WO1997036487A1 - Disinfectant solutions containing polyhexamethylene biguanides - Google Patents

Disinfectant solutions containing polyhexamethylene biguanides Download PDF

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Publication number
WO1997036487A1
WO1997036487A1 PCT/GB1997/000907 GB9700907W WO9736487A1 WO 1997036487 A1 WO1997036487 A1 WO 1997036487A1 GB 9700907 W GB9700907 W GB 9700907W WO 9736487 A1 WO9736487 A1 WO 9736487A1
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Prior art keywords
solution
solution according
compound
ppm
polyhexanide
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PCT/GB1997/000907
Other languages
French (fr)
Inventor
Chris De Bruijn
David Fakes
Original Assignee
Norton Healthcare Ltd.
Lapis Lazuli International N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Norton Healthcare Ltd., Lapis Lazuli International N.V. filed Critical Norton Healthcare Ltd.
Priority to GB9821090A priority Critical patent/GB2329126B/en
Priority to AU22993/97A priority patent/AU2299397A/en
Publication of WO1997036487A1 publication Critical patent/WO1997036487A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/14—Organic compounds not covered by groups A61L12/10 or A61L12/12
    • A61L12/141—Biguanides, e.g. chlorhexidine
    • A61L12/142—Polymeric biguanides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof

Definitions

  • This application relates to disinfectant solutions particularly, contact lens cleaning solutions designed to remove microorganisms from contact lenses.
  • the invention is specifically concerned with solutions containing Polyhexanide (Polyhexamethylene Biguanide) .
  • Polyhexanide is an antimicrobial agent and is particularly useful because of its properties in killing Acanthamoeba.
  • Acanthamoeba is a dangerous organism as it is pathogenic to man causing a rare but fatal encephalitis in the immuno compromised host and with a far greater frequency, a potentially blinding infection of the cornea (Keratitis) in previously healthy persons.
  • Acanthamoeba keratitis is most frequently found in contact lens wearers, accounting for approximately 90% of all reported cases.
  • Acanthamoeba is a genus of small free-living amoeba characterised by a feeding and replicating trophozoite and a dormant cyst stage. The resistance of the cyst form to extremes of temperature, desiccation and disinfection accounts for the almost ubiquitous distribution of Acanthamoeba in the environment.
  • contact lens disinfectants have proven efficacy against the resistant cyst form of Acanthamoeba to prevent keratitis in the eye.
  • Polyhexanide has been suggested previously as a suitable agent for disinfecting contact lenses against some bacteria strains.
  • GB 1432345 describes such solutions, using formulations of 5 - 500 ppm, and more specifically 5 - 25 ppm for soft contact lenses, and 10 - 100 ppm for hard contact lenses.
  • These formulations were reported in another patent EP 180309 to cause corneal staining due to their high biguanide levels and this patent claimed the use of a far lower level of biguanide 0.01 - 3 ppm.
  • a disinfecting solution containing at least one, compound, or a salt thereof, of the formula:-
  • R1 , R2 are an amino group or a group of formula:-
  • n 3 - 30, the compound or compounds being present at 3.0 to 5.0 ppm in total .
  • n ranges from 3 - 10 and most preferably 4 - 8.
  • a mixed molecular weight compound may be present in which the average value of n is in the ranges given.
  • the solution is an Acanthamoeba disinfecting solution.
  • the compound is polyhexanide ie polyhexamethylene biguanide.
  • the compound may be present at a concentration with a lower limit of 3.05, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.7, 3.8 or 3.9 ppm.
  • the upper concentration limit may be 4.95, 4.9, 4.8, 4.7, 4".6, 4.5, 4.3, 4.2 or 4.1 ppm.
  • the disinfecting solution contains one or more of surfactant, buffering agent, sequestering agent and sodium chloride.
  • surfactant e.g., sodium sulfate
  • buffering agent e.g., sodium sulfate
  • sequestering agent e.g., sodium sulfate
  • sodium chloride e.g., sodium sulfate
  • the surfactant is present at between 0.05 and 0.2 weight% and most preferably 0.1 weight% + or - 10%.
  • the surfactant may be a polysorbate, and in particular polysorbate 80.
  • the buffering agent may be based on borate or phosphate buffer systems.
  • a borate buffer is provided in which the ratio of boric acid to borax, or other borate salt, is in the range 6:1 to 4: 1.
  • the buffer may be present in the solution at between 0.5 and 3 weight%.
  • a preferred sequestering agent is an edetic acid salt, such as, disodium edetate. Potassium edetate salts are also envisaged.
  • the sequestering agent may be present at between 0.002 and 0.02 weight% and preferably 0.01 weight% .
  • the solution is isotonic or substantially isotonic, in particular with tear fluid.
  • Sodium chloride is a preferred compound for addition at suitable levels in the solution to render it isotonic.
  • the solution contains 3.5 - 4.5 ppm polyhexanide, 0.05 - 0.2% polysorbate, 0.5 - 3% borate or phosphate buffer, 0.002 - 0.10% potassium or sodium edetate and sufficient sodium chloride to make the solution isotonic, the solution being made up in water.
  • a compound or compounds according to the formula of the first aspect for disinfecting Acanthamoeba.
  • the use in a contact lens disinfecting solution for this purpose is particularly preferred.
  • Polyhexanide is preferred as the compound.
  • Concentrations according to the first aspect, and 3.5 to 4.5 ppm in particular are preferred.
  • a third aspect of the invention we provide the use of a compound or compounds according to the formula of the first aspect, for the manufacture of a contact lens disinfecting solutions for disinfecting against Acanthamoeba.
  • Polyhexanide is the preferred compound.
  • the concentration may be provided at any of the levels or ranges provided above. 3.5 to 4.5 ppm is a preferred range.
  • the manufacture of the disinfecting solution may provide any of the features discussed elsewhere in this application with regard to the polyhexanide or other constituents of the solution.
  • Trophozoites grown in the laboratory were adjusted to a concentration of 1 x 10Vml in 200ml of encyst ent medium and agitated for 5 days at the end of which time microscopic examination showed >90% mature cysts. They were removed by centrifugation, washed and stored at 4°C for up to 7 days.
  • the cyst suspension was enumerated using a Modified Fuch's Rosenthal cell counting chamber and adjusted to a concentration of 1 x lO ml in strength Ringer's solution. Two ml of the calibrated cyst suspension was centrifuged at 2000 x g for 15 minutes and the pellet resuspended in 200ml strength Ringer's solution. To 10ml of test solution, 100ml of the cyst suspension was added to give an initial inoculum size of approximately 1 x 10 ' ' cysts/ml. All assays were performed at 25°C. At time intervals of 0, 1, 2, 4, 6, 8 and 24 hours, Recovery Medium. After mixing thoroughly, the solution was left at room temperature for ten minutes.
  • the plates were allowed to dry at room temperature before being incubated at 32°C in sealed polythene bags. Under these incubation conditions, the E. Coli grows on the Plaque Forming Agar Medium to produce a confluent bacterial lawn. Viable Acan thamoeba excyst (hatch) in response to the live bacterium and the emergent trophozoite feed and replicate to produce zones of clearing, termed plaques, in the E. Col i lawn. Thus the number of discrete plaques in the lawn can be related to the number of viable cysts inoculated on to the medium. The plates were examined daily for up to ten days and the number of amoebal trophozoite plaques counted. The number of viable cysts at each sample point was then calculated with reference to the initial control count.
  • test solutions left in the Universal container after the final 24 hour time samples were cultured for any remaining viable cysts.
  • the solutions were transferred to conical bottomed tubes and centrifuged at 2000 x g for 10 minutes.
  • the pellets were resuspended in 5 ml of Recovery Medium and left for 10 minutes. After centrifugation and washing once with strength Ringer's solution the pellets were resuspended in 1 ml of £ strength Ringer's solution and cultured on a Plaque Forming Agar Medium plate with E. Col i as described above.
  • a new formulation (laboratory code C10657) has sufficient disinfectant properties without causing eye irritation to the user.
  • the new solution has a sufficient reduction in Acanthamoeba levels, bearing in mind that the lenses normally remain in this disinfecting solution overnight or at least for 6 hours according to the instructions .
  • the polysorbate is a surfactant
  • the Boric Acid and borax are buffering agents
  • the Disodium Edetate is a sequestering agent
  • the Sodium chloride is to produce isotonicity.
  • Cosmocil CQ 20% is a proprietary brand of polyhexanide supplied by Zeneca Biocides.
  • the ingredients are all of pharmaceutical quality.

Abstract

A disinfecting solution containing at least one compound, or a salt thereof, of formula (I), in which R1, R2 are an amino or a group of formula (II), and where Z represents an organic divalent bridging group which may be the same or different throughout the polymer and n is 3-30, the compound or compounds being present at 3 to 5 ppm in total.

Description

DISINFECTANT SOLUTIONS CONTAINING POLYHEXAMETHYLENE BIGUANIDES.
This application relates to disinfectant solutions particularly, contact lens cleaning solutions designed to remove microorganisms from contact lenses.
In particular the invention is specifically concerned with solutions containing Polyhexanide (Polyhexamethylene Biguanide) .
Polyhexanide is an antimicrobial agent and is particularly useful because of its properties in killing Acanthamoeba. Acanthamoeba is a dangerous organism as it is pathogenic to man causing a rare but fatal encephalitis in the immuno compromised host and with a far greater frequency, a potentially blinding infection of the cornea (Keratitis) in previously healthy persons. Acanthamoeba keratitis is most frequently found in contact lens wearers, accounting for approximately 90% of all reported cases. Acanthamoeba is a genus of small free-living amoeba characterised by a feeding and replicating trophozoite and a dormant cyst stage. The resistance of the cyst form to extremes of temperature, desiccation and disinfection accounts for the almost ubiquitous distribution of Acanthamoeba in the environment.
It is important therefore that contact lens disinfectants have proven efficacy against the resistant cyst form of Acanthamoeba to prevent keratitis in the eye.
Polyhexanide has been suggested previously as a suitable agent for disinfecting contact lenses against some bacteria strains. GB 1432345 describes such solutions, using formulations of 5 - 500 ppm, and more specifically 5 - 25 ppm for soft contact lenses, and 10 - 100 ppm for hard contact lenses. These formulations were reported in another patent EP 180309 to cause corneal staining due to their high biguanide levels and this patent claimed the use of a far lower level of biguanide 0.01 - 3 ppm.
Neither of these two patents address the problem with Acanthamoeba. Indeed whilst there are a number of products in the market place all of them face problems. We have found that those with levels of 5 ppm or over are satisfactory with regard to disinfection of Acanthamoeba but are unsatisfactory in use as they cause irritancy in the eye of the contact lens wearer. Alternatively the use of solutions with the lower levels while being acceptable to the wearer have been found to be insufficiently active against Acanthamoeba and may not prevent keratitis occurring. These comments on irritancy are bases on actual experience in the market place, not previous literature some of which incorrectly claims no irritancy in solutions with high Polyhexanide levels.
According to a first aspect of the invention we provide a disinfecting solution containing at least one, compound, or a salt thereof, of the formula:-
R1 - [ Z - NH - C NH ] n - R2
Figure imgf000004_0001
in which R1 , R2 are an amino group or a group of formula:-
Figure imgf000004_0002
and where Z represents an organic divalent bridging group which may be the same or different throughout the polymer and n is 3 - 30, the compound or compounds being present at 3.0 to 5.0 ppm in total .
Preferably n ranges from 3 - 10 and most preferably 4 - 8. A mixed molecular weight compound may be present in which the average value of n is in the ranges given. Pre'ferably the solution is an Acanthamoeba disinfecting solution.
Preferably the compound is polyhexanide ie polyhexamethylene biguanide.
The compound may be present at a concentration with a lower limit of 3.05, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.7, 3.8 or 3.9 ppm. The upper concentration limit may be 4.95, 4.9, 4.8, 4.7, 4".6, 4.5, 4.3, 4.2 or 4.1 ppm.
A concentration of 3.5 to 4.5 ppm is preferred. Preferably the disinfecting solution contains one or more of surfactant, buffering agent, sequestering agent and sodium chloride. One or more different compounds serving such functions may be provided.
Preferably the surfactant is present at between 0.05 and 0.2 weight% and most preferably 0.1 weight% + or - 10%. The surfactant may be a polysorbate, and in particular polysorbate 80.
The buffering agent may be based on borate or phosphate buffer systems. Preferably a borate buffer ,is provided in which the ratio of boric acid to borax, or other borate salt, is in the range 6:1 to 4: 1. The buffer may be present in the solution at between 0.5 and 3 weight%.
A preferred sequestering agent is an edetic acid salt, such as, disodium edetate. Potassium edetate salts are also envisaged. The sequestering agent may be present at between 0.002 and 0.02 weight% and preferably 0.01 weight% .
Preferably the solution is isotonic or substantially isotonic, in particular with tear fluid. Sodium chloride is a preferred compound for addition at suitable levels in the solution to render it isotonic.
In a particularly preferred embodiment the solution contains 3.5 - 4.5 ppm polyhexanide, 0.05 - 0.2% polysorbate, 0.5 - 3% borate or phosphate buffer, 0.002 - 0.10% potassium or sodium edetate and sufficient sodium chloride to make the solution isotonic, the solution being made up in water.
According to a second aspect of the invention we provide the use of a compound or compounds according to the formula of the first aspect, for disinfecting Acanthamoeba. The use in a contact lens disinfecting solution for this purpose is particularly preferred. Polyhexanide is preferred as the compound. Concentrations according to the first aspect, and 3.5 to 4.5 ppm in particular are preferred.
Compounds put to this use may include any of the other features provided above for the first aspect of the invention.
According to a third aspect of the invention we provide the use of a compound or compounds according to the formula of the first aspect, for the manufacture of a contact lens disinfecting solutions for disinfecting against Acanthamoeba.
Polyhexanide is the preferred compound. The concentration may be provided at any of the levels or ranges provided above. 3.5 to 4.5 ppm is a preferred range.
The manufacture of the disinfecting solution may provide any of the features discussed elsewhere in this application with regard to the polyhexanide or other constituents of the solution.
A study was carried out using two Acanthamoeba spp Ac/PHL/Ros and Ac/PHL/ eb isolated from Keratitis cases in 1995 as test organisms for the effectiveness of disinfecting solutions. These two strains show different mitochondrial DNA restriction fragment length polymorphisms and are therefore considered to be biologically distinct.
Trophozoites grown in the laboratory were adjusted to a concentration of 1 x 10Vml in 200ml of encyst ent medium and agitated for 5 days at the end of which time microscopic examination showed >90% mature cysts. They were removed by centrifugation, washed and stored at 4°C for up to 7 days.
All glassware etc was soaked in the disinfectant solutions and then washed to prevent loss due to absorption during the test.
To accurately assess the efficacy of disinfecting solution, it is necessary to stop the action of the antimicrobial agent at the time of sampling. Therefore, a standard recovery medium was employed in the assay procedure to inactivate the disinfectant at the various sampling times.
The cyst suspension was enumerated using a Modified Fuch's Rosenthal cell counting chamber and adjusted to a concentration of 1 x lO ml in strength Ringer's solution. Two ml of the calibrated cyst suspension was centrifuged at 2000 x g for 15 minutes and the pellet resuspended in 200ml strength Ringer's solution. To 10ml of test solution, 100ml of the cyst suspension was added to give an initial inoculum size of approximately 1 x 10'' cysts/ml. All assays were performed at 25°C. At time intervals of 0, 1, 2, 4, 6, 8 and 24 hours, Recovery Medium. After mixing thoroughly, the solution was left at room temperature for ten minutes. Serial ten-fold dilutions were then made in strength Ringer's solution and 10ml of live Escheri chia col i (strain JM101 ) suspension added to each dilution. A 1ml aliquot of each dilution was then inoculated onto the surface of three Plaque Forming Agar Medium plates. As a control, assays were also performed using strength Ringer's solution.
The plates were allowed to dry at room temperature before being incubated at 32°C in sealed polythene bags. Under these incubation conditions, the E. Coli grows on the Plaque Forming Agar Medium to produce a confluent bacterial lawn. Viable Acan thamoeba excyst (hatch) in response to the live bacterium and the emergent trophozoite feed and replicate to produce zones of clearing, termed plaques, in the E. Col i lawn. Thus the number of discrete plaques in the lawn can be related to the number of viable cysts inoculated on to the medium. The plates were examined daily for up to ten days and the number of amoebal trophozoite plaques counted. The number of viable cysts at each sample point was then calculated with reference to the initial control count.
The test solutions left in the Universal container after the final 24 hour time samples were cultured for any remaining viable cysts. The solutions were transferred to conical bottomed tubes and centrifuged at 2000 x g for 10 minutes. The pellets were resuspended in 5 ml of Recovery Medium and left for 10 minutes. After centrifugation and washing once with strength Ringer's solution the pellets were resuspended in 1 ml of £ strength Ringer's solution and cultured on a Plaque Forming Agar Medium plate with E. Col i as described above.
The efficacy of the solutions against the cysts of the two Acanthamoeba strains were plotted and the Decimal Reduction rates (D values) calculated. This is the time to reduce the viable cysts by 90% (ie 1 log unit).
Figure imgf000008_0001
After 24 hours viable Acanthamoeba could be cultured from product a) but not from b) or c).
It will be seen therefore that 1 ppm polyhexanide is insufficient to disinfect this organism. Whilst 5 ppm is satisfactory from a microbiological point of view it is unsatisfactory to the patients due to the incidence of eye irritation .
It has been surprisingly found that a new formulation (laboratory code C10657) has sufficient disinfectant properties without causing eye irritation to the user. The new solution has a sufficient reduction in Acanthamoeba levels, bearing in mind that the lenses normally remain in this disinfecting solution overnight or at least for 6 hours according to the instructions .
This formulation was:
Cos ocil CQ20% 0.020mg/ml
(equivalent to polyhexanide 4 ppm)
Polysorbate 80 1.00 mg/ml
Boric Acid 15.00mg/ml
Borax 3. OOmg/ml
Disodium Edetate 0.1 Omg/ l Sodium Chlor i de 1.13mg/ml Water for inj ect ions to 1.00ml
The polysorbate is a surfactant, the Boric Acid and borax are buffering agents, the Disodium Edetate is a sequestering agent, the Sodium chloride is to produce isotonicity.
Cosmocil CQ 20% is a proprietary brand of polyhexanide supplied by Zeneca Biocides.
The ingredients are all of pharmaceutical quality.

Claims

CLAIMS :
1. A disinfecting solution containing at least one compound, or a salt thereof, of the formula:-
R1 - [ Z - NH - C - NH - C - NH ] „ - R2
II II
NH NH
in which R1 , R2 are an amino group or a group of formula:-
Figure imgf000010_0001
and where Z represents an organic divalent bridging group which may be the same or different throughout the polymer and n is 3 - 30, the compound or compounds being present at 3 to 5 ppm in total .
2. A solution according to claim 1 in which the compound is polyhexanide together with normal pharmaceutical adjiuvants.
3. A solution according to claim 1 or claim 2 in which the solution is a contact lens disinfecting solution.
4. A solution according to any of claims 1 to 3 and containing one or more of a surfactant, buffering agent, sequestering agent and sodium chloride.
5. A solution according to any preceding claim which is isotonic.
6. A solution according to claim 4 or 5 where the buffering agents are based on Borate or Phosphate buffers.
7. A solution according to claim 6 containing a Borate buffer comprising a ratio of 6:1 to 4: 1 ratio of Boric Acid to Borax or other Borate salts to give a similar effect.
8. A solution according to any of claims 4 to 7 where the surfactant is a Polysorbate.
9. A solution according to claim 8 where the Polysorbate is Polysorbate 80.
10. A solution according to any of claims 4 to 9 where the sequestering agent s a salt of edetic acid.
11. A contact lens disinfecting solution according to any preceding claim containing 3.5 - 4.5 ppm Polyhexanide, 0.05 - 0.2% Polysorbate 0.5 - 3% Borate or Phosphate buffer, 0.002 - 0.020% Potassium or Sodium Edetate and sufficient Sodium Chloride to make the solution isotonic.
12. A contact lens disinfecting solution according to claim 11 containing 4 ppm Polyhexanide 0.1% Polysorbate 80, 1.5% Boric Acid, 0.3% Borax, 0.01% Disodium Edetate and 0.13% Sodium Chloride, all percentages by weight in water.
13. The use of a compound or compounds according to claim 1 , preferably polyhexanide, at a concentration of 3 to 5 ppm in total in a solution, for disinfecting against Acanthamoeba.
14. The use of claim 13 in which the solution is a contact lens disinfecting solution.
15. The use of a compound or compounds according to claim 1 , preferably polyhexanide, for the manufacture of a contact lens disinfecting solution containing 3 to 5 ppm of the compound or compounds in total, for disinfecting against Acanthamoeba.
PCT/GB1997/000907 1996-04-01 1997-04-01 Disinfectant solutions containing polyhexamethylene biguanides WO1997036487A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9821090A GB2329126B (en) 1996-04-01 1997-04-01 Disinfectant solutions
AU22993/97A AU2299397A (en) 1996-04-01 1997-04-01 Disinfectant solutions containing polyhexamethylene biguanides

Applications Claiming Priority (2)

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GB9606868.9 1996-04-01
GBGB9606868.9A GB9606868D0 (en) 1996-04-01 1996-04-01 Disinfectant solutions

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Cited By (6)

* Cited by examiner, † Cited by third party
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WO2000035862A1 (en) * 1998-12-18 2000-06-22 Alcon Laboratories, Inc. Amido polybiguanides and the use thereof as antimicrobial agents
US6316669B1 (en) 1998-12-18 2001-11-13 Alcon Manufacturing, Ltd. Bis-amido polybiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions
WO2004030710A1 (en) * 2002-09-30 2004-04-15 Bausch & Lomb Incorporated Compositions with enhanced antimicrobial efficacy against acanthamoebae
JP2004535420A (en) * 2001-06-05 2004-11-25 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Axial-substituted cyclohexane derivatives cross-linked by CF2O
EP1852133A2 (en) * 2002-09-30 2007-11-07 Bausch & Lomb Incorporated Compositions with enhanced antimicrobial efficacy against acanthamoebae
WO2013154209A1 (en) * 2012-04-12 2013-10-17 Santen Pharmaceutical Co., Ltd. Antiprotozoan composition containing caspofungin or its salt and biguanide compound or its salt

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RU2462267C1 (en) * 2011-10-12 2012-09-27 Владимир Николаевич Каргаев Disinfectant with detergent effect

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EP0575290A1 (en) * 1992-06-17 1993-12-22 Ciba-Geigy Ag Product for care of hard or soft contact lenses
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WO1994027440A1 (en) * 1993-05-26 1994-12-08 Fresenius Ag Anti-infective agents
EP0701821A1 (en) * 1994-09-19 1996-03-20 Tomey Technology Corporation Solution for contact lenses

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035862A1 (en) * 1998-12-18 2000-06-22 Alcon Laboratories, Inc. Amido polybiguanides and the use thereof as antimicrobial agents
US6316669B1 (en) 1998-12-18 2001-11-13 Alcon Manufacturing, Ltd. Bis-amido polybiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions
US6423748B1 (en) 1998-12-18 2002-07-23 Alcon Manufacturing, Ltd. Amido polybiguanides and the use thereof as antimicrobial agents
JP2004535420A (en) * 2001-06-05 2004-11-25 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Axial-substituted cyclohexane derivatives cross-linked by CF2O
WO2004030710A1 (en) * 2002-09-30 2004-04-15 Bausch & Lomb Incorporated Compositions with enhanced antimicrobial efficacy against acanthamoebae
JP2006501301A (en) * 2002-09-30 2006-01-12 ボシュ・アンド・ロム・インコーポレイテッド Compositions with enhanced antimicrobial efficacy against acanthamoebae
EP1852133A2 (en) * 2002-09-30 2007-11-07 Bausch & Lomb Incorporated Compositions with enhanced antimicrobial efficacy against acanthamoebae
EP1852133A3 (en) * 2002-09-30 2009-08-26 Bausch & Lomb Incorporated Compositions with enhanced antimicrobial efficacy against acanthamoebae
WO2013154209A1 (en) * 2012-04-12 2013-10-17 Santen Pharmaceutical Co., Ltd. Antiprotozoan composition containing caspofungin or its salt and biguanide compound or its salt

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GB2329126B (en) 2000-04-12
GB9821090D0 (en) 1998-11-18
AU2299397A (en) 1997-10-22
GB9606868D0 (en) 1996-06-05

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