CN1285866A - Disinfecting contact lenses with bis (biguanides) and polymeric biguanides - Google Patents
Disinfecting contact lenses with bis (biguanides) and polymeric biguanides Download PDFInfo
- Publication number
- CN1285866A CN1285866A CN98811015A CN98811015A CN1285866A CN 1285866 A CN1285866 A CN 1285866A CN 98811015 A CN98811015 A CN 98811015A CN 98811015 A CN98811015 A CN 98811015A CN 1285866 A CN1285866 A CN 1285866A
- Authority
- CN
- China
- Prior art keywords
- solution
- biguanides
- eyeglass
- contact lenses
- group
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 229940123208 Biguanide Drugs 0.000 title claims abstract description 75
- 150000004283 biguanides Chemical class 0.000 title claims description 48
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- 238000000034 method Methods 0.000 claims abstract description 32
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- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 238000004659 sterilization and disinfection Methods 0.000 claims description 50
- -1 alkoxyalkyl ether Chemical compound 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 25
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- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
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- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
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- 230000000474 nursing effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000001194 polyoxyethylene (40) stearate Substances 0.000 description 1
- 235000011185 polyoxyethylene (40) stearate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
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- 229940068968 polysorbate 80 Drugs 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
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- 235000019633 pungent taste Nutrition 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229940098362 serratia marcescens Drugs 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- 229940033663 thimerosal Drugs 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 235000015870 tripotassium citrate Nutrition 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
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- 230000003442 weekly effect Effects 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/66—Non-ionic compounds
- C11D1/722—Ethers of polyoxyalkylene glycols having mixed oxyalkylene groups; Polyalkoxylated fatty alcohols or polyalkoxylated alkylaryl alcohols with mixed oxyalkylele groups
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/0005—Other compounding ingredients characterised by their effect
- C11D3/0078—Compositions for cleaning contact lenses, spectacles or lenses
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/26—Organic compounds containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/26—Organic compounds containing nitrogen
- C11D3/32—Amides; Substituted amides
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/37—Polymers
- C11D3/3703—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
- C11D3/3719—Polyamides or polyimides
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/37—Polymers
- C11D3/3746—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
- C11D3/3769—(Co)polymerised monomers containing nitrogen, e.g. carbonamides, nitriles or amines
- C11D3/3773—(Co)polymerised monomers containing nitrogen, e.g. carbonamides, nitriles or amines in liquid compositions
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/008—Polymeric surface-active agents
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D2111/00—Cleaning compositions characterised by the objects to be cleaned; Cleaning compositions characterised by non-standard cleaning or washing processes
- C11D2111/40—Specific cleaning or washing processes
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Wood Science & Technology (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Detergent Compositions (AREA)
- Eyeglasses (AREA)
Abstract
The present invention is directed to an ophthalmically safe disinfecting solution for contact lenses comprising a biguanide polymer in combination with a bis(biguanide), and a method of using the composition, in the form of an aqueous solution, for disinfecting and/or preserving contact lenses, especially soft contact lenses. The invention can be used to formulate products having greater convenience and/or benefits compared to traditional disinfecting products for contact lenses and can provide a broader, more potent and faster antimicrobial activity overall.
Description
Invention field
The present invention relates to the novel and improved solution of treatment of contact lenses and with the method for this solution-treated contact lenses.Especially, the present invention relates to comprise two kinds of sterilizing agents, i.e. the disinfecting system of the novel combination of two (biguanides) and polymeric biguanide.
Background of invention
Usually, widely used contact lenses is included into three classes: (1) rigid (hard) eyeglass, by the resulting material of acrylic ester polymerization, such as polymethylmethacrylate (PMMA) formation, (2) firm ventilative property (rigid gas permeable, RGP) eyeglass, formed by siloxanes acrylate and fluorosilicone methacrylic ester, and (3) gel, hydrogel or soft class eyeglass, by polymeric wetting ability or hydrophobic monomer, made as methacrylic acid 2-hydroxyethyl ester (HEMA).Rigidity acrylic type contact lenses is characterised in that the effect of low water vapor diffusion constant, fast light, oxygen and hydrolysis, and only absorbs a small amount of waterborne liquid.Because the weather resistance of contact lens,hard sheet, it has the tendency that does not absorb suitable water gaging in addition, and is just not crucial comparatively speaking to the selection of suitable sterilizing agent, sanitising agent or other lens care compounds.
Yet, being different from rigid eyeglass, soft class contact lenses has combination and concentrates sterilant in quite a large amount of fluid, the pollutent in the environment, the impurity in the water and the lens care solution and the tendency of other activeconstituentss.Under many circumstances, when use was proper, the composition of low levels in the lens care solution did not cause the stimulation to ocular tissue.Yet, especially since the proteinosis thing itself to the keying action of soft lens material, some sterilizing agents and sanitas tend in the lens surface accumulation, and may be concentrated to the harmful level of potential, to such an extent as to when being released, may causing the cornea inflammation and other ocular tissues are produced stimulation.
Found that some antibacterial agents and contact lenses are more compatible, and shown and lessly combine with lens surface.In one case, found chlorhexidine (chlorhexidine), a kind of biguanides is littler 7 times than benzalkonium chloride (benzalkoniumchloride) with combining of soft lens material.Yet, if on eyeglass, there is proteic oil-containing tear film settling, with the adsorptive capacity that makes chlorhexidine on eyeglass 2 times for the cleaning eyeglass.United States Patent (USP) 4,354,952 disclose very rare sterilization and the cleaning soln that contains chlorhexidine or its salt, wherein also have a certain amount of both sexes or nonionic surface active agent.Find that these solution have reduced the binding capacity of chlorhexidine on the hydrophilic soft contact lens sheet.Although obtained the reduction of binding capacity by this invention,, use chlorhexidine to cause such compromise proposal really.When using these amphotericses, the fungicidal activity of chlorhexidine may be lowered.And, according to reports, if do not use with suitable ratio, unless also use nonionic surface active agent, tensio-active agent and sterilizing agent can precipitate.
English Patent 1,432,345 disclose the contact lenses sterilization composition that contains polymeric biguanide and a kind of mixed phosphate salt buffer agent.Yet,, have 17% or higher cornea value of staining (comeal staining value), far above the receptible amount of patient as composition by this patent disclosure.
The United States Patent (USP) 4,758,595 of authorizing people such as Ogunbiyi discloses a kind of contact lenses solution, when making up with borate buffer, have the enhanced effect, contain polyaminopropyl biguanide (PAPB) in the described solution, also be known as poly hexamethylene biguanide (PHMB).When being used for soft class contact lenses, itself and hypotoxicity are connected, it is especially noticeable that these sterilizations and listerine kill for bacterium and the Fungicidally active at the wide spectrum under the lower concentration for it.
The United States Patent (USP) 5,453,435 of authorizing people such as Raheja discloses a kind of protective system, and this system comprises the combination of chlorhexidine and poly hexamethylene biguanide.Find that this protective system that is used for the commercially available prod of firm gas permeable lenses shows the combination of improved efficient and low eye irritation.
Contain PHMB and boratory composition oneself in various products by commercialization, but when being used for SCL, its amount is about 1ppm or lower.Usually, but require to provide the alap content of kill bacteria, keep required disinfection efficacy level simultaneously, think that security and comfortableness provide a wide surplus.
Some modal products that eyeglass is carried out disinfection are multi-usage solution, can be used to contact lenses clean, sterilization and moistening, directly insert (placing intraocular) then and needn't wash.Obviously, can use the single solution that is used for contact lens care to have superiority.Yet this solution must be gentle to eyes especially, because as foregoing, when eyeglass is inserted eyes, some in this solution will keep on the eyeglass, and and eye contact.
Adopt conventional contact lenses sanitising agent or sterilizing agent, comprise multi-usage solution, in the treatment of contact lenses process, the eyeglass wearer need or manually crumple contact lenses (typically between finger and the palm or between finger) with finger usually.The necessity of daily " rubbing " contact lenses has prolonged the time of daily nursing contact lenses and has increased the effort of for this reason having done.Many contact lenses wearers are reluctant by this rules operation, think that perhaps such work is too inconvenient.Some wearers may neglect suitable " rubbing " rules, and this will cause the uncomfortable or other problems of contact lenses.Sometimes, if crumple to such an extent that too exert oneself, the person has this tendency especially just to wear the eyeglass, may damage eyeglass.When the replacing of eyeglass can not obtain at once, this can become problem.
The contact lenses solution of qualified becoming " chemical disinfection solution (Chemical Disinfecting Solution) " does not need to crumple the standard (being used to kill representational bacterium and fungi) that satisfies the Biocidal performance, and this standard is before sales announcement (510k) policy paper of being formulated for the contact lens care product on May 1st, 1997 by U.S. food and drug administration (FDA).On the contrary, contact lenses solution is referred to as " chemical disinfection system (ChemicalDisinfecting System) ", still disqualification becomes chemical disinfection solution, still needs to crumple rules and comes by Biocidal performance standard.Traditionally, multi-usage solution (being used for sterilization and moistening or be used for sterilization, cleaning and moistening) is qualified to become the chemical disinfection system, but disqualification becomes chemical disinfection solution.
Chemical disinfection solution general requirement has more effective or stronger sterilizing agent than chemical disinfection system.Yet this stronger killing bacteria usefulness of solution more likely demonstrates toxicity or eyeglass wearer's comfortableness is had negative impact.For example, be used for otherwise many very effective killing bacteria agent, as mouth-washes, makeup or shampoo etc., though being used in these products is safe enough, but it is too big to using toxicity on the ophthalmology, during in particular for soft lens, this is because above-mentioned soft lens has in conjunction with the proneness of chemical substance and to the pungency of ocular tissue.Similarly, be used for the solution of SCL, the concentration of these killing bacteria agent may be in other products in the lower bound of the concentration range of the solution of eyeglass that use or that be used for other types, especially do not go Shi Gengying like this from the eccysis of contact lenses upper punch this solution before contact lenses is inserted eyes.
Therefore, require to obtain a kind of contact lenses solution, the level of the bio-killing activity that (1) improve and/or wideer biocidal spectrum are provided simultaneously, and (2) are to the low magnitude toxicity of ocular tissue, make after this solution is used to treatment of contact lenses, eyeglass can be placed in intraocular, and the solution on needn't the flush away eyeglass.And still challenging, be also to require to obtain a kind of chemical disinfection solution, this solution is used for SCL, and allows directly to be placed intraocular after with this solution soaking and/or flushing and rewetting profit.This product will provide the effect of lifting, cause the eyeglass wearer is more protected, and to resist the infection that microorganism causes, simultaneously, provide maximum convenience.At last, require the biocidal effect of this sterilized solution enough high, with for contact lenses with regard to bacterium and fungi, in any case, when the wearer of contact lenses this contact lenses solution of no use comprises the rules of mechanicalness rubbing etc., finally can both obtain effective sterilization or be not the invalid sterilization of inherent at least.
Summary of the invention
The present invention relates to be used for the sterilized solution of safety on the ophthalmology of contact lenses, it comprises two (biguanides) of the dihydrochloride form of (a) about 0.10 to about 4.0 ppm, or identical two (biguanides) or the different water-soluble salts of the free alkali form of corresponding concentration, this two (biguanides) has following general formula:
Or the form of its water-soluble salt, wherein, R
1And R
2Be independently selected from the group of forming by ramose or unbranched alkyl, alkoxyalkyl or alkyl sulfur compounds group, and n is 4 to 16; And (b) about 0.1 polymeric biguanide to about 3.0 ppm, have following general formula
Wherein, Z is organic divalent abutment, can be identical or different in whole polymkeric substance, and the mean value of n is at least 3, and X
1And X
2Be independently selected from-NH
2With
Group;
(c) effective amount of buffer; And
(d) its amount is at least about the water of 80wt%.
Preferably, composition of the present invention also comprises one or more tensio-active agents.In one embodiment of the invention, this tensio-active agent is neutral or nonionic surface active agent.
The invention still further relates to and a kind of contact lenses is carried out disinfection or the method for cleaning and disinfection, comprise eyeglass is immersed in one given period in the above-mentioned aqueous solution, then directly will this treated eyeglass place wear have in mind in.In an embodiment of this method, do not need contact lenses to be crumpled the disinfection of reaching necessity with this solution.
Brief description of drawings
Fig. 1 is the histogram of Biocidal effect, shows after 15 minutes, contains two kinds of sterilizing agents, promptly the theory of the Biocidal effect of the independent solution of the Biocidal effect of the solution of the combination of two (biguanides) and ide polymers and each sterilizing agent and comparison.With respect to theoretical and the combination effect of increase be the measuring of synergy of this combination.Especially, Fig. 1 shown for Candida albicans (C.albicans) microorganism after being exposed to wherein 15 minutes, descends with the actual logarithm of Win-21904 and the PHMB theoretical logarithm of comparing that descends.
Fig. 2 is the histogram of Biocidal effect, shows after 30 minutes, contain the Biocidal effect of solution of combination of two (biguanides) and ide polymers and each sterilizing agent independent solution the Biocidal effect theory and comparison.Especially Fig. 2 has shown for Candida albicans (C.albicans) microorganism after being exposed to wherein 30 minutes, descends with the actual logarithm of Win-21904 and the PHMB theoretical logarithm of comparing that descends
The detailed description of invention
As described above, the present invention relates to the composition of the ide polymers and two (biguanides) that is used in combination comprising of a kind of aqueous solution form, and use said composition to be used for the method for sterilizing and/or preserving haptic lens, especially SCL. Its synergy provides maximum convenience when the effect of raising is provided, therefore, compare to the conventional sterile products that is used for haptic lens, better protection is provided, and has been unlikely the infringement that is subject to microorganism. Based on the representational bacterium and the fungi that are usually used in testing, wide spectrum, more effective and whole bactericidal activity faster in the scope of whole microorganism, are provided more by solution of the present invention. Especially, antiseptic solution of the present invention is effective for the broad-spectrum micro-organisms that includes but not limited to staphylococcus aureus (Staphylococcus aureus), green copper pseudomonad (pseudomonas aeruginosa), serratia marcescens (Serratia marcescens), Candida albicans (Candida albicans) and fusarium solani (Fusarium solani) when low concentration.
Antiseptic solution is generally defined as and (for example contains one or more active components, bactericide and/or anticorrisive agent) the contact lens care product, described active component has enough concentration to kill at the lip-deep harmful microorganism of haptic lens in the shortest soak time of being advised. The shortest soak time of advising is what to be included in for the package insert of this antiseptic solution. Term " antiseptic solution " is not got rid of this solution and is used as preserving the possibility that solution (preserving solution) uses yet, perhaps this antiseptic solution also can be used for other purposes, such as daily cleaning, wash and deposit the possibility of haptic lens, and decide on concrete prescription. Solution of the present invention, and its container or bottle and packing comprise that the specification that uses according to particular protocol combines, and can be considered to new and improved kit for contact lens care, packing or system.
Term " soft lens " refers to have a certain proportion of hydrophilic repeating unit, thereby so that in use the water content of eyeglass be at least the eyeglass of 20wt%. Term " SCL " generally refers to be easy to those crooked haptic lenses under less active force as used herein. Typically, SCL be by have special ratios derived from the prescription manufacturing of the polymer of the crosslinked repetitive of hydroxyethyl methacrylate and/or other hydrophilic monomers, typical and a kind of crosslinking agent. But newer soft lens is made by height-Dk silicone-containing material.
For haptic lens solution, term " on the ophthalmology safely " refers to the haptic lens with this solution-treated, need not wash, generally be safe for directly placing intraocular, that is, this solution for daily via being safe by the haptic lens of this solution wetted and with contacting of eyes and being comfortable. The solution of safety has the tension force compatible with eyes (tonicity) and pH on the ophthalmology, and comprises some materials, and the amount of these materials is atoxic according to the regulation of iso standard and U.S. FDA (Food and Drug Administration).
Can be used for to SCL clean, chemical disinfection, the solution depositing and wash be referred to as " multipurpose solution " at this. Multipurpose solution is not got rid of a kind of like this possibility, be some wearers, for example, those may would rather use another kind of solution to chemosterilant or the responsive especially wearer of other chemical reagent before haptic lens is inserted eyes, for example, sterile saline solution, flushing or moistening haptic lens. Term " multipurpose solution " do not get rid of yet be not based on every day the periodicity cleaning agent in other words conj.or perhaps typically based on the use of weekly refill of detergent with except deproteinize, such as the enzyme cleaning agent. Term " cleaning " refers to that solution contains one or more cleaning agents, described cleaning agent has enough concentration to unclamp or to remove eyeglass deposit and lip-deep other pollutants of haptic lens of loose maintenance, especially ought be in conjunction with usefulness finger manipulation (as crumpling by hand eyeglass with solution) or in conjunction with auxiliary equipment, stir the solution that contacts with eyeglass, use during such as a kind of mechanical cleaning auxiliary equipment. The critical micelle concentration that contains surfactant solution is to estimate a kind of mode of its cleaning efficiency.
Term " effective multipurpose solution " is meant the solution that can be used for daily chemical disinfection, deposits and wash contact lenses approx, this solution does not require the cleaning contact lenses, but this solution has still been got rid of the needs that are used for other solution of daily cleaning to any, promptly, do not need all other solution and solution of the present invention are joined together every day or combine use yet.Can get loose or stop the sedimental tensio-active agent of eyeglass or other reagent to a certain extent though these solution also comprise itself, these solution needn't clean contact lenses.Therefore, effective multipurpose solution only is used for the eyeglass of limited duration of service, as promptly abandoning type or often replacement type eyeglass.
Routinely, the multi-usage solution on the market need comprise the rules of contact lenses and the rubbing of multi-usage solution machinery, so that required sterilization to be provided.This rules are that governability office (as FDA or U.S. food and drug administration) is desired to the chemical disinfection system that disqualification becomes chemical disinfection solution.An advantage of the invention is and to make a kind of product, on the one hand, enough gentle as sterilizing agent and wetting agent use the time, on the other hand, can satisfy the Biocidal performance standard (on May 1st, 1997) of the chemical disinfection solution that is used for the contact lens care product of U.S. FDA formulation, this standard does not comprise the rules (even this rubbing can provide the removal of microorganisms effect of further raising) of eyeglass rubbing.In other words, optionally prepare by composition of the present invention and satisfy FDA or be used for the requirement of the ISO stand-alone program (ISO Stand-Alone Procedure) of contact lenses sterilized product.Therefore, might make this preparation allow more traditional sterilization of patient or sterilization and cleaning product have more to defer to and make it is accepted more widely.
Notice that the combination of ide polymers and two (biguanides) provides the enhanced effect, do not stimulate eyes again or eyes are done not feel like oneself simultaneously that this is important forever, and is that tool is challenging in the contact lens care field.Therefore, reach the effect identical in the hope of raising and can produce serious further stimulation eyes with this combination by the consumption of ide polymers own.Especially, have been found that and reach by the amount itself that improves ide polymers that necessary disinfection will produce unacceptable irritation to eyes for chemical disinfection solution.Even when using solution of the present invention, recommended the rubbing rules; the enhanced bio-killing activity can cause better protection and protect from infection, if especially insufficient by the rubbing that the wearer carried out of contact lenses or because ignored or despised product description and all the more so when not crumpling.
According to the present invention, two (biguanides) sterilant that is used for solution of the present invention comprises compound with following general formula and their water-soluble salt:
Wherein, R
1And R
2Be independently selected from (promptly identical or different) by branch or unbranched alkyl with individual, preferred 6-10 the carbon of 4-12, alkoxyalkyl (as ether) or alkyl sulfur compounds (as thioether or dialkyl sulfide) with individual, preferred 6-10 the carbon atom of 4-12 perhaps have the cycloalkyl of individual, preferred 7-10 the carbon atom of 5-12 or the group that cycloalkyl-alkyl is formed; And n is 4 to 16, preferred 6 to 10.Term in cycloalkyl or the cycloalkyl-alkyl " cycloalkyl " is meant cycloalkyl unsubstituted or that replace, its substituting group be one or more 1-6 of having carbon atom alkyl, alkoxyl group (OR) or alkylthio (SR) base.
In sterilized solution of the present invention, based on the whole aqueous solution, the total amount of the biguanides of logical formula I is 0.1-4.0 ppm suitably, is preferably 1.0-3.0 ppm.More preferably, the consumption of these two (biguanides) is 1.5-2.5 ppm, most preferably is about 2.0 ppm.The concentration of these two (biguanides) is directly related with its germ-killing efficiency in the solution.Term " ppm " refers to " 1,000,000/", and 1.0 ppm are corresponding to 0.0001wt%.It, is meant the gross weight of this aqueous antiseptic solution here based on the gross weight of composition.
In this application, that refer to preparation by the amount of two in the solution of the present invention (biguanides) or other components and join amount in this solution when the preparation solution.Exceed the time limit (as, surpass 18 preservation perives) time, the amount of analysis of two (biguanides) descends some in the solution.
Preferably, this two (biguanides) compound is the compound with above-mentioned logical formula I, wherein, and R
1And R
2Be independently selected from the group of forming by ramose or unbranched alkyl, alkoxyalkyl (being ether) or alkyl sulfur compounds (thioether) group, and n is 5-7.
R in the above-mentioned logical formula I
1And R
2Can be, for example, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, neo-pentyl, octyl group, 2-ethylhexyl, dodecyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopentyl-methyl or cyclohexyl methyl.2-ethylhexyl (Win-21904), 1 preferably, 5-dimethyl hexyl, 1-methyl hexyl, 1,3-dimethyl amyl group, 1,4-dimethyl amyl group, cyclohexyl methyl, 2-norcamphyl (norbomyl), propoxy-octyl group and propoxy-butyl.
The hydrochlorate that adds of the present invention can be derived by inorganic or organic acid and obtained.Under modal situation, preferably these salt are by soluble in water and provide the acid that is suitable for the human negatively charged ion (for example acceptable negatively charged ion on the pharmacology) that uses to derive to obtain.These sour examples are spirit of salt, Hydrogen bromide, phosphoric acid, sulfuric acid, acetate, D-glyconic acid, 2-pyrrolidyl (pyrrolidino)-5-carboxylic acid, methylsulfonic acid, carbonic acid, lactic acid and L-glutamic acid.The hydrogen chlorate is preferred.
Two (biguanides) of logical formula I have hydrophobic relatively end group.Preferably, the log P of this compound is 5-10,6-8 more preferably, and wherein, P is the partition ratio of free alkali, uses following formula, and wherein, C is two (biguanides) volumetric molar concentration in each phase, and α is the ionization degree of two (biguanides):
In order to obtain the partition ratio of two (biguanides), this compound is distributed in after slowly shaking under the room temperature (26 ℃) with the saturated 0.05M phosphate buffer (pH11) of octanol with phosphoric acid buffer agent between the saturated octanol.Select this biphase volume ratio and sample size, make after distribution, make blank with 1-cm sample pool and buffered soln, buffer layer sample absorbancy is between 0.2-0.9.By under Stationary pH, operating known or calculating pKa, the available above-mentioned formula calculating of P value.Referring to, Warner, V. and Lynch, D., at J.Med.Chem, 1979, VoL.22, No.4, " biguanides, Carbamidates and two biguanides are as the quantitative structure-activity relation (QuantitativeStructure-Activity Relationships for Biguanides; Carbamidates, andBisbiguanides as Inhibitors of Streptococcus mutans No.6715) of the inhibitor of staphylococcus mutant No.6715 " in 359,365 pages; With Albert and Serjeant, E. " determining ionization and stability constant (Determination ofIonization and Stability Constants) ", Bulter and Tanner company limited, London, 1962, two pieces of documents all are incorporated herein by reference at this.
Especially preferred two (biguanides) of the present invention compound is 2-(decyl sulphomethyl)-pentane-1,5-two (5-sec.-propyl biguanides), 2-(decyl sulfo--methyl) pentane-1,5-two (5,5-diethyl biguanides), and hexane-1,6-(2-ethylhexyl biguanides), the latter also is known as Win-21904 (alexidine) or 1,1 '-hexa-methylene two (5-(2-ethylhexyl)-biguanides) dihydrochloride.Other preferred two (biguanides) comprise 1,1 '-hexa-methylene two (5-heptyl-biguanides) dihydrochloride, 1,1 '-hexa-methylene two (5-octyl group-biguanides) dihydrochloride and 1,1 '-hexa-methylene two (5-hexyl-biguanides) dihydrochloride.
The biguanide compound of logical formula I can be by two cyanoguanidines of following general formula
With a kind of amine R that adds the hydrochlorate form
1NH
2, perhaps two kinds of different amine R
1NH
2And R
2NH
2Prepared in reaction under 100-170 ℃ temperature, wherein, R
1And R
2Have meaning same as described above, A is the alkylidene group with required carbonatoms.Preferred amine salt is a hydrochloride.Most diamines can be buied from various commercial sources.
Reactant is heated together until reacting completely.Temperature of reaction is high more, and reaction is carried out soon more, if but thermostability can go wrong, reaction should be carried out the long time under lower temperature.When not having solvent, most convenient, be that reactant is fused together, but if desired, can use inert solvent, or use the mixture of these solvents as DMSO, 2-methyl cellosolve, cellosolvo, oil of mirbane, tetramethylene sulfone (sulpholane), Virahol, propyl carbinol, glycol dimethyl ether or water.
Two cyanoguanidines of logical formula VI can be by known parent material preparation, as the hexa-methylene dintrile, its for example is reduced into corresponding diamine (VIII) with hydrogen and Raney nickel or with borine in dimethyl thioether, and, this adds the diamines of hydrochlorate form, is dihydrochloride easily, with dicyanamide sodium or other suitable reactant salts, form required parent material (VI), by as follows.
Wherein, M is a sodium, potassium, zinc or other suitable salt.Sodium salt can obtain from commercial channels.
Compound of the present invention can also be by will adding down the hydrochlorate form at 100-170 ℃ general formula (VIII) diamines with as shown in the formula the cyanoguanidine reaction
Perhaps with the cyanoguanidine of general formula (IX) and as shown in the formula cyanoguanidine react and prepare:
Wherein, R
1And R
2Has meaning as hereinbefore.
The salt of suitable diamines is, for example, and dihydrochloride.Reactant is heated together until reacting completely.Temperature is high more, and reaction is carried out soon more, if but the problematic words of thermostability, reaction should be carried out the long time under lower temperature.If can form molten mass under such temperature, reactant can be fused together in the presence of the solvent easily not having.If can not, perhaps alternatively, with reactant heating together in suitable inert solvent, these solvents those for once mentioning above for example.The hydrochlorate that adds of the present invention can be by method acquisition easily.
Can be by will be in suitable inert solvent as the cyanoguanidine of the general formula (IX) of the starting raw material of aforesaid method and (X), dicyanamide sodium and add the suitable amine R of hydrochlorate (being dihydrochloride easily) form
1NH
2Or R
2NH
2Reaction obtains.
For example, two (biguanides) that are known as Win-21904 can obtain by following reaction sequence.
Compound (XI) is that (MW 189 for the hexamethylene-diamine dihydrochloride, compound (XII) is a dicyanamide sodium, compound X III is HMBDA, hexa-methylene two (cyanoguanidine base), compound (X IV) are 2-ethyl-hexylamine hydrochloride (MW 165.7), and compound (X V) is the Win-21904 dihydrochloride, have another name called [1,6-two-(2-ethylhexyl biguanides base] the hexane dihydrochloride, also be called hexane-1,6-two (2-ethylhexyl biguanides) dihydrochloride.The molecular weight of this compound (MW) is 581.7 g/mol, empirical formula C
26H
56N
10-2HCl.Compound (X V) can obtain from various commercial sources, comprises Sigma Chemical Co. (St.Louis, Missouri).
The method of synthetic The compounds of this invention also has been disclosed in the open No.0125 092 of european patent application (open day 14.11.84); Rose, F.L. and Swain, G., " two biguanides (Bisdiguanide Having Antibacterial Activity) ", J.Chem.Soc.p.4422-4425 (1956) with antibacterial activity; And Warner, Victor D. and Lynch, Donald, " biguanides, Carbamimidates and bisdiguanide are as the quantitative structure-activity relation (Quanfitafive Structure-Activity Relationships ofBisguanide, Carbamimidates, and Bidiguanides as Inhibitors ofStreptococcus Mutans No.6715) of staphylococcus mutant No.6715 inhibitor ", J.Med.Chem., Vol.22, No.6 is p.359-366 in (1979).
Two (biguanides) (formula I) of the present invention can be used in combination with one or more polymeric biguanide and its water-soluble salts with following general formula:
Wherein, Z is organic divalent abutment, can be identical or different in whole polymkeric substance, and the mean value of n is at least 3, and is preferred 5 to 20, and X
1And X
2Be independently selected from-NH
2With
Group.
The group of a preferred water-soluble polymeric biguanides will have at least 1,000 molecular-weight average, more preferably 1,000 to 50,000 molecular-weight average.The suitable water-soluble salt of these free alkalis includes, but are not limited to hydrochloride, borate, acetate, gluconate, sulfonate, tartrate and Citrate trianion.
Above disclosed biguanides and preparation method openly in the literature.For example, United States Patent (USP) 3,428,576 have described the method for preparing polymeric biguanide from two amine salt of diamines and its salt and dicyan imide (dicyanimide).
The polymeric biguanide that is used in combination with two (biguanides) is effective when its concentration is low to moderate 0.00001 wt% (0.1ppm) in the present invention.Find also, be used in combination that the bacterial activity of killing of solution is strengthened, or its activity profile is expanded by compound with this polymeric biguanide and above-mentioned logical formula I.In the present invention, total the significant quantity of polymeric biguanide (no matter be the form of concrete salt or whether used free alkali) can be low to moderate about 0.000010 wt% (0.10 ppm), and up to about 0.00030 wt% (3.0ppm), and no matter be the water-soluble salt or the form of free alkali.Preferably, with the polymeric biguanide total amount of the total amount of above-mentioned logical formula I compound combination be about 0.3 to 2.0 ppm, be more preferably 0.4 to 1.0, most preferably from about 0.5 to 0.8 ppm.
Polymeric hexamethylene biguan-ide most preferably, form that can its hydrochloride from Zeneca (Delaware State Wilmington) with Cosmocil
TMThe trade mark of CQ is buied.Such polymkeric substance and water-soluble salt are referred to as poly hexamethylene biguanide (PHMB) or polyaminopropyl biguanide (PAPB).Term PHMB or PAPB are meant and comprise one or more biguanides as used herein, have following general formula:
Wherein, X
1And X
2As defined above, n is 1 to 500.
Based on the mode of preparation biguanides, the main compound that drops in the above-mentioned general formula has different X
1And X
2Group, perhaps identical group also has more a spot of other compounds in this general formula.These compounds are known, and at United States Patent (USP) 4,758,595 and English Patent 1,432,345 in described, at this, these patents are incorporated herein by reference.Preferably, water-soluble salt is that the mean value of n is 2 to 15,3 to 12 compound most preferably.
Sterilizing agent/sterilant the component that can use selectivity to add in the present invention is used for further strengthening, replenishes or expands fungicidal spectrum of the present invention.This comprises and the non-setting sterilant compatible with this solution of sterilization significant quantity, based on concrete sterilizing agent, its concentration range about 0.000001 to about 0.5wt%, as those skilled in the art are to understand.Suitable additional sterilant includes, but not limited to Thiomersalate (thimerosal), Sorbic Acid, the alkyl trolamine, phenyl mercuric salt, quaternary ammonium compound and season Natvosol (polyquatemium) multipolymer and its mixture.Suitable salt is at room temperature water-soluble, and reaches the degree of 0.5wt% at least.These salt comprise gluconate, isethionate, (2-isethionate), formate, acetate, glutaminate, succinate, single di-alcohol hydrochlorate (monodiglycollate), mesylate, lactic acid salt, isobutyrate and gluceptate.The representative example of quaternary ammonium compound is the composition that contains the equilibrium mixture of positive alkyl dimethyl benzyl ammonium chloride.Be used for ophthalmic applications season HEC polymer an example comprise Polyquatemium 1_ (chemical registration number 75345-27-6), can buy from Onyx company.
Solution of the present invention optionally contains at least a tensio-active agent.Suitable tensio-active agent can be amphoteric, cationic, anionic or non-ionic type, its amount (independent or combination) can up to composition or solution 15%, preferably up to 5% (w/v).Preferred surfactants is both sexes or nonionic surface active agent, and during use, it can give composition with cleaning and conditioning functions.Tensio-active agent should be dissolved in the lens care solution, and ocular tissue is not stimulated.Many nonionic surface active agent comprise one or more having olefin oxide (O-R-) chain of repeating unit or polymerization component, wherein R has 2-6 carbon atom.Preferred nonionic surfactants comprises the block polymer of the olefin oxide repeating unit of two or more different sortses, and wherein the ratio of different repeat units has determined the HLB of this tensio-active agent.Gratifying nonionic surface active agent comprises the macrogol ester of lipid acid such as coconut acid (coconut), polysorbate, higher alkane (C
12-C
18) polyoxyethylene or polyoxytrimethylene ether.Preferred example comprises Polysorbate 20 (trade(brand)name with Tween_20 obtains), polyoxyethylene (23) lauryl ether (Brij_35), polyoxyethylene (40) stearate (Myrj_52), polyoxyethylene (25) propylene glycol stearate (Atlas_G 2612).Have about 7 by the nonionic surface active agent that poly-(propylene oxide)-poly-(ethylene oxide) addition quadrol is formed particularly, 500 to about 27,000 molecular weight, wherein the described affixture of 40wt% is poly-(ethylene oxide) at least, when having found that this tensio-active agent uses with about 0.01 to about 15wt%, can be particularly advantageous for cleaning and nurse one's health soft and the contact lens,hard sheet.CTFA Cosmetic Ingredient Dictionary (CTFA used for cosmetic composition dictionary) is poloxamine to the title that such tensio-active agent adopts.This type of tensio-active agent can obtain with " Tetronic " registered trademark from the BASFWyandotte Corp. of Michigan State Wyandotte.Be applicable to that the similar series tensio-active agent among the present invention is a poloxamer series, it is can be with poly-(ethylene oxide) that " Pluronic " trade mark obtains poly-(propylene oxide) block polymer (can buy from BASF).
In view of the above, sanitising agent and emulsifying agent (McCutcheon ' sDetergents and Emulsifiers from McCutcheon, the North America version, McCutcheon branch office of MC publishing company, address: Glen Rock, NJ 07452) and the international cosmetic composition handbook of CTFA (CTFAIntemational Cosmetic Ingredient Handbook, TheCosmetic by the Washington D.C., Toiletry, and Fragrance Association publishes) in can determine to be applicable to various other ionic and both sexes and aniorfic surfactant of the present invention.
Be applicable to that the commercially available material of a class that provides with trade(brand)name " Miranol " is provided the amphoterics in the present composition.The example of other spendable amphotericses is cocoa acyl aminopropyl trimethyl-glycines, and it can be obtained from various sources by commercial sources.
When using with the buffer reagent toughener, the consumption of above-mentioned tensio-active agent is generally 0.01 to 5.0% (w/w), is preferably 0.1 to 5.0%.
Be typically, the also available tonicity agents of the aqueous solution (tonicity agents) that is used for treatment of contact lenses of the present invention is regulated, and reaches the osmotic pressure near normal tear fluid, is equivalent to 0.9% sodium chloride solution or 2.5% glycerine solution.It is isoosmotic basically that this solution is made with physiological saline independent or combination, otherwise, if only be and the aqua sterilisa blending, and make hypotonic or make that height oozes, then eyeglass can lose its required optical parametric.Relatively, excessive salt solution may cause the formation of hypertonic solution, and this will cause shouting pain, and eyes are produced to stimulate.
The pH of solution of the present invention should remain in 5.0 to 8.0 the scope, and is more preferably about 6.0 to 8.0, most preferably is approximately 6.5 to 7.8, can add suitable reducing, as boric acid, Sodium Tetraborate, Tripotassium Citrate, citric acid, sodium bicarbonate, TRIS, and various blended phosphate buffer (comprises Na
2HPO
4, NaH
2PO
4And KH
2PO
4Combination) and composition thereof.Borate buffer is preferred, in particular for strengthening the effect of biguanides.Generally, buffer reagent uses with the amount in about 0.05 to 2.5wt% scope, is preferably 0.1 to 1.5%.Sterilization of the present invention/listerine preferred package boronic acid containing salt buffer system contains one or more boric acid, Sodium Tetraborate, potassium tetraborate, potassium metaborate or its mixture.
Except buffer reagent, need in solution, add sequestering agent in some cases, this is in order to accumulate in the metal ion on the eyeglass in conjunction with those may react with eyeglass and/or proteinosis thing conversely.Ethylenediamine tetraacetic acid (EDTA) (EDTA) and salt (disodium) thereof are preferred examples.Its add-on usually about 0.01 to about 0.2wt%.Other suitable sequestering agents comprise glyconic acid, citric acid, tartrate and their salt, as, sodium salt.Preferred sequestering agent is the phosphonate compounds described in WO 97/31659, and they also are effective to removing the proteinosis thing.
No matter whether other additives are arranged, the aqueous solution of the present invention is particularly useful for SCL.However, solution of the present invention can be mixed with specific contact lens care solution, as moistening solution, and soaking solution, cleaning and conditioning solution, and multi-usage type lens care solution, or the like, and their mixture.Finally, these solution can be applied to eye outer or within the eye contact lenses still, for example, the form of drops.
Can also in solution of the present invention, add water-soluble viscosity intensifier.Because their lubrication, viscosity intensifier is by forming a film on lens surface, and available buffer improves eyeglass wearer's comfort thus to the surging force of eyes.Water-soluble viscosity intensifier comprises cellulose polymer compound, as hydroxyethyl or hydroxypropylcellulose, carboxymethyl cellulose, and polyvinyl pyrrolidone (povidone), polyvinyl alcohol, or the like.The consumption of this type of viscosity intensifier is generally about 0.01 to about 4.0wt% or lower.Solution of the present invention also optionally comprises demulcen (demulcents).
The aqueous solution of the present invention can be effectively applied to the sterilization of contact lenses by any known method.Eyeglass can at room temperature be handled about 5 minutes to about 12 hours time with " cold " infusion method.Then, eyeglass is taken out from this solution, with identical or different solution flushing, for example, the normal isotonic saline solution of preservation, and then place intraocular.
Just as described above, the contact lenses wearer usually require to the daily cleaning of contact lenses and/or when carrying out disinfection with finger or manual rubbing contact lenses (typically, between a finger and palm or between finger).In one embodiment of the invention, provide a kind of method, between eyeglass being shifted out eyes and after lens care, inserting again, in the process of handling with solution of the present invention, do not needed rubbing.In a preferred embodiment as this method, with multi-usage solution or effective multipurpose solution soft lens is carried out disinfection or carries out disinfection and cleans, this multi-usage solution is to be used to handle the unique required solution a kind of used in everyday of an outer lens.Therefore, in an embodiment of the inventive method, described solution is used to treatment of contact lenses, and does not need rubbing, and this method comprises:
(a) will in solution, soak one specific period without the contact lenses of rubbing, and
(b) treated contact lenses is directly placed wearer's intraocular.
Typically, step (a) can comprise contact lenses is immersed in this solution.Immersion can selectivity comprise the container that shakes or stir similarly this solution with the artificial method.Preferably, step (a) comprises soaks contact lenses for some time in container, and wherein, this contact lenses immerses in this solution fully.Term " directly place " this be meant this solution do not have diluted or with different contact lenses solution in " insertion " or place before the eye this solution of flush away from the eyeglass.In an especially preferred embodiment, this method has used preparation to become the product of multi-usage or effective multipurpose solution, wherein, in the daily cleaning of eyeglass, except the enzyme sanitising agent may use, does not need other solution or product.
In another embodiment according to the inventive method, solution of the present invention can be used for cleaning frequent replacement eyeglass (frequent replacement lens, FRL), this eyeglass uses in eye and is no more than about 3 months and will replaces, or in eye, use and be no more than about 30 days and will replace, or in eye, use to be no more than and will replace in about 2 weeks.Preferably, this eyeglass is made derived from the polymkeric substance of the repeating unit of hydroxyethyl methylacrylate and the crosslinked repeating unit of about 0.5-5mol% by the repeating unit derived from methacrylic acid (MAA) that comprises about 0.0-5 mol%, 10-99 mol%.Crosslinked repeating unit can be derived from the monomer as ethylene glycol dimethacrylate, Vinylstyrene and trimethyl propane trimethacrylate.
The following examples are used to illustrate the compositions and methods of the invention.
Embodiment 1
The present embodiment explanation is as the preparation of 1,6 two (cyanoguanidine) hexane of the present invention's two (biguanides) parent material.Dicyanamide sodium (the NaC of suspension 35.80 g (0.402 mol) in 400 mL1-butanols
2N
3).Then, add 1 of 23.60 g (0.204 mol), 6-hexane diamines and 33.0mL concentrated hydrochloric acid aqueous solution (0.400 mol).Occur the milky white precipitation immediately, this precipitation may be amine salt acid (amine hydrochloride).Then, this mixture was refluxed 3.5 hours.This suspension is cooled to room temperature and filtration.With distilled water thorough washing white solid, dry under vacuum then.Output 46.38 g; 93.1%.C10H18N8 calculates: C 48.0%; H7.20%; N 44.80%; Record: C 47.7%; H 7.40%; N 45.12%.300?MHz
1HNMR(d
6-DMSO)6.60?ppm(6p，br?m)；2.93?ppm(4p，m)；1.34?ppm(4p，br?s)；1.15(4p，br?s)。IR (KBr sheet, cm
-1) 3142 (m); 2943; 2912; 2862 (w); 2179 (s); 1658; 1609 (s).
Embodiment 2
The present embodiment explanation is used for the preparation that is known as two (biguanides) of Win-21904 (alexidine) of the present invention.The hexa-methylene two (cyanoguanidine) of 1.003 g (0.004498 mol) is placed flask.To wherein adding 1.474 mL (1.163g; 0.008996 2 ethyl hexylamine mol).Then, the dense HCl with 0.74 mL (0.008996 mol) adds wherein.Mixture is heated to H in flask
2The O boiling is removed.Remove H
2Behind the O, the temperature of melts is risen to 195 ℃.Cool the temperature to 150-160 ℃, under this temperature, kept 1 hour.This material is cooled to room temperature.The gained solid can be dissolved in the hot water and make it crystallization.
Embodiment 3
The preparation of present embodiment explanation poly-(hexamethylene biguan-ide), it also is referred to as PAPB or PHMB, is used in combination with two (biguanides) in the present invention.1 of 25.08 g (0.100 mol) that in the distilled water of 500 mL, suspend, 1 of 6-two (cyanoguanidine) hexane and 18.99 g (0.100 mol), 6-hexane diamines dihydrochloride (1,6-hexanediamine dihydrochloride).With dilute hydrochloric acid with the pH of this mixture near 6.8.Then, underpressure distillation removes and anhydrates.Afterwards, white solid is transferred in the three-necked flask that mechanical stirrer and heating jacket are housed.Then, the solid dense mixture is placed under the nitrogen, and mixture temperature is risen to 150-55 ℃.This molten reaction mixture has the denseness of honey.Before this mixture is cooled to room temperature, it was stirred 1-1.5 hour down at 150-55 ℃.Obtain poly-(hexamethylene biguan-ide) of vitreous solid.Output is quantitative basically.Fusion range 105-125 ℃.300?MHz
1HNMR(D
2O)?3.13?ppm?(21.1p，br?t)；2.93?ppm?(2p，t)；1.49?ppm?(21.1p，brs)；1.28?ppm(21.1p，br?s)。IR (KBr sheet, cm
-1) 3325; 2301 (s); 2931; 2858 (m); 2175 (m-w); 1631; 1589; 1550 (s).
Embodiment 4
Present embodiment explanation contains the preparation of aqueous antiseptic solution of the present invention of the combination of Win-21904 and poly hexamethylene biguanide (also being referred to as PHMB).Used following component, represented by the weight percentage that accounts for this overall solution volume:
* molecular weight 14,500, Tetronic_1107, poly-(ethylene oxide) block copolymerization adducts of a kind of poly-(propylene oxide) of quadrol, the trade mark of the BASF WyandotteCorp. of Michigan State Wyandotte.
| Percentage ratio (w/v) | |
| PHMB | 0.00008 |
| Win-21904 2HCl | 0.0002 |
| Poloxamine 1107 ** | 1.0 |
| Na 2EDTA | 0.11 |
| Boric acid | 0.66 |
| Sodium Tetraborate | 0.10 |
| Sodium-chlor | 0.54 |
| Distilled water (qs) | 100.0 |
This solution dissolves the EDTA disodium therein simultaneously and prepares by gradually 80% water being heated to 80 ℃.In EDTA two sodium solutions of heating, add boric acid and Sodium Tetraborate, and make it dissolving.Then, in this solution, add sodium-chlor and dissolve it, then add tensio-active agent.Solution is through 120 ℃ of 45 minutes autoclavings.Cool off this solution to room temperature, and add Win-21904 two (biguanides) and PHMB, add the distilled water of equal amount then by sterilization filter.This solution is packaged in the sterilization plastic containers.
Embodiment 5
The present embodiment explanation is at the biocidal efficacies of the combination of aqueous antiseptic solution Win-21904 that is used for contact lenses and poly hexamethylene biguanide (PHMB).Biocidal efficacies to the various compositions that are used for the contact lenses chemical disinfection is estimated one by one.
With green copper pseudomonas (Pseudomonas aeruginosa, ATCC 9027), streptococcus aureus (Staphylococcus aureus, ATCC 6538), serratia marcescens (Serratiamarcescens, ATCC 13880), Candida albicans (Candida albicans, ATCC 10231) and fusarium solani (Fusarium solani, ATCC 36031) preparation microorganism attack inoculum.This test microorganism is cultivated on suitable agar, and gathers in the crops this culture with sterilization DPBST (phosphate buffered saline (PBS) of Dulbecco adds 0.05% (w/v) Polysorbate 80) or suitable diluent, and is transferred in the suitable containers.Spore suspension filters with the glass wool of sterilization, removes the hyphal fragment sheet.Serratia marcescens is suitably filtered (as by 1.2 μ filters) and is come clarified suspension.After the results, with this suspension under 20-25 ℃ with the centrifugal time that is no more than 30 minutes of the speed that is no more than 5000xg.Decant goes out supernatant liquor, is resuspended in DPBST or other suitable diluent.Centrifugal this suspension is resuspended in DPBST or other suitable diluent for the second time.All attack bacteria and fungal cell's suspension are adjusted to 1 * 10 with DPBST or other suitable diluent
7-10
8Cfu/mL.Turbidity by measuring suspension is estimated cell concentration suitably, for example, uses the wavelength of selecting in advance, as the spectrophotometer under the 490nm.Prepare a pipe, wherein comprise the minimum 10 mL testing liquids of each attack micro organisms.The tested solution of wanting in each root pipe is inoculated with the suspension of test microorganism, presents in an amount at least sufficient to reach 1.0 * 10
5-10
6The final counting of cfu/mL, and the volume of inoculum is no more than 1% of sample volume.The dispersion of inoculum is guaranteed by the vortex that sample was carried out 15 seconds at least.The inoculation sample leaves 10-25 ℃ in.The aliquots containig of getting inoculation sample 1.0 mL is determined the viable count after sterilization during this period of time.When the soak time of suggestion rules was 4 hours, for bacterium, time point was for example 1,2,3 and 4 hours.At additional time point, promptly 〉=16 hour (4 times rules times), yeast and mould are tested.By at least 5 seconds strong vortex, this suspension of uniform mixing.The 1.0 mL aliquots containigs of taking out by the timed interval of determining are carried out ten times of suitable serial dilutions in certified and in the substratum (validated neutralizing media).Suspension is by intense mixing, and cultivates one section reasonable time with this microbial preparation that neutralizes.Determine the viable count of these microorganisms with suitable dilution by three parts of multiple flat boards that prepare tryptone beans peptone agar (TSA) for bacterium and prepare Sabouraud dextrose agar (SDA) for mould and yeast.This bacteria resuscitation flat board is incubated 2-4 days down at 30-35 ℃.Yeast is incubated 2-4 days under 20-30 ℃, be incubated 3-7 days and the mould recovery is dull and stereotyped down at 20-25 ℃.At the mean number of determining on the count enable flat board on the colony-forming unit.For bacterium and yeast, what the count enable flat board was measured is 30-300 cfu/ plate, for mould, is the 8-80cfu/ plate, except when only to 10
0Or 10
-1Outside the viewed bacterium colony of dilution plate.Then, at specific time point, calculate the amount that microorganism reduces.In order to prove the suitability of the substratum that is used for the growth test microorganism, and provide the estimation of initial inoculation concentration, be dispersed in the suitable dilution agent by inoculum identical aliquots containig, DPBST for example is used for preparing the inoculum contrast by the thinner of the equal volume of suspension microorganism as mentioned above.Inoculation and cultivating after one section reasonable time in certified and in the meat soup, inoculum contrast must be in 1.0 * 10
5-1.0 * 10
6Between the cfu/mL.
(be designated hereinafter simply as " independent experiment (stand-alone test) " based on being referred to as " being used for the stand-alone program (Stand-Alone Procedure) of sterilized product " to its performance demands with based on contact lens care effect product sterilization efficacy test, solution is estimated, and the latter announces (510 (k)) policy paper defined by U.S. food and Ophthalmologic apparatus portion of drug administration in the before sales of the contact lens care product of formulation on May 1st, 1997.The requirement of this aspect of performance can be used for contact lenses disinfectant iso standard (nineteen ninety-five revision) at present and compare favourably.Independent experiment is a kind of challenge for the sterilized product with the microbial inoculant body in the representative scope of standard, and has set up the degree and the product degree that compares favourably during use of survivability reduction (viability loss) in the predetermined timed interval.For given disinfecting time at interval the primary standard of (corresponding to the shortest possible suggestion disinfecting time) be that the quantity of every mL bacteria resuscitation in given disinfecting time will reduce the mean value that is no less than 3.0 logs.The mould and the zymic quantity of every mL recovery will reduce the mean value that is no less than 1.0 log in the shortest suggestion disinfecting time, do not increase in 4 times the shortest suggestion disinfecting time.
After above-mentioned testing sequence, determine when the timed interval of 5 minutes, 15 minutes, 30 minutes and 4 hours, whether to have passed through described primary standard of performance.In this series of trials, Win-21904 is prepared in the scope of 0.0-0.4ppm, with the PAPB of its combination be 0.0 or 0.8ppm, the amount that be used for soft lens commercial multi-usage solution PAPB of the latter for adopting at present.The results are shown in the following table 1.
Table 1
The result shows, Win-21904 is added poly hexamethylene biguanide improved biocidal efficacies, when about 4.0 ppm, it has improved effect and has reached practical compromise, makes any improved biocidal efficacies not regulated by sterilant toxicity enhanced possibility under greater concn.For Candida albicans, collaborative effect appears when the timed interval of 15 minutes and 30 minutes, when the combination of 2.6 ppm guanidine pyridines and 0.8 ppmPAPB, show than 2.6 ppm Win-21904s itself and the stronger effect of the sum of 0.8 ppm PAPB own.
Embodiment 6
The present embodiment explanation is by the biocidal efficacies of solution of the present invention.Adopt above-mentioned testing sequence to estimate the biocidal efficacies of sterilized solution to anti-candida albicans, the for example preparation in embodiment 4 of this sterilized solution, but the concentration of wherein contained two (biguanides) Win-21904 is at 1 ppm to 4ppm, and the concentration of ide polymers changes between 0.3 to 1.5 ppm.Result after soaking in 5 minutes is presented in the table 2, and the result after the immersion in 15 minutes is presented in the table 3, and the result after the immersion in 30 minutes is presented in the table 4, and the result after the immersion in 45 minutes is presented in the table 5.Table 6-9 is corresponding to table 2-5, compared the theoretical bactericidal amount (theoretical kill) based on single sterilizing agent sum and the actual bactericidal amount (actual kill) of combination of employing sterilizing agent.Adopt following formula to calculate: log 10 (exp10 (PHMB)+exp10 (Win-21904)).In other words,, the logarithm of each independent sterilizing agent is reduced sterilizing value is transformed to the microbial numbers of killing for the log kill of the theory of computation, then, these values are added and, to it with carry out new logarithm and calculate.
Table 2
(5 minutes)
Table 3
(15 minutes)
Table 4
(30 minutes)
Table 5
(45 minutes)
Table 6
(5 minutes)
Table 7
(15 minutes)
Table 8
(30 minutes)
Table 9
(45 minutes)
The above results has shown the synergy to anti-candida albicans, wherein, is higher than single sterilizing agent sum with the log kill of the combination of Win-21904 under the better ratio situation and PHMB, and its synergy is obvious after 15 minutes result.At 45 minutes, more the microorganism of vast scale was killed, and at this moment, it is not too obvious that these synergies become.Based on above-mentioned data, Fig. 1 has shown that testing liquid in the combination of comparing based on the theoretical effect of the single solution sum that contains Win-21904 and PHMB respectively separately that contains Win-21904 and PHMB is to the Biocidal effect of anti-candida albicans after 15 minutes.Fig. 2 has shown the testing liquid compared with the theoretical effect Biocidal effect to anti-candida albicans after 30 minutes.
Although the present invention together describes together with embodiment, these embodiment only are used for illustrative purposes.Therefore, many variations, improvement and change all will be conspicuous for those skilled in the art according to above description, therefore, wish these variations, improvement and change are included in the spirit and scope of accompanying Claim book.
Claims (15)
1, the sterilized solution of safety on a kind of ophthalmology that is used for contact lenses comprises a kind of aqueous solution, and this aqueous solution comprises following component:
(a) two (biguanides) of the sterilization significant quantity of about 0.10 to about 4.0 ppm water-soluble salt or free alkali form, this two (biguanides) has following general formula:
Wherein, R
1And R
2Be independently selected from by the alkyl of a ramose or the unbranched 4-12 of a having carbon atom, alkoxyalkyl ether or alkyl sulfur compounds group or have the cycloalkyl of 5-12 carbon atom or the group that cycloalkyl-alkyl is formed, and n is 4 to 16 with 4-12 carbon atom; (b) its total amount is about 0.10 polymeric biguanide to about 3.0 ppm, has following general formula
Wherein, Z is organic divalent abutment, can be identical or different in whole polymkeric substance, and the mean value of n is at least 3, and X
1And X
2Be independently selected from-NH
2With
Group;
(c) effective amount of buffer; And
(d) its amount is at least about the water of 80wt%.
2, the sterilized solution of safety on the ophthalmology as claimed in claim 1, wherein, described R
1And R
2Be independently selected from the group of forming by alkyl, alkoxyalkyl ether or the alkyl sulfur compounds sulfide group of a ramose or the unbranched 6-10 of a having carbon atom, and n is 4 to 10.
3, the sterilized solution of safety on the ophthalmology as claimed in claim 1 comprises a kind of polymeric biguanide, and this polymeric biguanide is the mixture of following general formula molecule:
Wherein, X
1And X
2As defined above, and the mean value of n be 5-20.
4, the sterilized solution of safety on the ophthalmology as claimed in claim 1 further comprises a kind of tensio-active agent, and its amount is 0.01 to 5.0%.
5, the sterilized solution of safety on the ophthalmology as claimed in claim 4, wherein, this tensio-active agent is neutrality or the nonionic surface active agent with a plurality of poly-(oxyalkylene) chains, each poly-(oxyalkylene) comprises (OR) repeating unit, wherein, R is independently for having the alkylidene group of 2 to 6 carbon atoms.
6, the sterilized solution of safety on the ophthalmology as claimed in claim 4, wherein, this tensio-active agent is neutrality or the nonionic surface active agent that comprises poly-(oxyethane) and poly-(propylene oxide) segmental segmented copolymer.
7, the sterilized solution of safety on the ophthalmology as claimed in claim 1, wherein, the amount of these two (biguanides) is 1.0 to 3.0 ppm.
8, the sterilized solution of safety on the ophthalmology as claimed in claim 1, wherein, the amount of this polymeric biguanide is 0.1 to 2.0 ppm.
9, a kind of with multi-usage solution or effective multipurpose solution disinfection, or the method for cleaning and disinfection SCL, this method comprises:
(a) this eyeglass is immersed in a kind of solution, to obtain this solution to the acceptable disinfection of this contact lenses, this solution comprises following component in its prescription:
(ⅰ) two (biguanides) of the sterilization significant quantity of about 0.1 to about 4.0 ppm water-soluble salt or free alkali form, this two (biguanides) has following general formula:
Wherein, R
1And R
2Be independently selected from by the alkyl of a ramose or the unbranched 4-12 of a having carbon atom, alkoxyalkyl ether or alkyl sulfur compounds group or have the cycloalkyl of 5-12 carbon atom or the group that cycloalkyl-alkyl is formed with 4-12 carbon atom; And n is 4 to 16;
(ⅱ) total amount is about 0.10 polymeric biguanide to about 3.0 ppm, and this polymeric biguanide has following general formula
Wherein, Z is organic divalent abutment, can be identical or different in whole polymkeric substance, and the mean value of n is at least 3, and X
1And X
2Be independently selected from-NH
2With
Group; And
(ⅲ) effective amount of buffer; With
(b) treated eyeglass is directly placed wearer's intraocular, wherein (ⅰ) do not need to wash with different solution before placing intraocular, and the daily processing of (ⅱ) eyeglass being carried out does not need other solution.
10, method as claimed in claim 9, wherein, as the working instructions of this product were desired, this method does not comprise with this solution crumpled this eyeglass.
11, as claim 9 or 10 described methods, wherein, R
1And R
2Be independently selected from the group of forming by ramose or unbranched alkyl, alkoxyalkyl ether or alkyl sulfur compounds sulfide group, and n is 4 to 10.
12, method as claimed in claim 11, wherein, this polymeric biguanide is the mixture with polymeric biguanide of following general formula:
Wherein, X
1And X
2As defined above, and the mean value of n be 5-20.
13, as claim 9 or 10 described methods, wherein, this solution be used for cleaning as or be prepared for the eyeglass of replacing after being no more than about 30 days wearing.
14, method as claimed in claim 13, wherein, this eyeglass is to be prepared for or as the eyeglass of replacing after being no more than about 14 days wearing.
15, as claim 9 or 10 described methods, wherein, this solution is used for cleaning the eyeglass of being made by the polymkeric substance derived from the repeating unit of methacrylic acid hydroxyethyl ester and about crosslinked repeating unit of 0.5 to 5mol% of a kind of repeating unit derived from methacrylic acid (MMA) that comprises about 0.0 to 5 mol%, 10 to 99 mol%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6550197P | 1997-11-12 | 1997-11-12 | |
| US60/065,501 | 1997-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1285866A true CN1285866A (en) | 2001-02-28 |
Family
ID=22063167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98811015A Pending CN1285866A (en) | 1997-11-12 | 1998-11-10 | Disinfecting contact lenses with bis (biguanides) and polymeric biguanides |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1030902A1 (en) |
| JP (1) | JP2001522672A (en) |
| KR (1) | KR20010031986A (en) |
| CN (1) | CN1285866A (en) |
| BR (1) | BR9813994A (en) |
| CA (1) | CA2307664A1 (en) |
| ID (1) | ID25783A (en) |
| WO (1) | WO1999024542A1 (en) |
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| CN102993056A (en) * | 2012-12-04 | 2013-03-27 | 甘肃省化工研究院 | Preparation method of chlorhexidine compound |
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| JP3564067B2 (en) * | 1998-08-21 | 2004-09-08 | 千寿製薬株式会社 | Agent for contact lenses |
| US6309596B1 (en) * | 1998-12-15 | 2001-10-30 | Bausch & Lomb Incorporated | Treatment of contact lenses with aqueous solution comprising a biguanide disinfectant stabilized by a poloxamine |
| JP2001242428A (en) * | 1999-12-20 | 2001-09-07 | Tomey Corp | Liquid agent for contact lens and method for cleaning, disinfecting and preserving soft contact lens |
| MY128134A (en) | 2000-09-28 | 2007-01-31 | Novartis Ag | Compositions and methods for cleaning contact lenses |
| WO2004112848A1 (en) * | 2003-06-16 | 2004-12-29 | Bausch & Lomb Incorporated | Lens care solutions for hydrogel contact lenses |
| WO2005016994A1 (en) * | 2003-08-18 | 2005-02-24 | Sk Chemicals Co., Ltd. | Method for preparing polyalkylenebiguanidine salt |
| US20060292105A1 (en) * | 2005-06-28 | 2006-12-28 | Lever O W Jr | Topical preservative compositions |
| CN102993057B (en) * | 2012-12-04 | 2014-09-17 | 甘肃省化工研究院 | Synthesis method of 1,6-bis(cyano-guanidino) hexane |
| CN110121548A (en) * | 2017-01-03 | 2019-08-13 | 陈煌兴 | Branched polymeric biguanide compound and application thereof |
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|---|---|---|---|---|
| GB1432345A (en) * | 1972-04-13 | 1976-04-14 | Smith Enphew Research Ltd | Ophthalmic compositions and contact lens disinfecting compo sitions |
| US4758595A (en) * | 1984-12-11 | 1988-07-19 | Bausch & Lomb Incorporated | Disinfecting and preserving systems and methods of use |
| EP0232250B1 (en) * | 1985-07-22 | 1990-01-31 | BAUSCH & LOMB INCORPORATED | Methods and solution for desinfecting and preserving contact lenses |
| US4891423A (en) * | 1989-03-20 | 1990-01-02 | Stockel Richard F | Polymeric biguanides |
| EP0690728B1 (en) * | 1993-01-07 | 1998-11-25 | Polymer Technology Corporation | Preservative system for contact lens solutions |
| JPH0892017A (en) * | 1994-09-19 | 1996-04-09 | Tomey Technol Corp | Solution preparation for contact lens |
| KR20000053221A (en) * | 1996-11-13 | 2000-08-25 | 스티븐 에이. 헬렁 | Compositions and methods in which bis(biguanides) provide enhanced antimicrobial efficacy for disinfecting contact lenses |
| CA2268822C (en) * | 1996-11-13 | 2005-02-01 | Bausch & Lomb Incorporated | Method for providing rapid disinfection of contact lenses |
-
1998
- 1998-11-10 ID IDW20000877A patent/ID25783A/en unknown
- 1998-11-10 KR KR1020007005096A patent/KR20010031986A/en not_active Application Discontinuation
- 1998-11-10 CN CN98811015A patent/CN1285866A/en active Pending
- 1998-11-10 CA CA002307664A patent/CA2307664A1/en not_active Abandoned
- 1998-11-10 JP JP2000520538A patent/JP2001522672A/en active Pending
- 1998-11-10 BR BR9813994-0A patent/BR9813994A/en not_active IP Right Cessation
- 1998-11-10 WO PCT/US1998/023818 patent/WO1999024542A1/en not_active Application Discontinuation
- 1998-11-10 EP EP98957702A patent/EP1030902A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993056A (en) * | 2012-12-04 | 2013-03-27 | 甘肃省化工研究院 | Preparation method of chlorhexidine compound |
Also Published As
| Publication number | Publication date |
|---|---|
| ID25783A (en) | 2000-11-02 |
| JP2001522672A (en) | 2001-11-20 |
| BR9813994A (en) | 2000-09-26 |
| KR20010031986A (en) | 2001-04-16 |
| EP1030902A1 (en) | 2000-08-30 |
| WO1999024542A1 (en) | 1999-05-20 |
| CA2307664A1 (en) | 1999-05-20 |
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