers, preservatives, surfactants, and antimicrobial agents.


The B family of vitamins includes thiamine (B1), riboflavin (B2), niacin (B3), dexpanthenol, panthenol, pantothenic acid (B5), pyridoxine (B6), and cobalamin (B12). While each form of B vitamin is chemically distinct, they are often found in the same nutritional sources and hence deficiency in one is often related to deficiency in the other forms. Metabolically, they work with one another to bolster metabolism, enhance immune and nervous system function, maintain healthy skin and muscle tone, and promote cell growth and division. They may also relieve stress, depression, and cardiovascular disease. A deficiency in one B vitamin often means that intake of all B vitamins is low which is why B vitamins as a nutritional source are often provided in multivitamin or B-complex formulae.


Niacin contributes to a great number of bodily processes. Among other things niacin helps convert food into energy, build red blood cells, synthesize hormones, fatty-acids and steroids. The body uses niacin in the process of releasing energy from carbohydrates. Niacin is also needed to form fat from carbohydrates and to process alcohol. Niacin also helps regulate cholesterol.


Pyridoxine is needed to make serotonin, melatonin, and dopamine. Vitamin B-6 is an essential nutrient in the regulation of mental processes and possibly assists in mood and many other health concerns Cobalamin is needed for normal nerve cell activity. Vitamin B-12 is also needed for DNA replication, and production of the mood-affecting substance called SAMe (S-adenosyl-L-methionine). Vitamin B-12 works with folic acid to control homocysteine levels. An excess of homocysteine, which is an amino acid (protein building block), may increase the risk of heart disease, stroke, and perhaps osteoporosis and Alzheimer's disease.


Other compounds such as folic acid or folate are active in combination with the B vitamins and are needed to synthesize DNA. DNA allows cells to replicate normally. Folic acid is especially important for the cells of a fetus when a woman is pregnant. Folic Acid is also needed to make SAMe and keep homocysteine levels in the blood from rising. Folic Acid (pteroylglutamic acid) is not active as such in the mammalian organism, but rather is enzymatically reduced to tetrahydrofolic acid (THFA), the coenzyme form. An interrelationship exists with vitamin B12 and folate metabolism that further involves vitamin B6: folate coenzymes participate in a large number of metabolic reactions in which there is a transfer of a one-carbon unit.


Pantothenic Acid, also sometimes referred to as coenzyme A, is the physiologically active form of pantothenic acid, and serves a vital role in metabolism as a coenzyme for a variety of enzyme-catablyzed reactions involving transfer of acetyl (two-carbon) groups. Surprisingly, pantothenic acid is essential for the growth of various microorganisms, including many strains of pathogenic bacteria.


In the form of contact lens rinsing solutions and/or pharmaceutical agent delivery system the solutions will contain, in addition to the lens or the pharmaceutical agent 0.00001 to about 10.0 weight percent of one of the vitamin B forms or a vitamin B co-metabolite chosen from the group including, but not limited to, thiamine (B1), riboflavin (B2), niacin (B3), dexpanthenol, panthenol, pantothenic acid (B5), pyridoxine (B6), and cobalamin (B12); and at least 0.00001 weight percent of a preservative.


The preservatives that are specifically useful are cationic preservatives such as polyhexamethylene biguanide (phmb), POLYQUADTM, chlorhexidne, and benzalkonium chloride, as well as other cationic preservatives that may prove useful in the present invention as well. The cationic preservatives are used at effective amounts as preservatives, and in the instance of PHMB from 0.0001 percent by weight to higher levels of about 0.01 weight percent.


The formulations may also include buffers such as phosphates, bicarbonate, citrate, borate, ACES, BES, BICINE, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS, PIPES, TAPS, TES, TRIS and Tricine.


Surfactants that might be employed include polysorbate surfactants, polyoxyethylene surfactants, phosphonates, saponins and polyethoxylated castor oils, but preferably the polyethoxylated castor oils. These surfactants are commercially available. The polyethoxylated castor oils are sold by BASF under the trademark Cremophor.


The solutions of the present invention may contain other additives including but not limited to buffers, tonicity agents, demulcents, wetting agents, preservatives, sequestering agents (chelating agents), surface active agents, and enzymes. In one embodiment between about 0.01% and 5.0% of a simple saccharide is present. Examples of simple saccharides include mannitol; sorbitol; sucrose; dextrose and glycerin.


Other aspects include adding to the solution from 0.001 to 1 weight percent chelating agent (preferably disodium EDTA) and/or additional microbicide, (preferably 0.00001 to 0.1) weight percent polyhexamethylene biquanide (PHMB), N-alkyl-2-pyrrolidone, chlorhexidine, polyquaternium-1, hexetidine, bronopol, alexidine, low concentrations of hydrogen peroxide, and ophthalmologically acceptable salts thereof.


Ophthalmologically acceptable chelating agents useful in the present invention include amino carboxylic acid compounds or water-soluble salts thereof, including ethylenediaminetetraacetic acid, nitrilotriacetic acid, diethylenetriamine pentaacetic acid, hydroxyethylethylenediaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, ethylene glycol bis (beta-aminoethyl ether) in N,N,N′,N′tetraacetic acid (EGTA), iminodiacetic acid and hydroxyethylamino diacetic acid. These acids can be used in the form of their water soluble salts, particularly their alkali metal salts. Especially preferred chelating agents are the di-, tri- and tetra-sodium salts of ethylenediaminetetraacetic acid (EDTA), most preferably disodium EDTA (Disodium Edetate).


Other chelating agents such as citrates and polyphosphates can also be used in the present invention. The citrates which can be used in the present invention include citric acid and its mono-, di-, and tri-alkaline metal salts. The polyphosphates which can be used include pyrophosphates, triphosphates, tetraphosphates, trimetaphosphates, tetrametaphosphates, as well as more highly condensed phosphates in the form of the neutral or acidic alkali metal salts such as the sodium and potassium salts as well as the ammonium salt.


The pH of the solutions should be adjusted to be compatible with the eye and the contact lens, such as between 6.0 to 8.0, preferably between 6.8 to 7.8 or between 7.0 to 7.6. Significant deviations from neutral (pH 7.3) will cause changes in the physical parameters (i.e. diameter) in some contact lenses. Low pH (pH less than 5.5) can cause burning and stinging of the eyes, while very low or very high pH (less than 3.0 or greater than 10) can cause ocular damage.


The additional preservatives employed in the present invention are known, such as polyhexamethylene biguanide, N-alkyl-2-pyrrolidone, chlorhexidine, polyhexamethylenebiguanide, alexidine, polyquaternium-1, hexetidine, bronopol and a very low concentration of hydrogen peroxide, e.g., 30 to 200 ppm.


The solutions of the invention are compatible with both rigid gas permeable and hydrophilic contact lenses during storage, cleaning, wetting, soaking, rinsing and disinfection.


A typical aqueous solution of the present invention may contain additional ingredients which would not affect the basic and novel characteristics of the active ingredients described earlier, such as tonicity agents, surfactants and viscosity inducing agents, which may aid in either the lens cleaning or in providing lubrication to the eye. Suitable tonicity agents include sodium chloride, potassium chloride, glycerol or mixtures thereof the tonicity of the solution is typically adjusted to approximately 240-310 milliosmoles per kilogram solution (mOsm/kg) to render the solution compatible with ocular tissue and with hydrophilic contact lenses. In one embodiment, the solution contains 0.01 to 0.2 weight percent sodium chloride. The important factor is to keep the concentrations of such additives to a degree no greater than that would supply a chloride concentration of no greater than about 0.2 mole percent.


Suitable viscosity inducing agents can include lecithin or the cellulose derivatives such as hydroxyethylcellulose, hydroxypropylmethylcellulose and methylcellulose in amounts similar to those for surfactants, above.


EXAMPLE 1

Formulations containing Pyridoxine HCl (Spectrum) and Thiamine HCl (Fisher) were prepared in a 0.2% phosphate buffer. The solutions were made isotonic with sodium chloride and preserved with polyhexamethylene biguanide at 0.0001%. The pH was adjusted to 7.2 with either 1 N sodium hydroxide or 1 N hydrochloric acid. The in vitro microbicidal activity of the solutions was determined by exposing C. albicans to 10 ml of each solution at room temperature for 4 hours. Subsequently, an aliquot of each solution was serial diluted onto agar plates and incubated for 48 hours at elevated temperatures. At the conclusion of the incubation period the plates are examined for the development of colonies. The log reduction was determined based on a comparison to the inoculum control. The following table provides the results of the in vitro studies.
















Additive
4 Hour Log Reduction









Pyridoxine HCl (0.5%)
2.0



Thiamine HCl (0.5%)
1.0



Buffer Control
0.8










The solution containing pyridoxine HC1 and thiamine HCl showed an improvement in the activity against C. albicans as compared to the buffer control.


EXAMPLE 2

Formulations containing dexpanthenol were prepared in a 0.25% Bis-Tris Propane buffer. The solutions were made isotonic with sodium chloride and preserved with polyhexamethylene biquanide at 0.00005%. The pH was adjusted to 7.2 with either 1 N sodium hydroxide or 1 N hydrochloric acid. The in vitro microbicidal activity of the solutions was determined by exposing C. albicans to 10 ml of each solution at room temperature for 4 hours. Subsequently, an aliquot of each solution was serial diluted onto agar plates and incubated for 48 hours at elevated temperatures. At the conclusion of the incubation period the plates are examined for the development of colonies. The log reduction was determined based on a comparison to the inoculum control. The following table provides the results of the in vitro studies.




















Log






Reduction






Calibicans


Buffer
Additive
Preservative
Dexpanthenol
4 hour







Bis-Tris
Cremophor 0.20%
PHMB 0.5
None
3.8


Propane
Inositol 3.0%
ppm




0.25%
Allantoin 0.1%





Bis-Tris
Cremophor 0.20%
PHMB 0.5
Dexpanthenol
4.9


Propane
Inositol 3.0%
ppm
0.1%



0.25%
Allantoin 0.1%









This data shows that the dexpanthenol has improved preservative efficacy over a solution with a preservative alone.


EXAMPLE 3

Formulations containing Dexpanthanol (Spectrum), Pyridoxine HCl (Spectrum) Thiamine HCl (Spectrum), and no Vitamin B control were prepared in a 0.5% Tris buffer containing 0.6% sodium chloride. The pH was adjusted with 1 N HC1 to a final pH of 7.2. Polyhexamethylene biquanide (PHMB) at 0.0001% was added to each formulation. The in vitro anti-microbial activity of the solutions was determined by exposing E. coli to 10 ml of each solution at room temperature for 1 hours. Subsequently, an aliquot of each solution was serial diluted onto agar plates and incubated for 48 hours at elevated temperatures. At the conclusion of the incubation period the plates are examined for the development of colonies. The log reduction was determined based on a comparison to the inoculum control. The following table provides the results of the in vitro studies.













Solution
Log Reduction at 1 hr


















0.5% Dexpanthenol
0.5% Tris
1 ppm PHMB
4.82


0.5% Pyridoxine
0.5% Tris
1 ppm PHMB
4.34


HCl





0.5% Thiamine HCl
0.5% Tris
1 ppm PHMB
5.12


None
0.5% Tris
1 ppm PHMB
0.42









The results showed an enhancement of the preservative in the presence of the Dexpanthanol, Pyridoxine, and Thiamine.


EXAMPLE 4

Formulations containing Dexpanthanol (Spectrum), Pyridoxine HCl (Spectrum) Thiamine HCl (Spectrum), and no Vitamin B control were prepared in a 0.5% Tris buffer containing 0.6% sodium chloride. The pH was adjusted with 1 N HCl to a final pH of 7.2. Benzalkonium Chloride (BAK) at 0.0025% was added to each formulation. The in vitro anti-microbial activity of the solutions was determined by exposing E. coli to 10 ml of each solution at room temperature for 1 hour. Subsequently, an aliquot of each solution was serial diluted onto agar plates and incubated for 48 hours at elevated temperatures. At the conclusion of the incubation period the plates are examined for the development of colonies. The log reduction was determined based on a comparison to the inoculum control. The following table provides the results of the in vitro studies.













Solution
Log Reduction at 1 hr


















0.5% Dexpanthenol
0.5% Tris
25 PPM BAK
>5.12


0.5% Pyridoxine
0.5% Tris
25 PPM BAK
>5.12


HCl





0.5% Thiamine HCl
0.5% Tris
25 PPM BAK
3.30


None
0.5% Tris
1 ppm PHMB
0.42









The results showed an enhancement of the preservative in the presence of the Dexpanthanol and Pyridoxine.

Claims
  • 1. A contact lens solution comprising: at least 0.00001 weight percent of a cationic preservative selected from the group consisting of polyhexamethylene biguanide and polyquaternium-1;between 0.00001 and 10 weight percent of dexpanthenol that functions as a preservative enhancer;a physiologically compatible buffer selected from the group consisting of phosphate, bicarbonate, citrate, borate, ACES, BES, BICINE, BIS, BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS, PIPES, TRIS, TAPS, TES, an amino acid, and Tricine;wherein the contact lens solution has a low chloride concentration of less than 0.1 mole percent chloride, and the combination of the cationic preservative, the dexpanthenol, and the low chloride concentration provide an enhanced preservative effect relative to a corresponding contact lens solution having a chloride concentration of more than 0.2 mole percent.
  • 2. The contact lens solution of claim 1, wherein the cationic preservative is present in a concentration between 0.1 parts per million and 10,000 parts per million.
  • 3. The contact lens solution of claim 1, wherein the physiologically compatible buffer is BIS-Tris Propane.
  • 4. The contact lens solution of claim 1 further comprising a wetting agent.
  • 5. The contact lens solution of claim 4, wherein the wetting agent is selected from the group consisting of a polysorbate surfactant, a polyoxyethylene surfactant, a phosphonate, a saponin, a polyethyoxylated glyceride, and a polyethoxylated castor oil.
  • 6. The contact lens solution of claim 1 further comprising a polyethoxylated castor oil.
  • 7. The contact lens solution of claim 1, further comprising between 0.01% and 5.0% of at least one simple saccharide.
  • 8. The contact lens solution of claim 7, wherein the simple saccharide is selected from the group consisting of mannitol; sorbitol; sucrose; dextrose, glycerin and combinations thereof.
  • 9. The contact lens solution of claim 1, further comprising between 0. 001% and 1% of a chelating agent.
  • 10. The contact lens solution of claim 9, wherein the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid or a salt thereof, citric acid or a salt thereof, an amino carboxylic acid or a salt thereof, nitrilotriacetic acid or a salt thereof, diethylene triamine pentaacetic acid or a salt thereof, hydroxyethylethylenediaminetriacetic acid or a salt thereof, 1,2-diaminocyclohexanetetraacetic acid or a salt thereof, ethylene glycol bis (beta-aminoethyl ether) —N, N, N′, N′ tetraacetic acid (EGTA) or a salt thereof, iminodiacetic acid or a salt thereof, hydroxyethylamino diacetic acid or a salt thereof and a polyphosphate salt.
  • 11. The contact lens solution of claim 1, further comprising between 0.001% and 1% of ethylenediaminetetraacetic acid or a salt thereof.
  • 12. The contact lens solution of claim 1, further comprising between 0.00001% and 0.1% of a microbicide.
  • 13. The contact lens solution of claim 12, wherein the microbicide is selected from the group consisting of N-alkyl-2-pyrrolidone, chlorhexidine, polyquaternium-1, hexetidine, bronopol, alexidine, hydrogen peroxide, and salts thereof.
  • 14. The contact lens solution of claim 1, wherein the contact lens solution has a pH between 7.0 and 7.6.
  • 15. The contact lens solution of claim 1, further comprising a tonicity agent.
  • 16. The contact lens solution of claim 15, wherein the tonicity agent is selected from the group consisting of sodium chloride, potassium chloride, glycerol and mixtures thereof.
  • 17. The contact lens solution of claim 15, wherein the tonicity agent adjusts a tonicity of the contact lens solution to 240-310 milliosmoles per kilogram solution (mOsm/kg).
  • 18. A contact lens solution comprising: at least 0.00001 weight percent of a polyhexamethylene biguanide;between 0.1 parts per million and 10,000 parts per million of dexpanthenol that functions as a preservative enhancer;a physiologically compatible buffer selected from the group consisting of phosphate, bicarbonate, citrate, borate, ACES, BES, BICINE, BIS, BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS, PIPES, TRIS, TAPS, TES, an amino acid, and Tricine;wherein the contact lens solution has a low chloride concentration of less than 0.1 mole percent chloride, and the combination of the polyhexamethylene biguanide, the dexpanthenol, and the low chloride concentration provide an enhanced preservative effect relative to a corresponding contact lens solution having a chloride concentration of more than 0.2 mole percent.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and is a continuation of, U.S. patent application Ser. No. 15/055,749 (filed Feb. 29, 2016) which is a continuation of Ser. No. 13/679,605 (filed Nov. 16, 2012) which is a continuation-in-part of U.S. patent application Ser. No. 11/620,318 (filed Jan. 5, 2007) which is a continuation-in-part of U.S. patent application Ser. No. 10/544,150 (filed Aug. 1, 2005), which is a national stage entry of PCT/US01/46841 (filed Nov. 8, 2001) which claims the benefit of U.S. Provisional Patent Applications 60/246,689 (filed Nov. 8, 2000) 60/246,707 (filed Nov. 8, 2000) 60/246,708 (filed Nov. 8, 2000) and 60/246,709 (filed Nov. 8, 2000). The contents of the aforementioned applications are hereby incorporated by reference.

US Referenced Citations (118)
Number Name Date Kind
1432345 Lasker Oct 1922 A
2445366 Rigby Jul 1948 A
2976576 Wichterle Mar 1961 A
3044937 Krezanoski Jul 1962 A
3428576 Dickinson Feb 1969 A
3429576 Ikeda Feb 1969 A
3503393 Manley Mar 1970 A
3591329 Chromecek Jul 1971 A
3689673 Phares Sep 1972 A
3755561 Rankin Aug 1973 A
3873696 Randerl Mar 1975 A
3876768 Blank Apr 1975 A
3888782 Boghosian Jun 1975 A
3910296 Karageozian Oct 1975 A
3911107 Krezanoski Oct 1975 A
3912450 Boucher Oct 1975 A
3943251 Medow Mar 1976 A
4022834 Gundersen May 1977 A
4029817 Blanco Jun 1977 A
4046706 Krezanoski Sep 1977 A
4136173 Pramoda Jan 1979 A
4136175 Rideout Jan 1979 A
4136534 Villa Jan 1979 A
4209817 McGinnis Jun 1980 A
4354952 Riedhammer Oct 1982 A
4361458 Grajek Nov 1982 A
4361548 Smith Nov 1982 A
4361549 Kung Nov 1982 A
4394381 Sherrill Jul 1983 A
4409205 Shively Oct 1983 A
4439417 Matsunaga Mar 1984 A
4525346 Stark Jun 1985 A
4537746 Ogunbiyi Aug 1985 A
4599360 Fukami Jul 1986 A
RE32672 Huth May 1988 E
4748189 Su May 1988 A
4758595 Ogunbiyi Jul 1988 A
4783488 Ogunbiyi Nov 1988 A
4804454 Asakura Feb 1989 A
4820352 Riedhammer Apr 1989 A
4826879 Yamamoto et al. May 1989 A
4836986 Ogunbiyi Jun 1989 A
4863900 Pollock Sep 1989 A
4891423 Stockel Jan 1990 A
4988710 Olney Jan 1991 A
4997626 Dziabo Mar 1991 A
5030721 Kasai Jul 1991 A
5078908 Ripley Jan 1992 A
5089261 Nitecki Feb 1992 A
5122354 Tsuji Jun 1992 A
5174872 Scott Dec 1992 A
5175161 Yokoyama Dec 1992 A
5182258 Chiou Jan 1993 A
5192535 Davis Mar 1993 A
5279673 Dziabo Jan 1994 A
5300296 Holly Apr 1994 A
5306440 Ripley Apr 1994 A
5361287 Williamson Nov 1994 A
5380303 Holly Jan 1995 A
5439572 Pankow Aug 1995 A
5449658 Unhoch Sep 1995 A
5460808 Mausner Oct 1995 A
5494937 Asgharian Feb 1996 A
5547990 Hall Aug 1996 A
5591426 Dabrowski Jan 1997 A
5591773 Grunberger Jan 1997 A
5607681 Galley Mar 1997 A
5624958 Isaacs Apr 1997 A
5661130 Meezan Aug 1997 A
5674450 Lin Oct 1997 A
5691379 Ulrich Nov 1997 A
5718895 Asgharian Feb 1998 A
5719110 Cook Feb 1998 A
5741817 Chowhan Apr 1998 A
5770582 von Borstel Jun 1998 A
5780450 Shade Jul 1998 A
5807585 Martin Sep 1998 A
5811446 Thomas Sep 1998 A
5817277 Mowrey McKee Oct 1998 A
5854303 Powell Dec 1998 A
5869468 Freeman Feb 1999 A
5888950 Potinl Mar 1999 A
5891733 Inoue Apr 1999 A
5925317 Rogalskyj Jul 1999 A
5925320 Jones Jul 1999 A
5925371 Ishiwatari Jul 1999 A
5942218 Kirschner Aug 1999 A
5945446 Laub Aug 1999 A
5965736 Akhavan Tafti Oct 1999 A
5968904 Julian Oct 1999 A
6001805 Jaynes Dec 1999 A
6008195 Selsted Dec 1999 A
6022732 Bakhit Feb 2000 A
6024954 Park Feb 2000 A
6056920 Lepre May 2000 A
6117869 Picard Sep 2000 A
6121327 Tsuzuki Sep 2000 A
6126706 Matsumoto Oct 2000 A
6139646 Asgharian Oct 2000 A
6143244 Xia Nov 2000 A
6153568 McCanna Nov 2000 A
6162393 De Bruiju Dec 2000 A
6191110 Jaynes Feb 2001 B1
6309596 Xia Oct 2001 B1
6309658 Xia Oct 2001 B1
6432983 Cullinan Aug 2002 B1
6456563 Kajimoto Sep 2002 B1
6550862 Kain Apr 2003 B2
6617291 Smith Sep 2003 B1
6624203 Smith Sep 2003 B1
9308264 Smith Apr 2016 B2
9585394 Smith Mar 2017 B2
20020155961 Schwind Oct 2002 A1
20030190258 Smith Oct 2003 A1
20050042198 Smith Feb 2005 A1
20060142169 Smith Jun 2006 A1
20060148665 Smith Jul 2006 A1
20070104744 Smith May 2007 A1
Foreign Referenced Citations (41)
Number Date Country
734732 Oct 1996 EP
812592 Dec 1997 EP
0923950 Jun 1999 EP
1323426 Jul 2003 EP
1398058 Jun 1975 GB
1431841 Apr 1976 GB
58010517 Jan 1983 JP
05-017355 Jan 1993 JP
05017355 Jan 1993 JP
8104636 Apr 1996 JP
10108899 Apr 1998 JP
11199899 Jul 1999 JP
2000016965 Jan 2000 JP
2001302518 Oct 2001 JP
2002104971 Apr 2002 JP
2006089403 Apr 2006 JP
2006206565 Aug 2006 JP
2008152584 Jul 2008 JP
1803110 Jul 1990 RU
2127100 Mar 1999 RU
WO1991001763 Feb 1991 WO
WO1992004905 Apr 1992 WO
WO1992011876 Jul 1992 WO
WO1992021049 Nov 1992 WO
WO1993004706 Mar 1993 WO
WO1994000160 Jan 1994 WO
WO1995000176 Jan 1995 WO
WO1996006603 Mar 1996 WO
WO1997034834 Sep 1997 WO
WO1997041215 Nov 1997 WO
WO1999023887 May 1999 WO
WO1999037295 Jul 1999 WO
WO2000007634 Feb 2000 WO
WO2000011514 Mar 2000 WO
WO2002038161 May 2002 WO
WO2002060495 Jun 2002 WO
WO2002055118 Jul 2002 WO
WO2002062260 Aug 2002 WO
WO2004024855 Mar 2004 WO
WO2004054629 Jul 2004 WO
WO2008077110 Jun 2008 WO
Non-Patent Literature Citations (17)
Entry
Ballweber et al.; “In Vitro Microbicical Activities . . . ” Antimicrobial Agetns and Chemotherapy, Jan. 2002; pp. 34-41; vol. 46, No. 1.
Creighton, Thomas; “Proteins Structures and Molecular Properties”, W.H. Freeman & col, NY, 1994, pp. 179-182.
De Luccca “Fungicidal Properties, Sterol Binding . . . ” Can. J. of Micrbiology, Jun. 1998, pp. 514-520, vol. 44, No. 6.
Goebbels, Martin; “Efficacy of Dexpanthenol-containing artificial tears . . . ”; Klinische Monatsblaetter Fuer, Augenheilkunde, vol. 29, No. 2-3, 1996, pp. 84-88.
Keay, L. et al.; “Differentiation of Alkaline Proteases” Biochemical and Biophysical Research Comm. 1969, pp. 600-604, vol. 34, No. 5.
Keay, L. et al.; “Proteases of the Genus Bacillus II” Biotechnology & Bioengineering, Mar. 1970; pp. 213-249.
Moore, John A et al. “An assessment of Boric Acid and Borax . . . ”; Reproductive Toxicol, 123, 128 (1997).
Schutte, L. et al. “The Substitution Reaction of Histidine and Some Other Imidazole Derivatives with Iodone” Tetrahedron, Supp. No. 7, 1965, pp. 295-306.
Search report dated Aug. 2, 2002 in PCT/US01/46841.
Search report dated Jun. 29, 2009 in PCT/US2008/050375.
Search report dated Oct. 17, 2008 for EP08014693.
Search report dated Dec. 6, 2005 for EP01999161.
Translation of RU2121825, Nov. 20, 1998.
Yanovskaya et al, “Effect of Low-Dose Emoxypine . . . ” Bulletin of Experimental Biology and Medicine, vol. 115, No. 5, pp. 517-520, 1993.
Derwent; Pyrotonik ocular drops; XP002329199; 1999.
European Search Report in EP12007769.8 dated Jan. 30, 2013.
Martin Gobbels & Dorthea Gross; Klinische Studie zur Wirksamkeit eines dexpanthenolhaltigen Tranenersatzmittels (Siccaprotect) bei der Behandlung Trockener Augen (1996).
Related Publications (1)
Number Date Country
20170127679 A1 May 2017 US
Provisional Applications (4)
Number Date Country
60246689 Nov 2000 US
60246707 Nov 2000 US
60246708 Nov 2000 US
60246709 Nov 2000 US
Continuations (2)
Number Date Country
Parent 15055749 Feb 2016 US
Child 15412496 US
Parent 13679605 Nov 2012 US
Child 15055749 US
Continuation in Parts (2)
Number Date Country
Parent 11620318 Jan 2007 US
Child 13679605 US
Parent 10544150 US
Child 11620318 US